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Sample records for cancer genome atlas

  1. Feature selection and survival modeling in The Cancer Genome Atlas

    Directory of Open Access Journals (Sweden)

    Kim H

    2013-09-01

    Full Text Available Hyunsoo Kim,1 Markus Bredel2 1Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, USA; 2Department of Radiation Oncology, and Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL, USA Purpose: Personalized medicine is predicated on the concept of identifying subgroups of a common disease for better treatment. Identifying biomarkers that predict disease subtypes has been a major focus of biomedical science. In the era of genome-wide profiling, there is controversy as to the optimal number of genes as an input of a feature selection algorithm for survival modeling. Patients and methods: The expression profiles and outcomes of 544 patients were retrieved from The Cancer Genome Atlas. We compared four different survival prediction methods: (1 1-nearest neighbor (1-NN survival prediction method; (2 random patient selection method and a Cox-based regression method with nested cross-validation; (3 least absolute shrinkage and selection operator (LASSO optimization using whole-genome gene expression profiles; or (4 gene expression profiles of cancer pathway genes. Results: The 1-NN method performed better than the random patient selection method in terms of survival predictions, although it does not include a feature selection step. The Cox-based regression method with LASSO optimization using whole-genome gene expression data demonstrated higher survival prediction power than the 1-NN method, but was outperformed by the same method when using gene expression profiles of cancer pathway genes alone. Conclusion: The 1-NN survival prediction method may require more patients for better performance, even when omitting censored data. Using preexisting biological knowledge for survival prediction is reasonable as a means to understand the biological system of a cancer, unless the analysis goal is to identify completely unknown genes relevant to cancer biology. Keywords: brain, feature selection

  2. Large-scale profiling of microRNAs for The Cancer Genome Atlas.

    Science.gov (United States)

    Chu, Andy; Robertson, Gordon; Brooks, Denise; Mungall, Andrew J; Birol, Inanc; Coope, Robin; Ma, Yussanne; Jones, Steven; Marra, Marco A

    2016-01-01

    The comprehensive multiplatform genomics data generated by The Cancer Genome Atlas (TCGA) Research Network is an enabling resource for cancer research. It includes an unprecedented amount of microRNA sequence data: ~11 000 libraries across 33 cancer types. Combined with initiatives like the National Cancer Institute Genomics Cloud Pilots, such data resources will make intensive analysis of large-scale cancer genomics data widely accessible. To support such initiatives, and to enable comparison of TCGA microRNA data to data from other projects, we describe the process that we developed and used to generate the microRNA sequence data, from library construction through to submission of data to repositories. In the context of this process, we describe the computational pipeline that we used to characterize microRNA expression across large patient cohorts.

  3. DO CANCER CLINICAL TRIAL POPULATIONS TRULY REPRESENT CANCER PATIENTS? A COMPARISON OF OPEN CLINICAL TRIALS TO THE CANCER GENOME ATLAS.

    Science.gov (United States)

    Geifman, Nophar; Butte, Atul J

    2016-01-01

    Open clinical trial data offer many opportunities for the scientific community to independently verify published results, evaluate new hypotheses and conduct meta-analyses. These data provide a springboard for scientific advances in precision medicine but the question arises as to how representative clinical trials data are of cancer patients overall. Here we present the integrative analysis of data from several cancer clinical trials and compare these to patient-level data from The Cancer Genome Atlas (TCGA). Comparison of cancer type-specific survival rates reveals that these are overall lower in trial subjects. This effect, at least to some extent, can be explained by the more advanced stages of cancer of trial subjects. This analysis also reveals that for stage IV cancer, colorectal cancer patients have a better chance of survival than breast cancer patients. On the other hand, for all other stages, breast cancer patients have better survival than colorectal cancer patients. Comparison of survival in different stages of disease between the two datasets reveals that subjects with stage IV cancer from the trials dataset have a lower chance of survival than matching stage IV subjects from TCGA. One likely explanation for this observation is that stage IV trial subjects have lower survival rates since their cancer is less likely to respond to treatment. To conclude, we present here a newly available clinical trials dataset which allowed for the integration of patient-level data from many cancer clinical trials. Our comprehensive analysis reveals that cancer-related clinical trials are not representative of general cancer patient populations, mostly due to their focus on the more advanced stages of the disease. These and other limitations of clinical trials data should, perhaps, be taken into consideration in medical research and in the field of precision medicine.

  4. The Cancer Genome Atlas expression profiles of low-grade gliomas.

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    Gonda, David D; Cheung, Vincent J; Muller, Karra A; Goyal, Amit; Carter, Bob S; Chen, Clark C

    2014-04-01

    Differentiating between low-grade gliomas (LGGs) of astrocytic and oligodendroglial origin remains a major challenge in neurooncology. Here the authors analyzed The Cancer Genome Atlas (TCGA) profiles of LGGs with the goal of identifying distinct molecular characteristics that would afford accurate and reliable discrimination of astrocytic and oligodendroglial tumors. They found that 1) oligodendrogliomas are more likely to exhibit the glioma-CpG island methylator phenotype (G-CIMP), relative to low-grade astrocytomas; 2) relative to oligodendrogliomas, low-grade astrocytomas exhibit a higher expression of genes related to mitosis, replication, and inflammation; and 3) low-grade astrocytic tumors harbor microRNA profiles similar to those previously described for glioblastoma tumors. Orthogonal intersection of these molecular characteristics with existing molecular markers, such as IDH1 mutation, TP53 mutation, and 1p19q status, should facilitate accurate and reliable pathological diagnosis of LGGs.

  5. Endometrial and acute myeloid leukemia cancer genomes characterized

    Science.gov (United States)

    Two studies from The Cancer Genome Atlas (TCGA) program reveal details about the genomic landscapes of acute myeloid leukemia (AML) and endometrial cancer. Both provide new insights into the molecular underpinnings of these cancers.

  6. The Genome Atlas Resource

    DEFF Research Database (Denmark)

    Azam Qureshi, Matloob; Rotenberg, Eva; Stærfeldt, Hans Henrik;

    2010-01-01

    with scripts and algorithms developed in a variety of programming languages at the Centre for Biological Sequence Analysis in order to create a three-tier software application for genome analysis. The results are made available via a web interface developed in Java, PHP and Perl CGI. User...

  7. Cancer genomics

    DEFF Research Database (Denmark)

    Norrild, Bodil; Guldberg, Per; Ralfkiær, Elisabeth Methner

    2007-01-01

    Almost all cells in the human body contain a complete copy of the genome with an estimated number of 25,000 genes. The sequences of these genes make up about three percent of the genome and comprise the inherited set of genetic information. The genome also contains information that determines whe...

  8. Smoking correlates with increased cytoskeletal protein-related coding region mutations in the lung and head and neck datasets of the cancer genome atlas.

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    Yavorski, John M; Blanck, George

    2016-12-01

    Cancer from smoking tobacco is considered dependent on mutagens, but significant molecular aspects of smoking-specific, cancer development remain unknown. We defined sets of coding regions for oncoproteins, tumor suppressor proteins, and cytoskeletal-related proteins that were compared between nonsmokers and smokers, for mutation occurrences, in the lung adenocarcinoma (LUAD), head and neck squamous carcinoma (HNSC), bladder carcinoma (BLCA), and pancreatic adenocarcinoma ( PAAD) datasets from the cancer genome atlas (TCGA). We uncovered significant differences in overall mutation rates, and in mutation rates in cytoskeletal protein-related coding regions (CPCRs, including extracellular matrix protein coding regions), between nonsmokers and smokers in LUAD and HNSC (P < 0.001), raising the question of whether the CPCR mutation differences lead to different clinical courses for nonsmoker and smoker cancers. Another important question inspired by these results is, whether high smoker cancer mutation rates would facilitate genotoxicity or neoantigen-based therapies. No significant, mutation-based differences were found in the BLCA or PAAD datasets, between nonsmokers and smokers. However, a significant difference was uncovered for the average number of overall cancer mutations, in LUAD, for persons who stopped smoking more than 15 years ago, compared with more recent smokers (P < 0.032).

  9. Expression profiles of pivotal microRNAs and targets in thyroid papillary carcinoma: an analysis of The Cancer Genome Atlas

    Directory of Open Access Journals (Sweden)

    Cong D

    2015-08-01

    Full Text Available Dan Cong,1 Mengzi He,2 Silin Chen,2 Xiaoli Liu,1 Xiaodong Liu,2 Hui Sun11Jilin Provincial Key Laboratory of Surgical Translational Medicine, Department of Thyroid and Parathyroid Surgery, People’s Republic of China–Japan Union Hospital, 2Key Laboratory of Radiobiology (Ministry of Health, School of Public Health, Jilin University, Changchun, Jilin, People’s Republic of ChinaAbstract: In the present study, we analyzed microRNA (miRNA and gene expression profiles using 499 papillary thyroid carcinoma (PTC samples and 58 normal thyroid tissues obtained from The Cancer Genome Atlas database. A pivotal regulatory network of 18 miRNA and 16 targets was identified. Upregulated miRNAs (miR-222, miR-221, miR-146b, miR-181a/b/d, miR-34a, and miR-424 and downregulated miRNAs (miR-9-1, miR-138, miR-363, miR-20b, miR-195, and miR-152 were identified. Among them, the upregulation of miR-424 and downregulation of miR-363, miR-195, and miR-152 were not previously identified. The genes CCNE2 (also known as cyclin E2, E2F1, RARA, CCND1 (cyclin D1, RUNX1, ITGA2, MET, CDKN1A (p21, and COL4A1 were overexpressed, and AXIN2, TRAF6, BCL2, RARB, HSP90B1, FGF7, and PDGFRA were downregulated. Among them, CCNE2, COL4A1, TRAF6, and HSP90B1 were newly identified. Based on receiver operating characteristic curves, several miRNAs (miR-222, miR-221, and miR-34a and genes (CCND1 and MET were ideal diagnostic indicators, with sensitivities and specificities greater than 90%. The combination of inversely expressed miRNAs and targets improved diagnostic accuracy. In a clinical feature analysis, several miRNAs (miR-34a, miR-424, miR-20b, and miR-152 and genes (CCNE2, COL4A1, TRAF6, and HSP90B1 were associated with aggressive clinical features, which have not previously been reported. Our study not only identified a pivotal miRNA regulatory network associated with PTC but also provided evidence that miRNAs and target genes can be used as biomarkers in PTC diagnosis and clinical

  10. Data and analysis of the cancer genome atlas%癌症基因组图谱计划数据及分析

    Institute of Scientific and Technical Information of China (English)

    邓祯祥(综述); 李金明(审校)

    2014-01-01

    Multiple chromosomal aberrations, nucleotide substitutions, and epigenetic modifications may occur in human cancer cells, which drive malignant transformation. The Cancer Genome Atlas (TCGA) project aims to promote large-scale multi-dimensional analysis of these molecular characteristics in human cancer and rapidly provide data to researchers. In this study, we introduce four flow paths of the production of TCGA data, the collections of various cancer types, the data category and level, and the standardized pipeline of data analysis, as well as several existing data analytical tools. We used ovarian cancer as an example to introduce the application of the TCGA data in the analyses of mutation, copy number, analysis, and expression. We summarized the important findings of glioblasto-ma by TCGA teams.%人类癌症细胞中通常藏匿着多种引起恶性病变的染色体变异,核酸替换和表观遗传修饰。癌症基因组图谱(the can-cer genome atlas,TCGA)计划的目标是获取、刻画并分析人类癌症中大规模、多种变异的分子特征,并且为癌症研究者迅速地提供数据。本文对TCGA数据的四个产生流程以及包含的癌症种类、数据类型、数据水平、分析流程和常用的几种分析工具等进行阐述,同时以卵巢癌(ovarian cancer)为例详细介绍了TCGA数据在突变分析、拷贝数分析、表达分析和通路分析等方面的应用,并对TCGA研究团队近几年有关胶质母细胞瘤(glioblastoma,GBM)的研究方法和结果以及已经完成分析的癌症类型进行综述。

  11. Center for Cancer Genomics | Office of Cancer Genomics

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    The Center for Cancer Genomics (CCG) was established to unify the National Cancer Institute's activities in cancer genomics, with the goal of advancing genomics research and translating findings into the clinic to improve the precise diagnosis and treatment of cancers. In addition to promoting genomic sequencing approach

  12. Weighted gene co-expression network analysis in identification of metastasis-related genes of lung squamous cell carcinoma based on the Cancer Genome Atlas database

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    Tian, Feng; Zhao, Jinlong; Kang, Zhenxing

    2017-01-01

    Background Lung squamous cell carcinoma (lung SCC) is a common type of malignancy. Its pathogenesis mechanism of tumor development is unclear. The aim of this study was to identify key genes for diagnosis biomarkers in lung SCC metastasis. Methods We searched and downloaded mRNA expression data and clinical data from The Cancer Genome Atlas (TCGA) database to identify differences in mRNA expression of primary tumor tissues from lung SCC with and without metastasis. Gene co-expression network analysis, protein-protein interaction (PPI) network, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and quantitative real-time polymerase chain reactions (qRT-PCR) were used to explore the biological functions of the identified dysregulated genes. Results Four hundred and eighty-two differentially expressed genes (DEGs) were identified between lung SCC with and without metastasis. Nineteen modules were identified in lung SCC through weighted gene co-expression network analysis (WGCNA). Twenty-three DEGs and 26 DEGs were significantly enriched in the respective pink and black module. KEGG pathway analysis displayed that 26 DEGs in the black module were significantly enriched in bile secretion pathway. Forty-nine DEGs in the two gene co-expression module were used to construct PPI network. CFTR in the black module was the hub protein, had the connectivity with 182 genes. The results of qRT-PCR displayed that FIGF, SFTPD, DYNLRB2 were significantly down-regulated in the tumor samples of lung SCC with metastasis and CFTR, SCGB3A2, SSTR1, SCTR, ROPN1L had the down-regulation tendency in lung SCC with metastasis compared to lung SCC without metastasis. Conclusions The dysregulated genes including CFTR, SCTR and FIGF might be involved in the pathology of lung SCC metastasis and could be used as potential diagnosis biomarkers or therapeutic targets for lung SCC.

  13. Genomic Data Commons | Office of Cancer Genomics

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    The NCI’s Center for Cancer Genomics launches the Genomic Data Commons (GDC), a unified data sharing platform for the cancer research community. The mission of the GDC is to enable data sharing across the entire cancer research community, to ultimately support precision medicine in oncology.

  14. Significance of the BRAF mRNA Expression Level in Papillary Thyroid Carcinoma: An Analysis of The Cancer Genome Atlas Data.

    Directory of Open Access Journals (Sweden)

    Young Jun Chai

    Full Text Available BRAFV600E is the most common mutation in papillary thyroid carcinoma (PTC, and it is associated with high-risk prognostic factors. However, the significance of the BRAF mRNA level in PTC remains unknown. We evaluated the significance of BRAF mRNA expression level by analyzing PTC data from The Cancer Genome Atlas (TCGA database.Data from 499 patients were downloaded from the TCGA database. After excluding other PTC variants, we selected 353 cases of classic PTC, including 193 cases with BRAFV600E and 160 cases with the wild-type BRAF. mRNA abundances were measured using RNA-Seq with the Expectation Maximization algorithm.The mean BRAF mRNA level was significantly higher in BRAFV600E patients than in patients with wild-type BRAF (197.6 vs. 179.3, p = 0.031. In wild-type BRAF patients, the mean BRAF mRNA level was higher in cases with a tumor > 2 cm than those with a tumor ≤ 2.0 cm (189.4 vs. 163.8, p = 0.046, and was also higher in cases with lymph node metastasis than in those without lymph node metastasis (188.5 vs. 157.9, p = 0.040. Within BRAFV600E patients, higher BRAF mRNA expression was associated with extrathyroidal extension (186.4 vs. 216.4, p = 0.001 and higher T stage (188.1 vs. 210.2, p = 0.016.A higher BRAF mRNA expression level was associated with tumor aggressiveness in classic PTC regardless of BRAF mutational status. Evaluation of BRAF mRNA level may be helpful in prognostic risk stratification of PTC.

  15. Pan-cancer analysis of ROS1 genomic aberrations

    OpenAIRE

    Wang, Yidan; 王奕丹

    2015-01-01

    The ROS proto-oncogene 1 (ROS1) encodes the ROS1 receptor kinase. ROS1 rearrangements are known to be oncogenic in glioblastoma, non–small-cell lung carcinoma (NSCLC) and cholangiocarcinoma. The clinical relevance of ROS1 genomic aberrations in other human cancers is largely unexamined. Here, we performed a pan-cancer analysis of ROS1 genomic aberrations across 20 cancer sites by interrogating the whole-exome sequencing data of the Cancer Genome Atlas (TCGA) via the cBioportal (www.cbioportal...

  16. Reconstructing cancer genomes from paired-end sequencing data

    Directory of Open Access Journals (Sweden)

    Oesper Layla

    2012-04-01

    Full Text Available Abstract Background A cancer genome is derived from the germline genome through a series of somatic mutations. Somatic structural variants - including duplications, deletions, inversions, translocations, and other rearrangements - result in a cancer genome that is a scrambling of intervals, or "blocks" of the germline genome sequence. We present an efficient algorithm for reconstructing the block organization of a cancer genome from paired-end DNA sequencing data. Results By aligning paired reads from a cancer genome - and a matched germline genome, if available - to the human reference genome, we derive: (i a partition of the reference genome into intervals; (ii adjacencies between these intervals in the cancer genome; (iii an estimated copy number for each interval. We formulate the Copy Number and Adjacency Genome Reconstruction Problem of determining the cancer genome as a sequence of the derived intervals that is consistent with the measured adjacencies and copy numbers. We design an efficient algorithm, called Paired-end Reconstruction of Genome Organization (PREGO, to solve this problem by reducing it to an optimization problem on an interval-adjacency graph constructed from the data. The solution to the optimization problem results in an Eulerian graph, containing an alternating Eulerian tour that corresponds to a cancer genome that is consistent with the sequencing data. We apply our algorithm to five ovarian cancer genomes that were sequenced as part of The Cancer Genome Atlas. We identify numerous rearrangements, or structural variants, in these genomes, analyze reciprocal vs. non-reciprocal rearrangements, and identify rearrangements consistent with known mechanisms of duplication such as tandem duplications and breakage/fusion/bridge (B/F/B cycles. Conclusions We demonstrate that PREGO efficiently identifies complex and biologically relevant rearrangements in cancer genome sequencing data. An implementation of the PREGO algorithm is

  17. Collaborators | Office of Cancer Genomics

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    The TARGET initiative is jointly managed within the National Cancer Institute (NCI) by the Office of Cancer Genomics (OCG)Opens in a New Tab and the Cancer Therapy Evaluation Program (CTEP)Opens in a New Tab.

  18. Translating the cancer genome: Going beyond p values

    Energy Technology Data Exchange (ETDEWEB)

    Chin, Lynda; Chin, Lynda; Gray, Joe W.

    2008-04-03

    Cancer cells are endowed with diverse biological capabilities driven by myriad inherited and somatic genetic and epigenetic aberrations that commandeer key cancer-relevant pathways. Efforts to elucidate these aberrations began with Boveri's hypothesis of aberrant mitoses causing cancer and continue today with a suite of powerful high-resolution technologies that enable detailed catalogues of genomic aberrations and epigenomic modifications. Tomorrow will likely bring the complete atlas of reversible and irreversible alteration in individual cancers. The challenge now is to discern causal molecular abnormalities from genomic and epigenomic 'noise', to understand how the ensemble of these aberrations collaborate to drive cancer pathophysiology. Here, we highlight lessons learned from now classical examples of successful translation of genomic discoveries into clinical practice, lessons that may be used to guide and accelerate translation of emerging genomic insights into practical clinical endpoints that can impact on practice of cancer medicine.

  19. Programs | Office of Cancer Genomics

    Science.gov (United States)

    OCG facilitates cancer genomics research through a series of highly-focused programs. These programs generate and disseminate genomic data for use by the cancer research community. OCG programs also promote advances in technology-based infrastructure and create valuable experimental reagents and tools. OCG programs encourage collaboration by interconnecting with other genomics and cancer projects in order to accelerate translation of findings into the clinic. Below are OCG’s current, completed, and initiated programs:

  20. The Genomic Landscape and Clinical Relevance of A-to-I RNA Editing in Human Cancers | Office of Cancer Genomics

    Science.gov (United States)

    Adenosine-to-inosine (A-to-I) RNA editing is a widespread post-transcriptional mechanism, but its genomic landscape and clinical relevance in cancer have not been investigated systematically. We characterized the global A-to-I RNA editing profiles of 6,236 patient samples of 17 cancer types from The Cancer Genome Atlas and revealed a striking diversity of altered RNA-editing patterns in tumors relative to normal tissues. We identified an appreciable number of clinically relevant editing events, many of which are in noncoding regions.

  1. Genomic Datasets for Cancer Research

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    A variety of datasets from genome-wide association studies of cancer and other genotype-phenotype studies, including sequencing and molecular diagnostic assays, are available to approved investigators through the Extramural National Cancer Institute Data Access Committee.

  2. The Global Cancer Genomics Consortium: interfacing genomics and cancer medicine.

    Science.gov (United States)

    2012-08-01

    The Global Cancer Genomics Consortium (GCGC) is an international collaborative platform that amalgamates cancer biologists, cutting-edge genomics, and high-throughput expertise with medical oncologists and surgical oncologists; they address the most important translational questions that are central to cancer research and treatment. The annual GCGC symposium was held at the Advanced Centre for Treatment Research and Education in Cancer, Mumbai, India, from November 9 to 11, 2011. The symposium showcased international next-generation sequencing efforts that explore cancer-specific transcriptomic changes, single-nucleotide polymorphism, and copy number variations in various types of cancers, as well as the structural genomics approach to develop new therapeutic targets and chemical probes. From the spectrum of studies presented at the symposium, it is evident that the translation of emerging cancer genomics knowledge into clinical applications can only be achieved through the integration of multidisciplinary expertise. In summary, the GCGC symposium provided practical knowledge on structural and cancer genomics approaches, as well as an exclusive platform for focused cancer genomics endeavors.

  3. Contact | Office of Cancer Genomics

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    For more information about the Office of Cancer Genomics, please contact: Office of Cancer Genomics National Cancer Institute 31 Center Drive, 10A07 Bethesda, Maryland 20892-2580 Phone: (301) 451-8027 Fax: (301) 480-4368 Email: ocg@mail.nih.gov *Please note that this site will not function properly in Internet Explorer unless you completely turn off the Compatibility View*

  4. Validation and calibration of next-generation sequencing to identify Epstein-Barr virus-positive gastric cancer in The Cancer Genome Atlas.

    Science.gov (United States)

    Camargo, M Constanza; Bowlby, Reanne; Chu, Andy; Pedamallu, Chandra Sekhar; Thorsson, Vesteinn; Elmore, Sandra; Mungall, Andrew J; Bass, Adam J; Gulley, Margaret L; Rabkin, Charles S

    2016-04-01

    The Epstein-Barr virus (EBV)-positive subtype of gastric adenocarcinoma is conventionally identified by in situ hybridization (ISH) for viral nucleic acids, but next-generation sequencing represents a potential alternative. We therefore determined normalized EBV read counts by whole-genome, whole-exome, mRNA and miRNA sequencing for 295 fresh-frozen gastric tumor samples. Formalin-fixed, paraffin-embedded tissue sections were retrieved for ISH confirmation of 13 high-EBV and 11 low-EBV cases. In pairwise comparisons, individual samples were either concordantly high or concordantly low by all genomic methods for which data were available. Empiric cutoffs of sequencing counts identified 26 (9 %) tumors as EBV positive. EBV positivity or negativity by molecular testing was confirmed by EBER-ISH in all but one tumor evaluated by both approaches (kappa = 0.91). EBV-positive gastric tumors can be accurately identified by quantifying viral sequences in genomic data. Simultaneous analyses of human and viral DNA, mRNA and miRNA could streamline tumor profiling for clinical care and research.

  5. International network of cancer genome projects

    NARCIS (Netherlands)

    Hudson, Thomas J.; Anderson, Warwick; Aretz, Axel; Barker, Anna D.; Bell, Cindy; Bernabe, Rosa R.; Bhan, M. K.; Calvo, Fabien; Eerola, Iiro; Gerhard, Daniela S.; Guttmacher, Alan; Guyer, Mark; Hemsley, Fiona M.; Jennings, Jennifer L.; Kerr, David; Klatt, Peter; Kolar, Patrik; Kusuda, Jun; Lane, David P.; Laplace, Frank; Lu, Youyong; Nettekoven, Gerd; Ozenberger, Brad; Peterson, Jane; Rao, T. S.; Remacle, Jacques; Schafer, Alan J.; Shibata, Tatsuhiro; Stratton, Michael R.; Vockley, Joseph G.; Watanabe, Koichi; Yang, Huanming; Yuen, Matthew M. F.; Knoppers, M.; Bobrow, Martin; Cambon-Thomsen, Anne; Dressler, Lynn G.; Dyke, Stephanie O. M.; Joly, Yann; Kato, Kazuto; Kennedy, Karen L.; Nicolas, Pilar; Parker, Michael J.; Rial-Sebbag, Emmanuelle; Romeo-Casabona, Carlos M.; Shaw, Kenna M.; Wallace, Susan; Wiesner, Georgia L.; Zeps, Nikolajs; Lichter, Peter; Biankin, Andrew V.; Chabannon, Christian; Chin, Lynda; Clement, Bruno; de Alava, Enrique; Degos, Francoise; Ferguson, Martin L.; Geary, Peter; Hayes, D. Neil; Johns, Amber L.; Nakagawa, Hidewaki; Penny, Robert; Piris, Miguel A.; Sarin, Rajiv; Scarpa, Aldo; Shibata, Tatsuhiro; van de Vijver, Marc; Futreal, P. Andrew; Aburatani, Hiroyuki; Bayes, Monica; Bowtell, David D. L.; Campbell, Peter J.; Estivill, Xavier; Grimmond, Sean M.; Gut, Ivo; Hirst, Martin; Lopez-Otin, Carlos; Majumder, Partha; Marra, Marco; Nakagawa, Hidewaki; Ning, Zemin; Puente, Xose S.; Ruan, Yijun; Shibata, Tatsuhiro; Stratton, Michael R.; Stunnenberg, Hendrik G.; Swerdlow, Harold; Velculescu, Victor E.; Wilson, Richard K.; Xue, Hong H.; Yang, Liu; Spellman, Paul T.; Bader, Gary D.; Boutros, Paul C.; Campbell, Peter J.; Flicek, Paul; Getz, Gad; Guigo, Roderic; Guo, Guangwu; Haussler, David; Heath, Simon; Hubbard, Tim J.; Jiang, Tao; Jones, Steven M.; Li, Qibin; Lopez-Bigas, Nuria; Luo, Ruibang; Pearson, John V.; Puente, Xose S.; Quesada, Victor; Raphael, Benjamin J.; Sander, Chris; Shibata, Tatsuhiro; Speed, Terence P.; Stuart, Joshua M.; Teague, Jon W.; Totoki, Yasushi; Tsunoda, Tatsuhiko; Valencia, Alfonso; Wheeler, David A.; Wu, Honglong; Zhao, Shancen; Zhou, Guangyu; Stein, Lincoln D.; Guigo, Roderic; Hubbard, Tim J.; Joly, Yann; Jones, Steven M.; Lathrop, Mark; Lopez-Bigas, Nuria; Ouellette, B. F. Francis; Spellman, Paul T.; Teague, Jon W.; Thomas, Gilles; Valencia, Alfonso; Yoshida, Teruhiko; Kennedy, Karen L.; Axton, Myles; Dyke, Stephanie O. M.; Futreal, P. Andrew; Gunter, Chris; Guyer, Mark; McPherson, John D.; Miller, Linda J.; Ozenberger, Brad; Kasprzyk, Arek; Zhang, Junjun; Haider, Syed A.; Wang, Jianxin; Yung, Christina K.; Cross, Anthony; Liang, Yong; Gnaneshan, Saravanamuttu; Guberman, Jonathan; Hsu, Jack; Bobrow, Martin; Chalmers, Don R. C.; Hasel, Karl W.; Joly, Yann; Kaan, Terry S. H.; Kennedy, Karen L.; Knoppers, Bartha M.; Lowrance, William W.; Masui, Tohru; Nicolas, Pilar; Rial-Sebbag, Emmanuelle; Rodriguez, Laura Lyman; Vergely, Catherine; Yoshida, Teruhiko; Grimmond, Sean M.; Biankin, Andrew V.; Bowtell, David D. L.; Cloonan, Nicole; Defazio, Anna; Eshleman, James R.; Etemadmoghadam, Dariush; Gardiner, Brooke A.; Kench, James G.; Scarpa, Aldo; Sutherland, Robert L.; Tempero, Margaret A.; Waddell, Nicola J.; Wilson, Peter J.; Gallinger, Steve; Tsao, Ming-Sound; Shaw, Patricia A.; Petersen, Gloria M.; Mukhopadhyay, Debabrata; Chin, Lynda; DePinho, Ronald A.; Thayer, Sarah; Muthuswamy, Lakshmi; Shazand, Kamran; Beck, Timothy; Sam, Michelle; Timms, Lee; Ballin, Vanessa; Lu, Youyong; Ji, Jiafu; Zhang, Xiuqing; Chen, Feng; Hu, Xueda; Zhou, Guangyu; Yang, Qi; Tian, Geng; Zhang, Lianhai; Xing, Xiaofang; Li, Xianghong; Zhu, Zhenggang; Yu, Yingyan; Yu, Jun; Yang, Huanming; Lathrop, Mark; Tost, Joerg; Brennan, Paul; Holcatova, Ivana; Zaridze, David; Brazma, Alvis; Egevad, Lars; Prokhortchouk, Egor; Banks, Rosamonde Elizabeth; Uhlen, Mathias; Cambon-Thomsen, Anne; Viksna, Juris; Ponten, Fredrik; Skryabin, Konstantin; Stratton, Michael R.; Futreal, P. Andrew; Birney, Ewan; Borg, Ake; Borresen-Dale, Anne-Lise; Caldas, Carlos; Foekens, John A.; Martin, Sancha; Reis-Filho, Jorge S.; Richardson, Andrea L.; Sotiriou, Christos; Stunnenberg, Hendrik G.; Thomas, Gilles; van de Vijver, Marc; van't Veer, Laura; Birnbaum, Daniel; Blanche, Helene; Boucher, Pascal; Boyault, Sandrine; Chabannon, Christian; Gut, Ivo; Masson-Jacquemier, Jocelyne D.; Lathrop, Mark; Pauporte, Iris; Pivot, Xavier; Vincent-Salomon, Anne; Tabone, Eric; Theillet, Charles; Thomas, Gilles; Tost, Joerg; Treilleux, Isabelle; Bioulac-Sage, Paulette; Clement, Bruno; Decaens, Thomas; Degos, Francoise; Franco, Dominique; Gut, Ivo; Gut, Marta; Heath, Simon; Lathrop, Mark; Samuel, Didier; Thomas, Gilles; Zucman-Rossi, Jessica; Lichter, Peter; Eils, Roland; Brors, Benedikt; Korbel, Jan O.; Korshunov, Andrey; Landgraf, Pablo; Lehrach, Hans; Pfister, Stefan; Radlwimmer, Bernhard; Reifenberger, Guido; Taylor, Michael D.; von Kalle, Christof; Majumder, Partha P.; Sarin, Rajiv; Scarpa, Aldo; Pederzoli, Paolo; Lawlor, Rita T.; Delledonne, Massimo; Bardelli, Alberto; Biankin, Andrew V.; Grimmond, Sean M.; Gress, Thomas; Klimstra, David; Zamboni, Giuseppe; Shibata, Tatsuhiro; Nakamura, Yusuke; Nakagawa, Hidewaki; Kusuda, Jun; Tsunoda, Tatsuhiko; Miyano, Satoru; Aburatani, Hiroyuki; Kato, Kazuto; Fujimoto, Akihiro; Yoshida, Teruhiko; Campo, Elias; Lopez-Otin, Carlos; Estivill, Xavier; Guigo, Roderic; de Sanjose, Silvia; Piris, Miguel A.; Montserrat, Emili; Gonzalez-Diaz, Marcos; Puente, Xose S.; Jares, Pedro; Valencia, Alfonso; Himmelbaue, Heinz; Quesada, Victor; Bea, Silvia; Stratton, Michael R.; Futreal, P. Andrew; Campbell, Peter J.; Vincent-Salomon, Anne; Richardson, Andrea L.; Reis-Filho, Jorge S.; van de Vijver, Marc; Thomas, Gilles; Masson-Jacquemier, Jocelyne D.; Aparicio, Samuel; Borg, Ake; Borresen-Dale, Anne-Lise; Caldas, Carlos; Foekens, John A.; Stunnenberg, Hendrik G.; van't Veer, Laura; Easton, Douglas F.; Spellman, Paul T.; Martin, Sancha; Chin, Lynda; Collins, Francis S.; Compton, Carolyn C.; Ferguson, Martin L.; Getz, Gad; Gunter, Chris; Guyer, Mark; Hayes, D. Neil; Lander, Eric S.; Ozenberger, Brad; Penny, Robert; Peterson, Jane; Sander, Chris; Speed, Terence P.; Spellman, Paul T.; Wheeler, David A.; Wilson, Richard K.; Chin, Lynda; Knoppers, Bartha M.; Lander, Eric S.; Lichter, Peter; Stratton, Michael R.; Bobrow, Martin; Burke, Wylie; Collins, Francis S.; DePinho, Ronald A.; Easton, Douglas F.; Futreal, P. Andrew; Green, Anthony R.; Guyer, Mark; Hamilton, Stanley R.; Hubbard, Tim J.; Kallioniemi, Olli P.; Kennedy, Karen L.; Ley, Timothy J.; Liu, Edison T.; Lu, Youyong; Majumder, Partha; Marra, Marco; Ozenberger, Brad; Peterson, Jane; Schafer, Alan J.; Spellman, Paul T.; Stunnenberg, Hendrik G.; Wainwright, Brandon J.; Wilson, Richard K.; Yang, Huanming

    2010-01-01

    The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic

  6. Genomic Resources for Cancer Epidemiology

    Science.gov (United States)

    This page provides links to research resources, complied by the Epidemiology and Genomics Research Program, that may be of interest to genetic epidemiologists conducting cancer research, but is not exhaustive.

  7. Cancer Genome Anatomy Project | Office of Cancer Genomics

    Science.gov (United States)

    The National Cancer Institute (NCI) Cancer Genome Anatomy Project (CGAP) is an online resource designed to provide the research community access to biological tissue characterization data. Request a free copy of the CGAP Website Virtual Tour CD from ocg@mail.nih.gov.

  8. A network medicine approach to build a comprehensive atlas for the prognosis of human cancer.

    Science.gov (United States)

    Zhang, Fan; Ren, Chunyan; Lau, Kwun Kit; Zheng, Zihan; Lu, Geming; Yi, Zhengzi; Zhao, Yongzhong; Su, Fei; Zhang, Shaojun; Zhang, Bin; Sobie, Eric A; Zhang, Weijia; Walsh, Martin J

    2016-11-01

    The Cancer Genome Atlas project has generated multi-dimensional and highly integrated genomic data from a large number of patient samples with detailed clinical records across many cancer types, but it remains unclear how to best integrate the massive amount of genomic data into clinical practice. We report here our methodology to build a multi-dimensional subnetwork atlas for cancer prognosis to better investigate the potential impact of multiple genetic and epigenetic (gene expression, copy number variation, microRNA expression and DNA methylation) changes on the molecular states of networks that in turn affects complex cancer survivorship. We uncover an average of 38 novel subnetworks in the protein-protein interaction network that correlate with prognosis across four prominent cancer types. The clinical utility of these subnetwork biomarkers was further evaluated by prognostic impact evaluation, functional enrichment analysis, drug target annotation, tumor stratification and independent validation. Some pathways including the dynactin, cohesion and pyruvate dehydrogenase-related subnetworks are identified as promising new targets for therapy in specific cancer types. In conclusion, this integrative analysis of existing protein interactome and cancer genomics data allows us to systematically dissect the molecular mechanisms that underlie unexpected outcomes for cancer, which could be used to better understand and predict clinical outcomes, optimize treatment and to provide new opportunities for developing therapeutics related to the subnetworks identified.

  9. Genomic determinants of cancer immunotherapy.

    Science.gov (United States)

    Miao, Diana; Van Allen, Eliezer M

    2016-08-01

    Cancer immunotherapies - including therapeutic vaccines, adoptive cell transfer, oncolytic viruses, and immune checkpoint blockade - yield durable responses in many cancer types, but understanding of predictors of response is incomplete. Genomic characterization of human cancers has already contributed to the success of targeted therapies; in cancer immunotherapy, identification of tumor-specific antigens through whole-exome sequencing may be key to designing individualized, highly immunogenic therapeutic vaccines. Additionally, pre-treatment tumor mutational and gene expression signatures can predict which patients are most likely to benefit from cancer immunotherapy. Continued work in harnessing genomic, transcriptomic, and immunological data from clinical cohorts of immunotherapy-treated patients will bring the promises of precision medicine to immuno-oncology.

  10. Expression of lactate/H⁺ symporters MCT1 and MCT4 and their chaperone CD147 predicts tumor progression in clear cell renal cell carcinoma: immunohistochemical and The Cancer Genome Atlas data analyses.

    Science.gov (United States)

    Kim, Younghye; Choi, Jung-Woo; Lee, Ju-Han; Kim, Young-Sik

    2015-01-01

    Clear cell renal cell carcinomas (ccRCCs) have inactivation of the von Hippel-Lindau protein, leading to the accumulation of hypoxia-inducible factor-α (HIF-α). HIF-1α induces aerobic glycolysis, the Warburg effect, whereas HIF-2α functions as an oncoprotein. Lactate transport through monocarboxylate transporters (MCTs) and the chaperone CD147 is essential for high glycolytic cancer cell survival. To elucidate the clinical significance of MCT1, MCT4, and CD147 expression, we investigated their expressions by immunohistochemistry in ccRCC specimens and validated the results by an open-access The Cancer Genome Atlas data analysis. Overexpression of MCT1, MCT4, and CD147 was observed in 49.4% (89/180), 39.4% (71/180), and 79.4% (143/180) of ccRCC patients, respectively. High MCT1 expression was associated with older age (P = .017), larger tumor size (P = .015), and advanced TNM stage (P = .012). However, MCT4 overexpression was not related to any variables. CD147 overexpression correlated with high grade (P = .005), tumor necrosis (P = .016), and larger tumor size (P = .038). In univariate analysis, high expression of MCT1 (P CD147 (P = .02) was linked to short progression-free survival. In multivariate analysis, high MCT1 expression was associated with worse progression-free survival (P = .001). In conclusion, high expression of MCT1 and CD147 is associated with poor prognostic factors. Overexpression of MCT1, MCT4, and CD147 predicts tumor progression. Reversing the Warburg effect by targeting the lactate transporters may be a useful strategy to prevent ccRCC progression.

  11. Functional Genomics for Personalized Cancer Therapy

    Science.gov (United States)

    Tyner, Jeffrey W.

    2017-01-01

    Integration of functional and genomic screening strategies reveals clinically actionable genetic events that impact the effectiveness of cancer treatment regimens and the outcomes of cancer patients. PMID:24990879

  12. Genomic profiling of breast cancer.

    Science.gov (United States)

    Pandey, Anjita; Singh, Alok Kumar; Maurya, Sanjeev Kumar; Rai, Rajani; Tewari, Mallika; Kumar, Mohan; Shukla, Hari S

    2009-05-01

    Genome study provides significant changes in the advancement of molecular diagnosis and treatment in Breast cancer. Several recent critical advances and high-throughput techniques identified the genomic trouble and dramatically accelerated the pace of research in preventing and curing this malignancy. Tumor-suppressor genes, proto-oncogenes, DNA-repair genes, carcinogen-metabolism genes are critically involved in progression of breast cancer. We reviewed imperative finding in breast genetics, ongoing work to segregate further susceptible genes, and preliminary studies on molecular profiling.

  13. Cancer Genome Anatomy Project (CGAP) | Office of Cancer Genomics

    Science.gov (United States)

    CGAP generated a wide range of genomics data on cancerous cells that are accessible through easy-to-use online tools. Researchers, educators, and students can find "in silico" answers to biological questions through the CGAP website. Request a free copy of the CGAP Website Virtual Tour CD from ocg@mail.nih.gov to learn how to navigate the website.

  14. Dana-Farber Cancer Institute | Office of Cancer Genomics

    Science.gov (United States)

    Functional Annotation of Cancer Genomes Principal Investigator: William C. Hahn, M.D., Ph.D. The comprehensive characterization of cancer genomes has and will continue to provide an increasingly complete catalog of genetic alterations in specific cancers. However, most epithelial cancers harbor hundreds of genetic alterations as a consequence of genomic instability. Therefore, the functional consequences of the majority of mutations remain unclear.

  15. Translating genomics in cancer care.

    Science.gov (United States)

    Bombard, Yvonne; Bach, Peter B; Offit, Kenneth

    2013-11-01

    There is increasing enthusiasm for genomics and its promise in advancing personalized medicine. Genomic information has been used to personalize health care for decades, spanning the fields of cardiovascular disease, infectious disease, endocrinology, metabolic medicine, and hematology. However, oncology has often been the first test bed for the clinical translation of genomics for diagnostic, prognostic, and therapeutic applications. Notable hereditary cancer examples include testing for mutations in BRCA1 or BRCA2 in unaffected women to identify those at significantly elevated risk for developing breast and ovarian cancers, and screening patients with newly diagnosed colorectal cancer for mutations in 4 mismatch repair genes to reduce morbidity and mortality in their relatives. Somatic genomic testing is also increasingly used in oncology, with gene expression profiling of breast tumors and EGFR testing to predict treatment response representing commonly used examples. Health technology assessment provides a rigorous means to inform clinical and policy decision-making through systematic assessment of the evidentiary base, along with precepts of clinical effectiveness, cost-effectiveness, and consideration of risks and benefits for health care delivery and society. Although this evaluation is a fundamental step in the translation of any new therapeutic, procedure, or diagnostic test into clinical care, emerging developments may threaten this standard. These include "direct to consumer" genomic risk assessment services and the challenges posed by incidental results generated from next-generation sequencing (NGS) technologies. This article presents a review of the evidentiary standards and knowledge base supporting the translation of key cancer genomic technologies along the continuum of validity, utility, cost-effectiveness, health service impacts, and ethical and societal issues, and offers future research considerations to guide the responsible introduction of

  16. Pan-cancer analysis of the extent and consequences of intratumor heterogeneity | Office of Cancer Genomics

    Science.gov (United States)

    Intratumor heterogeneity (ITH) drives neoplastic progression and therapeutic resistance. We used the bioinformatics tools 'expanding ploidy and allele frequency on nested subpopulations' (EXPANDS) and PyClone to detect clones that are present at a ≥10% frequency in 1,165 exome sequences from tumors in The Cancer Genome Atlas. 86% of tumors across 12 cancer types had at least two clones. ITH in the morphology of nuclei was associated with genetic ITH (Spearman's correlation coefficient, ρ = 0.24-0.41; P < 0.001).

  17. Comparative genomic analysis of esophageal cancers.

    Science.gov (United States)

    Caygill, Christine P J; Gatenby, Piers A C; Herceg, Zdenko; Lima, Sheila C S; Pinto, Luis F R; Watson, Anthony; Wu, Ming-Shiang

    2014-09-01

    The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on comparative genomic analysis of esophageal cancers: genomic polymorphisms, the genetic and epigenetic drivers in esophageal cancers, and the collection of data in the UK Barrett's Oesophagus Registry.

  18. Smoking correlates with increased cytoskeletal protein‐related coding region mutations in the lung and head and neck datasets of the cancer genome atlas

    OpenAIRE

    Yavorski, John M.; Blanck, George

    2016-01-01

    Abstract Cancer from smoking tobacco is considered dependent on mutagens, but significant molecular aspects of smoking‐specific, cancer development remain unknown. We defined sets of coding regions for oncoproteins, tumor suppressor proteins, and cytoskeletal‐related proteins that were compared between nonsmokers and smokers, for mutation occurrences, in the lung adenocarcinoma (LUAD), head and neck squamous carcinoma (HNSC), bladder carcinoma (BLCA), and pancreatic adenocarcinoma ( PAAD) dat...

  19. Genomic instability and cancer: an introduction

    Institute of Scientific and Technical Information of China (English)

    Zhiyuan Shen

    2011-01-01

    @@ Genomic instability as a major driving force of tumorigenesis.The ultimate goal of cell division for most non-cancerous somatic cells is to accurately duplicate the genome and then evenly divide the duplicated genome into the two daughter cells.This ensures that the daughter cells will have exactly the same genetic material as their parent cell.

  20. Complete mitochondrial genome of the atlas moth, Attacus atlas (Lepidoptera: Saturniidae) and the phylogenetic relationship of Saturniidae species.

    Science.gov (United States)

    Chen, Miao-Miao; Li, Yan; Chen, Mo; Wang, Huan; Li, Qun; Xia, Run-Xi; Zeng, Cai-Yun; Li, Yu-Ping; Liu, Yan-Qun; Qin, Li

    2014-07-15

    Mitochondrial genome (mitogenome) can provide information for genomic structure as well as for phylogenetic analysis and evolutionary biology. In this study, we present the complete mitogenome of the atlas moth, Attacus atlas (Lepidoptera: Saturniidae), a well-known silk-producing and ornamental insect with the largest wing surface area of all moths. The mitogenome of A. atlas is a circular molecule of 15,282 bp long, and its nucleotide composition shows heavily biased towards As and Ts, accounting for 79.30%. This genome comprises 13 protein-coding genes (PCGs), two ribosomal RNA genes (rRNAs), 22 transfer RNA genes (tRNAs), and an A+T-rich region. It is of note that this genome exhibits a slightly positive AT skew, which is different from the other known Saturniidae species. All PCGs are initiated by ATN codons, except for COI with CGA instead. Only six PCGs use a common stop codon of TAA or TAG, whereas the remaining seven use an incomplete termination codon T or TA. All tRNAs have the typical clover-leaf structure, with an exception for tRNA(Ser)(AGN). The A. atlas A+T-rich region contains non-repetitive sequences, but harbors several features common to the Bombycoidea insects. The phylogenetic relationships based on Maximum Likelihood method provide a well-supported outline of Saturniidae, which is in accordance with the traditional morphological classification and recent molecular works.

  1. Integration of genomics in cancer care

    DEFF Research Database (Denmark)

    Santos, Erika Maria Monteiro; Edwards, Quannetta T; Floria-Santos, Milena

    2013-01-01

    cancer syndromes, epigenetics factors, and management of care considerations. METHODS: Peer-reviewed literature and expert professional guidelines were reviewed to address concepts of genetics-genomics in cancer care. FINDINGS: Cancer is now known to be heterogeneous at the molecular level, with genetic...

  2. Multi-OMICs and Genome Editing Perspectives on Liver Cancer Signaling Networks

    Science.gov (United States)

    Lin, Shengda; Yin, Yi A.; Jiang, Xiaoqian; Sahni, Nidhi; Yi, Song

    2016-01-01

    The advent of the human genome sequence and the resulting ~20,000 genes provide a crucial framework for a transition from traditional biology to an integrative “OMICs” arena (Lander et al., 2001; Venter et al., 2001; Kitano, 2002). This brings in a revolution for cancer research, which now enters a big data era. In the past decade, with the facilitation by next-generation sequencing, there have been a huge number of large-scale sequencing efforts, such as The Cancer Genome Atlas (TCGA), the HapMap, and the 1000 genomes project. As a result, a deluge of genomic information becomes available from patients stricken by a variety of cancer types. The list of cancer-associated genes is ever expanding. New discoveries are made on how frequent and highly penetrant mutations, such as those in the telomerase reverse transcriptase (TERT) and TP53, function in cancer initiation, progression, and metastasis. Most genes with relatively frequent but weakly penetrant cancer mutations still remain to be characterized. In addition, genes that harbor rare but highly penetrant cancer-associated mutations continue to emerge. Here, we review recent advances related to cancer genomics, proteomics, and systems biology and suggest new perspectives in targeted therapy and precision medicine. PMID:27403431

  3. Multi-OMICs and Genome Editing Perspectives on Liver Cancer Signaling Networks

    Directory of Open Access Journals (Sweden)

    Shengda Lin

    2016-01-01

    Full Text Available The advent of the human genome sequence and the resulting ~20,000 genes provide a crucial framework for a transition from traditional biology to an integrative “OMICs” arena (Lander et al., 2001; Venter et al., 2001; Kitano, 2002. This brings in a revolution for cancer research, which now enters a big data era. In the past decade, with the facilitation by next-generation sequencing, there have been a huge number of large-scale sequencing efforts, such as The Cancer Genome Atlas (TCGA, the HapMap, and the 1000 genomes project. As a result, a deluge of genomic information becomes available from patients stricken by a variety of cancer types. The list of cancer-associated genes is ever expanding. New discoveries are made on how frequent and highly penetrant mutations, such as those in the telomerase reverse transcriptase (TERT and TP53, function in cancer initiation, progression, and metastasis. Most genes with relatively frequent but weakly penetrant cancer mutations still remain to be characterized. In addition, genes that harbor rare but highly penetrant cancer-associated mutations continue to emerge. Here, we review recent advances related to cancer genomics, proteomics, and systems biology and suggest new perspectives in targeted therapy and precision medicine.

  4. Prostate Cancer Genomics: Toward a New Understanding

    OpenAIRE

    John S Witte

    2008-01-01

    Recent genetics and genomics studies of prostate cancer help clarify the genetic basis of this common but complex disease. Genome-wide studies have detected numerous variants associated with disease as well as common gene fusions and expression ‘signatures’ in prostate tumors. Based on these results, some advocate gene-based individualized screening for prostate cancer, although such testing may only be worthwhile to distinguish disease aggressiveness. Lessons learned here provide strategies ...

  5. Pathway and network analysis of cancer genomes

    DEFF Research Database (Denmark)

    Creixell, Pau; Reimand, Jueri; Haider, Syed

    2015-01-01

    Genomic information on tumors from 50 cancer types cataloged by the International Cancer Genome Consortium (ICGC) shows that only a few well-studied driver genes are frequently mutated, in contrast to many infrequently mutated genes that may also contribute to tumor biology. Hence there has been...... large interest in developing pathway and network analysis methods that group genes and illuminate the processes involved. We provide an overview of these analysis techniques and show where they guide mechanistic and translational investigations....

  6. Novel patterns of cancer genome evolution

    Institute of Scientific and Technical Information of China (English)

    Xia Zhang; Xiaodi Deng; Yu Zhang; Zhiguang Li

    2015-01-01

    Cells usually undergo a long journey of evolution during the progression from normal to precancerous cells and finally to full-fledged cancer cells. Multiple genomic aberrations are acquired during this journey that could either act as drivers to confer significant growth advantages or act as passengers with little effect on the tumor growth. Recent advances in sequencing technology have made it feasible to decipher the evolutionary course of a cancer cell on a genome-wide level by evaluating the relative number of mutated alleles. Novel terms such as chromothripsis and chromoplexy have been introduced to describe the newly identified patterns of cancer genome evolution. These new insights have greatly expanded our understanding of the initiation and progression of cancers, which should aid in improving the efficiency of cancer management and treatment.

  7. The genomic landscape of prostate cancer

    Directory of Open Access Journals (Sweden)

    Sylvan eBaca

    2012-05-01

    Full Text Available Prostate cancer is a common malignancy in men, with a markedly variable clinical course. Somatic alterations in DNA drive the growth of prostate cancers and may underlie the behavior of aggressive versus indolent tumors. The accelerating application of genomic technologies over the last two decades has identified mutations that drive prostate cancer formation, progression, and therapeutic resistance. Here, we discuss exemplary somatic mutations in prostate cancer, and highlight mutated cellular pathways with biological and possible therapeutic importance. Examples include mutated genes involved in androgen signaling, cell cycle regulation, signal transduction and development. Some genetic alterations may also predict the clinical course of disease or response to therapy, although the molecular heterogeneity of prostate tumors poses challenges to genomic biomarker identification. The widespread application of massively parallel sequencing technology to the analysis of prostate cancer genomes should continue to advance both discovery-oriented and diagnostic avenues.

  8. Identification of cancer risk lncRNAs and cancer risk pathways regulated by cancer risk lncRNAs based on genome sequencing data in human cancers.

    Science.gov (United States)

    Li, Yiran; Li, Wan; Liang, Binhua; Li, Liansheng; Wang, Li; Huang, Hao; Guo, Shanshan; Wang, Yahui; He, Yuehan; Chen, Lina; He, Weiming

    2016-12-19

    Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. The complexity of cancer can be reduced to a small number of underlying principles like cancer hallmarks which could govern the transformation of normal cells to cancer. Besides, the growth and metastasis of cancer often relate to combined effects of long non-coding RNAs (lncRNAs). Here, we performed comprehensive analysis for lncRNA expression profiles and clinical data of six types of human cancer patients from The Cancer Genome Atlas (TCGA), and identified six risk pathways and twenty three lncRNAs. In addition, twenty three cancer risk lncRNAs which were closely related to the occurrence or development of cancer had a good classification performance for samples of testing datasets of six cancer datasets. More important, these lncRNAs were able to separate samples in the entire cancer dataset into high-risk group and low-risk group with significantly different overall survival (OS), which was further validated in ten validation datasets. In our study, the robust and effective cancer biomarkers were obtained from cancer datasets which had information of normal-tumor samples. Overall, our research can provide a new perspective for the further study of clinical diagnosis and treatment of cancer.

  9. Cancer Genome Sequencing and Its Implications for Personalized Cancer Vaccines

    Directory of Open Access Journals (Sweden)

    William E. Gillanders

    2011-11-01

    Full Text Available New DNA sequencing platforms have revolutionized human genome sequencing. The dramatic advances in genome sequencing technologies predict that the $1,000 genome will become a reality within the next few years. Applied to cancer, the availability of cancer genome sequences permits real-time decision-making with the potential to affect diagnosis, prognosis, and treatment, and has opened the door towards personalized medicine. A promising strategy is the identification of mutated tumor antigens, and the design of personalized cancer vaccines. Supporting this notion are preliminary analyses of the epitope landscape in breast cancer suggesting that individual tumors express significant numbers of novel antigens to the immune system that can be specifically targeted through cancer vaccines.

  10. Cancer Genome Sequencing and Its Implications for Personalized Cancer Vaccines

    Energy Technology Data Exchange (ETDEWEB)

    Li, Lijin [Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110 (United States); Goedegebuure, Peter [Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110 (United States); The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO 63110 (United States); Mardis, Elaine R. [The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO 63110 (United States); The Genome Institute at Washington University School of Medicine, St. Louis, MO 63108 (United States); Ellis, Matthew J.C. [The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO 63110 (United States); Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110 (United States); Zhang, Xiuli; Herndon, John M. [Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110 (United States); Fleming, Timothy P. [Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110 (United States); The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO 63110 (United States); Carreno, Beatriz M. [The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO 63110 (United States); Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110 (United States); Hansen, Ted H. [The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO 63110 (United States); Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110 (United States); Gillanders, William E., E-mail: gillandersw@wudosis.wustl.edu [Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110 (United States); The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO 63110 (United States)

    2011-11-25

    New DNA sequencing platforms have revolutionized human genome sequencing. The dramatic advances in genome sequencing technologies predict that the $1,000 genome will become a reality within the next few years. Applied to cancer, the availability of cancer genome sequences permits real-time decision-making with the potential to affect diagnosis, prognosis, and treatment, and has opened the door towards personalized medicine. A promising strategy is the identification of mutated tumor antigens, and the design of personalized cancer vaccines. Supporting this notion are preliminary analyses of the epitope landscape in breast cancer suggesting that individual tumors express significant numbers of novel antigens to the immune system that can be specifically targeted through cancer vaccines.

  11. Genomic rearrangements of PTEN in prostate cancer

    Directory of Open Access Journals (Sweden)

    Sopheap ePhin

    2013-09-01

    Full Text Available The phosphatase and tensin homolog gene on chromosome 10q23.3 (PTEN is a negative regulator of the PIK3/Akt survival pathway and is the most frequently deleted tumor suppressor gene in prostate cancer. Monoallelic loss of PTEN is present in up to 60% of localized prostate cancers and complete loss of PTEN in prostate cancer is linked to metastasis and androgen independent progression. Studies on the genomic status of PTEN in prostate cancer initially used a two-color fluorescence in-situ hybridization (FISH assay for PTEN copy number detection in formalin fixed paraffin embedded tissue preparations. More recently, a four-color FISH assay containing two additional control probes flanking the PTEN locus with a lower false-positive rate was reported. Combined with the detection of other critical genomic biomarkers for prostate cancer such as ERG, AR, and MYC, the evaluation of PTEN genomic status has proven to be invaluable for patient stratification and management. Although less frequent than allelic deletions, point mutations in the gene and epigenetic silencing are also known to contribute to loss of PTEN function, and ultimately to prostate cancer initiation. Overall, it is clear that PTEN is a powerful biomarker for prostate cancer. Used as a companion diagnostic for emerging therapeutic drugs, FISH analysis of PTEN is promisingly moving human prostate cancer closer to more effective cancer management and therapies.

  12. Characterizing genomic alterations in cancer by complementary functional associations | Office of Cancer Genomics

    Science.gov (United States)

    Systematic efforts to sequence the cancer genome have identified large numbers of mutations and copy number alterations in human cancers. However, elucidating the functional consequences of these variants, and their interactions to drive or maintain oncogenic states, remains a challenge in cancer research. We developed REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene dependency of oncogenic pathways or sensitivity to a drug treatment.

  13. Director's Update - Office of Cancer Clinical Proteomics Research

    Science.gov (United States)

    The National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium (NCI-CPTAC) has recently begun the proteomic interrogation of genomically-characterized tumors from The Cancer Genome Atlas.

  14. Cancer genomics object model: an object model for multiple functional genomics data for cancer research.

    Science.gov (United States)

    Park, Yu Rang; Lee, Hye Won; Cho, Sung Bum; Kim, Ju Han

    2007-01-01

    The development of functional genomics including transcriptomics, proteomics and metabolomics allow us to monitor a large number of key cellular pathways simultaneously. Several technology-specific data models have been introduced for the representation of functional genomics experimental data, including the MicroArray Gene Expression-Object Model (MAGE-OM), the Proteomics Experiment Data Repository (PEDRo), and the Tissue MicroArray-Object Model (TMA-OM). Despite the increasing number of cancer studies using multiple functional genomics technologies, there is still no integrated data model for multiple functional genomics experimental and clinical data. We propose an object-oriented data model for cancer genomics research, Cancer Genomics Object Model (CaGe-OM). We reference four data models: Functional Genomic-Object Model, MAGE-OM, TMAOM and PEDRo. The clinical and histopathological information models are created by analyzing cancer management workflow and referencing the College of American Pathology Cancer Protocols and National Cancer Institute Common Data Elements. The CaGe-OM provides a comprehensive data model for integrated storage and analysis of clinical and multiple functional genomics data.

  15. Human Cancer Models Initiative | Office of Cancer Genomics

    Science.gov (United States)

    The Human Cancer Models Initiative (HCMI) is an international consortium that is generating novel human tumor-derived culture models, which are annotated with genomic and clinical data. In an effort to advance cancer research and more fully understand how in vitro findings are related to clinical biology, HCMI-developed models and related data will be available as a community resource for cancer research.

  16. Childhood Cancer Genomics Gaps and Opportunities - Workshop Summary

    Science.gov (United States)

    NCI convened a workshop of representative research teams that have been leaders in defining the genomic landscape of childhood cancers to discuss the influence of genomic discoveries on the future of childhood cancer research.

  17. Genome scale metabolic modeling of cancer

    DEFF Research Database (Denmark)

    Nilsson, Avlant; Nielsen, Jens

    2016-01-01

    been used as scaffolds for analysis of high throughput data to allow mechanistic interpretation of changes in expression. Finally, GEMs allow quantitative flux predictions using flux balance analysis (FBA). Here we critically review the requirements for successful FBA simulations of cancer cells......Cancer cells reprogram metabolism to support rapid proliferation and survival. Energy metabolism is particularly important for growth and genes encoding enzymes involved in energy metabolism are frequently altered in cancer cells. A genome scale metabolic model (GEM) is a mathematical formalization...... of metabolism which allows simulation and hypotheses testing of metabolic strategies. It has successfully been applied to many microorganisms and is now used to study cancer metabolism. Generic models of human metabolism have been reconstructed based on the existence of metabolic genes in the human genome...

  18. Open-Access Cancer Genomics - Office of Cancer Clinical Proteomics Research

    Science.gov (United States)

    The completion of the Human Genome Project sparked a revolution in high-throughput genomics applied towards deciphering genetically complex diseases, like cancer. Now, almost 10 years later, we have a mountain of genomics data on many different cancer type

  19. Genome organization, instabilities, stem cells, and cancer

    Directory of Open Access Journals (Sweden)

    Senthil Kumar Pazhanisamy

    2009-01-01

    Full Text Available It is now widely recognized that advances in exploring genome organization provide remarkable insights on the induction and progression of chromosome abnormalities. Much of what we know about how mutations evolve and consequently transform into genome instabilities has been characterized in the spatial organization context of chromatin. Nevertheless, many underlying concepts of impact of the chromatin organization on perpetuation of multiple mutations and on propagation of chromosomal aberrations remain to be investigated in detail. Genesis of genome instabilities from accumulation of multiple mutations that drive tumorigenesis is increasingly becoming a focal theme in cancer studies. This review focuses on structural alterations evolve to raise a variety of genome instabilities that are manifested at the nucleotide, gene or sub-chromosomal, and whole chromosome level of genome. Here we explore an underlying connection between genome instability and cancer in the light of genome architecture. This review is limited to studies directed towards spatial organizational aspects of origin and propagation of aberrations into genetically unstable tumors.

  20. An atlas of bovine gene expression reveals novel distinctive tissue characteristics and evidence for improving genome annotation

    Science.gov (United States)

    Background A comprehensive transcriptome survey, or gene atlas, provides information essential for a complete understanding of the genomic biology of an organism. We present an atlas of RNA abundance for 92 adult, juvenile and fetal cattle tissues and three cattle cell lines. Results The Bovine Gene...

  1. Single-cell analysis in cancer genomics

    Science.gov (United States)

    Saadatpour, Assieh; Lai, Shujing; Guo, Guoji; Yuan, Guo-Cheng

    2017-01-01

    Genetic changes and environmental differences result in cellular heterogeneity among cancer cells within the same tumor, thereby complicating treatment outcomes. Recent advances in single-cell technologies have opened new avenues to characterize the intra-tumor cellular heterogeneity, identify rare cell types, measure mutation rates, and, ultimately, guide diagnosis and treatment. In this paper, we review the recent single-cell technological and computational advances at the genomic, transcriptomic, and proteomic levels, and discuss their applications in cancer research. PMID:26450340

  2. Overview | Office of Cancer Genomics

    Science.gov (United States)

    The Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative uses comprehensive molecular characterization to determine the genetic changes that drive the initiation and progression of hard-to-treat childhood cancers. TARGET aims to identify therapeutic targets and prognostic markers so that new, more effective treatment strategies can be developed and applied. Novel pediatric cancer treatments are needed because:

  3. Genomic analysis of epithelial ovarian cancer

    Institute of Scientific and Technical Information of China (English)

    John Farley; Laurent L Ozbun; Michael J Birrer

    2008-01-01

    Ovarian cancer is a major health problem for women in the United States.Despite evidence of considerable heterogeneity,most cases of ovarian cancer are treated in a similar fashion.The molecular basis for the clinicopathologic characteristics of these tumors remains poorly defined.Whole genome expression profiling is a genomic tool,which can identify dysregulated genes and uncover unique sub-classes of tumors.The application of this technology to ovarian cancer has provided a solid molecular basis for differences in histology and grade of ovarian tumors.Differentially expressed genes identified pathways implicated in cell proliferation,invasion,motility,chromosomal instability,and gene silencing and provided new insights into the origin and potential treatment of these cancers.The added knowledge provided by global gene expression profiling should allow for a more rational treatment of ovarian cancers.These techniques are leading to a paradigm shift from empirical treatment to an individually tailored approach.This review summarizes the new genomic data on epithelial ovarian cancers of different histology and grade and the impact it will have on our understanding and treatment of this disease.

  4. Genome-wide identification of significant aberrations in cancer genome

    Directory of Open Access Journals (Sweden)

    Yuan Xiguo

    2012-07-01

    Full Text Available Abstract Background Somatic Copy Number Alterations (CNAs in human genomes are present in almost all human cancers. Systematic efforts to characterize such structural variants must effectively distinguish significant consensus events from random background aberrations. Here we introduce Significant Aberration in Cancer (SAIC, a new method for characterizing and assessing the statistical significance of recurrent CNA units. Three main features of SAIC include: (1 exploiting the intrinsic correlation among consecutive probes to assign a score to each CNA unit instead of single probes; (2 performing permutations on CNA units that preserve correlations inherent in the copy number data; and (3 iteratively detecting Significant Copy Number Aberrations (SCAs and estimating an unbiased null distribution by applying an SCA-exclusive permutation scheme. Results We test and compare the performance of SAIC against four peer methods (GISTIC, STAC, KC-SMART, CMDS on a large number of simulation datasets. Experimental results show that SAIC outperforms peer methods in terms of larger area under the Receiver Operating Characteristics curve and increased detection power. We then apply SAIC to analyze structural genomic aberrations acquired in four real cancer genome-wide copy number data sets (ovarian cancer, metastatic prostate cancer, lung adenocarcinoma, glioblastoma. When compared with previously reported results, SAIC successfully identifies most SCAs known to be of biological significance and associated with oncogenes (e.g., KRAS, CCNE1, and MYC or tumor suppressor genes (e.g., CDKN2A/B. Furthermore, SAIC identifies a number of novel SCAs in these copy number data that encompass tumor related genes and may warrant further studies. Conclusions Supported by a well-grounded theoretical framework, SAIC has been developed and used to identify SCAs in various cancer copy number data sets, providing useful information to study the landscape of cancer genomes

  5. Genome evolution during progression to breast cancer

    KAUST Repository

    Newburger, D. E.

    2013-04-08

    Cancer evolution involves cycles of genomic damage, epigenetic deregulation, and increased cellular proliferation that eventually culminate in the carcinoma phenotype. Early neoplasias, which are often found concurrently with carcinomas and are histologically distinguishable from normal breast tissue, are less advanced in phenotype than carcinomas and are thought to represent precursor stages. To elucidate their role in cancer evolution we performed comparative whole-genome sequencing of early neoplasias, matched normal tissue, and carcinomas from six patients, for a total of 31 samples. By using somatic mutations as lineage markers we built trees that relate the tissue samples within each patient. On the basis of these lineage trees we inferred the order, timing, and rates of genomic events. In four out of six cases, an early neoplasia and the carcinoma share a mutated common ancestor with recurring aneuploidies, and in all six cases evolution accelerated in the carcinoma lineage. Transition spectra of somatic mutations are stable and consistent across cases, suggesting that accumulation of somatic mutations is a result of increased ancestral cell division rather than specific mutational mechanisms. In contrast to highly advanced tumors that are the focus of much of the current cancer genome sequencing, neither the early neoplasia genomes nor the carcinomas are enriched with potentially functional somatic point mutations. Aneuploidies that occur in common ancestors of neoplastic and tumor cells are the earliest events that affect a large number of genes and may predispose breast tissue to eventual development of invasive carcinoma.

  6. Comprehensive genomic characterization defines human glioblastoma genes and core pathways

    NARCIS (Netherlands)

    Chin, L.; Meyerson, M.; Aldape, K.; Bigner, D.; Mikkelsen, T.; VandenBerg, S.; Kahn, A.; Penny, R.; Gerhard, D. S.; Getz, G.; Brennan, C.; Taylor, B. S.; Winckler, W.; Park, P.; Ladanyi, M.; Hoadley, K. A.; Verhaak, R. G. W.; Hayes, D. N.; Spellman, Paul T.; Absher, D.; Weir, B. A.; Ding, L.; Wheeler, D.; Lawrence, M. S.; Cibulskis, K.; Mardis, E.; Zhang, Jinghui; Wilson, R. K.; Donehower, L.; Wheeler, D. A.; Purdom, E.; Wallis, J.; Laird, P. W.; Herman, J. G.; Schuebel, K. E.; Weisenberger, D. J.; Baylin, S. B.; Schultz, N.; Yao, Jun; Wiedemeyer, R.; Weinstein, J.; Sander, C.; Gibbs, R. A.; Gray, J.; Kucherlapati, R.; Lander, E. S.; Myers, R. M.; Perou, C. M.; McLendon, Roger; Friedman, Allan; Van Meir, Erwin G; Brat, Daniel J; Mastrogianakis, Gena Marie; Olson, Jeffrey J; Lehman, Norman; Yung, W. K. Alfred; Bogler, Oliver; Berger, Mitchel; Prados, Michael; Muzny, Donna; Morgan, Margaret; Scherer, Steve; Sabo, Aniko; Nazareth, Lynn; Lewis, Lora; Hall, Otis; Zhu, Yiming; Ren, Yanru; Alvi, Omar; Yao, Jiqiang; Hawes, Alicia; Jhangiani, Shalini; Fowler, Gerald; San Lucas, Anthony; Kovar, Christie; Cree, Andrew; Dinh, Huyen; Santibanez, Jireh; Joshi, Vandita; Gonzalez-Garay, Manuel L.; Miller, Christopher A.; Milosavljevic, Aleksandar; Sougnez, Carrie; Fennell, Tim; Mahan, Scott; Wilkinson, Jane; Ziaugra, Liuda; Onofrio, Robert; Bloom, Toby; Nicol, Rob; Ardlie, Kristin; Baldwin, Jennifer; Gabriel, Stacey; Fulton, Robert S.; McLellan, Michael D.; Larson, David E.; Shi, Xiaoqi; Abbott, Rachel; Fulton, Lucinda; Chen, Ken; Koboldt, Daniel C.; Wendl, Michael C.; Meyer, Rick; Tang, Yuzhu; Lin, Ling; Osborne, John R.; Dunford-Shore, Brian H.; Miner, Tracie L.; Delehaunty, Kim; Markovic, Chris; Swift, Gary; Courtney, William; Pohl, Craig; Abbott, Scott; Hawkins, Amy; Leong, Shin; Haipek, Carrie; Schmidt, Heather; Wiechert, Maddy; Vickery, Tammi; Scott, Sacha; Dooling, David J.; Chinwalla, Asif; Weinstock, George M.; O'Kelly, Michael; Robinson, Jim; Alexe, Gabriele; Beroukhim, Rameen; Carter, Scott; Chiang, Derek; Gould, Josh; Gupta, Supriya; Korn, Josh; Mermel, Craig; Mesirov, Jill; Monti, Stefano; Nguyen, Huy; Parkin, Melissa; Reich, Michael; Stransky, Nicolas; Garraway, Levi; Golub, Todd; Protopopov, Alexei; Perna, Ilana; Aronson, Sandy; Sathiamoorthy, Narayan; Ren, Georgia; Kim, Hyunsoo; Kong, Sek Won; Xiao, Yonghong; Kohane, Isaac S.; Seidman, Jon; Cope, Leslie; Pan, Fei; Van Den Berg, David; Van Neste, Leander; Yi, Joo Mi; Li, Jun Z.; Southwick, Audrey; Brady, Shannon; Aggarwal, Amita; Chung, Tisha; Sherlock, Gavin; Brooks, James D.; Jakkula, Lakshmi R.; Lapuk, Anna V.; Marr, Henry; Dorton, Shannon; Choi, Yoon Gi; Han, Ju; Ray, Amrita; Wang, Victoria; Durinck, Steffen; Robinson, Mark; Wang, Nicholas J.; Vranizan, Karen; Peng, Vivian; Van Name, Eric; Fontenay, Gerald V.; Ngai, John; Conboy, John G.; Parvin, Bahram; Feiler, Heidi S.; Speed, Terence P.; Socci, Nicholas D.; Olshen, Adam; Lash, Alex; Reva, Boris; Antipin, Yevgeniy; Stukalov, Alexey; Gross, Benjamin; Cerami, Ethan; Wang, Wei Qing; Qin, Li-Xuan; Seshan, Venkatraman E.; Villafania, Liliana; Cavatore, Magali; Borsu, Laetitia; Viale, Agnes; Gerald, William; Topal, Michael D.; Qi, Yuan; Balu, Sai; Shi, Yan; Wu, George; Bittner, Michael; Shelton, Troy; Lenkiewicz, Elizabeth; Morris, Scott; Beasley, Debbie; Sanders, Sheri; Sfeir, Robert; Chen, Jessica; Nassau, David; Feng, Larry; Hickey, Erin; Schaefer, Carl; Madhavan, Subha; Buetow, Ken; Barker, Anna; Vockley, Joseph; Compton, Carolyn; Vaught, Jim; Fielding, Peter; Collins, Francis; Good, Peter; Guyer, Mark; Ozenberger, Brad; Peterson, Jane; Thomson, Elizabeth

    2008-01-01

    Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas ( TCGA) pilot project aims to assess the value of large- scale multi- dimensional analysis of these molecular char

  7. Distributed usability evaluation of the Pennsylvania Cancer Atlas

    Directory of Open Access Journals (Sweden)

    MacEachren Alan M

    2008-07-01

    Full Text Available Abstract Background The Pennsylvania Cancer Atlas (PA-CA is an interactive online atlas to help policy-makers, program managers, and epidemiologists with tasks related to cancer prevention and control. The PA-CA includes maps, graphs, tables, that are dynamically linked to support data exploration and decision-making with spatio-temporal cancer data. Our Atlas development process follows a user-centered design approach. To assess the usability of the initial versions of the PA-CA, we developed and applied a novel strategy for soliciting user feedback through multiple distributed focus groups and surveys. Our process of acquiring user feedback leverages an online web application (e-Delphi. In this paper we describe the PA-CA, detail how we have adapted e-Delphi web application to support usability and utility evaluation of the PA-CA, and present the results of our evaluation. Results We report results from four sets of users. Each group provided structured individual and group assessments of the PA-CA as well as input on the kinds of users and applications for which it is best suited. Overall reactions to the PA-CA are quite positive. Participants did, however, provide a range of useful suggestions. Key suggestions focused on improving interaction functions, enhancing methods of temporal analysis, addressing data issues, and providing additional data displays and help functions. These suggestions were incorporated in each design and implementation iteration for the PA-CA and used to inform a set of web-atlas design principles. Conclusion For the Atlas, we find that a design that utilizes linked map, graph, and table views is understandable to and perceived to be useful by the target audience of cancer prevention and control professionals. However, it is clear that considerable variation in experience using maps and graphics exists and for those with less experience, integrated tutorials and help features are needed. In relation to our usability

  8. Glossary | Office of Cancer Genomics

    Science.gov (United States)

    A   B   C   D   E   F   G   H   I   J   K   L   M   N   O   P   Q   R   S   T   U   V   W   X   Y   Z     B Bioinformatics The use of computing tools to manage and analyze genomic and molecular biological data.

  9. A prostate MRI atlas of biochemical failures following cancer treatment

    Science.gov (United States)

    Rusu, Mirabela; Kurhanewicz, John; Tewari, Ashutosh; Madabhushi, Anant

    2014-03-01

    Radical prostatectomy (RP) and radiation therapy (RT) are the most common treatment options for prostate cancer (PCa). Despite advancements in radiation delivery and surgical procedures, RP and RT can result in failure rates as high as 40% and >25%, respectively. Treatment failure is characterized by biochemical recurrence (BcR), which is defined in terms of prostate specific antigen (PSA) concentrations and its variation following treatment. PSA is expected to decrease following treatment, thereby its presence in even small concentrations (e.g 0.2 ng/ml for surgery or 2 ng/ml over the nadir PSA for radiation therapy) is indicative of treatment failure. Early identification of treatment failure may enable the use of more aggressive or neo-adjuvant therapies. Moreover, predicting failure prior to treatment may spare the patient from a procedure that is unlikely to be successful. Our goal is to identify differences on pre-treatment MRI between patients who have BcR and those who remain disease-free at 5 years post-treatment. Specifically, we focus on (1) identifying statistically significant differences in MRI intensities, (2) establishing morphological differences in prostatic anatomic structures, and (3) comparing these differences with the natural variability of prostatic structures. In order to attain these objectives, we use an anatomically constrained registration framework to construct BcR and non-BcR statistical atlases based on the pre-treatment magnetic resonance images (MRI) of the prostate. The patients included in the atlas either underwent RP or RT and were followed up for at least 5 years. The BcR atlas was constructed from a combined population of 12 pre-RT 1.5 Tesla (T) MRI and 33 pre-RP 3T MRI from patients with BcR within 5 years of treatment. Similarly, the non-BcR atlas was built based on a combined cohort of 20 pre-RT 1.5T MRI and 41 pre-RP 3T MRI from patients who remain disease-free 5 years post treatment. We chose the atlas framework as it

  10. TCGA researchers identify 4 subtypes of stomach cancer

    Science.gov (United States)

    Stomach cancers fall into four distinct molecular subtypes, researchers with The Cancer Genome Atlas (TCGA) Network have found. Scientists report that this discovery could change how researchers think about developing treatments for stomach cancer, also c

  11. Study Points to Genetic Subtypes of Esophageal Cancer

    Science.gov (United States)

    A Cancer Currents blog post about a study by The Cancer Genome Atlas Research Network that identified distinct genetic and molecular changes in esophageal cancers that could improve their classification and identify potential new treatments.

  12. Childhood Cancer Genomics (PDQ®)—Health Professional Version

    Science.gov (United States)

    Expert-reviewed information summary about the genomics of childhood cancer. The summary describes the molecular subtypes for specific pediatric cancers and their associated clinical characteristics, the recurring genomic alterations that characterize each subtype at diagnosis or relapse, and the therapeutic and prognostic significance of the genomic alterations. The genomic alterations associated with brain tumors, kidney tumors, leukemias, lymphomas, sarcomas, and other cancers are discussed.

  13. Genomic Instability and Breast Cancer

    Science.gov (United States)

    2011-01-01

    medium containing 10% bovine serum and penicillin /streptomycin. Transient transfection was performed with the polyethyleni- mine (25 kDa) method. Stable...mutations in 13 Fanc genes and renders cells hypersensitive to DNA interstrand cross-linking (ICL) agents. A central event in the FA pathway is mono...interstrand cross-links. Fanconi anemia (FA) is characterized bycongenital malformations, bone marrowfailure, cancer, and hypersensitivity toDNA interstrand

  14. Identifying driver mutations in sequenced cancer genomes

    DEFF Research Database (Denmark)

    Raphael, Benjamin J; Dobson, Jason R; Oesper, Layla

    2014-01-01

    High-throughput DNA sequencing is revolutionizing the study of cancer and enabling the measurement of the somatic mutations that drive cancer development. However, the resulting sequencing datasets are large and complex, obscuring the clinically important mutations in a background of errors, noise......, and random mutations. Here, we review computational approaches to identify somatic mutations in cancer genome sequences and to distinguish the driver mutations that are responsible for cancer from random, passenger mutations. First, we describe approaches to detect somatic mutations from high-throughput DNA...... sequencing data, particularly for tumor samples that comprise heterogeneous populations of cells. Next, we review computational approaches that aim to predict driver mutations according to their frequency of occurrence in a cohort of samples, or according to their predicted functional impact on protein...

  15. The Genomic Evolution of Prostate Cancer

    Science.gov (United States)

    2015-10-01

    clone can give rise to both low grade and high grade disease. Conversely, lymph node metastases are closely related to high grade cancer. Alterations...going. Because of the overall low quality of the DNA (including whole genome amplification) the analysis is taking longer than expected but still...a postbaccalaureate student and am actively recruiting for a postdoctoral position. Opportunities for Training As per the SOW, I have attended

  16. DNA secondary structures and epigenetic determinants of cancer genome evolution

    OpenAIRE

    2010-01-01

    An unstable genome is a hallmark of many cancers. It is unclear, however, whether some mutagenic features driving somatic alterations in cancer are encoded in the genome sequence and whether they can operate in a tissue-specific manner. We performed a genome-wide analysis of 663,446 DNA breakpoints associated with somatic copy-number alterations (SCNAs) from 2,792 cancer samples classified into 26 cancer types. Many SCNA breakpoints are spatially clustered in cancer genomes. We observed a sig...

  17. Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes

    DEFF Research Database (Denmark)

    Johnatty, Sharon E; Tyrer, Jonathan P; Kar, Siddhartha;

    2015-01-01

    PURPOSE: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. EXPERIMENTAL DESIGN: We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment...... for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥ 4 cycles of paclitaxel and carboplatin...... at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis. RESULTS: Five SNPs were significantly...

  18. Review of State Comprehensive Cancer Control Plans for Genomics Content

    Directory of Open Access Journals (Sweden)

    Robert C. Millikan, DVM, PhD

    2005-03-01

    Full Text Available Introduction The goals of this study were to determine U.S. states with Comprehensive Cancer Control plans that include genomics in some capacity and to review successes with and barriers to implementation of genomics-related cancer control initiatives. Methods This study was conducted in two phases. Phase one included a content analysis of written state Comprehensive Cancer Control plans (n = 30 for terms related to genomics, or “genomic components” (n = 18. The second phase involved telephone interviews with the Comprehensive Cancer Control plan coordinators in states with plans that contained genomic components (n = 16. The interview was designed to gather more detailed information about the genomics-related initiatives within the state’s Comprehensive Cancer Control plan and the successes with and barriers to plan implementation, as defined by each state. Results Eighteen of the 30 Comprehensive Cancer Control plans analyzed contained genomics components. We noted a large variability among these 18 plans in the types of genomics components included. Nine (56% of the 16 states interviewed had begun to implement the genomics components in their plan. Most states emphasized educating health care providers and the public about the role of genomics in cancer control. Many states consider awareness of family history to be an important aspect of their Comprehensive Cancer Control plan. Approximately 67% of states with family history components in their plans had begun to implement these goals. Virtually all states reported they would benefit from additional training in cancer genetics and general public health genomics. Conclusion The number of states incorporating genomics into their Comprehensive Cancer Control plans is increasing. Family history is a public health application of genomics that could be implemented more fully into Comprehensive Cancer Control plans.

  19. Genomic and epigenomic alterations in prostate cancer

    Directory of Open Access Journals (Sweden)

    Anna Maria eAschelter

    2012-11-01

    Full Text Available Prostate cancer (PC is the second most frequently diagnosed cancer and the second leading cause of cancer deaths in man. The treatment of localized PC includes surgery or radiation therapy. In case of relapse after a definitive treatment or in patients with locally advanced or metastatic disease, the standard treatment includes the androgen-deprivation therapy (ADT. By reducing the levels of Testosterone and dihydrotestosterone (DHT under the castration threshold, the ADT acts on the androgen receptor (AR, even if indirectly. The effects of the ADT are usually temporary and nearly all patients, initially sensitive to the androgen ablation therapy, have a disease progression after a 18-24 months medium term. This is probably due to the selection of the cancer cell clones and to their acquisition of critical somatic genome and epigenomic changes. This review aims to provide an overview about the genetic and epigenetic alterations having a crucial role in the carcinogenesis and in the disease progression toward the castration resistant prostate cancer (CRPC. We focused on the role of the androgen receptor, on its signaling cascade and on the clinical implications that the knowledge of these aspects would have on hormonal therapy, on its failure and its toxicity.

  20. KRAS Genomic Status Predicts the Sensitivity of Ovarian Cancer Cells to Decitabine | Office of Cancer Genomics

    Science.gov (United States)

    Decitabine, a cancer therapeutic that inhibits DNA methylation, produces variable antitumor response rates in patients with solid tumors that might be leveraged clinically with identification of a predictive biomarker. In this study, we profiled the response of human ovarian, melanoma, and breast cancer cells treated with decitabine, finding that RAS/MEK/ERK pathway activation and DNMT1 expression correlated with cytotoxic activity. Further, we showed that KRAS genomic status predicted decitabine sensitivity in low-grade and high-grade serous ovarian cancer cells.

  1. Integrated proteo-genomic approach for early diagnosis and prognosis of cancer.

    Science.gov (United States)

    Shukla, Hem D; Mahmood, Javed; Vujaskovic, Zeljko

    2015-12-01

    Cancer is the leading cause of mortality among men and women worldwide. Despite the availability of numerous diagnostic techniques for various cancers, the overall survival rate remains low and the majority of patients die due to late diagnosis and advanced stage of the disease. Diagnosing and treating cancer at its early stages ideally during the precancerous phase could significantly increase survival rate with the possibility of cure and prolong survival. Cancer is a genetic disease and it is illicitly activated by the acquisition of somatic DNA lesions and aberrations in genome structure and defects in maintenance and repair. These somatic DNA mutations known as driver mutations seem to be the prime cause in initiating tumorigenesis. The advances in genomic technologies have immensely facilitated the understanding of cancer progression and metastasis, and the discovery of novel biomarkers. However, changes in somatic mutational landscape of the oncogenome are translated into aberrantly regulated oncoproteome which drives the cancer initiation. Thus, combination of proteomic and genomic technologies is urgently required to discover biomarkers for early diagnosis. The recent advances in human genome based detection of cancer using advanced genomic technologies like NextGen Sequencing, digital PCR, cfDNA technology have shown promise; for example oncogenic somatic mutation variants, transcriptomic analysis, copy number variant, and methylation data from the Cancer Genome Atlas. Similarly, oncoproteomics has the potential to revolutionize clinical management of the disease, including cancer diagnosis and screening based on new proteomic database which embodies somatic variants and post translational modifications, thus devising proteomic technologies as a complement to histopathology. Further, the use of multiple proteomic and genomic biomarkers rather than a single gene or protein could greatly improve diagnostic accuracy and enhance the predictive power for

  2. Genome-wide Association Studies from the Cancer Genetic Markers of Susceptibility (CGEMS) Initiative | Office of Cancer Genomics

    Science.gov (United States)

    CGEMS identifies common inherited genetic variations associated with a number of cancers, including breast and prostate. Data from these genome-wide association studies (GWAS) are available through the Division of Cancer Epidemiology & Genetics website.

  3. TCGA divides gastric cancer into four molecular subtypes:implications for individualized therapeutics

    Institute of Scientific and Technical Information of China (English)

    Wei Zhang

    2014-01-01

    Gastric cancer is a leading cause of cancer deaths in the world. The treatment of gastric cancer is chalenging because of its highly heterogeneous etiology and clinical characteristics. Recent genomic and molecular characterization of gastric cancer, especialy the findings reported by the Cancer Genome Atlas (TCGA), have shed light on the heterogeneity and potential targeted therapeutics for four different subtypes of gastric cancer.

  4. Genetics and genomics of prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Michael Dean; Hong Lou

    2013-01-01

    Prostate cancer (PCa) is one of the most common malignancies in the world with over 890 000 cases and over 258 000 deaths worldwide each year.Nearly all mortalities from PCa are due to metastatic disease,typically through tumors that evolve to be hormone-refractory or castrate-resistant.Despite intensive epidemiological study,there are few known environmental risk factors,and age and family history are the major determinants.However,there is extreme heterogeneity in PCa incidence worldwide,suggesting that major determining factors have not been described.Genome-wide association studies have been performed and a considerable number of significant,but low-risk loci have been identified.In addition,several groups have analyzed PCa by determination of genomic copy number,fusion gene generation and targeted resequencing of candidate genes,as well as exome and whole genome sequencing.These initial studies have examined both primary and metastatic tumors as well as murine xenografts and identified somatic alterations in TP53 and other potential driver genes,and the disturbance of androgen response and cell cycle pathways.It is hoped that continued characterization of risk factors as well as gene mutation and misregulation in tumors will aid in understanding,diagnosing and better treating PCa.

  5. Genomic alterations in pancreatic cancer and their relevance to therapy

    Institute of Scientific and Technical Information of China (English)

    Erina; Takai; Shinichi; Yachida

    2015-01-01

    Pancreatic cancer is a highly lethal cancer type, for which there are few viable therapeutic options. But, with the advance of sequencing technologies for global genomic analysis, the landscape of genomic alterations in pancreatic cancer is becoming increasingly well understood. In this review, we summarize current knowledge of genomic alterations in 12 core signaling pathways or cellular processes in pancreatic ductal adenocarcinoma, which is the most common type of malignancy in the pancreas, including four commonly mutated genes and many other genes that are mutated at low frequencies. We also describe the potential implications of these genomic alterations for development of novel therapeutic approaches in the context of personalized medicine.

  6. Kidney cancer progression linked to shifts in tumor metabolism

    Science.gov (United States)

    Investigators in The Cancer Genome Atlas Research Network have uncovered a connection between how tumor cells use energy from metabolic processes and the aggressiveness of the most common form of kidney cancer, clear cell renal cell carcinoma.

  7. Cancer genetic association studies in the genome-wide age

    OpenAIRE

    Savage, Sharon A

    2008-01-01

    Genome-wide association studies of hundreds of thousands of SNPs have led to a deluge of studies of genetic variation in cancer and other common diseases. Large case–control and cohort studies have identified novel SNPs as markers of cancer risk. Genome-wide association study SNP data have also advanced understanding of population-specific genetic variation. While studies of risk profiles, combinations of SNPs that may increase cancer risk, are not yet clinically applicable, future, large-sca...

  8. ATLAS

    Data.gov (United States)

    Federal Laboratory Consortium — ATLAS is a particle physics experiment at the Large Hadron Collider at CERN, the European Organization for Nuclear Research. Scientists from Brookhaven have played...

  9. Computational approaches to identify functional genetic variants in cancer genomes

    DEFF Research Database (Denmark)

    Gonzalez-Perez, Abel; Mustonen, Ville; Reva, Boris;

    2013-01-01

    The International Cancer Genome Consortium (ICGC) aims to catalog genomic abnormalities in tumors from 50 different cancer types. Genome sequencing reveals hundreds to thousands of somatic mutations in each tumor but only a minority of these drive tumor progression. We present the result of discu...... of discussions within the ICGC on how to address the challenge of identifying mutations that contribute to oncogenesis, tumor maintenance or response to therapy, and recommend computational techniques to annotate somatic variants and predict their impact on cancer phenotype....

  10. Evolution of cancer suppression as revealed by mammalian comparative genomics.

    Science.gov (United States)

    Tollis, Marc; Schiffman, Joshua D; Boddy, Amy M

    2017-02-02

    Cancer suppression is an important feature in the evolution of large and long-lived animals. While some tumor suppression pathways are conserved among all multicellular organisms, others mechanisms of cancer resistance are uniquely lineage specific. Comparative genomics has become a powerful tool to discover these unique and shared molecular adaptations in respect to cancer suppression. These findings may one day be translated to human patients through evolutionary medicine. Here, we will review theory and methods of comparative cancer genomics and highlight major findings of cancer suppression across mammals. Our current knowledge of cancer genomics suggests that more efficient DNA repair and higher sensitivity to DNA damage may be the key to tumor suppression in large or long-lived mammals.

  11. Translational genomics in cancer research:converting proifles into personalized cancer medicine

    Institute of Scientific and Technical Information of China (English)

    Lalit Patel; Brittany Parker; Da Yang; Wei Zhang

    2013-01-01

    Cancer genomics is a rapidly growing discipline in which the genetic molecular basis of malignancy is studied at the scale of whole genomes. While the discipline has been successful with respect to identifying specific oncogenes and tumor suppressors involved in oncogenesis, it is also challenging our approach to managing patients suffering from this deadly disease. Speciifcally cancer genomics is driving clinical oncology to take a more molecular approach to diagnosis, prognostication, and treatment selection. We review here recent work undertaken in cancer genomics with an emphasis on translation of genomic ifndings. Finally, we discuss scientiifc challenges and research opportunities emerging from ifndings derived through analysis of tumors with high-depth sequencing.

  12. [HPV-associated head and neck cancer : mutational signature and genomic aberrations].

    Science.gov (United States)

    Wagner, S; Würdemann, N; Hübbers, C; Reuschenbach, M; Prigge, E-S; Wichmann, G; Hess, J; Dietz, A; Dürst, M; Tinhofer, I; von Knebel-Döberitz, M; Wittekindt, C; Klussmann, J P

    2015-11-01

    A significantly increasing proportion of oropharyngeal head and neck carcinomas (OSCC) in North America and Europe are associated with human papillomavirus (HPV) infections. HPV-related OSCC is regarded as a distinct tumor type with regard to its cellular, biologic, and clinical characteristics. Patients with HPV-related OSCC have significantly better local control, but higher rates of regional lymph node and distant metastases as compared to patients with HPV-negative OSCC. Classical molecular genetic investigations demonstrated specific chromosomal aberration signatures in HPV-related OSCC, and recent developments in next generation sequencing (NGS) technology have rendered possible the sequencing of entire genomes, and thus detection of specific mutations, in just a few days. Initial data from The Cancer Genome Atlas (TCGA) project obtained by using genome-wide high throughput methods have confirmed that HPV-related OSCC contain fewer, albeit more specific mutations than HPV-negative tumors. Additionally, these data revealed the presence of specific-potentially therapeutically targetable-activating driver mutations in subgroups of HPV-positive OSCC, some of which have a prognostic impact. Specific targeted NGS technologies provide new possibilities for identification of diagnostic, prognostic, and predictive biomarkers and the development of personalized cancer treatment. Patients with HPV-positive tumors are likely to profit from these developments in the future, since the genetic alterations are relatively homogenous and frequently lead to signal pathway activation. There is an urgent need for network research activities to carry out the necessary basic research in prospective cohort studies.

  13. Cancer Genomics: Diversity and Disparity Across Ethnicity and Geography.

    Science.gov (United States)

    Tan, Daniel S W; Mok, Tony S K; Rebbeck, Timothy R

    2016-01-01

    Ethnic and geographic differences in cancer incidence, prognosis, and treatment outcomes can be attributed to diversity in the inherited (germline) and somatic genome. Although international large-scale sequencing efforts are beginning to unravel the genomic underpinnings of cancer traits, much remains to be known about the underlying mechanisms and determinants of genomic diversity. Carcinogenesis is a dynamic, complex phenomenon representing the interplay between genetic and environmental factors that results in divergent phenotypes across ethnicities and geography. For example, compared with whites, there is a higher incidence of prostate cancer among Africans and African Americans, and the disease is generally more aggressive and fatal. Genome-wide association studies have identified germline susceptibility loci that may account for differences between the African and non-African patients, but the lack of availability of appropriate cohorts for replication studies and the incomplete understanding of genomic architecture across populations pose major limitations. We further discuss the transformative potential of routine diagnostic evaluation for actionable somatic alterations, using lung cancer as an example, highlighting implications of population disparities, current hurdles in implementation, and the far-reaching potential of clinical genomics in enhancing cancer prevention, diagnosis, and treatment. As we enter the era of precision cancer medicine, a concerted multinational effort is key to addressing population and genomic diversity as well as overcoming barriers and geographical disparities in research and health care delivery.

  14. ATLAS

    CERN Multimedia

    2002-01-01

    Barrel and END-CAP Toroids In order to produce a powerful magnetic field to bend the paths of the muons, the ATLAS detector uses an exceptionally large system of air-core toroids arranged outside the calorimeter volumes. The large volume magnetic field has a wide angular coverage and strengths of up to 4.7tesla. The toroids system contains over 100km of superconducting wire and has a design current of 20 500 amperes. (ATLAS brochure: The Technical Challenges)

  15. Cancer genetics and genomics: essentials for oncology nurses.

    Science.gov (United States)

    Boucher, Jean; Habin, Karleen; Underhill, Meghan

    2014-06-01

    Cancer genetics and genomics are rapidly evolving, with new discoveries emerging in genetic mutations, variants, genomic sequencing, risk-reduction methods, and targeted therapies. To educate patients and families, state-of-the-art care requires nurses to understand terminology, scientific and technological advances, and pharmacogenomics. Clinical application of cancer genetics and genomics involves working in interdisciplinary teams to properly identify patient risk through assessing family history, facilitating genetic testing and counseling services, applying risk-reduction methods, and administering and monitoring targeted therapies.

  16. Comprehensive genomic characterization of squamous cell lung cancers

    NARCIS (Netherlands)

    Hammerman, Peter S.; Lawrence, Michael S.; Voet, Douglas; Jing, Rui; Cibulskis, Kristian; Sivachenko, Andrey; Stojanov, Petar; McKenna, Aaron; Lander, Eric S.; Gabriel, Stacey; Getz, Gad; Sougnez, Carrie; Imielinski, Marcin; Helman, Elena; Hernandez, Bryan; Pho, Nam H.; Meyerson, Matthew; Chu, Andy; Chun, Hye-Jung E.; Mungall, Andrew J.; Pleasance, Erin; Robertson, A. Gordon; Sipahimalani, Payal; Stoll, Dominik; Balasundaram, Miruna; Birol, Inanc; Butterfield, Yaron S. N.; Chuah, Eric; Coope, Robin J. N.; Corbett, Richard; Dhalla, Noreen; Guin, Ranabir; Hirst, Anhe Carrie; Hirst, Martin; Holt, Robert A.; Lee, Darlene; Li, Haiyan I.; Mayo, Michael; Moore, Richard A.; Mungall, Karen; Nip, Ka Ming; Olshen, Adam; Schein, Jacqueline E.; Slobodan, Jared R.; Tam, Angela; Thiessen, Nina; Varhol, Richard; Zeng, Thomas; Zhao, Yongjun; Jones, Steven J. M.; Marra, Marco A.; Saksena, Gordon; Cherniack, Andrew D.; Schumacher, Stephen E.; Tabak, Barbara; Carter, Scott L.; Pho, Nam H.; Nguyen, Huy; Onofrio, Robert C.; Crenshaw, Andrew; Ardlie, Kristin; Beroukhim, Rameen; Winckler, Wendy; Hammerman, Peter S.; Getz, Gad; Meyerson, Matthew; Protopopov, Alexei; Zhang, Jianhua; Hadjipanayis, Angela; Lee, Semin; Xi, Ruibin; Yang, Lixing; Ren, Xiaojia; Zhang, Hailei; Shukla, Sachet; Chen, Peng-Chieh; Haseley, Psalm; Lee, Eunjung; Chin, Lynda; Park, Peter J.; Kucherlapati, Raju; Socci, Nicholas D.; Liang, Yupu; Schultz, Nikolaus; Borsu, Laetitia; Lash, Alex E.; Viale, Agnes; Sander, Chris; Ladanyi, Marc; Auman, J. Todd; Hoadley, Katherine A.; Wilkerson, Matthew D.; Shi, Yan; Liquori, Christina; Meng, Shaowu; Li, Ling; Turman, Yidi J.; Topal, Michael D.; Tan, Donghui; Waring, Scot; Buda, Elizabeth; Walsh, Jesse; Jones, Corbin D.; Mieczkowski, Piotr A.; Singh, Darshan; Wu, Junyuan; Gulabani, Anisha; Dolina, Peter; Bodenheimer, Tom; Hoyle, Alan P.; Simons, Janae V.; Soloway, Matthew G.; Mose, Lisle E.; Jefferys, Stuart R.; Balu, Saianand; O'Connor, Brian D.; Prins, Jan F.; Liu, Jinze; Chiang, Derek Y.; Hayes, D. Neil; Perou, Charles M.; Cope, Leslie; Danilova, Ludmila; Weisenberger, Daniel J.; Maglinte, Dennis T.; Pan, Fei; Van den Berg, David J.; Triche, Timothy; Herman, James G.; Baylin, Stephen B.; Laird, Peter W.; Getz, Gad; Noble, Michael; Voet, Doug; Saksena, Gordon; Gehlenborg, Nils; DiCara, Daniel; Zhang, Jinhua; Zhang, Hailei; Wu, Chang-Jiun; Liu, Spring Yingchun; Lawrence, Michael S.; Zou, Lihua; Sivachenko, Andrey; Lin, Pei; Stojanov, Petar; Jing, Rui; Cho, Juok; Nazaire, Marc-Danie; Robinson, Jim; Thorvaldsdottir, Helga; Mesirov, Jill; Park, Peter J.; Chin, Lynda; Schultz, Nikolaus; Sinha, Rileen; Ciriello, Giovanni; Cerami, Ethan; Gross, Benjamin; Jacobsen, Anders; Gao, Jianjiong; Aksoy, B. Arman; Weinhold, Nils; Ramirez, Ricardo; Taylor, Barry S.; Antipin, Yevgeniy; Reva, Boris; Shen, Ronglai; Mo, Qianxing; Seshan, Venkatraman; Paik, Paul K.; Ladanyi, Marc; Sander, Chris; Akbani, Rehan; Zhang, Nianxiang; Broom, Bradley M.; Casasent, Tod; Unruh, Anna; Wakefield, Chris; Cason, R. Craig; Baggerly, Keith A.; Weinstein, John N.; Haussler, David; Benz, Christopher C.; Stuart, Joshua M.; Zhu, Jingchun; Szeto, Christopher; Scott, Gary K.; Yau, Christina; Ng, Sam; Goldstein, Ted; Waltman, Peter; Sokolov, Artem; Ellrott, Kyle; Collisson, Eric A.; Zerbino, Daniel; Wilks, Christopher; Ma, Singer; Craft, Brian; Wilkerson, Matthew D.; Auman, J. Todd; Hoadley, Katherine A.; Du, Ying; Cabanski, Christopher; Walter, Vonn; Singh, Darshan; Wu, Junyuan; Gulabani, Anisha; Bodenheimer, Tom; Hoyle, Alan P.; Simons, Janae V.; Soloway, Matthew G.; Mose, Lisle E.; Jefferys, Stuart R.; Balu, Saianand; Marron, J. S.; Liu, Yufeng; Wang, Kai; Liu, Jinze; Prins, Jan F.; Hayes, D. Neil; Perou, Charles M.; Creighton, Chad J.; Zhang, Yiqun; Travis, William D.; Rekhtman, Natasha; Yi, Joanne; Aubry, Marie C.; Cheney, Richard; Dacic, Sanja; Flieder, Douglas; Funkhouser, William; Illei, Peter; Myers, Jerome; Tsao, Ming-Sound; Penny, Robert; Mallery, David; Shelton, Troy; Hatfield, Martha; Morris, Scott; Yena, Peggy; Shelton, Candace; Sherman, Mark; Paulauskis, Joseph; Meyerson, Matthew; Baylin, Stephen B.; Govindan, Ramaswamy; Akbani, Rehan; Azodo, Ijeoma; Beer, David; Bose, Ron; Byers, Lauren A.; Carbone, David; Chang, Li-Wei; Chiang, Derek; Chu, Andy; Chun, Elizabeth; Collisson, Eric; Cope, Leslie; Creighton, Chad J.; Danilova, Ludmila; Ding, Li; Getz, Gad; Hammerman, Peter S.; Hayes, D. Neil; Hernandez, Bryan; Herman, James G.; Heymach, John; Ida, Cristiane; Imielinski, Marcin; Johnson, Bruce; Jurisica, Igor; Kaufman, Jacob; Kosari, Farhad; Kucherlapati, Raju; Kwiatkowski, David; Ladanyi, Marc; Lawrence, Michael S.; Maher, Christopher A.; Mungall, Andy; Ng, Sam; Pao, William; Peifer, Martin; Penny, Robert; Robertson, Gordon; Rusch, Valerie; Sander, Chris; Schultz, Nikolaus; Shen, Ronglai; Siegfried, Jill; Sinha, Rileen; Sivachenko, Andrey; Sougnez, Carrie; Stoll, Dominik; Stuart, Joshua; Thomas, Roman K.; Tomaszek, Sandra; Tsao, Ming-Sound; Travis, William D.; Vaske, Charles; Weinstein, John N.; Weisenberger, Daniel; Wheeler, David; Wigle, Dennis A.; Wilkerson, Matthew D.; Wilks, Christopher; Yang, Ping; Zhang, Jianjua John; Jensen, Mark A.; Sfeir, Robert; Kahn, Ari B.; Chu, Anna L.; Kothiyal, Prachi; Wang, Zhining; Snyder, Eric E.; Pontius, Joan; Pihl, Todd D.; Ayala, Brenda; Backus, Mark; Walton, Jessica; Baboud, Julien; Berton, Dominique L.; Nicholls, Matthew C.; Srinivasan, Deepak; Raman, Rohini; Girshik, Stanley; Kigonya, Peter A.; Alonso, Shelley; Sanbhadti, Rashmi N.; Barletta, Sean P.; Greene, John M.; Pot, David A.; Tsao, Ming-Sound; Bandarchi-Chamkhaleh, Bizhan; Boyd, Jeff; Weaver, JoEllen; Wigle, Dennis A.; Azodo, Ijeoma A.; Tomaszek, Sandra C.; Aubry, Marie Christine; Ida, Christiane M.; Yang, Ping; Kosari, Farhad; Brock, Malcolm V.; Rogers, Kristen; Rutledge, Marian; Brown, Travis; Lee, Beverly; Shin, James; Trusty, Dante; Dhir, Rajiv; Siegfried, Jill M.; Potapova, Olga; Fedosenko, Konstantin V.; Nemirovich-Danchenko, Elena; Rusch, Valerie; Zakowski, Maureen; Iacocca, Mary V.; Brown, Jennifer; Rabeno, Brenda; Czerwinski, Christine; Petrelli, Nicholas; Fan, Zhen; Todaro, Nicole; Eckman, John; Myers, Jerome; Rathmell, W. Kimryn; Thorne, Leigh B.; Huang, Mei; Boice, Lori; Hill, Ashley; Penny, Robert; Mallery, David; Curley, Erin; Shelton, Candace; Yena, Peggy; Morrison, Carl; Gaudioso, Carmelo; Bartlett, Johnm. S.; Kodeeswaran, Sugy; Zanke, Brent; Sekhon, Harman; David, Kerstin; Juhl, Hartmut; Van Le, Xuan; Kohl, Bernard; Thorp, Richard; Tien, Nguyen Viet; Van Bang, Nguyen; Sussman, Howard; Phu, Bui Duc; Hajek, Richard; PhiHung, Nguyen; Khan, Khurram Z.; Muley, Thomas; Shaw, Kenna R. Mills; Sheth, Margi; Yang, Liming; Buetow, Ken; Davidsen, Tanja; Demchok, John A.; Eley, Greg; Ferguson, Martin; Dillon, Laura A. L.; Schaefer, Carl; Guyer, Mark S.; Ozenberger, Bradley A.; Palchik, Jacqueline D.; Peterson, Jane; Sofia, Heidi J.; Thomson, Elizabeth; Meyerson, Matthew

    2012-01-01

    Lung squamous cell carcinoma is a common type of lung cancer, causing approximately 400,000 deaths per year worldwide. Genomic alterations in squamous cell lung cancers have not been comprehensively characterized, and no molecularly targeted agents have been specifically developed for its treatment.

  17. Whole genome sequencing for childhood cancer in Denmark

    DEFF Research Database (Denmark)

    Gupta, Ramneek

    of host, tumour and gut microbiome’s genomes. In Europe, cancer accounts for approximately 25% of all deaths in children >1 year. Most cured patients are burdened by late effects, including risk of second cancer and debilitating toxicities. Recent advancements in genetic sequencing technology...

  18. Candidate serological biomarkers for cancer identified from the secretomes of 23 cancer cell lines and the human protein atlas.

    Science.gov (United States)

    Wu, Chih-Ching; Hsu, Chia-Wei; Chen, Chi-De; Yu, Chia-Jung; Chang, Kai-Ping; Tai, Dar-In; Liu, Hao-Ping; Su, Wen-Hui; Chang, Yu-Sun; Yu, Jau-Song

    2010-06-01

    Although cancer cell secretome profiling is a promising strategy used to identify potential body fluid-accessible cancer biomarkers, questions remain regarding the depth to which the cancer cell secretome can be mined and the efficiency with which researchers can select useful candidates from the growing list of identified proteins. Therefore, we analyzed the secretomes of 23 human cancer cell lines derived from 11 cancer types using one-dimensional SDS-PAGE and nano-LC-MS/MS performed on an LTQ-Orbitrap mass spectrometer to generate a more comprehensive cancer cell secretome. A total of 31,180 proteins was detected, accounting for 4,584 non-redundant proteins, with an average of 1,300 proteins identified per cell line. Using protein secretion-predictive algorithms, 55.8% of the proteins appeared to be released or shed from cells. The identified proteins were selected as potential marker candidates according to three strategies: (i) proteins apparently secreted by one cancer type but not by others (cancer type-specific marker candidates), (ii) proteins released by most cancer cell lines (pan-cancer marker candidates), and (iii) proteins putatively linked to cancer-relevant pathways. We then examined protein expression profiles in the Human Protein Atlas to identify biomarker candidates that were simultaneously detected in the secretomes and highly expressed in cancer tissues. This analysis yielded 6-137 marker candidates selective for each tumor type and 94 potential pan-cancer markers. Among these, we selectively validated monocyte differentiation antigen CD14 (for liver cancer), stromal cell-derived factor 1 (for lung cancer), and cathepsin L1 and interferon-induced 17-kDa protein (for nasopharyngeal carcinoma) as potential serological cancer markers. In summary, the proteins identified from the secretomes of 23 cancer cell lines and the Human Protein Atlas represent a focused reservoir of potential cancer biomarkers.

  19. Databases and web tools for cancer genomics study.

    Science.gov (United States)

    Yang, Yadong; Dong, Xunong; Xie, Bingbing; Ding, Nan; Chen, Juan; Li, Yongjun; Zhang, Qian; Qu, Hongzhu; Fang, Xiangdong

    2015-02-01

    Publicly-accessible resources have promoted the advance of scientific discovery. The era of genomics and big data has brought the need for collaboration and data sharing in order to make effective use of this new knowledge. Here, we describe the web resources for cancer genomics research and rate them on the basis of the diversity of cancer types, sample size, omics data comprehensiveness, and user experience. The resources reviewed include data repository and analysis tools; and we hope such introduction will promote the awareness and facilitate the usage of these resources in the cancer research community.

  20. Databases and Web Tools for Cancer Genomics Study

    Institute of Scientific and Technical Information of China (English)

    Yadong Yang; Xunong Dong; Bingbing Xie; Nan Ding; Juan Chen; Yongjun Li; Qian Zhang; Hongzhu Qu; Xiangdong Fang

    2015-01-01

    Publicly-accessible resources have promoted the advance of scientific discovery. The era of genomics and big data has brought the need for collaboration and data sharing in order to make effective use of this new knowledge. Here, we describe the web resources for cancer genomics research and rate them on the basis of the diversity of cancer types, sample size, omics data com-prehensiveness, and user experience. The resources reviewed include data repository and analysis tools;and we hope such introduction will promote the awareness and facilitate the usage of these resources in the cancer research community.

  1. Genome Science and Personalized Cancer Treatment (LBNL Summer Lecture Series)

    Energy Technology Data Exchange (ETDEWEB)

    Gray, Joe

    2009-08-04

    Summer Lecture Series 2009: Results from the Human Genome Project are enabling scientists to understand how individual cancers form and progress. This information, when combined with newly developed drugs, can optimize the treatment of individual cancers. Joe Gray, director of Berkeley Labs Life Sciences Division and Associate Laboratory Director for Life and Environmental Sciences, will focus on this approach, its promise, and its current roadblocks — particularly with regard to breast cancer.

  2. Clinical implications of genomics for cancer risk genetics.

    Science.gov (United States)

    Thomas, David M; James, Paul A; Ballinger, Mandy L

    2015-06-01

    The study of human genetics has provided substantial insight into cancer biology. With an increase in sequencing capacity and a reduction in sequencing costs, genomics will probably transform clinical cancer genetics. A heritable basis for many cancers is accepted, but so far less than half the genetic drivers have been identified. Genomics will increasingly be applied to populations irrespective of family history, which will change the framework of phenotype-directed genetic testing. Panel testing and whole genome sequencing will identify novel, polygenic, and de-novo determinants of cancer risk, often with lower penetrance, which will challenge present binary clinical classification systems and management algorithms. In the future, genotype-stratified public screening and prevention programmes could form part of tailored population risk management. The integration of research with clinical practice will result in so-called discovery cohorts that will help identify clinically significant genetic variation.

  3. SIGMA: A System for Integrative Genomic Microarray Analysis of Cancer Genomes

    Directory of Open Access Journals (Sweden)

    Davies Jonathan J

    2006-12-01

    Full Text Available Abstract Background The prevalence of high resolution profiling of genomes has created a need for the integrative analysis of information generated from multiple methodologies and platforms. Although the majority of data in the public domain are gene expression profiles, and expression analysis software are available, the increase of array CGH studies has enabled integration of high throughput genomic and gene expression datasets. However, tools for direct mining and analysis of array CGH data are limited. Hence, there is a great need for analytical and display software tailored to cross platform integrative analysis of cancer genomes. Results We have created a user-friendly java application to facilitate sophisticated visualization and analysis such as cross-tumor and cross-platform comparisons. To demonstrate the utility of this software, we assembled array CGH data representing Affymetrix SNP chip, Stanford cDNA arrays and whole genome tiling path array platforms for cross comparison. This cancer genome database contains 267 profiles from commonly used cancer cell lines representing 14 different tissue types. Conclusion In this study we have developed an application for the visualization and analysis of data from high resolution array CGH platforms that can be adapted for analysis of multiple types of high throughput genomic datasets. Furthermore, we invite researchers using array CGH technology to deposit both their raw and processed data, as this will be a continually expanding database of cancer genomes. This publicly available resource, the System for Integrative Genomic Microarray Analysis (SIGMA of cancer genomes, can be accessed at http://sigma.bccrc.ca.

  4. Identification of genetic determinants of breast cancer immune phenotypes by integrative genome-scale analysis

    Science.gov (United States)

    Simeone, Ines; Anjum, Samreen; Mokrab, Younes; Bertucci, François; Finetti, Pascal; Curigliano, Giuseppe; Cerulo, Luigi; Tomei, Sara; Delogu, Lucia Gemma; Maccalli, Cristina; Miller, Lance D.; Ceccarelli, Michele

    2017-01-01

    ABSTRACT Cancer immunotherapy is revolutionizing the clinical management of several tumors, but has demonstrated limited activity in breast cancer. The development of more effective treatments is hindered by incomplete knowledge of the genetic determinant of immune responsiveness. To fill this gap, we mined copy number alteration, somatic mutation, and expression data from The Cancer Genome Atlas (TCGA). By using RNA-sequencing data from 1,004 breast cancers, we defined distinct immune phenotypes characterized by progressive expression of transcripts previously associated with immune-mediated rejection. The T helper 1 (Th-1) phenotype (ICR4), which also displays upregulation of immune-regulatory transcripts such as PDL1, PD1, FOXP3, IDO1, and CTLA4, was associated with prolonged patients' survival. We validated these findings in an independent meta-cohort of 1,954 breast cancer gene expression data. Chromosome segment 4q21, which includes genes encoding for the Th-1 chemokines CXCL9-11, was significantly amplified only in the immune favorable phenotype (ICR4). The mutation and neoantigen load progressively decreased from ICR4 to ICR1 but could not fully explain immune phenotypic differences. Mutations of TP53 were enriched in the immune favorable phenotype (ICR4). Conversely, the presence of MAP3K1 and MAP2K4 mutations were tightly associated with an immune-unfavorable phenotype (ICR1). Using both the TCGA and the validation dataset, the degree of MAPK deregulation segregates breast tumors according to their immune disposition. These findings suggest that mutation-driven perturbations of MAPK pathways are linked to the negative regulation of intratumoral immune response in breast cancer. Modulations of MAPK pathways could be experimentally tested to enhance breast cancer immune sensitivity. PMID:28344865

  5. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

    Science.gov (United States)

    Gusev, Alexander; Shi, Huwenbo; Kichaev, Gleb; Pomerantz, Mark; Li, Fugen; Long, Henry W.; Ingles, Sue A.; Kittles, Rick A.; Strom, Sara S.; Rybicki, Benjamin A.; Nemesure, Barbara; Isaacs, William B.; Zheng, Wei; Pettaway, Curtis A.; Yeboah, Edward D.; Tettey, Yao; Biritwum, Richard B.; Adjei, Andrew A.; Tay, Evelyn; Truelove, Ann; Niwa, Shelley; Chokkalingam, Anand P.; John, Esther M.; Murphy, Adam B.; Signorello, Lisa B.; Carpten, John; Leske, M. Cristina; Wu, Suh-Yuh; Hennis, Anslem J. M.; Neslund-Dudas, Christine; Hsing, Ann W.; Chu, Lisa; Goodman, Phyllis J.; Klein, Eric A.; Witte, John S.; Casey, Graham; Kaggwa, Sam; Cook, Michael B.; Stram, Daniel O.; Blot, William J.; Eeles, Rosalind A.; Easton, Douglas; Kote-Jarai, ZSofia; Al Olama, Ali Amin; Benlloch, Sara; Muir, Kenneth; Giles, Graham G.; Southey, Melissa C.; Fitzgerald, Liesel M.; Gronberg, Henrik; Wiklund, Fredrik; Aly, Markus; Henderson, Brian E.; Schleutker, Johanna; Wahlfors, Tiina; Tammela, Teuvo L. J.; Nordestgaard, Børge G.; Key, Tim J.; Travis, Ruth C.; Neal, David E.; Donovan, Jenny L.; Hamdy, Freddie C.; Pharoah, Paul; Pashayan, Nora; Khaw, Kay-Tee; Stanford, Janet L.; Thibodeau, Stephen N.; McDonnell, Shannon K.; Schaid, Daniel J.; Maier, Christiane; Vogel, Walther; Luedeke, Manuel; Herkommer, Kathleen; Kibel, Adam S.; Cybulski, Cezary; Wokolorczyk, Dominika; Kluzniak, Wojciech; Cannon-Albright, Lisa; Teerlink, Craig; Brenner, Hermann; Dieffenbach, Aida K.; Arndt, Volker; Park, Jong Y.; Sellers, Thomas A.; Lin, Hui-Yi; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Batra, Jyotsna; Spurdle, Amanda; Clements, Judith A.; Teixeira, Manuel R.; Pandha, Hardev; Michael, Agnieszka; Paulo, Paula; Maia, Sofia; Kierzek, Andrzej; Cook, Margaret; Guy, Michelle; Govindasami, Koveela; Leongamornlert, Daniel; Sawyer, Emma J.; Wilkinson, Rosemary; Saunders, Edward J.; Tymrakiewicz, Malgorzata; Dadaev, Tokhir; Morgan, Angela; Fisher, Cyril; Hazel, Steve; Livni, Naomi; Lophatananon, Artitaya; Pedersen, John; Hopper, John L.; Adolfson, Jan; Stattin, Paer; Johansson, Jan-Erik; Cavalli-Bjoerkman, Carin; Karlsson, Ami; Broms, Michael; Auvinen, Anssi; Kujala, Paula; Maeaettaenen, Liisa; Murtola, Teemu; Taari, Kimmo; Weischer, Maren; Nielsen, Sune F.; Klarskov, Peter; Roder, Andreas; Iversen, Peter; Wallinder, Hans; Gustafsson, Sven; Cox, Angela; Brown, Paul; George, Anne; Marsden, Gemma; Lane, Athene; Davis, Michael; Zheng, Wei; Signorello, Lisa B.; Blot, William J.; Tillmans, Lori; Riska, Shaun; Wang, Liang; Rinckleb, Antje; Lubiski, Jan; Stegmaier, Christa; Pow-Sang, Julio; Park, Hyun; Radlein, Selina; Rincon, Maria; Haley, James; Zachariah, Babu; Kachakova, Darina; Popov, Elenko; Mitkova, Atanaska; Vlahova, Aleksandrina; Dikov, Tihomir; Christova, Svetlana; Heathcote, Peter; Wood, Glenn; Malone, Greg; Saunders, Pamela; Eckert, Allison; Yeadon, Trina; Kerr, Kris; Collins, Angus; Turner, Megan; Srinivasan, Srilakshmi; Kedda, Mary-Anne; Alexander, Kimberly; Omara, Tracy; Wu, Huihai; Henrique, Rui; Pinto, Pedro; Santos, Joana; Barros-Silva, Joao; Conti, David V.; Albanes, Demetrius; Berg, Christine; Berndt, Sonja I.; Campa, Daniele; Crawford, E. David; Diver, W. Ryan; Gapstur, Susan M.; Gaziano, J. Michael; Giovannucci, Edward; Hoover, Robert; Hunter, David J.; Johansson, Mattias; Kraft, Peter; Le Marchand, Loic; Lindström, Sara; Navarro, Carmen; Overvad, Kim; Riboli, Elio; Siddiq, Afshan; Stevens, Victoria L.; Trichopoulos, Dimitrios; Vineis, Paolo; Yeager, Meredith; Trynka, Gosia; Raychaudhuri, Soumya; Schumacher, Frederick R.; Price, Alkes L.; Freedman, Matthew L.; Haiman, Christopher A.; Pasaniuc, Bogdan

    2016-01-01

    Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa. PMID:27052111

  6. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.

    Science.gov (United States)

    Gusev, Alexander; Shi, Huwenbo; Kichaev, Gleb; Pomerantz, Mark; Li, Fugen; Long, Henry W; Ingles, Sue A; Kittles, Rick A; Strom, Sara S; Rybicki, Benjamin A; Nemesure, Barbara; Isaacs, William B; Zheng, Wei; Pettaway, Curtis A; Yeboah, Edward D; Tettey, Yao; Biritwum, Richard B; Adjei, Andrew A; Tay, Evelyn; Truelove, Ann; Niwa, Shelley; Chokkalingam, Anand P; John, Esther M; Murphy, Adam B; Signorello, Lisa B; Carpten, John; Leske, M Cristina; Wu, Suh-Yuh; Hennis, Anslem J M; Neslund-Dudas, Christine; Hsing, Ann W; Chu, Lisa; Goodman, Phyllis J; Klein, Eric A; Witte, John S; Casey, Graham; Kaggwa, Sam; Cook, Michael B; Stram, Daniel O; Blot, William J; Eeles, Rosalind A; Easton, Douglas; Kote-Jarai, Zsofia; Al Olama, Ali Amin; Benlloch, Sara; Muir, Kenneth; Giles, Graham G; Southey, Melissa C; Fitzgerald, Liesel M; Gronberg, Henrik; Wiklund, Fredrik; Aly, Markus; Henderson, Brian E; Schleutker, Johanna; Wahlfors, Tiina; Tammela, Teuvo L J; Nordestgaard, Børge G; Key, Tim J; Travis, Ruth C; Neal, David E; Donovan, Jenny L; Hamdy, Freddie C; Pharoah, Paul; Pashayan, Nora; Khaw, Kay-Tee; Stanford, Janet L; Thibodeau, Stephen N; McDonnell, Shannon K; Schaid, Daniel J; Maier, Christiane; Vogel, Walther; Luedeke, Manuel; Herkommer, Kathleen; Kibel, Adam S; Cybulski, Cezary; Wokolorczyk, Dominika; Kluzniak, Wojciech; Cannon-Albright, Lisa; Teerlink, Craig; Brenner, Hermann; Dieffenbach, Aida K; Arndt, Volker; Park, Jong Y; Sellers, Thomas A; Lin, Hui-Yi; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Batra, Jyotsna; Spurdle, Amanda; Clements, Judith A; Teixeira, Manuel R; Pandha, Hardev; Michael, Agnieszka; Paulo, Paula; Maia, Sofia; Kierzek, Andrzej; Conti, David V; Albanes, Demetrius; Berg, Christine; Berndt, Sonja I; Campa, Daniele; Crawford, E David; Diver, W Ryan; Gapstur, Susan M; Gaziano, J Michael; Giovannucci, Edward; Hoover, Robert; Hunter, David J; Johansson, Mattias; Kraft, Peter; Le Marchand, Loic; Lindström, Sara; Navarro, Carmen; Overvad, Kim; Riboli, Elio; Siddiq, Afshan; Stevens, Victoria L; Trichopoulos, Dimitrios; Vineis, Paolo; Yeager, Meredith; Trynka, Gosia; Raychaudhuri, Soumya; Schumacher, Frederick R; Price, Alkes L; Freedman, Matthew L; Haiman, Christopher A; Pasaniuc, Bogdan

    2016-04-07

    Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

  7. [Current topics in mutations in the cancer genome].

    Science.gov (United States)

    Iwaya, Takeshi; Mimori, Koshi; Wakabayashi, Go

    2012-03-01

    Several oncogenes and tumor suppressor genes are involved in the multistep process of carcinogenesis in many cancer types. Recently, global mutational analyses have revealed that the cancer genome has far greater numbers of mutations than previously thought. Furthermore, the next-generation sequencing method, which has a different principle from conventional Sanger sequencing, has provided more information on the cancer genome such as new cancer-related genes and the existence of many rearrangements in solid cancers. Somatic mutations occurring in cancer cells are divided into "driver" and "passenger" mutations. Driver mutations confer a growth advantage upon the neoplastic clone and are crucial for carcinogenesis. The remaining large majority of mutations are passengers, which, by definition, do not confer a growth advantage. Driver genes with low-frequency mutation rates (less than 10%) are also involved in carcinogenesis along with well-known drivers with high-frequency mutations. There are now several celebrated examples of anticancer drugs of which the efficacy in cancer patients can be predicted based on the genotype of several driver genes, such as EGFR, KRAS, and BRAF on the EGFR signaling pathway. The complete catalogs of somatic mutations provided by the sequencing of the cancer genome are expected to prompt new approaches to diagnosis, therapy, and potentially prevention.

  8. Characterization of genomic alterations in radiation-associated breast cancer among childhood cancer survivors, using comparative genomic hybridization (CGH arrays.

    Directory of Open Access Journals (Sweden)

    Xiaohong R Yang

    Full Text Available Ionizing radiation is an established risk factor for breast cancer. Epidemiologic studies of radiation-exposed cohorts have been primarily descriptive; molecular events responsible for the development of radiation-associated breast cancer have not been elucidated. In this study, we used array comparative genomic hybridization (array-CGH to characterize genome-wide copy number changes in breast tumors collected in the Childhood Cancer Survivor Study (CCSS. Array-CGH data were obtained from 32 cases who developed a second primary breast cancer following chest irradiation at early ages for the treatment of their first cancers, mostly Hodgkin lymphoma. The majority of these cases developed breast cancer before age 45 (91%, n = 29, had invasive ductal tumors (81%, n = 26, estrogen receptor (ER-positive staining (68%, n = 19 out of 28, and high proliferation as indicated by high Ki-67 staining (77%, n = 17 out of 22. Genomic regions with low-copy number gains and losses and high-level amplifications were similar to what has been reported in sporadic breast tumors, however, the frequency of amplifications of the 17q12 region containing human epidermal growth factor receptor 2 (HER2 was much higher among CCSS cases (38%, n = 12. Our findings suggest that second primary breast cancers in CCSS were enriched for an "amplifier" genomic subgroup with highly proliferative breast tumors. Future investigation in a larger irradiated cohort will be needed to confirm our findings.

  9. Tolerance of Whole-Genome Doubling Propagates Chromosomal Instability and Accelerates Cancer Genome Evolution

    DEFF Research Database (Denmark)

    Dewhurst, Sally M.; McGranahan, Nicholas; Burrell, Rebecca A.;

    2014-01-01

    The contribution of whole-genome doubling to chromosomal instability (CIN) and tumor evolution is unclear. We use long-term culture of isogenic tetraploid cells from a stable diploid colon cancer progenitor to investigate how a genome-doubling event affects genome stability over time. Rare cells...... that survive genome doubling demonstrate increased tolerance to chromosome aberrations. Tetraploid cells do not exhibit increased frequencies of structural or numerical CIN per chromosome. However, the tolerant phenotype in tetraploid cells, coupled with a doubling of chromosome aberrations per cell, allows...... chromosome abnormalities to evolve specifically in tetraploids, recapitulating chromosomal changes in genomically complex colorectal tumors. Finally, a genome-doubling event is independently predictive of poor relapse-free survival in early-stage disease in two independent cohorts in multivariate analyses...

  10. HCMI Organization | Office of Cancer Genomics

    Science.gov (United States)

    Consortium HCMI was created and funded by the National Cancer Institute, Cancer Research UK, foundation Hubrecht Organoid Technology, and Wellcome Trust Sanger Institute. Together, these organizations develop policy and make programmatic decisions to contribute to the function of the HCMI. National Cancer Institute

  11. Integrated genomic analyses of ovarian carcinoma

    NARCIS (Netherlands)

    Bell, D.; Berchuck, A.; Birrer, M.; Chien, J.; Dao, F.; Dhir, R.; DiSaia, P.; Gabra, H.; Glenn, P.; Godwin, A. K.; Gross, J.; Hartmann, L.; Huang, M.; Huntsman, D. G.; Iacocca, M.; Imielinski, M.; Kalloger, S.; Karlan, B. Y.; Levine, D. A.; Mills, G. B.; Morrison, C.; Mutch, D.; Olvera, N.; Orsulic, S.; Park, K.; Petrelli, N.; Rabeno, B.; Rader, J. S.; Sikic, B. I.; Smith-McCune, K.; Sood, A. K.; Bowtell, D.; Penny, R.; Testa, J. R.; Chang, K.; Dinh, H. H.; Drummond, J. A.; Fowler, G.; Gunaratne, P.; Hawes, A. C.; Kovar, C. L.; Lewis, L. R.; Morgan, M. B.; Newsham, I. F.; Santibanez, J.; Reid, J. G.; Trevino, L. R.; Wu, Y. -Q.; Wang, M.; Muzny, D. M.; Wheeler, D. A.; Gibbs, R. A.; Getz, G.; Lawrence, M. S.; Cibulskis, K.; Sivachenko, A. Y.; Sougnez, C.; Voet, D.; Wilkinson, J.; Bloom, T.; Ardlie, K.; Fennell, T.; Baldwin, J.; Gabriel, S.; Lander, E. S.; Ding, L.; Fulton, R. S.; Koboldt, D. C.; McLellan, M. D.; Wylie, T.; Walker, J.; O'Laughlin, M.; Dooling, D. J.; Fulton, L.; Abbott, R.; Dees, N. D.; Zhang, Q.; Kandoth, C.; Wendl, M.; Schierding, W.; Shen, D.; Harris, C. C.; Schmidt, H.; Kalicki, J.; Delehaunty, K. D.; Fronick, C. C.; Demeter, R.; Cook, L.; Wallis, J. W.; Lin, L.; Magrini, V. J.; Hodges, J. S.; Eldred, J. M.; Smith, S. M.; Pohl, C. S.; Vandin, F.; Raphael, B. J.; Weinstock, G. M.; Mardis, R.; Wilson, R. K.; Meyerson, M.; Winckler, W.; Getz, G.; Verhaak, R. G. W.; Carter, S. L.; Mermel, C. H.; Saksena, G.; Nguyen, H.; Onofrio, R. C.; Lawrence, M. S.; Hubbard, D.; Gupta, S.; Crenshaw, A.; Ramos, A. H.; Ardlie, K.; Chin, L.; Protopopov, A.; Zhang, Juinhua; Kim, T. M.; Perna, I.; Xiao, Y.; Zhang, H.; Ren, G.; Sathiamoorthy, N.; Park, R. W.; Lee, E.; Park, P. J.; Kucherlapati, R.; Absher, D. M.; Waite, L.; Sherlock, G.; Brooks, J. D.; Li, J. Z.; Xu, J.; Myers, R. M.; Laird, P. W.; Cope, L.; Herman, J. G.; Shen, H.; Weisenberger, D. J.; Noushmehr, H.; Pan, F.; Triche, T.; Berman, B. P.; Van den Berg, D. J.; Buckley, J.; Baylin, S. B.; Spellman, P. T.; Purdom, E.; Neuvial, P.; Bengtsson, H.; Jakkula, L. R.; Durinck, S.; Han, J.; Dorton, S.; Marr, H.; Choi, Y. G.; Wang, V.; Wang, N. J.; Ngai, J.; Conboy, J. G.; Parvin, B.; Feiler, H. S.; Speed, T. P.; Gray, J. W.; Levine, D. A.; Socci, N. D.; Liang, Y.; Taylor, B. S.; Schultz, N.; Borsu, L.; Lash, A. E.; Brennan, C.; Viale, A.; Sander, C.; Ladanyi, M.; Hoadley, K. A.; Meng, S.; Du, Y.; Shi, Y.; Li, L.; Turman, Y. J.; Zang, D.; Helms, E. B.; Balu, S.; Zhou, X.; Wu, J.; Topal, M. D.; Hayes, D. N.; Perou, C. M.; Getz, G.; Voet, D.; Saksena, G.; Zhang, Junihua; Zhang, H.; Wu, C. J.; Shukla, S.; Cibulskis, K.; Lawrence, M. S.; Sivachenko, A.; Jing, R.; Park, R. W.; Liu, Y.; Park, P. J.; Noble, M.; Chin, L.; Carter, H.; Kim, D.; Karchin, R.; Spellman, P. T.; Purdom, E.; Neuvial, P.; Bengtsson, H.; Durinck, S.; Han, J.; Korkola, J. E.; Heiser, L. M.; Cho, R. J.; Hu, Z.; Parvin, B.; Speed, T. P.; Gray, J. W.; Schultz, N.; Cerami, E.; Taylor, B. S.; Olshen, A.; Reva, B.; Antipin, Y.; Shen, R.; Mankoo, P.; Sheridan, R.; Ciriello, G.; Chang, W. K.; Bernanke, J. A.; Borsu, L.; Levine, D. A.; Ladanyi, M.; Sander, C.; Haussler, D.; Benz, C. C.; Stuart, J. M.; Benz, S. C.; Sanborn, J. Z.; Vaske, C. J.; Zhu, J.; Szeto, C.; Scott, G. K.; Yau, C.; Hoadley, K. A.; Du, Y.; Balu, S.; Hayes, D. N.; Perou, C. M.; Wilkerson, M. D.; Zhang, N.; Akbani, R.; Baggerly, K. A.; Yung, W. K.; Mills, G. B.; Weinstein, J. N.; Penny, R.; Shelton, T.; Grimm, D.; Hatfield, M.; Morris, S.; Yena, P.; Rhodes, P.; Sherman, M.; Paulauskis, J.; Millis, S.; Kahn, A.; Greene, J. M.; Sfeir, R.; Jensen, M. A.; Chen, J.; Whitmore, J.; Alonso, S.; Jordan, J.; Chu, A.; Zhang, Jinghui; Barker, A.; Compton, C.; Eley, G.; Ferguson, M.; Fielding, P.; Gerhard, D. S.; Myles, R.; Schaefer, C.; Shaw, K. R. Mills; Vaught, J.; Vockley, J. B.; Good, P. J.; Guyer, M. S.; Ozenberger, B.; Peterson, J.; Thomson, E.; Cramer, D.W.

    2011-01-01

    A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients' lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade

  12. ATLAS

    CERN Multimedia

    Akhnazarov, V; Canepa, A; Bremer, J; Burckhart, H; Cattai, A; Voss, R; Hervas, L; Kaplon, J; Nessi, M; Werner, P; Ten kate, H; Tyrvainen, H; Vandelli, W; Krasznahorkay, A; Gray, H; Alvarez gonzalez, B; Eifert, T F; Rolando, G; Oide, H; Barak, L; Glatzer, J; Backhaus, M; Schaefer, D M; Maciejewski, J P; Milic, A; Jin, S; Von torne, E; Limbach, C; Medinnis, M J; Gregor, I; Levonian, S; Schmitt, S; Waananen, A; Monnier, E; Muanza, S G; Pralavorio, P; Talby, M; Tiouchichine, E; Tocut, V M; Rybkin, G; Wang, S; Lacour, D; Laforge, B; Ocariz, J H; Bertoli, W; Malaescu, B; Sbarra, C; Yamamoto, A; Sasaki, O; Koriki, T; Hara, K; Da silva gomes, A; Carvalho maneira, J; Marcalo da palma, A; Chekulaev, S; Tikhomirov, V; Snesarev, A; Buzykaev, A; Maslennikov, A; Peleganchuk, S; Sukharev, A; Kaplan, B E; Swiatlowski, M J; Nef, P D; Schnoor, U; Oakham, G F; Ueno, R; Orr, R S; Abouzeid, O; Haug, S; Peng, H; Kus, V; Vitek, M; Temming, K K; Dang, N P; Meier, K; Schultz-coulon, H; Geisler, M P; Sander, H; Schaefer, U; Ellinghaus, F; Rieke, S; Nussbaumer, A; Liu, Y; Richter, R; Kortner, S; Fernandez-bosman, M; Ullan comes, M; Espinal curull, J; Chiriotti alvarez, S; Caubet serrabou, M; Valladolid gallego, E; Kaci, M; Carrasco vela, N; Lancon, E C; Besson, N E; Gautard, V; Bracinik, J; Bartsch, V C; Potter, C J; Lester, C G; Moeller, V A; Rosten, J; Crooks, D; Mathieson, K; Houston, S C; Wright, M; Jones, T W; Harris, O B; Byatt, T J; Dobson, E; Hodgson, P; Hodgkinson, M C; Dris, M; Karakostas, K; Ntekas, K; Oren, D; Duchovni, E; Etzion, E; Oren, Y; Ferrer, L M; Testa, M; Doria, A; Merola, L; Sekhniaidze, G; Giordano, R; Ricciardi, S; Milazzo, A; Falciano, S; De pedis, D; Dionisi, C; Veneziano, S; Cardarelli, R; Verzegnassi, C; Soualah, R; Ochi, A; Ohshima, T; Kishiki, S; Linde, F L; Vreeswijk, M; Werneke, P; Muijs, A; Vankov, P H; Jansweijer, P P M; Dale, O; Lund, E; Bruckman de renstrom, P; Dabrowski, W; Adamek, J D; Wolters, H; Micu, L; Pantea, D; Tudorache, V; Mjoernmark, J; Klimek, P J; Ferrari, A; Abdinov, O; Akhoundov, A; Hashimov, R; Shelkov, G; Khubua, J; Ladygin, E; Lazarev, A; Glagolev, V; Dedovich, D; Lykasov, G; Zhemchugov, A; Zolnikov, Y; Ryabenko, M; Sivoklokov, S; Vasilyev, I; Shalimov, A; Lobanov, M; Paramoshkina, E; Mosidze, M; Bingul, A; Nodulman, L J; Guarino, V J; Yoshida, R; Drake, G R; Calafiura, P; Haber, C; Quarrie, D R; Alonso, J R; Anderson, C; Evans, H; Lammers, S W; Baubock, M; Anderson, K; Petti, R; Suhr, C A; Linnemann, J T; Richards, R A; Tollefson, K A; Holzbauer, J L; Stoker, D P; Pier, S; Nelson, A J; Isakov, V; Martin, A J; Adelman, J A; Paganini, M; Gutierrez, P; Snow, J M; Pearson, B L; Cleland, W E; Savinov, V; Wong, W; Goodson, J J; Li, H; Lacey, R A; Gordeev, A; Gordon, H; Lanni, F; Nevski, P; Rescia, S; Kierstead, J A; Liu, Z; Yu, W W H; Bensinger, J; Hashemi, K S; Bogavac, D; Cindro, V; Hoeferkamp, M R; Coelli, S; Iodice, M; Piegaia, R N; Alonso, F; Wahlberg, H P; Barberio, E L; Limosani, A; Rodd, N L; Jennens, D T; Hill, E C; Pospisil, S; Smolek, K; Schaile, D A; Rauscher, F G; Adomeit, S; Mattig, P M; Wahlen, H; Volkmer, F; Calvente lopez, S; Sanchis peris, E J; Pallin, D; Podlyski, F; Says, L; Boumediene, D E; Scott, W; Phillips, P W; Greenall, A; Turner, P; Gwilliam, C B; Kluge, T; Wrona, B; Sellers, G J; Millward, G; Adragna, P; Hartin, A; Alpigiani, C; Piccaro, E; Bret cano, M; Hughes jones, R E; Mercer, D; Oh, A; Chavda, V S; Carminati, L; Cavasinni, V; Fedin, O; Patrichev, S; Ryabov, Y; Nesterov, S; Grebenyuk, O; Sasso, J; Mahmood, H; Polsdofer, E; Dai, T; Ferretti, C; Liu, H; Hegazy, K H; Benjamin, D P; Zobernig, G; Ban, J; Brooijmans, G H; Keener, P; Williams, H H; Le geyt, B C; Hines, E J; Fadeyev, V; Schumm, B A; Law, A T; Kuhl, A D; Neubauer, M S; Shang, R; Gagliardi, G; Calabro, D; Conta, C; Zinna, M; Jones, G; Li, J; Stradling, A R; Hadavand, H K; Mcguigan, P; Chiu, P; Baldelomar, E; Stroynowski, R A; Kehoe, R L; De groot, N; Timmermans, C; Lach-heb, F; Addy, T N; Nakano, I; Moreno lopez, D; Grosse-knetter, J; Tyson, B; Rude, G D; Tafirout, R; Benoit, P; Danielsson, H O; Elsing, M; Fassnacht, P; Froidevaux, D; Ganis, G; Gorini, B; Lasseur, C; Lehmann miotto, G; Kollar, D; Aleksa, M; Sfyrla, A; Duehrssen-debling, K; Fressard-batraneanu, S; Van der ster, D C; Bortolin, C; Schumacher, J; Mentink, M; Geich-gimbel, C; Yau wong, K H; Lafaye, R; Crepe-renaudin, S; Albrand, S; Hoffmann, D; Pangaud, P; Meessen, C; Hrivnac, J; Vernay, E; Perus, A; Henrot versille, S L; Le dortz, O; Derue, F; Piccinini, M; Polini, A; Terada, S; Arai, Y; Ikeno, M; Fujii, H; Nagano, K; Ukegawa, F; Aguilar saavedra, J A; Conde muino, P; Castro, N F; Eremin, V; Kopytine, M; Sulin, V; Tsukerman, I; Korol, A; Nemethy, P; Bartoldus, R; Glatte, A; Chelsky, S; Van nieuwkoop, J; Bellerive, A; Sinervo, J K; Battaglia, A; Barbier, G J; Pohl, M; Rosselet, L; Alexandre, G B; Prokoshin, F; Pezoa rivera, R A; Batkova, L; Kladiva, E; Stastny, J; Kubes, T; Vidlakova, Z; Esch, H; Homann, M; Herten, L G; Zimmermann, S U; Pfeifer, B; Stenzel, H; Andrei, G V; Wessels, M; Buescher, V; Kleinknecht, K; Fiedler, F M; Schroeder, C D; Fernandez, E; Mir martinez, L; Vorwerk, V; Bernabeu verdu, J; Salt, J; Civera navarrete, J V; Bernard, R; Berriaud, C P; Chevalier, L P; Hubbard, R; Schune, P; Nikolopoulos, K; Batley, J R; Brochu, F M; Phillips, A W; Teixeira-dias, P J; Rose, M B D; Buttar, C; Buckley, A G; Nurse, E L; Larner, A B; Boddy, C; Henderson, J; Costanzo, D; Tarem, S; Maccarrone, G; Laurelli, P F; Alviggi, M; Chiaramonte, R; Izzo, V; Palumbo, V; Fraternali, M; Crosetti, G; Marchese, F; Yamaguchi, Y; Hessey, N P; Mechnich, J M; Liebig, W; Kastanas, K A; Sjursen, T B; Zalieckas, J; Cameron, D G; Banka, P; Kowalewska, A B; Dwuznik, M; Mindur, B; Boldea, V; Hedberg, V; Smirnova, O; Sellden, B; Allahverdiyev, T; Gornushkin, Y; Koultchitski, I; Tokmenin, V; Chizhov, M; Gongadze, A; Khramov, E; Sadykov, R; Krasnoslobodtsev, I; Smirnova, L; Kramarenko, V; Minaenko, A; Zenin, O; Beddall, A J; Ozcan, E V; Hou, S; Wang, S; Moyse, E; Willocq, S; Chekanov, S; Le compte, T J; Love, J R; Ciocio, A; Hinchliffe, I; Tsulaia, V; Gomez, A; Luehring, F; Zieminska, D; Huth, J E; Gonski, J L; Oreglia, M; Tang, F; Shochet, M J; Costin, T; Mcleod, A; Uzunyan, S; Martin, S P; Pope, B G; Schwienhorst, R H; Brau, J E; Ptacek, E S; Milburn, R H; Sabancilar, E; Lauer, R; Saleem, M; Mohamed meera lebbai, M R; Lou, X; Reeves, K B; Rijssenbeek, M; Novakova, P N; Rahm, D; Steinberg, P A; Wenaus, T J; Paige, F; Ye, S; Kotcher, J R; Assamagan, K A; Oliveira damazio, D; Maeno, T; Henry, A; Dushkin, A; Costa, G; Meroni, C; Resconi, S; Lari, T; Biglietti, M; Lohse, T; Gonzalez silva, M L; Monticelli, F G; Saavedra, A F; Patel, N D; Ciodaro xavier, T; Asevedo nepomuceno, A; Lefebvre, M; Albert, J E; Kubik, P; Faltova, J; Turecek, D; Solc, J; Schaile, O; Ebke, J; Losel, P J; Zeitnitz, C; Sturm, P D; Barreiro alonso, F; Modesto alapont, P; Soret medel, J; Garzon alama, E J; Gee, C N; Mccubbin, N A; Sankey, D; Emeliyanov, D; Dewhurst, A L; Houlden, M A; Klein, M; 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Fenyuk, A; Djobava, T; Salukvadze, G; Cetin, S A; Brau, B P; Pais, P R; Proudfoot, J; Van gemmeren, P; Zhang, Q; Beringer, J A; Ely, R; Leggett, C; Pengg, F X; Barnett, M R; Quick, R E; Williams, S; Gardner jr, R W; Huston, J; Brock, R; Wanotayaroj, C; Unel, G N; Taffard, A C; Frate, M; Baker, K O; Tipton, P L; Hutchison, A; Walsh, B J; Norberg, S R; Su, J; Tsybyshev, D; Caballero bejar, J; Ernst, M U; Wellenstein, H; Vudragovic, D; Vidic, I; Gorelov, I V; Toms, K; Alimonti, G; Petrucci, F; Kolanoski, H; Smith, J; Jeng, G; Watson, I J; Guimaraes ferreira, F; Miranda vieira xavier, F; Araujo pereira, R; Poffenberger, P; Sopko, V; Elmsheuser, J; Wittkowski, J; Glitza, K; Gorfine, G W; Ferrer soria, A; Fuster verdu, J A; Sanchis lozano, A; Reinmuth, G; Busato, E; Haywood, S J; Mcmahon, S J; Qian, W; Villani, E G; Laycock, P J; Poll, A J; Rizvi, E S; Foster, J M; Loebinger, F; Forti, A; Plano, W G; Brown, G J A; Kordas, K; Vegni, G; Ohsugi, T; Iwata, Y; Cherkaoui el moursli, R; Sahin, M; Akyazi, E; 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Pingel, A M; Massol, N; Elles, S L; Hallewell, G D; Rozanov, A; Vacavant, L; Fournier, D A; Poggioli, L; Puzo, P M; Tanaka, R; Escalier, M A; Makovec, N; Rezynkina, K; De cecco, S; Cavalleri, P G; Massa, I; Zoccoli, A; Tanaka, S; Odaka, S; Mitsui, S; Tomasio pina, J A; Santos, H F; Satsounkevitch, I; Harkusha, S; Baranov, S; Nechaeva, P; Kayumov, F; Kazanin, V; Asai, M; Mount, R P; Nelson, T K; Smith, D; Kenney, C J; Malone, C M; Kobel, M; Friedrich, F; Grohs, J P; Jais, W J; O'neil, D C; Warburton, A T; Vincter, M; Mccarthy, T G; Groer, L S; Pham, Q T; Taylor, W J; La marra, D; Perrin, E; Wu, X; Bell, W H; Delitzsch, C M; Feng, C; Zhu, C; Tokar, S; Bruncko, D; Kupco, A; Marcisovsky, M; Jakoubek, T; Bruneliere, R; Aktas, A; Narrias villar, D I; Tapprogge, S; Mattmann, J; Kroha, H; Crespo, J; Korolkov, I; Cavallaro, E; Cabrera urban, S; Mitsou, V; Kozanecki, W; Mansoulie, B; Pabot, Y; Etienvre, A; Bauer, F; Chevallier, F; Bouty, A R; Watkins, P; Watson, A; Faulkner, P J W; Curtis, C J; Murillo quijada, J A; Grout, Z J; Chapman, J D; Cowan, G D; George, S; Boisvert, V; Mcmahon, T R; Doyle, A T; Thompson, S A; Britton, D; Smizanska, M; Campanelli, M; Butterworth, J M; Loken, J; Renton, P; Barr, A J; Issever, C; Short, D; Crispin ortuzar, M; Tovey, D R; French, R; Rozen, Y; Alexander, G; Kreisel, A; Conventi, F; Raulo, A; Schioppa, M; Susinno, G; Tassi, E; Giagu, S; Luci, C; Nisati, A; Cobal, M; Ishikawa, A; Jinnouchi, O; Bos, K; Verkerke, W; Vermeulen, J; Van vulpen, I B; Kieft, G; Mora, K D; Olsen, F; Rohne, O M; Pajchel, K; Nilsen, J K; Wosiek, B K; Wozniak, K W; Badescu, E; Jinaru, A; Bohm, C; Johansson, E K; Sjoelin, J B R; Clement, C; Buszello, C P; Huseynova, D; Boyko, I; Popov, B; Poukhov, O; Vinogradov, V; Tsiareshka, P; Skvorodnev, N; Soldatov, A; Chuguev, A; Gushchin, V; Yazici, E; Lutz, M S; Malon, D; Vanyashin, A; Lavrijsen, W; Spieler, H; Biesiada, J L; Bahr, M; Kong, J; Tatarkhanov, M; Ogren, H; Van kooten, R J; Cwetanski, P; Butler, J M; Shank, J T; Chakraborty, D; Ermoline, I; Sinev, N; Whiteson, D O; Corso radu, A; Huang, J; Werth, M P; Kastoryano, M; Meirose da silva costa, B; Namasivayam, H; Hobbs, J D; Schamberger jr, R D; Guo, F; Potekhin, M; Popovic, D; Gorisek, A; Sokhrannyi, G; Hofsajer, I W; Mandelli, L; Ceradini, F; Graziani, E; Giorgi, F; Zur nedden, M E G; Grancagnolo, S; Volpi, M; Nunes hanninger, G; Rados, P K; Milesi, M; Cuthbert, C J; Black, C W; Fink grael, F; Fincke-keeler, M; Keeler, R; Kowalewski, R V; Berghaus, F O; Qi, M; Davidek, T; Tas, P; Jakubek, J; Duckeck, G; Walker, R; Mitterer, C A; Harenberg, T; Sandvoss, S A; Del peso, J; Llorente merino, J; Gonzalez millan, V; Irles quiles, A; Crouau, M; Gris, P L Y; Liauzu, S; Romano saez, S M; Gallop, B J; Jones, T J; Austin, N C; Morris, J; Duerdoth, I; Thompson, R J; Kelly, M P; Leisos, A; Garas, A; Pizio, C; Venda pinto, B A; Kudin, L; Qian, J; Wilson, A W; Mietlicki, D; Long, J D; Sang, Z; Arms, K E; Rahimi, A M; Moss, J J; Oh, S H; Parker, S I; Parsons, J; Cunitz, H; Vanguri, R S; Sadrozinski, H; Lockman, W S; Martinez-mc kinney, G; Goussiou, A; Jones, A; Lie, K; Hasegawa, Y; Olcese, M; Gilewsky, V; Harrison, P F; Janus, M; Spangenberg, M; De, K; Ozturk, N; Pal, A K; Darmora, S; Bullock, D J; Oviawe, O; Derkaoui, J E; Rahal, G; Sircar, A; Frey, A S; Stolte, P; Rosien, N; Zoch, K; Li, L; Schouten, D W; Catinaccio, A; Ciapetti, M; Delruelle, N; Ellis, N; Farthouat, P; Hoecker, A; Klioutchnikova, T; Macina, D; Malyukov, S; Spiwoks, R D; Unal, G P; Vandoni, G; Petersen, B A; Pommes, K; Nairz, A M; Wengler, T; Mladenov, D; Solans sanchez, C A; Lantzsch, K; Schmieden, K; Jakobsen, S; Ritsch, E; Sciuccati, A; Alves dos santos, A M; Ouyang, Q; Zhou, M; Brock, I C; Janssen, J; Katzy, J; Anders, C F; Nilsson, B S; Bazan, A; Di ciaccio, L; Yildizkaya, T; Collot, J; Malek, F; Trocme, B S; Breugnon, P; Godiot, S; Adam bourdarios, C; Coulon, J; Duflot, L; Petroff, P G; Zerwas, D; Lieuvin, M; Calderini, G; Laporte, D; Ocariz, J; Gabrielli, A; Ohska, T K; Kurochkin, Y; Kantserov, V; Vasilyeva, L; Speransky, M; Smirnov, S; Antonov, A; Bulekov, O; Tikhonov, Y; Sargsyan, L; Vardanyan, G; Budick, B; Kocian, M L; Luitz, S; Young, C C; Grenier, P J; Kelsey, M; Black, J E; Kneringer, E; Jussel, P; Horton, A J; Beaudry, J; Chandra, A; Ereditato, A; Topfel, C M; Mathieu, R; Bucci, F; Muenstermann, D; White, R M; He, M; Urban, J; Straka, M; Vrba, V; Schumacher, M; Parzefall, U; Mahboubi, K; Sommer, P O; Koepke, L H; Bethke, S; Moser, H; Wiesmann, M; Walkowiak, W A; Fleck, I J; Martinez-perez, M; Sanchez sanchez, C A; Jorgensen roca, S; Accion garcia, E; Sainz ruiz, C A; Valls ferrer, J A; Amoros vicente, G; Vives torrescasana, R; Ouraou, A; Formica, A; Hassani, S; Watson, M F; Cottin buracchio, G F; Bussey, P J; Saxon, D; Ferrando, J E; Collins-tooth, C L; Hall, D C; Cuhadar donszelmann, T; Dawson, I; Duxfield, R; Argyropoulos, T; Brodet, E; Livneh, R; Shougaev, K; Reinherz, E I; Guttman, N; Beretta, M M; Vilucchi, E; Aloisio, A; Patricelli, S; Caprio, M; Cevenini, F; De vecchi, C; Livan, M; Rimoldi, A; Vercesi, V; Ayad, R; Mastroberardino, A; Ciapetti, G; Luminari, L; Rescigno, M; Santonico, R; Salamon, A; Del papa, C; Kurashige, H; Homma, Y; Tomoto, M; Horii, Y; Sugaya, Y; Hanagaki, K; Bobbink, G; Kluit, P M; Koffeman, E N; Van eijk, B; Lee, H; Eigen, G; Dorholt, O; Strandlie, A; Strzempek, P B; Dita, S; Stoicea, G; Chitan, A; Leven, S S; Moa, T; Brenner, R; Ekelof, T J C; Olshevskiy, A; Roumiantsev, V; Chlachidze, G; Zimine, N; Gusakov, Y; Grigalashvili, N; Mineev, M; Potrap, I; Barashkou, A; Shoukavy, D; Shaykhatdenov, B; Pikelner, A; Gladilin, L; Ammosov, V; Abramov, A; Arik, M; Sahinsoy, M; Uysal, Z; Azizi, K; Hotinli, S C; Zhou, S; Berger, E; Blair, R; Underwood, D G; Einsweiler, K; Garcia-sciveres, M A; Siegrist, J L; Kipnis, I; Dahl, O; Holland, S; Barbaro galtieri, A; Smith, P T; Parua, N; Franklin, M; Mercurio, K M; Tong, B; Pod, E; Cole, S G; Hopkins, W H; Guest, D H; Severini, H; Marsicano, J J; Abbott, B K; Wang, Q; Lissauer, D; Ma, H; Takai, H; Rajagopalan, S; Protopopescu, S D; Snyder, S S; Undrus, A; Popescu, R N; Begel, M A; Blocker, C A; Amelung, C; Mandic, I; Macek, B; Tucker, B H; Citterio, M; Troncon, C; Orestano, D; Taccini, C; Romeo, G L; Dova, M T; Taylor, G N; Gesualdi manhaes, A; Mcpherson, R A; Sobie, R; Taylor, R P; Dolezal, Z; Kodys, P; Slovak, R; Sopko, B; Vacek, V; Sanders, M P; Hertenberger, R; Meineck, C; Becks, K; Kind, P; Sandhoff, M; Cantero garcia, J; De la torre perez, H; Castillo gimenez, V; Ros, E; Hernandez jimenez, Y; Chadelas, R; Santoni, C; Washbrook, A J; O'brien, B J; Wynne, B M; Mehta, A; Vossebeld, J H; Landon, M; Teixeira dias castanheira, M; Cerrito, L; Keates, J R; Fassouliotis, D; Chardalas, M; Manousos, A; Grachev, V; Seliverstov, D; Sedykh, E; Cakir, O; Ciftci, R; Edson, W; Prell, S A; Rosati, M; Stroman, T; Jiang, H; Neal, H A; Li, X; Gan, K K; Smith, D S; Kruse, M C; Ko, B R; Leung fook cheong, A M; Cole, B; Angerami, A R; Greene, Z S; Kroll, J I; Van berg, R P; Forbush, D A; Lubatti, H; Raisher, J; Shupe, M A; Wolin, S; Oshita, H; Gaudio, G; Das, R; Konig, A C; Croft, V A; Harvey, A; Maaroufi, F; Melo, I; Greenwood jr, Z D; Shabalina, E; Mchedlidze, G; Drechsler, E; Rieger, J K; Blackston, M; Colombo, T

    2002-01-01

    % ATLAS \\\\ \\\\ ATLAS is a general-purpose experiment for recording proton-proton collisions at LHC. The ATLAS collaboration consists of 144 participating institutions (June 1998) with more than 1750~physicists and engineers (700 from non-Member States). The detector design has been optimized to cover the largest possible range of LHC physics: searches for Higgs bosons and alternative schemes for the spontaneous symmetry-breaking mechanism; searches for supersymmetric particles, new gauge bosons, leptoquarks, and quark and lepton compositeness indicating extensions to the Standard Model and new physics beyond it; studies of the origin of CP violation via high-precision measurements of CP-violating B-decays; high-precision measurements of the third quark family such as the top-quark mass and decay properties, rare decays of B-hadrons, spectroscopy of rare B-hadrons, and $ B ^0 _{s} $-mixing. \\\\ \\\\The ATLAS dectector, shown in the Figure includes an inner tracking detector inside a 2~T~solenoid providing an axial...

  13. Genome Stability Pathways in Head and Neck Cancers

    Directory of Open Access Journals (Sweden)

    Glenn Jenkins

    2013-01-01

    Full Text Available Genomic instability underlies the transformation of host cells toward malignancy, promotes development of invasion and metastasis and shapes the response of established cancer to treatment. In this review, we discuss recent advances in our understanding of genomic stability in squamous cell carcinoma of the head and neck (HNSCC, with an emphasis on DNA repair pathways. HNSCC is characterized by distinct profiles in genome stability between similarly staged cancers that are reflected in risk, treatment response and outcomes. Defective DNA repair generates chromosomal derangement that can cause subsequent alterations in gene expression, and is a hallmark of progression toward carcinoma. Variable functionality of an increasing spectrum of repair gene polymorphisms is associated with increased cancer risk, while aetiological factors such as human papillomavirus, tobacco and alcohol induce significantly different behaviour in induced malignancy, underpinned by differences in genomic stability. Targeted inhibition of signalling receptors has proven to be a clinically-validated therapy, and protein expression of other DNA repair and signalling molecules associated with cancer behaviour could potentially provide a more refined clinical model for prognosis and treatment prediction. Development and expansion of current genomic stability models is furthering our understanding of HNSCC pathophysiology and uncovering new, promising treatment strategies.

  14. Molecular cytogenetic applications in analysis of the cancer genome.

    Science.gov (United States)

    Rao, Pulivarthi H; Nandula, Subhadra V; Murty, Vundavalli V

    2007-01-01

    Cancer cells exhibit nonrandom and complex chromosome abnormalities. The role of genomic changes in cancer is well established. However, the identification of complex and cryptic chromosomal changes is beyond the resolution of conventional banding methods. The fluorescence microscopy afforded by imaging technologies, developed recently, facilitates a precise identification of these chromosome alterations in cancer. The three most commonly utilized molecular cytogenetics methods comparative genomic hybridization, spectral karyotype, and fluorescence in situ hybridization, that have already become benchmark tools in cancer cytogenetics, are described in this chapter. Comparative genomic hybridization is a powerful tool for screening copy-number changes in tumor genomes without the need for preparation of metaphases from tumor cells. Multicolor spectral karyotype permits visualization of all chromosomes in one experiment permitting identification of precise chromosomal changes on metaphases derived from tumor cells. The uses of fluorescence in situ hybridization are diverse, including mapping of alteration in single copy genes, chromosomal regions, or entire chromosomes. The opportunities to detect genetic alterations in cancer cells continue to evolve with the use of these methodologies both in diagnosis and research.

  15. HUMAN CANCER IS A PARASITE SPREAD VIA INTRUSION IN GENOME

    Directory of Open Access Journals (Sweden)

    Sergey N. Rumyantsev

    2013-03-01

    Full Text Available The present article is devoted to further development of new paradigm about the biology of human cancer: the hypothesis of parasitic nature, origin and evolution of the phenomenon. The study included integrative reconsidering, and reinterpretation of the make-ups, traits and processes existing both in human and animal cancers. It was demonstrated that human cancer possesses nearly analogous set of traits characteristic of transmissible animal cancer. Undoubted analogies are seen in the prevalence, clinical exposure, progression of disease, origin of causative agents, immune response against invasion and especially in the intrinsic deviations of the leading traits of cancerous cells. Both human and animal cancers are highly exceptional pathogens. But in contrast to contagious animal cancers the cells of of human cancer can not pass between individuals as usual infectious agents. Exhaustive evidence of the parasitic nature and evolutionary origin of human cancer was revealed and interpreted. In contrast to animal cancer formed of solitary cell lineage, human cancer consists of a couple of lineages constructed under different genetic regulations and performed different structural and physiological functions. The complex make-up of cancer composition remains stable over sequential propagation. The subsistence of human cancer regularly includes obligatory interchange of its successive forms. Human cancer possesses its own biological watch and the ability to gobble its victim, transmit via the intrusion of the genome, perform intercommunications within the tumor components and between the dispersed subunits of cancer. Such intrinsic traits characterize human cancer as a primitively structured parasite that can be classified in Class Mammalians, Species Genomeintruder malevolent (G.malevolent.

  16. Cancer in Children and Adolescents | Office of Cancer Genomics

    Science.gov (United States)

    View a fact sheet that has statistics as well as information about types, causes, and treatments of cancers in children and adolescents in the United States. http://www.cancer.gov/cancertopics/factsheet/Sites-Types/childhood

  17. Integrated analysis of whole genome and transcriptome sequencing reveals diverse transcriptomic aberrations driven by somatic genomic changes in liver cancers.

    Directory of Open Access Journals (Sweden)

    Yuichi Shiraishi

    Full Text Available Recent studies applying high-throughput sequencing technologies have identified several recurrently mutated genes and pathways in multiple cancer genomes. However, transcriptional consequences from these genomic alterations in cancer genome remain unclear. In this study, we performed integrated and comparative analyses of whole genomes and transcriptomes of 22 hepatitis B virus (HBV-related hepatocellular carcinomas (HCCs and their matched controls. Comparison of whole genome sequence (WGS and RNA-Seq revealed much evidence that various types of genomic mutations triggered diverse transcriptional changes. Not only splice-site mutations, but also silent mutations in coding regions, deep intronic mutations and structural changes caused splicing aberrations. HBV integrations generated diverse patterns of virus-human fusion transcripts depending on affected gene, such as TERT, CDK15, FN1 and MLL4. Structural variations could drive over-expression of genes such as WNT ligands, with/without creating gene fusions. Furthermore, by taking account of genomic mutations causing transcriptional aberrations, we could improve the sensitivity of deleterious mutation detection in known cancer driver genes (TP53, AXIN1, ARID2, RPS6KA3, and identified recurrent disruptions in putative cancer driver genes such as HNF4A, CPS1, TSC1 and THRAP3 in HCCs. These findings indicate genomic alterations in cancer genome have diverse transcriptomic effects, and integrated analysis of WGS and RNA-Seq can facilitate the interpretation of a large number of genomic alterations detected in cancer genome.

  18. Highlights from the prostate cancer genome report

    Institute of Scientific and Technical Information of China (English)

    Shyh-Han Tan; Gyorgy Petrovics; Shiv Srivastava

    2011-01-01

    @@ Prostate cancer (Cap) is the second most frequently diagnosed cancer of men worldwide (899 000 new cases,13.6% of the total),with nearly 75% of the registered cases occurring in developed countries (644000 cases).1 Blood prostate-specific antigen test has revolutionized the early detection of Cap and organ-confined Cap is effectively managed by state-of-the-art treatments including radical prostatectomy or radiation therapy.2 In the past decade,tremendous progress has also been made in our understanding of the biology and common genomicalterations in Cap 3.4 New molecular marker assays have promise in improving CaP diagnosis.Despite these advances,major challenges remain with our ability to distinguish indolent cancers from the more aggressive cancers detected early due to widely used prostate-specific antigen test.Furthermore,development of molecular stratification of CaP for targeted and more effective therapies is critically needed.

  19. A Genome-wide Pleiotropy Scan for Prostate Cancer Risk

    Science.gov (United States)

    Panagiotou, Orestis A; Travis, Ruth C; Campa, Daniele; Berndt, Sonja I.; Lindstrom, Sara; Kraft, Peter; Schumacher, Fredrick R.; Siddiq, Afshan; Papatheodorou, Stefania I.; Stanford, Janet L.; Albanes, Demetrius; Virtamo, Jarmo; Weinstein, Stephanie J.; Diver, W. Ryan; Gapstur, Susan M.; Stevens, Victoria L.; Boeing, Heiner; Bueno-de-Mesquita, H. Bas; Gurrea, Aurelio Barricarte; Kaaks, Rudolf; Khaw, Kay-Tee; Krogh, Vittorio; Overvad, Kim; Riboli, Elio; Trichopoulos, Dimitrios; Giovannucci, Edward; Stampfer, Meir; Haiman, Christopher; Henderson, Brian; Le Marchand, Loic; Gaziano, J. Michael; Hunter, DavidJ.; Koutros, Stella; Yeager, Meredith; Hoover, Robert N.; Chanock, Stephen J.; Wacholder, Sholom; Key, Timothy J.; Tsilidis, Konstantinos K

    2014-01-01

    Background No single-nucleotide polymorphisms (SNPs) specific for aggressive prostate cancer have been identified in genome-wide association studies (GWAS). Objective To test if SNPs associated with other traits may also affect the risk of aggressive prostate cancer. Design, setting, and participants SNPs implicated in any phenotype other than prostate cancer (p ≤ 10−7) were identified through the catalog of published GWAS and tested in 2891 aggressive prostate cancer cases and 4592 controls from the Breast and Prostate Cancer Cohort Consortium (BPC3). The 40 most significant SNPs were followed up in 4872 aggressive prostate cancer cases and 24 534 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. Outcome measurements and statistical analysis Odds ratios (ORs) and 95% confidence intervals (CIs) for aggressive prostate cancer were estimated. Results and limitations A total of 4666 SNPs were evaluated by the BPC3. Two signals were seen in regions already reported for prostate cancer risk. rs7014346 at 8q24.21 was marginally associated with aggressive prostate cancer in the BPC3 trial (p = 1.6 × 10-6), whereas after meta-analysis by PRACTICAL the summary OR was 1.21 (95%CI 1.16–1.27; p = 3.22 × 10−18). rs9900242 at 17q24.3 was also marginally associated with aggressive disease in the meta-analysis (OR 0.90, 95% CI 0.86–0.94; p = 2.5 × 10−6). Neither of these SNPs remained statistically significant when conditioning on correlated known prostate cancer SNPs. The meta-analysis by BPC3 and PRACTICAL identified a third promising signal, marked by rs16844874 at 2q34, independent of known prostate cancer loci (OR 1.12,95% CI 1.06–1.19; p = 4.67 × 10−5); it has been shown that SNPs correlated with this signal affect glycine concentrations. The main limitation is the heterogeneity in the definition of aggressive prostate cancer between BPC3 and PRACTICAL. Conclusions We did

  20. National Cancer Moonshot Initiative platform | Office of Cancer Genomics

    Science.gov (United States)

    As part of the Vice President’s National Cancer Moonshot Initiative, the National Cancer Institute has launched an online engagement platform to enable the research community and the public to submit cancer research ideas to a Blue Ribbon Panel of scientific experts. Any member of the public is encouraged to submit his or her ideas for reducing the incidence of cancer and developing better ways to prevent, treat, and cure all types of cancer. Research ideas may be submitted in the following areas:

  1. CRISPR-Cas9: from Genome Editing to Cancer Research.

    Science.gov (United States)

    Chen, Si; Sun, Heng; Miao, Kai; Deng, Chu-Xia

    2016-01-01

    Cancer development is a multistep process triggered by innate and acquired mutations, which cause the functional abnormality and determine the initiation and progression of tumorigenesis. Gene editing is a widely used engineering tool for generating mutations that enhance tumorigenesis. The recent developed clustered regularly interspaced short palindromic repeats-CRISPR-associated 9 (CRISPR-Cas9) system renews the genome editing approach into a more convenient and efficient way. By rapidly introducing genetic modifications in cell lines, organs and animals, CRISPR-Cas9 system extends the gene editing into whole genome screening, both in loss-of-function and gain-of-function manners. Meanwhile, the system accelerates the establishment of animal cancer models, promoting in vivo studies for cancer research. Furthermore, CRISPR-Cas9 system is modified into diverse innovative tools for observing the dynamic bioprocesses in cancer studies, such as image tracing for targeted DNA, regulation of transcription activation or repression. Here, we view recent technical advances in the application of CRISPR-Cas9 system in cancer genetics, large-scale cancer driver gene hunting, animal cancer modeling and functional studies.

  2. Predicting human genetic interactions from cancer genome evolution.

    Directory of Open Access Journals (Sweden)

    Xiaowen Lu

    Full Text Available Synthetic Lethal (SL genetic interactions play a key role in various types of biological research, ranging from understanding genotype-phenotype relationships to identifying drug-targets against cancer. Despite recent advances in empirical measuring SL interactions in human cells, the human genetic interaction map is far from complete. Here, we present a novel approach to predict this map by exploiting patterns in cancer genome evolution. First, we show that empirically determined SL interactions are reflected in various gene presence, absence, and duplication patterns in hundreds of cancer genomes. The most evident pattern that we discovered is that when one member of an SL interaction gene pair is lost, the other gene tends not to be lost, i.e. the absence of co-loss. This observation is in line with expectation, because the loss of an SL interacting pair will be lethal to the cancer cell. SL interactions are also reflected in gene expression profiles, such as an under representation of cases where the genes in an SL pair are both under expressed, and an over representation of cases where one gene of an SL pair is under expressed, while the other one is over expressed. We integrated the various previously unknown cancer genome patterns and the gene expression patterns into a computational model to identify SL pairs. This simple, genome-wide model achieves a high prediction power (AUC = 0.75 for known genetic interactions. It allows us to present for the first time a comprehensive genome-wide list of SL interactions with a high estimated prediction precision, covering up to 591,000 gene pairs. This unique list can potentially be used in various application areas ranging from biotechnology to medical genetics.

  3. Chapter 27 -- Breast Cancer Genomics, Section VI, Pathology and Biological Markers of Invasive Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Spellman, Paul T.; Heiser, Laura; Gray, Joe W.

    2009-06-18

    Breast cancer is predominantly a disease of the genome with cancers arising and progressing through accumulation of aberrations that alter the genome - by changing DNA sequence, copy number, and structure in ways that that contribute to diverse aspects of cancer pathophysiology. Classic examples of genomic events that contribute to breast cancer pathophysiology include inherited mutations in BRCA1, BRCA2, TP53, and CHK2 that contribute to the initiation of breast cancer, amplification of ERBB2 (formerly HER2) and mutations of elements of the PI3-kinase pathway that activate aspects of epidermal growth factor receptor (EGFR) signaling and deletion of CDKN2A/B that contributes to cell cycle deregulation and genome instability. It is now apparent that accumulation of these aberrations is a time-dependent process that accelerates with age. Although American women living to an age of 85 have a 1 in 8 chance of developing breast cancer, the incidence of cancer in women younger than 30 years is uncommon. This is consistent with a multistep cancer progression model whereby mutation and selection drive the tumor's development, analogous to traditional Darwinian evolution. In the case of cancer, the driving events are changes in sequence, copy number, and structure of DNA and alterations in chromatin structure or other epigenetic marks. Our understanding of the genetic, genomic, and epigenomic events that influence the development and progression of breast cancer is increasing at a remarkable rate through application of powerful analysis tools that enable genome-wide analysis of DNA sequence and structure, copy number, allelic loss, and epigenomic modification. Application of these techniques to elucidation of the nature and timing of these events is enriching our understanding of mechanisms that increase breast cancer susceptibility, enable tumor initiation and progression to metastatic disease, and determine therapeutic response or resistance. These studies also

  4. In situ quantification of genomic instability in breast cancer progression

    Energy Technology Data Exchange (ETDEWEB)

    Ortiz de Solorzano, Carlos; Chin, Koei; Gray, Joe W.; Lockett, Stephen J.

    2003-05-15

    Genomic instability is a hallmark of breast and other solid cancers. Presumably caused by critical telomere reduction, GI is responsible for providing the genetic diversity required in the multi-step progression of the disease. We have used multicolor fluorescence in situ hybridization and 3D image analysis to quantify genomic instability cell-by-cell in thick, intact tissue sections of normal breast epithelium, preneoplastic lesions (usual ductal hyperplasia), ductal carcinona is situ or invasive carcinoma of the breast. Our in situ-cell by cell-analysis of genomic instability shows an important increase of genomic instability in the transition from hyperplasia to in situ carcinoma, followed by a reduction of instability in invasive carcinoma. This pattern suggests that the transition from hyperplasia to in situ carcinoma corresponds to telomere crisis and invasive carcinoma is a consequence of telomerase reactivation afertelomere crisis.

  5. Genomic connectivity networks based on the BrainSpan atlas of the developing human brain

    Science.gov (United States)

    Mahfouz, Ahmed; Ziats, Mark N.; Rennert, Owen M.; Lelieveldt, Boudewijn P. F.; Reinders, Marcel J. T.

    2014-03-01

    The human brain comprises systems of networks that span the molecular, cellular, anatomic and functional levels. Molecular studies of the developing brain have focused on elucidating networks among gene products that may drive cellular brain development by functioning together in biological pathways. On the other hand, studies of the brain connectome attempt to determine how anatomically distinct brain regions are connected to each other, either anatomically (diffusion tensor imaging) or functionally (functional MRI and EEG), and how they change over development. A global examination of the relationship between gene expression and connectivity in the developing human brain is necessary to understand how the genetic signature of different brain regions instructs connections to other regions. Furthermore, analyzing the development of connectivity networks based on the spatio-temporal dynamics of gene expression provides a new insight into the effect of neurodevelopmental disease genes on brain networks. In this work, we construct connectivity networks between brain regions based on the similarity of their gene expression signature, termed "Genomic Connectivity Networks" (GCNs). Genomic connectivity networks were constructed using data from the BrainSpan Transcriptional Atlas of the Developing Human Brain. Our goal was to understand how the genetic signatures of anatomically distinct brain regions relate to each other across development. We assessed the neurodevelopmental changes in connectivity patterns of brain regions when networks were constructed with genes implicated in the neurodevelopmental disorder autism (autism spectrum disorder; ASD). Using graph theory metrics to characterize the GCNs, we show that ASD-GCNs are relatively less connected later in development with the cerebellum showing a very distinct expression of ASD-associated genes compared to other brain regions.

  6. Analyzing Somatic Genome Rearrangements in Human Cancers by Using Whole-Exome Sequencing | Office of Cancer Genomics

    Science.gov (United States)

    Although exome sequencing data are generated primarily to detect single-nucleotide variants and indels, they can also be used to identify a subset of genomic rearrangements whose breakpoints are located in or near exons. Using >4,600 tumor and normal pairs across 15 cancer types, we identified over 9,000 high confidence somatic rearrangements, including a large number of gene fusions.

  7. Functional annotation of rare gene aberration drivers of pancreatic cancer | Office of Cancer Genomics

    Science.gov (United States)

    As we enter the era of precision medicine, characterization of cancer genomes will directly influence therapeutic decisions in the clinic. Here we describe a platform enabling functionalization of rare gene mutations through their high-throughput construction, molecular barcoding and delivery to cancer models for in vivo tumour driver screens. We apply these technologies to identify oncogenic drivers of pancreatic ductal adenocarcinoma (PDAC).

  8. Fenton reaction induced cancer in wild type rats recapitulates genomic alterations observed in human cancer.

    Directory of Open Access Journals (Sweden)

    Shinya Akatsuka

    Full Text Available Iron overload has been associated with carcinogenesis in humans. Intraperitoneal administration of ferric nitrilotriacetate initiates a Fenton reaction in renal proximal tubules of rodents that ultimately leads to a high incidence of renal cell carcinoma (RCC after repeated treatments. We performed high-resolution microarray comparative genomic hybridization to identify characteristics in the genomic profiles of this oxidative stress-induced rat RCCs. The results revealed extensive large-scale genomic alterations with a preference for deletions. Deletions and amplifications were numerous and sometimes fragmented, demonstrating that a Fenton reaction is a cause of such genomic alterations in vivo. Frequency plotting indicated that two of the most commonly altered loci corresponded to a Cdkn2a/2b deletion and a Met amplification. Tumor sizes were proportionally associated with Met expression and/or amplification, and clustering analysis confirmed our results. Furthermore, we developed a procedure to compare whole genomic patterns of the copy number alterations among different species based on chromosomal syntenic relationship. Patterns of the rat RCCs showed the strongest similarity to the human RCCs among five types of human cancers, followed by human malignant mesothelioma, an iron overload-associated cancer. Therefore, an iron-dependent Fenton chemical reaction causes large-scale genomic alterations during carcinogenesis, which may result in distinct genomic profiles. Based on the characteristics of extensive genome alterations in human cancer, our results suggest that this chemical reaction may play a major role during human carcinogenesis.

  9. Comprehensive genomic profiles of small cell lung cancer

    Science.gov (United States)

    George, Julie; Lim, Jing Shan; Jang, Se Jin; Cun, Yupeng; Ozretić, Luka; Kong, Gu; Leenders, Frauke; Lu, Xin; Fernández-Cuesta, Lynnette; Bosco, Graziella; Müller, Christian; Dahmen, Ilona; Jahchan, Nadine S.; Park, Kwon-Sik; Yang, Dian; Karnezis, Anthony N.; Vaka, Dedeepya; Torres, Angela; Wang, Maia Segura; Korbel, Jan O.; Menon, Roopika; Chun, Sung-Min; Kim, Deokhoon; Wilkerson, Matt; Hayes, Neil; Engelmann, David; Pützer, Brigitte; Bos, Marc; Michels, Sebastian; Vlasic, Ignacija; Seidel, Danila; Pinther, Berit; Schaub, Philipp; Becker, Christian; Altmüller, Janine; Yokota, Jun; Kohno, Takashi; Iwakawa, Reika; Tsuta, Koji; Noguchi, Masayuki; Muley, Thomas; Hoffmann, Hans; Schnabel, Philipp A.; Petersen, Iver; Chen, Yuan; Soltermann, Alex; Tischler, Verena; Choi, Chang-min; Kim, Yong-Hee; Massion, Pierre P.; Zou, Yong; Jovanovic, Dragana; Kontic, Milica; Wright, Gavin M.; Russell, Prudence A.; Solomon, Benjamin; Koch, Ina; Lindner, Michael; Muscarella, Lucia A.; la Torre, Annamaria; Field, John K.; Jakopovic, Marko; Knezevic, Jelena; Castaños-Vélez, Esmeralda; Roz, Luca; Pastorino, Ugo; Brustugun, Odd-Terje; Lund-Iversen, Marius; Thunnissen, Erik; Köhler, Jens; Schuler, Martin; Botling, Johan; Sandelin, Martin; Sanchez-Cespedes, Montserrat; Salvesen, Helga B.; Achter, Viktor; Lang, Ulrich; Bogus, Magdalena; Schneider, Peter M.; Zander, Thomas; Ansén, Sascha; Hallek, Michael; Wolf, Jürgen; Vingron, Martin; Yatabe, Yasushi; Travis, William D.; Nürnberg, Peter; Reinhardt, Christian; Perner, Sven; Heukamp, Lukas; Büttner, Reinhard; Haas, Stefan A.; Brambilla, Elisabeth; Peifer, Martin; Sage, Julien; Thomas, Roman K.

    2016-01-01

    We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer. PMID:26168399

  10. A Genomic Microchip for Oral Cancer.

    Science.gov (United States)

    Sarode, Gargi S; Sarode, Sachin C; Maniyar, Nikunj; Patil, Shankargouda

    2017-03-01

    A series of genetic mutations in somatic cell results in cancer. The cells of malignant tumor have the ability to acclimate to the microenvironmental changes. This can be attributed to the nature of tumor cell biology, i.e., based on effectual molecular signaling events.

  11. Significance of duon mutations in cancer genomes

    Science.gov (United States)

    Yadav, Vinod Kumar; Smith, Kyle S.; Flinders, Colin; Mumenthaler, Shannon M.; de, Subhajyoti

    2016-06-01

    Functional mutations in coding regions not only affect the structure and function of the protein products, but may also modulate their expression in some cases. This class of mutations, recently dubbed “duon mutations” due to their dual roles, can potentially have major impacts on downstream pathways. However their significance in diseases such as cancer remain unclear. In a survey covering 4606 samples from 19 cancer types, and integrating allelic expression, overall mRNA expression, regulatory motif perturbation, and chromatin signatures in one composite index called REDACT score, we identified potential duon mutations. Several such mutations are detected in known cancer genes in multiple cancer types. For instance a potential duon mutation in TP53 is associated with increased expression of the mutant allelic gene copy, thereby possibly amplifying the functional effects on the downstream pathways. Another potential duon mutation in SF3B1 is associated with abnormal splicing and changes in angiogenesis and matrix degradation related pathways. Our findings emphasize the need to interrogate the mutations in coding regions beyond their obvious effects on protein structures.

  12. The Drosophila melanogaster PeptideAtlas facilitates the use of peptide data for improved fly proteomics and genome annotation

    Directory of Open Access Journals (Sweden)

    King Nichole L

    2009-02-01

    Full Text Available Abstract Background Crucial foundations of any quantitative systems biology experiment are correct genome and proteome annotations. Protein databases compiled from high quality empirical protein identifications that are in turn based on correct gene models increase the correctness, sensitivity, and quantitative accuracy of systems biology genome-scale experiments. Results In this manuscript, we present the Drosophila melanogaster PeptideAtlas, a fly proteomics and genomics resource of unsurpassed depth. Based on peptide mass spectrometry data collected in our laboratory the portal http://www.drosophila-peptideatlas.org allows querying fly protein data observed with respect to gene model confirmation and splice site verification as well as for the identification of proteotypic peptides suited for targeted proteomics studies. Additionally, the database provides consensus mass spectra for observed peptides along with qualitative and quantitative information about the number of observations of a particular peptide and the sample(s in which it was observed. Conclusion PeptideAtlas is an open access database for the Drosophila community that has several features and applications that support (1 reduction of the complexity inherently associated with performing targeted proteomic studies, (2 designing and accelerating shotgun proteomics experiments, (3 confirming or questioning gene models, and (4 adjusting gene models such that they are in line with observed Drosophila peptides. While the database consists of proteomic data it is not required that the user is a proteomics expert.

  13. Genomic predictors for treatment of late stage prostate cancer

    Directory of Open Access Journals (Sweden)

    Daniel H Shevrin

    2016-01-01

    Full Text Available In spite of the development of new treatments for late stage prostate cancer, significant challenges persist to match individuals with effective targeted therapies. Genomic classification using high-throughput sequencing technologies has the potential to achieve this goal and make precision medicine a reality in the management of men with castrate-resistant prostate cancer. This chapter reviews some of the most recent studies that have resulted in significant progress in determining the landscape of somatic genomic alterations in this cohort and, more importantly, have provided clinically actionable information that could guide treatment decisions. This chapter reviews the current understanding of common alterations such as alterations of the androgen receptor and PTEN pathway, as well as ETS gene fusions and the growing importance of PARP inhibition. It also reviews recent studies that characterize the evolution to neuroendocrine tumors, which is becoming an increasingly important clinical problem. Finally, this chapter reviews recent innovative studies that characterize the compelling evolutionary history of lethal prostate cancer evidenced by polyclonal seeding and interclonal cooperation between metastasis and the importance of tumor clone dynamics measured serially in response to treatment. The genomic landscape of late stage prostate cancer is becoming better defined, and the prospect for assigning clinically actionable data to inform rationale treatment for individuals with this disease is becoming a reality.

  14. Integrated genomic analysis of breast cancers.

    Science.gov (United States)

    Addou-Klouche, L; Adélaïde, J; Cornen, S; Bekhouche, I; Finetti, P; Guille, A; Sircoulomb, F; Raynaud, S; Bertucci, F; Birnbaum, D; Chaffanet, M

    2012-12-01

    Breast cancer is the most frequent and the most deadly cancer in women in Western countries. Different classifications of disease (anatomoclinical, pathological, prognostic, genetic) are used for guiding the management of patients. Unfortunately, they fail to reflect the whole clinical heterogeneity of the disease. Consequently, molecularly distinct diseases are grouped in similar clinical classes, likely explaining the different clinical outcome between patients in a given class, and the fact that selection of the most appropriate diagnostic or therapeutic strategy for each patient is not done accurately. Today, treatment is efficient in only 70.0-75.0% of cases overall. Our repertoire of efficient drugs is limited but is being expanded with the discovery of new molecular targets for new drugs, based on the identification of candidate oncogenes and tumor suppressor genes (TSG) functionally relevant in disease. Development of new drugs makes therapeutical decisions even more demanding of reliable classifiers and prognostic/predictive tests. Breast cancer is a complex, heterogeneous disease at the molecular level. The combinatorial molecular origin and the heterogeneity of malignant cells, and the variability of the host background, create distinct subgroups of tumors endowed with different phenotypic features such as response to therapy and clinical outcome. Cellular and molecular analyses can identify new classes biologically and clinically relevant, as well as provide new clinically relevant markers and targets. The various stages of mammary tumorigenesis are not clearly defined and the genetic and epigenetic events critical to the development and aggressiveness of breast cancer are not precisely known. Because the phenotype of tumors is dependent on many genes, a large-scale and integrated molecular characterization of the genetic and epigenetic alterations and gene expression deregulation should allow the identification of new molecular classes clinically

  15. 19 July 2013 - Chairman of the Policy Committee, European Cancer Organisation, President, European Association for Cancer Research E. Celis visiting the ATLAS experimental cavern with ATLAS Collaboration Deputy Spokesperson, B. Heinemann and signing the Guest Book with Director for Accelerators and Technology S. Myers. Life Sciences Adviser M. Dosanjh present.

    CERN Multimedia

    Anna Pantelia

    2013-01-01

    19 July 2013 - Chairman of the Policy Committee, European Cancer Organisation, President, European Association for Cancer Research E. Celis visiting the ATLAS experimental cavern with ATLAS Collaboration Deputy Spokesperson, B. Heinemann and signing the Guest Book with Director for Accelerators and Technology S. Myers. Life Sciences Adviser M. Dosanjh present.

  16. Genome Sequence of a Helicobacter pylori Strain Isolated from a Mexican Patient with Intestinal Gastric Cancer

    Science.gov (United States)

    Larios-Serrato, Violeta; Olguín-Ruiz, Gabriela Edith; Sánchez-Vallejo, Carlos Javier; Torres-López, Roberto Carlos; Avilés-Jiménez, Francisco; Camorlinga-Ponce, Margarita

    2014-01-01

    Helicobacter pylori strains are the major risk factor for gastric cancer. Strains vary in their content of disease-associated genes, so genome-wide analysis of cancer-isolated strains will help elucidate their pathogenesis and genetic diversity. We present the draft genome sequence of H. pylori isolated from a Mexican patient with intestinal gastric cancer. PMID:24459275

  17. Genome rearrangement affects RNA virus adaptability on prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Kendra ePesko

    2015-04-01

    Full Text Available Gene order is often highly conserved within taxonomic groups, such that organisms with rearranged genomes tend to be less fit than wildtype gene orders, and suggesting natural selection favors genome architectures that maximize fitness. But it is unclear whether rearranged genomes hinder adaptability: capacity to evolutionarily improve in a new environment. Negative-sense nonsegmented RNA viruses (order Mononegavirales have specific genome architecture: 3′ UTR – core protein genes – envelope protein genes – RNA-dependent RNA-polymerase gene – 5′ UTR. To test how genome architecture affects RNA virus evolution, we examined vesicular stomatitis virus (VSV variants with the nucleocapsid (N gene moved sequentially downstream in the genome. Because RNA polymerase stuttering in VSV replication causes greater mRNA production in upstream genes, N-gene translocation towards the 5’ end leads to stepwise decreases in N transcription, viral replication and progeny production, and also impacts the activation of type 1 interferon mediated antiviral responses. We evolved VSV gene-order variants in two prostate cancer cell lines: LNCap cells deficient in innate immune response to viral infection, and PC3 cells that mount an IFN stimulated anti-viral response to infection. We observed that gene order affects phenotypic adaptability (reproductive growth; viral suppression of immune function, especially on PC3 cells that strongly select against virus infection. Overall, populations derived from the least-fit ancestor (most-altered N position architecture adapted fastest, consistent with theory predicting populations with low initial fitness should improve faster in evolutionary time. Also, we observed correlated responses to selection, where viruses improved across both hosts, rather than suffer fitness trade-offs on unselected hosts. Whole genomics revealed multiple mutations in evolved variants, some of which were conserved across selective

  18. Molecular genetics and genomics progress in urothelial bladder cancer.

    Science.gov (United States)

    Netto, George J

    2013-11-01

    The clinical management of solid tumor patients has recently undergone a paradigm shift as the result of the accelerated advances in cancer genetics and genomics. Molecular diagnostics is now an integral part of routine clinical management in lung, colon, and breast cancer patients. In a disappointing contrast, molecular biomarkers remain largely excluded from current management algorithms of urologic malignancies. The need for new treatment alternatives and validated prognostic molecular biomarkers that can help clinicians identify patients in need of early aggressive management is pressing. Identifying robust predictive biomarkers that can stratify response to newly introduced targeted therapeutics is another crucially needed development. The following is a brief discussion of some promising candidate biomarkers that may soon become a part of clinical management of bladder cancers.

  19. Integrated genomic and epigenomic analysis of breast cancer brain metastasis.

    Directory of Open Access Journals (Sweden)

    Bodour Salhia

    Full Text Available The brain is a common site of metastatic disease in patients with breast cancer, which has few therapeutic options and dismal outcomes. The purpose of our study was to identify common and rare events that underlie breast cancer brain metastasis. We performed deep genomic profiling, which integrated gene copy number, gene expression and DNA methylation datasets on a collection of breast brain metastases. We identified frequent large chromosomal gains in 1q, 5p, 8q, 11q, and 20q and frequent broad-level deletions involving 8p, 17p, 21p and Xq. Frequently amplified and overexpressed genes included ATAD2, BRAF, DERL1, DNMTRB and NEK2A. The ATM, CRYAB and HSPB2 genes were commonly deleted and underexpressed. Knowledge mining revealed enrichment in cell cycle and G2/M transition pathways, which contained AURKA, AURKB and FOXM1. Using the PAM50 breast cancer intrinsic classifier, Luminal B, Her2+/ER negative, and basal-like tumors were identified as the most commonly represented breast cancer subtypes in our brain metastasis cohort. While overall methylation levels were increased in breast cancer brain metastasis, basal-like brain metastases were associated with significantly lower levels of methylation. Integrating DNA methylation data with gene expression revealed defects in cell migration and adhesion due to hypermethylation and downregulation of PENK, EDN3, and ITGAM. Hypomethylation and upregulation of KRT8 likely affects adhesion and permeability. Genomic and epigenomic profiling of breast brain metastasis has provided insight into the somatic events underlying this disease, which have potential in forming the basis of future therapeutic strategies.

  20. Integrated genomic and epigenomic analysis of breast cancer brain metastasis.

    Science.gov (United States)

    Salhia, Bodour; Kiefer, Jeff; Ross, Julianna T D; Metapally, Raghu; Martinez, Rae Anne; Johnson, Kyle N; DiPerna, Danielle M; Paquette, Kimberly M; Jung, Sungwon; Nasser, Sara; Wallstrom, Garrick; Tembe, Waibhav; Baker, Angela; Carpten, John; Resau, Jim; Ryken, Timothy; Sibenaller, Zita; Petricoin, Emanuel F; Liotta, Lance A; Ramanathan, Ramesh K; Berens, Michael E; Tran, Nhan L

    2014-01-01

    The brain is a common site of metastatic disease in patients with breast cancer, which has few therapeutic options and dismal outcomes. The purpose of our study was to identify common and rare events that underlie breast cancer brain metastasis. We performed deep genomic profiling, which integrated gene copy number, gene expression and DNA methylation datasets on a collection of breast brain metastases. We identified frequent large chromosomal gains in 1q, 5p, 8q, 11q, and 20q and frequent broad-level deletions involving 8p, 17p, 21p and Xq. Frequently amplified and overexpressed genes included ATAD2, BRAF, DERL1, DNMTRB and NEK2A. The ATM, CRYAB and HSPB2 genes were commonly deleted and underexpressed. Knowledge mining revealed enrichment in cell cycle and G2/M transition pathways, which contained AURKA, AURKB and FOXM1. Using the PAM50 breast cancer intrinsic classifier, Luminal B, Her2+/ER negative, and basal-like tumors were identified as the most commonly represented breast cancer subtypes in our brain metastasis cohort. While overall methylation levels were increased in breast cancer brain metastasis, basal-like brain metastases were associated with significantly lower levels of methylation. Integrating DNA methylation data with gene expression revealed defects in cell migration and adhesion due to hypermethylation and downregulation of PENK, EDN3, and ITGAM. Hypomethylation and upregulation of KRT8 likely affects adhesion and permeability. Genomic and epigenomic profiling of breast brain metastasis has provided insight into the somatic events underlying this disease, which have potential in forming the basis of future therapeutic strategies.

  1. Cancer and aging: The importance of telomeres in genome maintenance

    Energy Technology Data Exchange (ETDEWEB)

    Rodier, Francis; Kim, Sahn-ho; Nijjar, Tarlochan; Yaswen, Paul; Campisi, Judith

    2004-10-01

    Telomeres are the specialized DNA-protein structures that cap the ends of linear chromosomes, thereby protecting them from degradation and fusion by cellular DNA repair processes. In vertebrate cells, telomeres consist of several kilobase pairs of DNA having the sequence TTAGGG, a few hundred base pairs of single-stranded DNA at the 3' end of the telomeric DNA tract, and a host of proteins that organize the telomeric double and single stranded DNA into a protective structure. Functional telomeres are essential for maintaining the integrity and stability of genomes. When combined with loss of cell cycle checkpoint controls, telomere dysfunction can lead to genomic instability, a common cause and hallmark of cancer. Consequently, normal mammalian cells respond to dysfunctional telomeres by undergoing apoptosis (programmed cell death) or cellular senescence (permanent cell cycle arrest), two cellular tumor suppressor mechanisms. These tumor suppressor mechanisms are potent suppressors of cancer, but recent evidence suggests that they can antagonistically also contribute to aging phenotypes. Here, we review what is known about the structure and function of telomeres in mammalian cells, particularly human cells, and how telomere dysfunction may arise and contribute to cancer and aging phenotypes.

  2. Proteomics Data on UCSC Genome Browser - Office of Cancer Clinical Proteomics Research

    Science.gov (United States)

    The National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium scientists are working together with the University of California, Santa Cruz (UCSC) Genomics Institute to provide public access to cancer proteomics data.

  3. CGCI Investigators Reveal Comprehensive Landscape of Diffuse Large B-Cell Lymphoma (DLBCL) Genomes | Office of Cancer Genomics

    Science.gov (United States)

    Researchers from British Columbia Cancer Agency used whole genome sequencing to analyze 40 DLBCL cases and 13 cell lines in order to fill in the gaps of the complex landscape of DLBCL genomes. Their analysis, “Mutational and structural analysis of diffuse large B-cell lymphoma using whole genome sequencing,” was published online in Blood on May 22. The authors are Ryan Morin, Marco Marra, and colleagues.  

  4. Pattern Analysis and Decision Support for Cancer through Clinico-Genomic Profiles

    Science.gov (United States)

    Exarchos, Themis P.; Giannakeas, Nikolaos; Goletsis, Yorgos; Papaloukas, Costas; Fotiadis, Dimitrios I.

    Advances in genome technology are playing a growing role in medicine and healthcare. With the development of new technologies and opportunities for large-scale analysis of the genome, genomic data have a clear impact on medicine. Cancer prognostics and therapeutics are among the first major test cases for genomic medicine, given that all types of cancer are related with genomic instability. In this paper we present a novel system for pattern analysis and decision support in cancer. The system integrates clinical data from electronic health records and genomic data. Pattern analysis and data mining methods are applied to these integrated data and the discovered knowledge is used for cancer decision support. Through this integration, conclusions can be drawn for early diagnosis, staging and cancer treatment.

  5. Genome profiling of ERBB2-amplified breast cancers

    Directory of Open Access Journals (Sweden)

    Ayed Farhat

    2010-10-01

    Full Text Available Abstract Background Around 20% of breast cancers (BC show ERBB2 gene amplification and overexpression of the ERBB2 tyrosine kinase receptor. They are associated with a poor prognosis but can benefit from targeted therapy. A better knowledge of these BCs, genomically and biologically heterogeneous, may help understand their behavior and design new therapeutic strategies. Methods We defined the high resolution genome and gene expression profiles of 54 ERBB2-amplified BCs using 244K oligonucleotide array-comparative genomic hybridization and whole-genome DNA microarrays. Expression of ERBB2, phosphorylated ERBB2, EGFR, IGF1R and FOXA1 proteins was assessed by immunohistochemistry to evaluate the functional ERBB2 status and identify co-expressions. Results First, we identified the ERBB2-C17orf37-GRB7 genomic segment as the minimal common 17q12-q21 amplicon, and CRKRS and IKZF3 as the most frequent centromeric and telomeric amplicon borders, respectively. Second, GISTIC analysis identified 17 other genome regions affected by copy number aberration (CNA (amplifications, gains, losses. The expression of 37 genes of these regions was deregulated. Third, two types of heterogeneity were observed in ERBB2-amplified BCs. The genomic profiles of estrogen receptor-postive (ER+ and negative (ER- ERBB2-amplified BCs were different. The WNT/β-catenin signaling pathway was involved in ER- ERBB2-amplified BCs, and PVT1 and TRPS1 were candidate oncogenes associated with ER+ ERBB2-amplified BCs. The size of the ERBB2 amplicon was different in inflammatory (IBC and non-inflammatory BCs. ERBB2-amplified IBCs were characterized by the downregulated and upregulated mRNA expression of ten and two genes in proportion to CNA, respectively. IHC results showed (i a linear relationship between ERBB2 gene amplification and its gene and protein expressions with a good correlation between ERBB2 expression and phosphorylation status; (ii a potential signaling cross-talk between

  6. Cancer models, genomic instability and somatic cellular Darwinian evolution

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    Little Mark P

    2010-04-01

    Full Text Available Abstract The biology of cancer is critically reviewed and evidence adduced that its development can be modelled as a somatic cellular Darwinian evolutionary process. The evidence for involvement of genomic instability (GI is also reviewed. A variety of quasi-mechanistic models of carcinogenesis are reviewed, all based on this somatic Darwinian evolutionary hypothesis; in particular, the multi-stage model of Armitage and Doll (Br. J. Cancer 1954:8;1-12, the two-mutation model of Moolgavkar, Venzon, and Knudson (MVK (Math. Biosci. 1979:47;55-77, the generalized MVK model of Little (Biometrics 1995:51;1278-1291 and various generalizations of these incorporating effects of GI (Little and Wright Math. Biosci. 2003:183;111-134; Little et al. J. Theoret. Biol. 2008:254;229-238. Reviewers This article was reviewed by RA Gatenby and M Kimmel.

  7. Biology of breast cancer during pregnancy using genomic profiling.

    Science.gov (United States)

    Azim, Hatem A; Brohée, Sylvain; Peccatori, Fedro A; Desmedt, Christine; Loi, Sherene; Lambrechts, Diether; Dell'Orto, Patrizia; Majjaj, Samira; Jose, Vinu; Rotmensz, Nicole; Ignatiadis, Michail; Pruneri, Giancarlo; Piccart, Martine; Viale, Giuseppe; Sotiriou, Christos

    2014-08-01

    Breast cancer during pregnancy is rare and is associated with relatively poor prognosis. No information is available on its biological features at the genomic level. Using a dataset of 54 pregnant and 113 non-pregnant breast cancer patients, we evaluated the pattern of hot spot somatic mutations and did transcriptomic profiling using Sequenom and Affymetrix respectively. We performed gene set enrichment analysis to evaluate the pathways associated with diagnosis during pregnancy. We also evaluated the expression of selected cancer-related genes in pregnant and non-pregnant patients and correlated the results with changes occurring in the normal breast using a pregnant murine model. We finally investigated aberrations associated with disease-free survival (DFS). No significant differences in mutations were observed. Of the total number of patients, 18.6% of pregnant and 23% of non-pregnant patients had a PIK3CA mutation. Around 30% of tumors were basal, with no differences in the distribution of breast cancer molecular subtypes between pregnant and non-pregnant patients. Two pathways were enriched in tumors diagnosed during pregnancy: the G protein-coupled receptor pathway and the serotonin receptor pathway (FDR pregnancy had higher expression of PD1 (PDCD1; P=0.015), PDL1 (CD274; P=0.014), and gene sets related to SRC (P=0.004), IGF1 (P=0.032), and β-catenin (P=0.019). Their expression increased almost linearly throughout gestation when evaluated on the normal breast using a pregnant mouse model underscoring the potential effect of the breast microenvironment on tumor phenotype. No genes were associated with DFS in a multivariate model, which could be due to low statistical power. Diagnosis during pregnancy impacts the breast cancer transcriptome including potential cancer targets.

  8. Whole genomes redefine the mutational landscape of pancreatic cancer

    Science.gov (United States)

    Waddell, Nicola; Pajic, Marina; Patch, Ann-Marie; Chang, David K.; Kassahn, Karin S.; Bailey, Peter; Johns, Amber L.; Miller, David; Nones, Katia; Quek, Kelly; Quinn, Michael C. J.; Robertson, Alan J.; Fadlullah, Muhammad Z. H.; Bruxner, Tim J. C.; Christ, Angelika N.; Harliwong, Ivon; Idrisoglu, Senel; Manning, Suzanne; Nourse, Craig; Nourbakhsh, Ehsan; Wani, Shivangi; Wilson, Peter J; Markham, Emma; Cloonan, Nicole; Anderson, Matthew J.; Fink, J. Lynn; Holmes, Oliver; Kazakoff, Stephen H.; Leonard, Conrad; Newell, Felicity; Poudel, Barsha; Song, Sarah; Taylor, Darrin; Waddell, Nick; Wood, Scott; Xu, Qinying; Wu, Jianmin; Pinese, Mark; Cowley, Mark J.; Lee, Hong C.; Jones, Marc D.; Nagrial, Adnan M.; Humphris, Jeremy; Chantrill, Lorraine A.; Chin, Venessa; Steinmann, Angela M.; Mawson, Amanda; Humphrey, Emily S.; Colvin, Emily K.; Chou, Angela; Scarlett, Christopher J.; Pinho, Andreia V.; Giry-Laterriere, Marc; Rooman, Ilse; Samra, Jaswinder S.; Kench, James G.; Pettitt, Jessica A.; Merrett, Neil D.; Toon, Christopher; Epari, Krishna; Nguyen, Nam Q.; Barbour, Andrew; Zeps, Nikolajs; Jamieson, Nigel B.; Graham, Janet S.; Niclou, Simone P.; Bjerkvig, Rolf; Grützmann, Robert; Aust, Daniela; Hruban, Ralph H.; Maitra, Anirban; Iacobuzio-Donahue, Christine A.; Wolfgang, Christopher L.; Morgan, Richard A.; Lawlor, Rita T.; Corbo, Vincenzo; Bassi, Claudio; Falconi, Massimo; Zamboni, Giuseppe; Tortora, Giampaolo; Tempero, Margaret A.; Gill, Anthony J.; Eshleman, James R.; Pilarsky, Christian; Scarpa, Aldo; Musgrove, Elizabeth A.; Pearson, John V.; Biankin, Andrew V.; Grimmond, Sean M.

    2015-01-01

    Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded. PMID:25719666

  9. Global copy number profiling of cancer genomes | Office of Cancer Genomics

    Science.gov (United States)

    In this article, we introduce a robust and efficient strategy for deriving global and allele-specific copy number alternations (CNA) from cancer whole exome sequencing data based on Log R ratios and B-allele frequencies. Applying the approach to the analysis of over 200 skin cancer samples, we demonstrate its utility for discovering distinct CNA events and for deriving ancillary information such as tumor purity. Availability and implementation: https://github.com/xfwang/CLOSE CONTACT: xuefeng.wang@stonybrook.edu or michael.krauthammer@yale.edu. (Publication Abstract)

  10. Atlas of Cancer Signalling Network: a systems biology resource for integrative analysis of cancer data with Google Maps.

    Science.gov (United States)

    Kuperstein, I; Bonnet, E; Nguyen, H-A; Cohen, D; Viara, E; Grieco, L; Fourquet, S; Calzone, L; Russo, C; Kondratova, M; Dutreix, M; Barillot, E; Zinovyev, A

    2015-01-01

    Cancerogenesis is driven by mutations leading to aberrant functioning of a complex network of molecular interactions and simultaneously affecting multiple cellular functions. Therefore, the successful application of bioinformatics and systems biology methods for analysis of high-throughput data in cancer research heavily depends on availability of global and detailed reconstructions of signalling networks amenable for computational analysis. We present here the Atlas of Cancer Signalling Network (ACSN), an interactive and comprehensive map of molecular mechanisms implicated in cancer. The resource includes tools for map navigation, visualization and analysis of molecular data in the context of signalling network maps. Constructing and updating ACSN involves careful manual curation of molecular biology literature and participation of experts in the corresponding fields. The cancer-oriented content of ACSN is completely original and covers major mechanisms involved in cancer progression, including DNA repair, cell survival, apoptosis, cell cycle, EMT and cell motility. Cell signalling mechanisms are depicted in detail, together creating a seamless 'geographic-like' map of molecular interactions frequently deregulated in cancer. The map is browsable using NaviCell web interface using the Google Maps engine and semantic zooming principle. The associated web-blog provides a forum for commenting and curating the ACSN content. ACSN allows uploading heterogeneous omics data from users on top of the maps for visualization and performing functional analyses. We suggest several scenarios for ACSN application in cancer research, particularly for visualizing high-throughput data, starting from small interfering RNA-based screening results or mutation frequencies to innovative ways of exploring transcriptomes and phosphoproteomes. Integration and analysis of these data in the context of ACSN may help interpret their biological significance and formulate mechanistic hypotheses

  11. [The application of CRISPR/Cas9 genome editing technology in cancer research].

    Science.gov (United States)

    Wang, Dayong; Ma, Ning; Hui, Yang; Gao, Xu

    2016-01-01

    The CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein-9 nuclease) genome editing technology has become more and more popular in gene editing because of its simple design and easy operation. Using the CRISPR/Cas9 system, researchers can perform site-directed genome modification at the base level. Moreover, it has been widely used in genome editing in multiple species and related cancer research. In this review, we summarize the application of the CRISPR/Cas9 system in cancer research based on the latest research progresses as well as our understanding of cancer research and genome editing techniques.

  12. FoldAtlas: a repository for genome-wide RNA structure probing data

    Science.gov (United States)

    Norris, Matthew; Kwok, Chun Kit; Cheema, Jitender; Hartley, Matthew; Morris, Richard J.; Aviran, Sharon; Ding, Yiliang

    2017-01-01

    Summary: Most RNA molecules form internal base pairs, leading to a folded secondary structure. Some of these structures have been demonstrated to be functionally significant. High-throughput RNA structure chemical probing methods generate millions of sequencing reads to provide structural constraints for RNA secondary structure prediction. At present, processed data from these experiments are difficult to access without computational expertise. Here we present FoldAtlas, a web interface for accessing raw and processed structural data across thousands of transcripts. FoldAtlas allows a researcher to easily locate, view, and retrieve probing data for a given RNA molecule. We also provide in silico and in vivo secondary structure predictions for comparison, visualized in the browser as circle plots and topology diagrams. Data currently integrated into FoldAtlas are from a new high-depth Structure-seq data analysis in Arabidopsis thaliana, released with this work. Availability and Implementation: The FoldAtlas website can be accessed at www.foldatlas.com. Source code is freely available at github.com/mnori/foldatlas under the MIT license. Raw reads data are available under the NCBI SRA accession SRP066985. Contact: yiliang.ding@jic.ac.uk or matthew.norris@jic.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27663500

  13. Australasian Gastrointestinal Trials Group (AGITG) Contouring Atlas and Planning Guidelines for Intensity-Modulated Radiotherapy in Anal Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Ng, Michael, E-mail: mng@radoncvic.com.au [Radiation Oncology Victoria, Victoria (Australia); Leong, Trevor [Department of Radiation Oncology, Peter MacCallum Cancer Centre, Victoria (Australia); University of Melbourne (Australia); Chander, Sarat; Chu, Julie [Department of Radiation Oncology, Peter MacCallum Cancer Centre, Victoria (Australia); Kneebone, Andrew [Department of Radiation Oncology, Northern Sydney Cancer Centre, Royal North Shore Hospital, NSW (Australia); University of Sydney (Australia); Carroll, Susan [Department of Radiation Oncology, Sydney Cancer Centre, Royal Prince Alfred Hospital, NSW (Australia); University of Sydney (Australia); Wiltshire, Kirsty [Department of Radiation Oncology, Peter MacCallum Cancer Centre, Victoria (Australia); Ngan, Samuel [Department of Radiation Oncology, Peter MacCallum Cancer Centre, Victoria (Australia); University of Melbourne (Australia); Kachnic, Lisa [Department of Radiation Oncology, Boston Medical Center, Boston University School of Medicine, Boston, MA (United States)

    2012-08-01

    Purpose: To develop a high-resolution target volume atlas with intensity-modulated radiotherapy (IMRT) planning guidelines for the conformal treatment of anal cancer. Methods and Materials: A draft contouring atlas and planning guidelines for anal cancer IMRT were prepared at the Australasian Gastrointestinal Trials Group (AGITG) annual meeting in September 2010. An expert panel of radiation oncologists contoured an anal cancer case to generate discussion on recommendations regarding target definition for gross disease, elective nodal volumes, and organs at risk (OARs). Clinical target volume (CTV) and planning target volume (PTV) margins, dose fractionation, and other IMRT-specific issues were also addressed. A steering committee produced the final consensus guidelines. Results: Detailed contouring and planning guidelines and a high-resolution atlas are provided. Gross tumor and elective target volumes are described and pictorially depicted. All elective regions should be routinely contoured for all disease stages, with the possible exception of the inguinal and high pelvic nodes for select, early-stage T1N0. A 20-mm CTV margin for the primary, 10- to 20-mm CTV margin for involved nodes and a 7-mm CTV margin for the elective pelvic nodal groups are recommended, while respecting anatomical boundaries. A 5- to 10-mm PTV margin is suggested. When using a simultaneous integrated boost technique, a dose of 54 Gy in 30 fractions to gross disease and 45 Gy to elective nodes with chemotherapy is appropriate. Guidelines are provided for OAR delineation. Conclusion: These consensus planning guidelines and high-resolution atlas complement the existing Radiation Therapy Oncology Group (RTOG) elective nodal ano-rectal atlas and provide additional anatomic, clinical, and technical instructions to guide radiation oncologists in the planning and delivery of IMRT for anal cancer.

  14. Using large-scale genome variation cohorts to decipher the molecular mechanism of cancer.

    Science.gov (United States)

    Habermann, Nina; Mardin, Balca R; Yakneen, Sergei; Korbel, Jan O

    2016-01-01

    Characterizing genomic structural variations (SVs) in the human genome remains challenging, and there is a growing interest to understand somatic SVs occurring in cancer, a disease of the genome. A havoc-causing SV process known as chromothripsis scars the genome when localized chromosome shattering and repair occur in a one-off catastrophe. Recent efforts led to the development of a set of conceptual criteria for the inference of chromothripsis events in cancer genomes and to the development of experimental model systems for studying this striking DNA alteration process in vitro. We discuss these approaches, and additionally touch upon current "Big Data" efforts that employ hybrid cloud computing to enable studies of numerous cancer genomes in an effort to search for commonalities and differences in molecular DNA alteration processes in cancer.

  15. Implementing an online tool for genome-wide validation of survival-associated biomarkers in ovarian-cancer using microarray data from 1287 patients

    DEFF Research Database (Denmark)

    Győrffy, Balázs; Lánczky, András; Szállási, Zoltán

    2012-01-01

    was set up using gene expression data and survival information of 1287 ovarian cancer patients downloaded from Gene Expression Omnibus and The Cancer Genome Atlas (Affymetrix HG-U133A, HG-U133A 2.0, and HG-U133 Plus 2.0 microarrays). After quality control and normalization, only probes present on all......). A Kaplan–Meier survival plot was generated and significance was computed. The tool can be accessed online at www.kmplot.com/ovar. We used this integrative data analysis tool to validate the prognostic power of 37 biomarkers identified in the literature. Of these, CA125 (MUC16; P=3.7x10–5, hazard ratio (HR...

  16. The Impact of dUTPase on Ribonucleotide Reductase-Induced Genome Instability in Cancer Cells

    Directory of Open Access Journals (Sweden)

    Chih-Wei Chen

    2016-08-01

    Full Text Available The appropriate supply of dNTPs is critical for cell growth and genome integrity. Here, we investigated the interrelationship between dUTP pyrophosphatase (dUTPase and ribonucleotide reductase (RNR in the regulation of genome stability. Our results demonstrate that reducing the expression of dUTPase increases genome stress in cancer. Analysis of clinical samples reveals a significant correlation between the combination of low dUTPase and high R2, a subunit of RNR, and a poor prognosis in colorectal and breast cancer patients. Furthermore, overexpression of R2 in non-tumorigenic cells progressively increases genome stress, promoting transformation. These cells display alterations in replication fork progression, elevated genomic uracil, and breaks at AT-rich common fragile sites. Consistently, overexpression of dUTPase abolishes R2-induced genome instability. Thus, the expression level of dUTPase determines the role of high R2 in driving genome instability in cancer cells.

  17. Systematic Functional Interrogation of Rare Cancer Variants Identifies Oncogenic Alleles | Office of Cancer Genomics

    Science.gov (United States)

    Cancer genome characterization efforts now provide an initial view of the somatic alterations in primary tumors. However, most point mutations occur at low frequency, and the function of these alleles remains undefined. We have developed a scalable systematic approach to interrogate the function of cancer-associated gene variants. We subjected 474 mutant alleles curated from 5,338 tumors to pooled in vivo tumor formation assays and gene expression profiling. We identified 12 transforming alleles, including two in genes (PIK3CB, POT1) that have not been shown to be tumorigenic.

  18. The Broad Institute: Screening for Dependencies in Cancer Cell Lines Using Small Molecules | Office of Cancer Genomics

    Science.gov (United States)

    Using cancer cell-line profiling, we established an ongoing resource to identify, as comprehensively as possible, the drug-targetable dependencies that specific genomic alterations impart on human cancers. We measured the sensitivity of hundreds of genetically characterized cancer cell lines to hundreds of small-molecule probes and drugs that have highly selective interactions with their targets, and that collectively modulate many distinct nodes in cancer cell circuitry.

  19. Genome-wide association analysis identifies three new breast cancer susceptibility loci

    DEFF Research Database (Denmark)

    Ghoussaini, Maya; Fletcher, Olivia; Michailidou, Kyriaki

    2012-01-01

    Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ...

  20. Genome-wide association analysis identifies three new breast cancer susceptibility loci

    NARCIS (Netherlands)

    Ghoussaini, M.; Fletcher, O.; Michailidou, K.; Turnbull, C.; Schmidt, M.K.; Dicks, E.; Dennis, J.; Wang, Q.; Humphreys, M.K.; Luccarini, C.; Baynes, C.; Conroy, D.; Maranian, M.; Ahmed, S.; Driver, K.; Johnson, N.; Orr, N.; dos Santos Silva, I.; Waisfisz, Q.; Meijers-Heijboer, H.; Uitterlinden, A.G.; Rivadeneira, F.; Hall, P.; Czene, K.; Irwanto, A.; Liu, J.; Nevanlinna, H.; Aittomaki, K.; Blomqvist, C.; Meindl, A.; Schmutzler, R.K.; Muller-Myhsok, B.; Lichtner, P.; Chang-Claude, J.; Hein, R.; Nickels, S.; Flesch-Janys, D.; Tsimiklis, H.; Makalic, E.; Schmidt, D.; Bui, M.; Hopper, J.L.; Apicella, C.; Park, D.J.; Southey, M.; Hunter, D.J.; Chanock, S.J.; Broeks, A.; Verhoef, S.; Hogervorst, F.B.; Fasching, P.A.; Lux, M.P.; Beckmann, M.W.; Ekici, A.B.; Sawyer, E.; Tomlinson, I.; Kerin, M.; Marme, F.; Schneeweiss, A.; Sohn, C.; Burwinkel, B.; Guenel, P.; Truong, T.; Cordina-Duverger, E.; Menegaux, F.; Bojesen, S.E.; Nordestgaard, B.G.; Nielsen, S.F.; Flyger, H.; Milne, R.L.; Alonso, M.R.; Gonzalez-Neira, A.; Benitez, J.; Anton-Culver, H.; Ziogas, A.; Bernstein, L.; Dur, C.C.; Brenner, H.; Muller, H.; Arndt, V.; Stegmaier, C.; Justenhoven, C.; Brauch, H.; Bruning, T.; Wang-Gohrke, S.; Eilber, U.; Dork, T.; Schurmann, P.; Bremer, M.; Hillemanns, P.; Bogdanova, N.V.; Antonenkova, N.N.; Rogov, Y.I.; Karstens, J.H.; Bermisheva, M.; Prokofieva, D.; Ligtenberg, M.J.

    2012-01-01

    Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for approximately 8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies

  1. Genome-wide association study identifies new prostate cancer susceptibility loci

    DEFF Research Database (Denmark)

    Schumacher, Fredrick R.; Berndt, Sonja I.; Siddiq, Afshan

    2011-01-01

    Prostate cancer (PrCa) is the most common non-skin cancer diagnosed among males in developed countries and the second leading cause of cancer mortality, yet little is known regarding its etiology and factors that influence clinical outcome. Genome-wide association studies (GWAS) of PrCa have iden...

  2. Pan-cancer analysis of genomic scar signatures associated with homologous recombination deficiency suggests novel indications for existing cancer drugs

    DEFF Research Database (Denmark)

    Marquard, Andrea Marion; Eklund, Aron Charles; Joshi, Tejal

    2015-01-01

    Ovarian and triple-negative breast cancers with BRCA1 or BRCA2 loss are highly sensitive to treatment with PARP inhibitors and platinum-based cytotoxic agents and show an accumulation of genomic scars in the form of gross DNA copy number aberrations. Cancers without BRCA1 or BRCA2 loss but with a......Ovarian and triple-negative breast cancers with BRCA1 or BRCA2 loss are highly sensitive to treatment with PARP inhibitors and platinum-based cytotoxic agents and show an accumulation of genomic scars in the form of gross DNA copy number aberrations. Cancers without BRCA1 or BRCA2 loss...

  3. Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer

    Science.gov (United States)

    Morrison, Carl D.; Liu, Pengyuan; Woloszynska-Read, Anna; Zhang, Jianmin; Luo, Wei; Qin, Maochun; Bshara, Wiam; Conroy, Jeffrey M.; Sabatini, Linda; Vedell, Peter; Xiong, Donghai; Liu, Song; Wang, Jianmin; Shen, He; Li, Yinwei; Omilian, Angela R.; Hill, Annette; Head, Karen; Guru, Khurshid; Kunnev, Dimiter; Leach, Robert; Eng, Kevin H.; Darlak, Christopher; Hoeflich, Christopher; Veeranki, Srividya; Glenn, Sean; You, Ming; Pruitt, Steven C.; Johnson, Candace S.; Trump, Donald L.

    2014-01-01

    Using complete genome analysis, we sequenced five bladder tumors accrued from patients with muscle-invasive transitional cell carcinoma of the urinary bladder (TCC-UB) and identified a spectrum of genomic aberrations. In three tumors, complex genotype changes were noted. All three had tumor protein p53 mutations and a relatively large number of single-nucleotide variants (SNVs; average of 11.2 per megabase), structural variants (SVs; average of 46), or both. This group was best characterized by chromothripsis and the presence of subclonal populations of neoplastic cells or intratumoral mutational heterogeneity. Here, we provide evidence that the process of chromothripsis in TCC-UB is mediated by nonhomologous end-joining using kilobase, rather than megabase, fragments of DNA, which we refer to as “stitchers,” to repair this process. We postulate that a potential unifying theme among tumors with the more complex genotype group is a defective replication–licensing complex. A second group (two bladder tumors) had no chromothripsis, and a simpler genotype, WT tumor protein p53, had relatively few SNVs (average of 5.9 per megabase) and only a single SV. There was no evidence of a subclonal population of neoplastic cells. In this group, we used a preclinical model of bladder carcinoma cell lines to study a unique SV (translocation and amplification) of the gene glutamate receptor ionotropic N-methyl D-aspertate as a potential new therapeutic target in bladder cancer. PMID:24469795

  4. An Integrative Pathway-based Clinical-genomic Model for Cancer Survival Prediction.

    Science.gov (United States)

    Chen, Xi; Wang, Lily; Ishwaran, Hemant

    2010-09-01

    Prediction models that use gene expression levels are now being proposed for personalized treatment of cancer, but building accurate models that are easy to interpret remains a challenge. In this paper, we describe an integrative clinical-genomic approach that combines both genomic pathway and clinical information. First, we summarize information from genes in each pathway using Supervised Principal Components (SPCA) to obtain pathway-based genomic predictors. Next, we build a prediction model based on clinical variables and pathway-based genomic predictors using Random Survival Forests (RSF). Our rationale for this two-stage procedure is that the underlying disease process may be influenced by environmental exposure (measured by clinical variables) and perturbations in different pathways (measured by pathway-based genomic variables), as well as their interactions. Using two cancer microarray datasets, we show that the pathway-based clinical-genomic model outperforms gene-based clinical-genomic models, with improved prediction accuracy and interpretability.

  5. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

    Science.gov (United States)

    Biankin, Andrew V; Waddell, Nicola; Kassahn, Karin S; Gingras, Marie-Claude; Muthuswamy, Lakshmi B; Johns, Amber L; Miller, David K; Wilson, Peter J; Patch, Ann-Marie; Wu, Jianmin; Chang, David K; Cowley, Mark J; Gardiner, Brooke B; Song, Sarah; Harliwong, Ivon; Idrisoglu, Senel; Nourse, Craig; Nourbakhsh, Ehsan; Manning, Suzanne; Wani, Shivangi; Gongora, Milena; Pajic, Marina; Scarlett, Christopher J; Gill, Anthony J; Pinho, Andreia V; Rooman, Ilse; Anderson, Matthew; Holmes, Oliver; Leonard, Conrad; Taylor, Darrin; Wood, Scott; Xu, Qinying; Nones, Katia; Fink, J Lynn; Christ, Angelika; Bruxner, Tim; Cloonan, Nicole; Kolle, Gabriel; Newell, Felicity; Pinese, Mark; Mead, R Scott; Humphris, Jeremy L; Kaplan, Warren; Jones, Marc D; Colvin, Emily K; Nagrial, Adnan M; Humphrey, Emily S; Chou, Angela; Chin, Venessa T; Chantrill, Lorraine A; Mawson, Amanda; Samra, Jaswinder S; Kench, James G; Lovell, Jessica A; Daly, Roger J; Merrett, Neil D; Toon, Christopher; Epari, Krishna; Nguyen, Nam Q; Barbour, Andrew; Zeps, Nikolajs; Kakkar, Nipun; Zhao, Fengmei; Wu, Yuan Qing; Wang, Min; Muzny, Donna M; Fisher, William E; Brunicardi, F Charles; Hodges, Sally E; Reid, Jeffrey G; Drummond, Jennifer; Chang, Kyle; Han, Yi; Lewis, Lora R; Dinh, Huyen; Buhay, Christian J; Beck, Timothy; Timms, Lee; Sam, Michelle; Begley, Kimberly; Brown, Andrew; Pai, Deepa; Panchal, Ami; Buchner, Nicholas; De Borja, Richard; Denroche, Robert E; Yung, Christina K; Serra, Stefano; Onetto, Nicole; Mukhopadhyay, Debabrata; Tsao, Ming-Sound; Shaw, Patricia A; Petersen, Gloria M; Gallinger, Steven; Hruban, Ralph H; Maitra, Anirban; Iacobuzio-Donahue, Christine A; Schulick, Richard D; Wolfgang, Christopher L; Morgan, Richard A; Lawlor, Rita T; Capelli, Paola; Corbo, Vincenzo; Scardoni, Maria; Tortora, Giampaolo; Tempero, Margaret A; Mann, Karen M; Jenkins, Nancy A; Perez-Mancera, Pedro A; Adams, David J; Largaespada, David A; Wessels, Lodewyk F A; Rust, Alistair G; Stein, Lincoln D; Tuveson, David A; Copeland, Neal G; Musgrove, Elizabeth A; Scarpa, Aldo; Eshleman, James R; Hudson, Thomas J; Sutherland, Robert L; Wheeler, David A; Pearson, John V; McPherson, John D; Gibbs, Richard A; Grimmond, Sean M

    2012-11-15

    Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

  6. Genomic Copy Number Dictates a Gene-Independent Cell Response to CRISPR/Cas9 Targeting | Office of Cancer Genomics

    Science.gov (United States)

    The CRISPR/Cas9 system enables genome editing and somatic cell genetic screens in mammalian cells. We performed genome-scale loss-of-function screens in 33 cancer cell lines to identify genes essential for proliferation/survival and found a strong correlation between increased gene copy number and decreased cell viability after genome editing. Within regions of copy-number gain, CRISPR/Cas9 targeting of both expressed and unexpressed genes, as well as intergenic loci, led to significantly decreased cell proliferation through induction of a G2 cell-cycle arrest.

  7. Genetic basis of kidney cancer: role of genomics for the development of disease-based therapeutics.

    Science.gov (United States)

    Linehan, W Marston

    2012-11-01

    Kidney cancer is not a single disease; it is made up of a number of different types of cancer, including clear cell, type 1 papillary, type 2 papillary, chromophobe, TFE3, TFEB, and oncocytoma. Sporadic, nonfamilial kidney cancer includes clear cell kidney cancer (75%), type 1 papillary kidney cancer (10%), papillary type 2 kidney cancer (including collecting duct and medullary RCC) (5%), the microphalmia-associated transcription (MiT) family translocation kidney cancers (TFE3, TFEB, and MITF), chromophobe kidney cancer (5%), and oncocytoma (5%). Each has a distinct histology, a different clinical course, responds differently to therapy, and is caused by mutation in a different gene. Genomic studies identifying the genes for kidney cancer, including the VHL, MET, FLCN, fumarate hydratase, succinate dehydrogenase, TSC1, TSC2, and TFE3 genes, have significantly altered the ways in which patients with kidney cancer are managed. While seven FDA-approved agents that target the VHL pathway have been approved for the treatment of patients with advanced kidney cancer, further genomic studies, such as whole genome sequencing, gene expression patterns, and gene copy number, will be required to gain a complete understanding of the genetic basis of kidney cancer and of the kidney cancer gene pathways and, most importantly, to provide the foundation for the development of effective forms of therapy for patients with this disease.

  8. Ectopic Expression of Testis Germ Cell Proteins in Cancer and Its Potential Role in Genomic Instability

    Directory of Open Access Journals (Sweden)

    Aaraby Yoheswaran Nielsen

    2016-06-01

    Full Text Available Genomic instability is a hallmark of human cancer and an enabling factor for the genetic alterations that drive cancer development. The processes involved in genomic instability resemble those of meiosis, where genetic material is interchanged between homologous chromosomes. In most types of human cancer, epigenetic changes, including hypomethylation of gene promoters, lead to the ectopic expression of a large number of proteins normally restricted to the germ cells of the testis. Due to the similarities between meiosis and genomic instability, it has been proposed that activation of meiotic programs may drive genomic instability in cancer cells. Some germ cell proteins with ectopic expression in cancer cells indeed seem to promote genomic instability, while others reduce polyploidy and maintain mitotic fidelity. Furthermore, oncogenic germ cell proteins may indirectly contribute to genomic instability through induction of replication stress, similar to classic oncogenes. Thus, current evidence suggests that testis germ cell proteins are implicated in cancer development by regulating genomic instability during tumorigenesis, and these proteins therefore represent promising targets for novel therapeutic strategies.

  9. Cross-cancer genome-wide analysis of lung, ovary, breast, prostate and colorectal cancer reveals novel pleiotropic associations

    NARCIS (Netherlands)

    Fehringer, Gordon; Kraft, Peter; Pharoah, Paul D P; Eeles, Rosalind A; Chatterjee, Nilanjan; Schumacher, Fredrick R; Schildkraut, Joellen M; Lindstrom, Sara; Brennan, Paul; Bickeböller, Heike; Houlston, Richard S; Landi, Maria Teresa; Caporaso, Neil E; Risch, Angela; Amin Al Olama, Ali; Berndt, Sonja I; Giovannucci, Edward; Gronberg, Henrik; Kote-Jarai, Zsofia; Ma, Jing; Muir, Kenneth; Stampfer, Meir J; Stevens, Victoria L; Wiklund, Fredrik; Willett, Walter C; Goode, Ellen L; Permuth, Jennifer B; Risch, Harvey A; Reid, Brett M; Bezieau, Stéphane; Brenner, Hermann; Chan, Andrew T; Chang-Claude, Jenny; Hudson, Thomas J; Kocarnik, Jonathan; Newcomb, Polly A; Schoen, Robert E; Slattery, Martha L; White, Emily; Adank, Muriel A; Ahsan, Habibul; Aittomaki, Kristiina; Baglietto, Laura; Blomquist, Carl; Canzian, Federico; Czene, Kamila; Dos Santos Silva, Isabel; Eliassen, A Heather; Figueroa, Jonine D; Flesch-Janys, Dieter; Fletcher, Olivia; Garcia-Closas, Montserrat; Gaudet, Mia M; Johnson, Nichola; Hall, Per; Hazra, Aditi; Hein, Rebecca; Hofman, Albert; Hopper, John L; Irwanto, Astrid; Johansson, Mattias; Kaaks, Rudolf; Kibriya, Muhammad G; Lichtner, Peter; Liu, Jian Jun; Lund, Eiliv; Makalic, Enes; Meindl, Alfons; Müller-Myhsok, Bertram; Muranen, Taru A; Nevanlinna, Heli; Peeters, Petra H; Peto, Julian; Prentice, Ross L; Rahman, Nazneen; Sanchez, Maria-Jose; Schmidt, Daniel F; Schmutzler, Rita K; Southey, Melissa C; Tamimi, Rulla M; Travis, Ruth C; Turnbull, Clare; Uitterlinden, Andre G; Wang, Zhaoming; Whittemore, Alice S; Yang, Xiaohong R; Zheng, Wei; Rafnar, Thorunn; Gudmundsson, Julius; Stacey, Simon N; Stefansson, Kari; Sulem, Patrick; Chen, Y Ann; Tyrer, Jonathan P; Christiani, David C; Wei, Yongyue; Shen, Hongbing; Hu, Zhibin; Shu, Xiao-Ou; Shiraishi, Kouya; Takahashi, Atsushi; Bossé, Yohan; Obeidat, Ma'en; Nickle, David; Timens, Wim; Freedman, Matthew L; Li, Qiyuan; Seminara, Daniela; Chanock, Stephen J; Gong, Jian; Peters, Ulrike; Gruber, Stephen B; Amos, Christopher I; Sellers, Thomas A; Easton, Douglas F; Hunter, David J; Haiman, Christopher A; Henderson, Brian E; Hung, Rayjean J

    2016-01-01

    Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-staged approach to conduct genome-wide association studies for lung, ovary, breast, prostate and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 c

  10. Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations

    NARCIS (Netherlands)

    Fehringer, Gordon; Kraft, Peter; Pharoah, Paul D.; Eeles, Rosalind A.; Chatterjee, Nilanjan; Schumacher, Fredrick R.; Schildkraut, Joellen M.; Lindstrom, Sara; Brennan, Paul; Bickeboller, Heike; Houlston, Richard S.; Landi, Maria Teresa; Caporaso, Neil; Risch, Angela; Al Olama, Ali Amin; Berndt, Sonja I.; Giovannucci, Edward L.; Gronberg, Henrik; Kote-Jarai, Zsofia; Ma, Jing; Muir, Kenneth; Stampfer, Meir J.; Stevens, Victoria L.; Wiklund, Fredrik; Willett, Walter C.; Goode, Ellen L.; Permuth, Jennifer B.; Risch, Harvey A.; Reid, Brett M.; Bezieau, Stephane; Brenner, Hermann; Chan, Andrew T.; Chang-Claude, Jenny; Hudson, Thomas J.; Kocarnik, Jonathan K.; Newcomb, Polly A.; Schoen, Robert E.; Slattery, Martha L.; White, Emily; Adank, Muriel A.; Ahsan, Habibul; Aittomaki, Kristiina; Baglietto, Laura; Blomquist, Carl; Canzian, Federico; Czene, Kamila; dos-Santos-Silva, Isabel; Eliassen, A. Heather; Figueroa, Jonine D.; Flesch-Janys, Dieter; Fletcher, Olivia; Garcia-Closas, Montserrat; Gaudet, Mia M.; Johnson, Nichola; Hall, Per; Hazra, Aditi; Hein, Rebecca; Hofman, Albert; Hopper, John L.; Irwanto, Astrid; Johansson, Mattias; Kaaks, Rudolf; Kibriya, Muhammad G.; Lichtner, Peter; Liu, Jianjun; Lund, Eiliv; Makalic, Enes; Meindl, Alfons; Muller-Myhsok, Bertram; Muranen, Taru A.; Nevanlinna, Heli; Peeters, Petra H.; Peto, Julian; Prentice, Ross L.; Rahman, Nazneen; Sanchez, Maria Jose; Schmidt, Daniel F.; Schmutzler, Rita K.; Southey, Melissa C.; Tamimi, Rulla; Travis, Ruth C.; Turnbull, Clare; Uitterlinden, Andre G.; Wang, Zhaoming; Whittemore, Alice S.; Yang, Xiaohong R.; Zheng, Wei; Buchanan, Daniel D.; Casey, Graham; Conti, David V.; Edlund, Christopher K.; Gallinger, Steven; Haile, Robert W.; Jenkins, Mark; Le Marchand, Loic; Li, Li; Lindor, Noralene M.; Schmit, Stephanie L.; Thibodeau, Stephen N.; Woods, Michael O.; Rafnar, Thorunn; Gudmundsson, Julius; Stacey, Simon N.; Stefansson, Kari; Sulem, Patrick; Chen, Y. Ann; Tyrer, Jonathan P.; Christiani, David C.; Wei, Yongyue; Shen, Hongbing; Hu, Zhibin; Shu, Xiao-Ou; Shiraishi, Kouya; Takahashi, Atsushi; Bosse, Yohan; Obeidat, Ma'en; Nickle, David; Timens, Wim; Freedman, Matthew L.; Li, Qiyuan; Seminara, Daniela; Chanock, Stephen J.; Gong, Jian; Peters, Ulrike; Gruber, Stephen B.; Amos, Christopher I.; Sellers, Thomas A.; Easton, Douglas F.; Hunter, David J.; Haiman, Christopher A.; Henderson, Brian E.; Hung, Rayjean J.

    2016-01-01

    Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 c

  11. Cross-cancer genome-wide analysis of lung, ovary, breast, prostate, and colorectal cancer reveals novel pleiotropic associations

    NARCIS (Netherlands)

    Fehringer, G. (Gordon); P. Kraft (Peter); P.D.P. Pharoah (Paul); R. Eeles (Rosalind); Chatterjee, N. (Nilanjan); F.R. Schumacher (Fredrick R); J.M. Schildkraut (Joellen); S. Lindstrom (Stephen); P. Brennan (Paul); H. Bickeböller (Heike); R. Houlston (Richard); M.T. Landi (Maria Teresa); N.E. Caporaso (Neil); Risch, A. (Angela); A.A. Al Olama (Ali Amin); S.I. Berndt (Sonja); Giovannucci, E.L. (Edward L.); H. Grönberg (Henrik); Z. Kote-Jarai; Ma, J. (Jing); K.R. Muir (K.); M.J. Stampfer (Meir J.); Stevens, V.L. (Victoria L.); F. Wiklund (Fredrik); W.C. Willett (Walter C.); E.L. Goode (Ellen); Permuth, J.B. (Jennifer B.); H. Risch (Harvey); Reid, B.M. (Brett M.); Bezieau, S. (Stephane); H. Brenner (Hermann); Chan, A.T. (Andrew T.); J. Chang-Claude (Jenny); T.J. Hudson (Thomas); Kocarnik, J.K. (Jonathan K.); P. Newcomb (Polly); Schoen, R.E. (Robert E.); Slattery, M.L. (Martha L.); White, E. (Emily); M.A. Adank (Muriel); H. Ahsan (Habibul); K. Aittomäki (Kristiina); Baglietto, L. (Laura); Blomquist, C. (Carl); F. Canzian (Federico); K. Czene (Kamila); I. dos Santos Silva (Isabel); Eliassen, A.H. (A. Heather); J.D. Figueroa (Jonine); D. Flesch-Janys (Dieter); O. Fletcher (Olivia); M. García-Closas (Montserrat); M.M. Gaudet (Mia); Johnson, N. (Nichola); P. Hall (Per); A. Hazra (Aditi); R. Hein (Rebecca); Hofman, A. (Albert); J.L. Hopper (John); A. Irwanto (Astrid); M. Johansson (Mattias); R. Kaaks (Rudolf); M.G. Kibriya (Muhammad); P. Lichtner (Peter); J. Liu (Jianjun); E. Lund (Eiliv); Makalic, E. (Enes); A. Meindl (Alfons); B. Müller-Myhsok (B.); Muranen, T.A. (Taru A.); H. Nevanlinna (Heli); P.H.M. Peeters; J. Peto (Julian); R. Prentice (Ross); N. Rahman (Nazneen); M.-J. Sanchez (Maria-Jose); D.F. Schmidt (Daniel); R.K. Schmutzler (Rita); M.C. Southey (Melissa); Tamimi, R. (Rulla); S.P.L. Travis (Simon); C. Turnbull (Clare); Uitterlinden, A.G. (Andre G.); Z. Wang (Zhaoming); A.S. Whittemore (Alice); X.R. Yang (Xiaohong); W. Zheng (Wei); D. Buchanan (Daniel); G. Casey (Graham); G. Conti (Giario); C.K. Edlund (Christopher); S. Gallinger (Steve); R. Haile (Robert); M. Jenkins (Mark); Marchand, L. (Loïcle); Li, L. (Li); N.M. Lindor (Noralane); Schmit, S.L. (Stephanie L.); S.N. Thibodeau (Stephen); M.O. Woods (Michael); T. Rafnar (Thorunn); J. Gudmundsson (Julius); S.N. Stacey (Simon); Stefansson, K. (Kari); P. Sulem (Patrick); Chen, Y.A. (Y. Ann); J.P. Tyrer (Jonathan); Christiani, D.C. (David C.); Wei, Y. (Yongyue); H. Shen (Hongbing); Z. Hu (Zhibin); X.-O. Shu (Xiao-Ou); Shiraishi, K. (Kouya); A. Takahashi (Atsushi); Y. Bossé (Yohan); M. Obeidat; D.C. Nickle (David C.); W. Timens (Wim); M. Freedman (Matthew); Li, Q. (Qiyuan); D. Seminara (Daniela); S.J. Chanock (Stephen); Gong, J. (Jian); U. Peters (Ulrike); S.B. Gruber (Stephen); Amos, C.I. (Christopher I.); T.A. Sellers (Thomas A.); D.F. Easton (Douglas F.); D. Hunter (David); C.A. Haiman (Christopher A.); B.E. Henderson (Brian); R.J. Hung (Rayjean)

    2016-01-01

    textabstractIdentifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cas

  12. Cross-cancer genome-wide analysis of lung, ovary, breast, prostate, and colorectal cancer reveals novel pleiotropic associations

    NARCIS (Netherlands)

    Fehringer, Gordon; Kraft, Peter; Pharoah, Paul D.; Eeles, Rosalind A.; Chatterjee, Nilanjan; Schumacher, Fredrick R.; Schildkraut, Joellen M.; Lindström, Sara; Brennan, Paul; Bickeböller, Heike; Houlston, Richard S.; Landi, Maria Teresa; Caporaso, Neil; Risch, Angela; Al Olama, Ali Amin; Berndt, Sonja I.; Giovannucci, Edward L.; Grönberg, Henrik; Kote-Jarai, Zsofia; Ma, Jing; Muir, Kenneth; Stampfer, Meir J.; Stevens, Victoria L.; Wiklund, Fredrik; Willett, Walter C.; Goode, Ellen L.; Permuth, Jennifer B.; Risch, Harvey A.; Reid, Brett M.; Bezieau, Stephane; Brenner, Hermann; Chan, Andrew T.; Chang-Claude, Jenny; Hudson, Thomas J.; Kocarnik, Jonathan K.; Newcomb, Polly A.; Schoen, Robert E.; Slattery, Martha L.; White, Emily; Adank, Muriel A.; Ahsan, Habibul; Aittomäki, Kristiina; Baglietto, Laura; Blomquist, Carl; Canzian, Federico; Czene, Kamila; Dos-Santos-silva, Isabel; Eliassen, A. Heather; Figueroa, Jonine D.; Flesch-Janys, Dieter; Fletcher, Olivia; Garcia-Closas, Montserrat; Gaudet, Mia M.; Johnson, Nichola; Hall, Per; Hazra, Aditi; Hein, Rebecca; Hofman, Albert; Hopper, John L.; Irwanto, Astrid; Johansson, Mattias; Kaaks, Rudolf; Kibriya, Muhammad G.; Lichtner, Peter; Liu, Jianjun; Lund, Eiliv; Makalic, Enes; Meindl, Alfons; Müller-Myhsok, Bertram; Muranen, Taru A.; Nevanlinna, Heli; Peeters, Petra H.; Peto, Julian; Prentice, Ross L.; Rahman, Nazneen; Sanchez, Maria Jose; Schmidt, Daniel F.; Schmutzler, Rita K.; Southey, Melissa C.; Tamimi, Rulla; Travis, Ruth C.; Turnbull, Clare; Uitterlinden, Andre G.; Wang, Zhaoming; Whittemore, Alice S.; Yang, Xiaohong R.; Zheng, Wei; Buchanan, Daniel D.; Casey, Graham; Conti, David V.; Edlund, Christopher K.; Gallinger, Steven; Haile, Robert W.; Jenkins, Mark; Marchand, Loïcle; Li, Li; Lindor, Noralene M.; Schmit, Stephanie L.; Thibodeau, Stephen N.; Woods, Michael O.; Rafnar, Thorunn; Gudmundsson, Julius; Stacey, Simon N.; Stefansson, Kari; Sulem, Patrick; Chen, Y. Ann; Tyrer, Jonathan P.; Christiani, David C.; Wei, Yongyue; Shen, Hongbing; Hu, Zhibin; Shu, Xiao Ou; Shiraishi, Kouya; Takahashi, Atsushi; Bossé, Yohan; Obeidat, Ma'en; Nickle, David; Timens, Wim; Freedman, Matthew L.; Li, Qiyuan; Seminara, Daniela; Chanock, Stephen J.; Gong, Jian; Peters, Ulrike; Gruber, Stephen B.; Amos, Christopher I.; Sellers, Thomas A.; Easton, Douglas F.; Hunter, David J.; Haiman, Christopher A.; Henderson, Brian E.; Hung, Rayjean J.

    2016-01-01

    Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 c

  13. Mutational and structural analysis of diffuse large B-cell lymphoma using whole genome sequencing | Office of Cancer Genomics

    Science.gov (United States)

    Abstract: Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous cancer comprising at least two molecular subtypes that differ in gene expression and distribution of mutations. Recently, application of genome/exome sequencing and RNA-seq to DLBCL has revealed numerous genes that are recurrent targets of somatic point mutation in this disease.

  14. The genomic landscape of breast cancer and its interaction with host immunity.

    Science.gov (United States)

    Luen, Stephen; Virassamy, Balaji; Savas, Peter; Salgado, Roberto; Loi, Sherene

    2016-10-01

    Molecular profiling of thousands of primary breast cancers has uncovered remarkable genomic diversity between breast cancer subtypes, and even within subtypes. Only a few driver genes are recurrently altered at high frequency highlighting great challenges for precision medicine. Considerable evidence also confirms the role of host immunosurveillance in influencing response to therapy and prognosis in HER2+ and triple negative breast cancer. The role of immunosurveillance in ER + disease remains unclear. Advances in both these fields have lead to intensified interest in the interaction between genomic landscapes and host anti-tumour immune responses in breast cancer. In this review, we discuss the potential genomic determinants of host anti-tumour immunity - mutational load, driver alterations, mutational processes and neoantigens - and their relationship with immunity in breast cancer. Significant differences exist in both the genomic and immune characteristics amongst breast cancer subtypes. While ER + disease appears to be less immunogenic than HER2+ and triple negative breast cancer, it displays the greatest degree of heterogeneity. Mutational and neoantigen load appears to incompletely explains immune responses in breast cancer. Driver alterations do not appear to increase immunogenicity. Instead, they could contribute to immune-evasion or an immunosuppressive microenvironment, and therefore represent potential therapeutic targets. Finally, we also discuss the tailoring of immunotherapeutic strategies by genomic alterations, with possible multimodal combination approaches to maximise clinical benefits.

  15. SIGMA2: A system for the integrative genomic multi-dimensional analysis of cancer genomes, epigenomes, and transcriptomes

    Directory of Open Access Journals (Sweden)

    MacAulay Calum

    2008-10-01

    Full Text Available Abstract Background High throughput microarray technologies have afforded the investigation of genomes, epigenomes, and transcriptomes at unprecedented resolution. However, software packages to handle, analyze, and visualize data from these multiple 'omics disciplines have not been adequately developed. Results Here, we present SIGMA2, a system for the integrative genomic multi-dimensional analysis of cancer genomes, epigenomes, and transcriptomes. Multi-dimensional datasets can be simultaneously visualized and analyzed with respect to each dimension, allowing combinatorial integration of the different assays belonging to the different 'omics. Conclusion The identification of genes altered at multiple levels such as copy number, loss of heterozygosity (LOH, DNA methylation and the detection of consequential changes in gene expression can be concertedly performed, establishing SIGMA2 as a novel tool to facilitate the high throughput systems biology analysis of cancer.

  16. Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients

    DEFF Research Database (Denmark)

    Sausen, Mark; Phallen, Jillian; Adleff, Vilmos;

    2015-01-01

    Pancreatic adenocarcinoma has the worst mortality of any solid cancer. In this study, to evaluate the clinical implications of genomic alterations in this tumour type, we perform whole-exome analyses of 24 tumours, targeted genomic analyses of 77 tumours, and use non-invasive approaches to examine...... imaging. These observations provide genetic predictors of outcome in pancreatic cancer and have implications for new avenues of therapeutic intervention....

  17. Delineation of Methyl-DNA Binding Protein Interactions in the Prostate Cancer Genome (PC110091)

    Science.gov (United States)

    2014-03-01

    DNA Binding Protein Interactions in the Prostate Cancer Genome (PC110091) PRINCIPAL INVESTIGATOR: Roderick T Hori, PhD...13. SUPPLEMENTARY NOTES Prostate Cancer, Methylated DNA, Methyl- CpG Binding Domain, Chromatin Immunoprecipitation 14. ABSTRACT The purpose...of this study is to generate a genome-wide association profile of Methyl- CpG Domain-containing (MBD) proteins, such as MeCP2, MBD1, MBD2 and MBD4, in

  18. Computational discovery of pathway-level genetic vulnerabilities in non-small-cell lung cancer | Office of Cancer Genomics

    Science.gov (United States)

    Novel approaches are needed for discovery of targeted therapies for non-small-cell lung cancer (NSCLC) that are specific to certain patients. Whole genome RNAi screening of lung cancer cell lines provides an ideal source for determining candidate drug targets. Unsupervised learning algorithms uncovered patterns of differential vulnerability across lung cancer cell lines to loss of functionally related genes. Such genetic vulnerabilities represent candidate targets for therapy and are found to be involved in splicing, translation and protein folding.

  19. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer

    NARCIS (Netherlands)

    Wang, Kai; Yuen, Siu Tsan; Xu, Jiangchun; Lee, Siu Po; Yan, Helen H N; Shi, Stephanie T; Siu, Hoi Cheong; Deng, Shibing; Chu, Kent Man; Law, Simon; Chan, Kok Hoe; Chan, Annie S Y; Tsui, Wai Yin; Ho, Siu Lun; Chan, Anthony K W; Man, Jonathan L K; Foglizzo, Valentina; Ng, Man Kin; Chan, April S; Ching, Yick Pang; Cheng, Grace H W; Xie, Tao; Fernandez, Julio; Li, Vivian S W; Clevers, Hans; Rejto, Paul A; Mao, Mao; Leung, Suet Yi

    2014-01-01

    Gastric cancer is a heterogeneous disease with diverse molecular and histological subtypes. We performed whole-genome sequencing in 100 tumor-normal pairs, along with DNA copy number, gene expression and methylation profiling, for integrative genomic analysis. We found subtype-specific genetic and e

  20. Genomic analyses identify molecular subtypes of pancreatic cancer.

    Science.gov (United States)

    Bailey, Peter; Chang, David K; Nones, Katia; Johns, Amber L; Patch, Ann-Marie; Gingras, Marie-Claude; Miller, David K; Christ, Angelika N; Bruxner, Tim J C; Quinn, Michael C; Nourse, Craig; Murtaugh, L Charles; Harliwong, Ivon; Idrisoglu, Senel; Manning, Suzanne; Nourbakhsh, Ehsan; Wani, Shivangi; Fink, Lynn; Holmes, Oliver; Chin, Venessa; Anderson, Matthew J; Kazakoff, Stephen; Leonard, Conrad; Newell, Felicity; Waddell, Nick; Wood, Scott; Xu, Qinying; Wilson, Peter J; Cloonan, Nicole; Kassahn, Karin S; Taylor, Darrin; Quek, Kelly; Robertson, Alan; Pantano, Lorena; Mincarelli, Laura; Sanchez, Luis N; Evers, Lisa; Wu, Jianmin; Pinese, Mark; Cowley, Mark J; Jones, Marc D; Colvin, Emily K; Nagrial, Adnan M; Humphrey, Emily S; Chantrill, Lorraine A; Mawson, Amanda; Humphris, Jeremy; Chou, Angela; Pajic, Marina; Scarlett, Christopher J; Pinho, Andreia V; Giry-Laterriere, Marc; Rooman, Ilse; Samra, Jaswinder S; Kench, James G; Lovell, Jessica A; Merrett, Neil D; Toon, Christopher W; Epari, Krishna; Nguyen, Nam Q; Barbour, Andrew; Zeps, Nikolajs; Moran-Jones, Kim; Jamieson, Nigel B; Graham, Janet S; Duthie, Fraser; Oien, Karin; Hair, Jane; Grützmann, Robert; Maitra, Anirban; Iacobuzio-Donahue, Christine A; Wolfgang, Christopher L; Morgan, Richard A; Lawlor, Rita T; Corbo, Vincenzo; Bassi, Claudio; Rusev, Borislav; Capelli, Paola; Salvia, Roberto; Tortora, Giampaolo; Mukhopadhyay, Debabrata; Petersen, Gloria M; Munzy, Donna M; Fisher, William E; Karim, Saadia A; Eshleman, James R; Hruban, Ralph H; Pilarsky, Christian; Morton, Jennifer P; Sansom, Owen J; Scarpa, Aldo; Musgrove, Elizabeth A; Bailey, Ulla-Maja Hagbo; Hofmann, Oliver; Sutherland, Robert L; Wheeler, David A; Gill, Anthony J; Gibbs, Richard A; Pearson, John V; Waddell, Nicola; Biankin, Andrew V; Grimmond, Sean M

    2016-03-01

    Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

  1. Seven prostate cancer susceptibility loci identified by a multi-stage genome-wide association study

    DEFF Research Database (Denmark)

    Kote-Jarai, Zsofia; Olama, Ali Amin Al; Giles, Graham G

    2011-01-01

    Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. We conducted a multi-stage genome-wide association study for PrCa and previously reported the results of the first two stages, which identified 16 PrCa susceptibility loci. We report here the results of st...

  2. BYSTANDERS, ADAPTIVE RESPONSES AND GENOMIC INSTABILITY - POTENTIAL MODIFIERS OF LOW-DOSE CANCER RESPONSES.

    Science.gov (United States)

    Bystanders, Adaptive Responses and Genomic Instability -Potential Modifiers ofLow-DoseCancer Responses.There has been a concerted effort in the field of radiation biology to better understand cellularresponses that could have an impact on the estin1ation of cancer...

  3. The Genomic Grade Assay Compared With Ki67 to Determine Risk of Distant Breast Cancer Recurrence

    DEFF Research Database (Denmark)

    Ignatiadis, Michail; Azim, Hatem A; Desmedt, Christine;

    2016-01-01

    Importance: The Genomic Grade Index (GGI) was previously developed, evaluated on frozen tissue, and shown to be prognostic in early breast cancer. To test the GGI in formalin-fixed, paraffin-embedded breast cancer tumors, a quantitative reverse transcriptase polymerase chain reaction assay was de...

  4. DNA copy number aberrations in breast cancer by array comparative genomic hybridization

    DEFF Research Database (Denmark)

    Li, J.; Wang, K.; Li, S.;

    2009-01-01

    Array comparative genomic hybridization (CGH) has been popularly used for analyzing DNA copy number variations in diseases like cancer. In this study, we investigated 82 sporadic samples from 49 breast cancer patients using 1-Mb resolution bacterial artificial chromosome CGH arrays. A number of h...

  5. Health psychology and translational genomic research: bringing innovation to cancer-related behavioral interventions.

    Science.gov (United States)

    McBride, Colleen M; Birmingham, Wendy C; Kinney, Anita Y

    2015-01-01

    The past decade has witnessed rapid advances in human genome sequencing technology and in the understanding of the role of genetic and epigenetic alterations in cancer development. These advances have raised hopes that such knowledge could lead to improvements in behavioral risk reduction interventions, tailored screening recommendations, and treatment matching that together could accelerate the war on cancer. Despite this optimism, translation of genomic discovery for clinical and public health applications has moved relatively slowly. To date, health psychologists and the behavioral sciences generally have played a very limited role in translation research. In this report we discuss what we mean by genomic translational research and consider the social forces that have slowed translational research, including normative assumptions that translation research must occur downstream of basic science, thus relegating health psychology and other behavioral sciences to a distal role. We then outline two broad priority areas in cancer prevention, detection, and treatment where evidence will be needed to guide evaluation and implementation of personalized genomics: (a) effective communication, to broaden dissemination of genomic discovery, including patient-provider communication and familial communication, and (b) the need to improve the motivational impact of behavior change interventions, including those aimed at altering lifestyle choices and those focusing on decision making regarding targeted cancer treatments and chemopreventive adherence. We further discuss the role that health psychologists can play in interdisciplinary teams to shape translational research priorities and to evaluate the utility of emerging genomic discoveries for cancer prevention and control.

  6. DNA Copy Number Aberrations in Breast Cancer by Array Comparative Genomic Hybridization

    Institute of Scientific and Technical Information of China (English)

    Jian Li; Kai Wang; Shengting Li; Vera Timmermans-Wielenga; Fritz Rank; Carsten Wiuf; Xiuqing Zhang; Huanming Yang; Lars Bolund

    2009-01-01

    Array comparative genomic hybridization (CGH) has been popularly used for an-alyzing DNA copy number variations in diseases like cancer. In this study, we investigated 82 sporadic samples from 49 breast cancer patients using 1-Mb reso-lution bacterial artificial chromosome CGH arrays. A number of highly frequent genomic aberrations were discovered, which may act as "drivers" of tumor pro-gression. Meanwhile, the genomic profiles of four "normal" breast tissue samples taken at least 2 cm away from the primary tumor sites were also found to have some genomic aberrations that recurred with high frequency in the primary tu-mors, which may have important implications for clinical therapy. Additionally, we performed class comparison and class prediction for various clinicopathological pa-rameters, and a list of characteristic genomic aberrations associated with different clinicopathological phenotypes was compiled. Our study provides clues for further investigations of the underlying mechanisms of breast carcinogenesis.

  7. Characterization of HPV and host genome interactions in primary head and neck cancers

    Science.gov (United States)

    Parfenov, Michael; Pedamallu, Chandra Sekhar; Gehlenborg, Nils; Freeman, Samuel S.; Danilova, Ludmila; Bristow, Christopher A.; Lee, Semin; Hadjipanayis, Angela G.; Ivanova, Elena V.; Wilkerson, Matthew D.; Protopopov, Alexei; Yang, Lixing; Seth, Sahil; Song, Xingzhi; Tang, Jiabin; Ren, Xiaojia; Zhang, Jianhua; Pantazi, Angeliki; Santoso, Netty; Xu, Andrew W.; Mahadeshwar, Harshad; Wheeler, David A.; Haddad, Robert I.; Jung, Joonil; Ojesina, Akinyemi I.; Issaeva, Natalia; Yarbrough, Wendell G.; Hayes, D. Neil; Grandis, Jennifer R.; El-Naggar, Adel K.; Meyerson, Matthew; Park, Peter J.; Chin, Lynda; Seidman, J. G.; Hammerman, Peter S.; Kucherlapati, Raju; Ally, Adrian; Balasundaram, Miruna; Birol, Inanc; Bowlby, Reanne; Butterfield, Yaron S.N.; Carlsen, Rebecca; Cheng, Dean; Chu, Andy; Dhalla, Noreen; Guin, Ranabir; Holt, Robert A.; Jones, Steven J.M.; Lee, Darlene; Li, Haiyan I.; Marra, Marco A.; Mayo, Michael; Moore, Richard A.; Mungall, Andrew J.; Robertson, A. Gordon; Schein, Jacqueline E.; Sipahimalani, Payal; Tam, Angela; Thiessen, Nina; Wong, Tina; Protopopov, Alexei; Santoso, Netty; Lee, Semin; Parfenov, Michael; Zhang, Jianhua; Mahadeshwar, Harshad S.; Tang, Jiabin; Ren, Xiaojia; Seth, Sahil; Haseley, Psalm; Zeng, Dong; Yang, Lixing; Xu, Andrew W.; Song, Xingzhi; Pantazi, Angeliki; Bristow, Christopher; Hadjipanayis, Angela; Seidman, Jonathan; Chin, Lynda; Park, Peter J.; Kucherlapati, Raju; Akbani, Rehan; Casasent, Tod; Liu, Wenbin; Lu, Yiling; Mills, Gordon; Motter, Thomas; Weinstein, John; Diao, Lixia; Wang, Jing; Fan, You Hong; Liu, Jinze; Wang, Kai; Auman, J. Todd; Balu, Saianand; Bodenheimer, Tom; Buda, Elizabeth; Hayes, D. Neil; Hoadley, Katherine A.; Hoyle, Alan P.; Jefferys, Stuart R.; Jones, Corbin D.; Kimes, Patrick K.; Marron, J.S.; Meng, Shaowu; Mieczkowski, Piotr A.; Mose, Lisle E.; Parker, Joel S.; Perou, Charles M.; Prins, Jan F.; Roach, Jeffrey; Shi, Yan; Simons, Janae V.; Singh, Darshan; Soloway, Mathew G.; Tan, Donghui; Veluvolu, Umadevi; Walter, Vonn; Waring, Scot; Wilkerson, Matthew D.; Wu, Junyuan; Zhao, Ni; Cherniack, Andrew D.; Hammerman, Peter S.; Tward, Aaron D.; Pedamallu, Chandra Sekhar; Saksena, Gordon; Jung, Joonil; Ojesina, Akinyemi I.; Carter, Scott L.; Zack, Travis I.; Schumacher, Steven E.; Beroukhim, Rameen; Freeman, Samuel S.; Meyerson, Matthew; Cho, Juok; Chin, Lynda; Getz, Gad; Noble, Michael S.; DiCara, Daniel; Zhang, Hailei; Heiman, David I.; Gehlenborg, Nils; Voet, Doug; Lin, Pei; Frazer, Scott; Stojanov, Petar; Liu, Yingchun; Zou, Lihua; Kim, Jaegil; Lawrence, Michael S.; Sougnez, Carrie; Lichtenstein, Lee; Cibulskis, Kristian; Lander, Eric; Gabriel, Stacey B.; Muzny, Donna; Doddapaneni, HarshaVardhan; Kovar, Christie; Reid, Jeff; Morton, Donna; Han, Yi; Hale, Walker; Chao, Hsu; Chang, Kyle; Drummond, Jennifer A.; Gibbs, Richard A.; Kakkar, Nipun; Wheeler, David; Xi, Liu; Ciriello, Giovanni; Ladanyi, Marc; Lee, William; Ramirez, Ricardo; Sander, Chris; Shen, Ronglai; Sinha, Rileen; Weinhold, Nils; Taylor, Barry S.; Aksoy, B. Arman; Dresdner, Gideon; Gao, Jianjiong; Gross, Benjamin; Jacobsen, Anders; Reva, Boris; Schultz, Nikolaus; Sumer, S. Onur; Sun, Yichao; Chan, Timothy; Morris, Luc; Stuart, Joshua; Benz, Stephen; Ng, Sam; Benz, Christopher; Yau, Christina; Baylin, Stephen B.; Cope, Leslie; Danilova, Ludmila; Herman, James G.; Bootwalla, Moiz; Maglinte, Dennis T.; Laird, Peter W.; Triche, Timothy; Weisenberger, Daniel J.; Van Den Berg, David J.; Agrawal, Nishant; Bishop, Justin; Boutros, Paul C.; Bruce, Jeff P; Byers, Lauren Averett; Califano, Joseph; Carey, Thomas E.; Chen, Zhong; Cheng, Hui; Chiosea, Simion I.; Cohen, Ezra; Diergaarde, Brenda; Egloff, Ann Marie; El-Naggar, Adel K.; Ferris, Robert L.; Frederick, Mitchell J.; Grandis, Jennifer R.; Guo, Yan; Haddad, Robert I.; Hammerman, Peter S.; Harris, Thomas; Hayes, D. Neil; Hui, Angela BY; Lee, J. Jack; Lippman, Scott M.; Liu, Fei-Fei; McHugh, Jonathan B.; Myers, Jeff; Ng, Patrick Kwok Shing; Perez-Ordonez, Bayardo; Pickering, Curtis R.; Prystowsky, Michael; Romkes, Marjorie; Saleh, Anthony D.; Sartor, Maureen A.; Seethala, Raja; Seiwert, Tanguy Y.; Si, Han; Tward, Aaron D.; Van Waes, Carter; Waggott, Daryl M.; Wiznerowicz, Maciej; Yarbrough, Wendell; Zhang, Jiexin; Zuo, Zhixiang; Burnett, Ken; Crain, Daniel; Gardner, Johanna; Lau, Kevin; Mallery, David; Morris, Scott; Paulauskis, Joseph; Penny, Robert; Shelton, Candance; Shelton, Troy; Sherman, Mark; Yena, Peggy; Black, Aaron D.; Bowen, Jay; Frick, Jessica; Gastier-Foster, Julie M.; Harper, Hollie A.; Lichtenberg, Tara M.; Ramirez, Nilsa C.; Wise, Lisa; Zmuda, Erik; Baboud, Julien; Jensen, Mark A.; Kahn, Ari B.; Pihl, Todd D.; Pot, David A.; Srinivasan, Deepak; Walton, Jessica S.; Wan, Yunhu; Burton, Robert; Davidsen, Tanja; Demchok, John A.; Eley, Greg; Ferguson, Martin L.; Shaw, Kenna R. Mills; Ozenberger, Bradley A.; Sheth, Margi; Sofia, Heidi J.; Tarnuzzer, Roy; Wang, Zhining; Yang, Liming; Zenklusen, Jean Claude; Saller, Charles; Tarvin, Katherine; Chen, Chu; Bollag, Roni; Weinberger, Paul; Golusiński, Wojciech; Golusiński, Paweł; Ibbs, Matthiew; Korski, Konstanty; Mackiewicz, Andrzej; Suchorska, Wiktoria; Szybiak, Bartosz; Wiznerowicz, Maciej; Burnett, Ken; Curley, Erin; Gardner, Johanna; Mallery, David; Penny, Robert; Shelton, Troy; Yena, Peggy; Beard, Christina; Mitchell, Colleen; Sandusky, George; Agrawal, Nishant; Ahn, Julie; Bishop, Justin; Califano, Joseph; Khan, Zubair; Bruce, Jeff P; Hui, Angela BY; Irish, Jonathan; Liu, Fei-Fei; Perez-Ordonez, Bayardo; Waldron, John; Boutros, Paul C.; Waggott, Daryl M.; Myers, Jeff; Lippman, Scott M.; Egea, Sophie; Gomez-Fernandez, Carmen; Herbert, Lynn; Bradford, Carol R.; Carey, Thomas E.; Chepeha, Douglas B.; Haddad, Andrea S.; Jones, Tamara R.; Komarck, Christine M.; Malakh, Mayya; McHugh, Jonathan B.; Moyer, Jeffrey S.; Nguyen, Ariane; Peterson, Lisa A.; Prince, Mark E.; Rozek, Laura S.; Sartor, Maureen A.; Taylor, Evan G.; Walline, Heather M.; Wolf, Gregory T.; Boice, Lori; Chera, Bhishamjit S.; Funkhouser, William K.; Gulley, Margaret L.; Hackman, Trevor G.; Hayes, D. Neil; Hayward, Michele C.; Huang, Mei; Rathmell, W. Kimryn; Salazar, Ashley H.; Shockley, William W.; Shores, Carol G.; Thorne, Leigh; Weissler, Mark C.; Wrenn, Sylvia; Zanation, Adam M.; Chiosea, Simion I.; Diergaarde, Brenda; Egloff, Ann Marie; Ferris, Robert L.; Romkes, Marjorie; Seethala, Raja; Brown, Brandee T.; Guo, Yan; Pham, Michelle; Yarbrough, Wendell G.

    2014-01-01

    Previous studies have established that a subset of head and neck tumors contains human papillomavirus (HPV) sequences and that HPV-driven head and neck cancers display distinct biological and clinical features. HPV is known to drive cancer by the actions of the E6 and E7 oncoproteins, but the molecular architecture of HPV infection and its interaction with the host genome in head and neck cancers have not been comprehensively described. We profiled a cohort of 279 head and neck cancers with next generation RNA and DNA sequencing and show that 35 (12.5%) tumors displayed evidence of high-risk HPV types 16, 33, or 35. Twenty-five cases had integration of the viral genome into one or more locations in the human genome with statistical enrichment for genic regions. Integrations had a marked impact on the human genome and were associated with alterations in DNA copy number, mRNA transcript abundance and splicing, and both inter- and intrachromosomal rearrangements. Many of these events involved genes with documented roles in cancer. Cancers with integrated vs. nonintegrated HPV displayed different patterns of DNA methylation and both human and viral gene expressions. Together, these data provide insight into the mechanisms by which HPV interacts with the human genome beyond expression of viral oncoproteins and suggest that specific integration events are an integral component of viral oncogenesis. PMID:25313082

  8. Gender-Associated Genomic Differences in Colorectal Cancer: Clinical Insight from Feminization of Male Cancer Cells

    Directory of Open Access Journals (Sweden)

    Rola H. Ali

    2014-09-01

    Full Text Available Gender-related differences in colorectal cancer (CRC are not fully understood. Recent studies have shown that CRC arising in females are significantly associated with CpG island methylator phenotype (CIMP-high. Using array comparative genomic hybridization, we analyzed a cohort of 116 CRCs (57 males, 59 females for chromosomal copy number aberrations (CNA and found that CRC in females had significantly higher numbers of gains involving chromosome arms 1q21.2–q21.3, 4q13.2, 6p21.1 and 16p11.2 and copy number losses of chromosome arm 11q25 compared to males. Interestingly, a subset of male CRCs (46% exhibited a "feminization" phenomenon in the form of gains of X chromosomes (or an arm of X and/or losses of the Y chromosome. Feminization of cancer cells was significantly associated with microsatellite-stable CRCs (p-value 0.003 and wild-type BRAF gene status (p-value 0.009. No significant association with other clinicopathological parameters was identified including disease-free survival. In summary, our data show that some CNAs in CRC may be gender specific and that male cancers characterized by feminization may constitute a specific subset of CRCs that warrants further investigation.

  9. Gender-associated genomic differences in colorectal cancer: clinical insight from feminization of male cancer cells.

    Science.gov (United States)

    Ali, Rola H; Marafie, Makia J; Bitar, Milad S; Al-Dousari, Fahad; Ismael, Samar; Bin Haider, Hussain; Al-Ali, Waleed; Jacob, Sindhu P; Al-Mulla, Fahd

    2014-09-29

    Gender-related differences in colorectal cancer (CRC) are not fully understood. Recent studies have shown that CRC arising in females are significantly associated with CpG island methylator phenotype (CIMP-high). Using array comparative genomic hybridization, we analyzed a cohort of 116 CRCs (57 males, 59 females) for chromosomal copy number aberrations (CNA) and found that CRC in females had significantly higher numbers of gains involving chromosome arms 1q21.2-q21.3, 4q13.2, 6p21.1 and 16p11.2 and copy number losses of chromosome arm 11q25 compared to males. Interestingly, a subset of male CRCs (46%) exhibited a "feminization" phenomenon in the form of gains of X chromosomes (or an arm of X) and/or losses of the Y chromosome. Feminization of cancer cells was significantly associated with microsatellite-stable CRCs (p-value 0.003) and wild-type BRAF gene status (p-value 0.009). No significant association with other clinicopathological parameters was identified including disease-free survival. In summary, our data show that some CNAs in CRC may be gender specific and that male cancers characterized by feminization may constitute a specific subset of CRCs that warrants further investigation.

  10. Atlas of genetics and cytogenetics in oncology and haematology in 2013.

    Science.gov (United States)

    Huret, Jean-Loup; Ahmad, Mohammad; Arsaban, Mélanie; Bernheim, Alain; Cigna, Jérémy; Desangles, François; Guignard, Jean-Christophe; Jacquemot-Perbal, Marie-Christine; Labarussias, Maureen; Leberre, Vanessa; Malo, Anne; Morel-Pair, Catherine; Mossafa, Hossein; Potier, Jean-Claude; Texier, Guillaume; Viguié, Franck; Yau Chun Wan-Senon, Sylvie; Zasadzinski, Alain; Dessen, Philippe

    2013-01-01

    The Atlas of Genetics and Cytogenetics in Oncology and Haematology (http://AtlasGeneticsOncology.org) is a peer-reviewed internet journal/encyclopaedia/database focused on genes implicated in cancer, cytogenetics and clinical entities in cancer and cancer-prone hereditary diseases. The main goal of the Atlas is to provide review articles that describe complementary topics, namely, genes, genetic abnormalities, histopathology, clinical diagnoses and a large iconography. This description, which was historically based on karyotypic abnormalities and in situ hybridization (fluorescence in situ hybridization) techniques, now benefits from comparative genomic hybridization and massive sequencing, uncovering a tremendous amount of genetic rearrangements. As the Atlas combines different types of information (genes, genetic abnormalities, histopathology, clinical diagnoses and external links), its content is currently unique. The Atlas is a cognitive tool for fundamental and clinical research and has developed into an encyclopaedic work. In clinical practice, it contributes to the cytogenetic diagnosis and may guide treatment decision making, particularly regarding rare diseases (because they are numerous and are frequently encountered). Readers as well as the authors of the Atlas are researchers and/or clinicians.

  11. Funding Opportunity: Genomic Data Centers

    Science.gov (United States)

    Funding Opportunity CCG, Funding Opportunity Center for Cancer Genomics, CCG, Center for Cancer Genomics, CCG RFA, Center for cancer genomics rfa, genomic data analysis network, genomic data analysis network centers,

  12. Clinic-Genomic Association Mining for Colorectal Cancer Using Publicly Available Datasets

    Directory of Open Access Journals (Sweden)

    Fang Liu

    2014-01-01

    Full Text Available In recent years, a growing number of researchers began to focus on how to establish associations between clinical and genomic data. However, up to now, there is lack of research mining clinic-genomic associations by comprehensively analysing available gene expression data for a single disease. Colorectal cancer is one of the malignant tumours. A number of genetic syndromes have been proven to be associated with colorectal cancer. This paper presents our research on mining clinic-genomic associations for colorectal cancer under biomedical big data environment. The proposed method is engineered with multiple technologies, including extracting clinical concepts using the unified medical language system (UMLS, extracting genes through the literature mining, and mining clinic-genomic associations through statistical analysis. We applied this method to datasets extracted from both gene expression omnibus (GEO and genetic association database (GAD. A total of 23517 clinic-genomic associations between 139 clinical concepts and 7914 genes were obtained, of which 3474 associations between 31 clinical concepts and 1689 genes were identified as highly reliable ones. Evaluation and interpretation were performed using UMLS, KEGG, and Gephi, and potential new discoveries were explored. The proposed method is effective in mining valuable knowledge from available biomedical big data and achieves a good performance in bridging clinical data with genomic data for colorectal cancer.

  13. A Genome-wide Breast Cancer Scan in African Americans

    Science.gov (United States)

    2012-06-01

    of Experimental Therapy and Molecular Pathology and Division of Epidemiology, Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital, Amsterdam...Centre, University of Oxford, Oxford, UK. 81Family Cancer Clinic, Netherlands Cancer Institut–Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands

  14. Genomic profiling toward precision medicine in non-small cell lung cancer: getting beyond EGFR

    Directory of Open Access Journals (Sweden)

    Richer AL

    2015-02-01

    Full Text Available Amanda L Richer,1 Jacqueline M Friel,1 Vashti M Carson,2 Landon J Inge,1 Timothy G Whitsett2 1Norton Thoracic Institute, St Joseph’s Hospital and Medical Center, 2Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA Abstract: Lung cancer remains the leading cause of cancer-related mortality worldwide. The application of next-generation genomic technologies has offered a more comprehensive look at the mutational landscape across the different subtypes of non-small cell lung cancer (NSCLC. A number of recurrent mutations such as TP53, KRAS, and epidermal growth factor receptor (EGFR have been identified in NSCLC. While targeted therapeutic successes have been demonstrated in the therapeutic targeting of EGFR and ALK, the majority of NSCLC tumors do not harbor these genomic events. This review looks at the current treatment paradigms for lung adenocarcinomas and squamous cell carcinomas, examining genomic aberrations that dictate therapy selection, as well as novel therapeutic strategies for tumors harboring mutations in KRAS, TP53, and LKB1 which, to date, have been considered “undruggable”. A more thorough understanding of the molecular alterations that govern NSCLC tumorigenesis, aided by next-generation sequencing, will lead to targeted therapeutic options expected to dramatically reduce the high mortality rate observed in lung cancer. Keywords: non-small cell lung cancer, precision medicine, epidermal growth factor receptor, Kirsten rat sarcoma viral oncogene homolog, serine/threonine kinase 11, tumor protein p53

  15. A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24

    DEFF Research Database (Denmark)

    Goode, Ellen L; Chenevix-Trench, Georgia; Song, Honglin;

    2010-01-01

    Ovarian cancer accounts for more deaths than all other gynecological cancers combined. To identify common low-penetrance ovarian cancer susceptibility genes, we conducted a genome-wide association study of 507,094 SNPs in 1,768 individuals with ovarian cancer (cases) and 2,354 controls, with foll...

  16. A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer

    NARCIS (Netherlands)

    Gudmundsson, J.; Sulem, P.; Gudbjartsson, D.F.; Masson, G.; Agnarsson, B.A.; Benediktsdottir, K.R.; Sigurdsson, A.; Magnusson, O.T.; Gudjonsson, S.A.; Magnusdottir, D.N.; Johannsdottir, H.; Helgadottir, H.T.; Stacey, S.N.; Jonasdottir, A.; Olafsdottir, S.B.; Thorleifsson, G.; Jonasson, J.G.; Tryggvadottir, L.; Navarrete, S.; Fuertes, F.; Helfand, B.T.; Hu, Q.; Csiki, I.E.; Mates, I.N.; Jinga, V.; Aben, K.K.H.; Oort, I.M. van; Vermeulen, S.; Donovan, J.L.; Hamdy, F.C.; Ng, C.F.; Chiu, P.K.; Lau, K.M.; Ng, M.C.; Gulcher, J.R.; Kong, A.; Catalona, W.J.; Mayordomo, J.I.; Einarsson, G.V.; Barkardottir, R.B.; Jonsson, E.; Mates, D.; Neal, D.E.; Kiemeney, L.A.L.M.; Thorsteinsdottir, U.; Rafnar, T.; Stefansson, K.

    2012-01-01

    In Western countries, prostate cancer is the most prevalent cancer of men and one of the leading causes of cancer-related death in men. Several genome-wide association studies have yielded numerous common variants conferring risk of prostate cancer. Here, we analyzed 32.5 million variants discovered

  17. CRISPRi and CRISPRa: New Functional Genomics Tools Provide Complementary Insights into Cancer Biology and Therapeutic Strategies | Office of Cancer Genomics

    Science.gov (United States)

    A central goal of research for targeted cancer therapy, or precision oncology, is to reveal the intrinsic vulnerabilities of cancer cells and exploit them as therapeutic targets. Examples of cancer cell vulnerabilities include driver oncogenes that are essential for the initiation and progression of cancer, or non-oncogene addictions resulting from the cancerous state of the cell. To identify vulnerabilities, scientists perform genetic “loss-of-function” and “gain-of-function” studies to better understand the roles of specific genes in cancer cells.

  18. Genome-wide association study of colorectal cancer in Hispanics

    Science.gov (United States)

    Schmit, Stephanie L.; Schumacher, Fredrick R.; Edlund, Christopher K.; Conti, David V.; Ihenacho, Ugonna; Wan, Peggy; Van Den Berg, David; Casey, Graham; Fortini, Barbara K.; Lenz, Heinz-Josef; Tusié-Luna, Teresa; Aguilar-Salinas, Carlos A.; Moreno-Macías, Hortensia; Huerta-Chagoya, Alicia; Ordóñez-Sánchez, María Luisa; Rodríguez-Guillén, Rosario; Cruz-Bautista, Ivette; Rodríguez-Torres, Maribel; Muñóz-Hernández, Linda Liliana; Arellano-Campos, Olimpia; Gómez, Donají; Alvirde, Ulices; González-Villalpando, Clicerio; González-Villalpando, María Elena; Le Marchand, Loic; Haiman, Christopher A.; Figueiredo, Jane C.

    2016-01-01

    Genome-wide association studies (GWAS) have identified 58 susceptibility alleles across 37 regions associated with the risk of colorectal cancer (CRC) with P < 5×10−8. Most studies have been conducted in non-Hispanic whites and East Asians; however, the generalizability of these findings and the potential for ethnic-specific risk variation in Hispanic and Latino (HL) individuals have been largely understudied. We describe the first GWAS of common genetic variation contributing to CRC risk in HL (1611 CRC cases and 4330 controls). We also examine known susceptibility alleles and implement imputation-based fine-mapping to identify potential ethnicity-specific association signals in known risk regions. We discovered 17 variants across 4 independent regions that merit further investigation due to suggestive CRC associations (P < 1×10−6) at 1p34.3 (rs7528276; Odds Ratio (OR) = 1.86 [95% confidence interval (CI): 1.47–2.36); P = 2.5×10−7], 2q23.3 (rs1367374; OR = 1.37 (95% CI: 1.21–1.55); P = 4.0×10−7), 14q24.2 (rs143046984; OR = 1.65 (95% CI: 1.36–2.01); P = 4.1×10−7) and 16q12.2 [rs142319636; OR = 1.69 (95% CI: 1.37–2.08); P=7.8×10−7]. Among the 57 previously published CRC susceptibility alleles with minor allele frequency ≥1%, 76.5% of SNPs had a consistent direction of effect and 19 (33.3%) were nominally statistically significant (P < 0.05). Further, rs185423955 and rs60892987 were identified as novel secondary susceptibility variants at 3q26.2 (P = 5.3×10–5) and 11q12.2 (P = 6.8×10−5), respectively. Our findings demonstrate the importance of fine mapping in HL. These results are informative for variant prioritization in functional studies and future risk prediction modeling in minority populations. PMID:27207650

  19. Genomics and epigenomics: new promises of personalized medicine for cancer patients.

    Science.gov (United States)

    Schweiger, Michal-Ruth; Barmeyer, Christian; Timmermann, Bernd

    2013-09-01

    Recent years have brought about a marked extension of our understanding of the somatic basis of cancer. Parallel to the large-scale investigation of diverse tumor genomes the knowledge arose that cancer pathologies are most often not restricted to single genomic events. In contrast, a large number of different alterations in the genomes and epigenomes come together and promote the malignant transformation. The combination of mutations, structural variations and epigenetic alterations differs between each tumor, making individual diagnosis and treatment strategies necessary. This view is summarized in the new discipline of personalized medicine. To satisfy the ideas of this approach each tumor needs to be fully characterized and individual diagnostic and therapeutic strategies designed. Here, we will discuss the power of high-throughput sequencing technologies for genomic and epigenomic analyses. We will provide insight into the current status and how these technologies can be transferred to routine clinical usage.

  20. Origins of DNA Replication and Amplification in the Breast Cancer Genome

    Science.gov (United States)

    2011-09-01

    identified 53,914 origins in the MCF-7 genome, with a median width of 1.5 kb using the methodology as follows: We used BEDTools ( Quinlan et al...are collaborating with David Gilbert (University of Florida – Tallahassee) to determine the replication foci higher order structure in the nucleus...Cancer Cell 10: 515-527. Quinlan AR, Hall IM. (2010) BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics. 26: 841-2

  1. Precision cancer mouse models through genome editing with CRISPR-Cas9

    OpenAIRE

    Mou, Haiwei; Kennedy, Zachary; Anderson, Daniel G.; Yin, Hao; Xue, Wen

    2015-01-01

    The cancer genome is highly complex, with hundreds of point mutations, translocations, and chromosome gains and losses per tumor. To understand the effects of these alterations, precise models are needed. Traditional approaches to the construction of mouse models are time-consuming and laborious, requiring manipulation of embryonic stem cells and multiple steps. The recent development of the clustered regularly interspersed short palindromic repeats (CRISPR)-Cas9 system, a powerful genome-edi...

  2. Identifying master regulators of cancer and their downstream targets by integrating genomic and epigenomic features.

    Science.gov (United States)

    Gevaert, Olivier; Plevritis, Sylvia

    2013-01-01

    Vast amounts of molecular data characterizing the genome, epigenome and transcriptome are becoming available for a variety of cancers. The current challenge is to integrate these diverse layers of molecular biology information to create a more comprehensive view of key biological processes underlying cancer. We developed a biocomputational algorithm that integrates copy number, DNA methylation, and gene expression data to study master regulators of cancer and identify their targets. Our algorithm starts by generating a list of candidate driver genes based on the rationale that genes that are driven by multiple genomic events in a subset of samples are unlikely to be randomly deregulated. We then select the master regulators from the candidate driver and identify their targets by inferring the underlying regulatory network of gene expression. We applied our biocomputational algorithm to identify master regulators and their targets in glioblastoma multiforme (GBM) and serous ovarian cancer. Our results suggest that the expression of candidate drivers is more likely to be influenced by copy number variations than DNA methylation. Next, we selected the master regulators and identified their downstream targets using module networks analysis. As a proof-of-concept, we show that the GBM and ovarian cancer module networks recapitulate known processes in these cancers. In addition, we identify master regulators that have not been previously reported and suggest their likely role. In summary, focusing on genes whose expression can be explained by their genomic and epigenomic aberrations is a promising strategy to identify master regulators of cancer.

  3. Genomic and expression array profiling of chromosome 20q amplicon in human colon cancer cells

    Directory of Open Access Journals (Sweden)

    Carter Jennifer

    2005-01-01

    Full Text Available Background: Gain of the q arm of chromosome 20 in human colorectal cancer has been associated with poorer survival time and has been reported to increase in frequency from adenomas to metastasis. The increasing frequency of chromosome 20q amplification during colorectal cancer progression and the presence of this amplification in carcinomas of other tissue origin has lead us to hypothesize that 20q11-13 harbors one or more genes which, when over expressed promote tumor invasion and metastasis. Aims: Generate genomic and expression profiles of the 20q amplicon in human cancer cell lines in order to identify genes with increased copy number and expression. Materials and Methods: Utilizing genomic sequencing clones and amplification mapping data from our lab and other previous studies, BAC/ PAC tiling paths spanning the 20q amplicon and genomic microarrays were generated. Array-CGH on the custom array with human cancer cell line DNAs was performed to generate genomic profiles of the amplicon. Expression array analysis with RNA from these cell lines using commercial oligo microarrays generated expression profiles of the amplicon. The data were then combined in order to identify genes with increased copy number and expression. Results: Over expressed genes in regions of increased copy number were identified and a list of potential novel genetic tumor markers was assembled based on biological functions of these genes Conclusions: Performing high-resolution genomic microarray profiling in conjunction with expression analysis is an effective approach to identify potential tumor markers.

  4. Crossing the LINE toward genomic instability: LINE-1 retrotransposition in cancer

    Science.gov (United States)

    Kemp, Jacqueline; Longworth, Michelle

    2015-12-01

    Retrotransposons are repetitive DNA sequences that are positioned throughout the human genome. Retrotransposons are capable of copying themselves and mobilizing new copies to novel genomic locations in a process called retrotransposition. While most retrotransposon sequences in the human genome are incomplete and incapable of mobilization, the LINE-1 retrotransposon, which comprises approximately 17% of the human genome, remains active. The disruption of cellular mechanisms that suppress retrotransposon activity is linked to the generation of aneuploidy, a potential driver of tumor development. When retrotransposons insert into a novel genomic region, they have the potential to disrupt the coding sequence of endogenous genes and alter gene expression, which can lead to deleterious consequences for the organism. Additionally, increased LINE-1 copy numbers provide more chances for recombination events to occur between retrotransposons, which can lead to chromosomal breaks and rearrangements. LINE-1 activity is increased in various cancer cell lines and in patient tissues resected from primary tumors. LINE-1 activity also correlates with increased cancer metastasis. This review aims to give a brief overview of the connections between LINE-1 retrotransposition and the loss of genome stability. We will also discuss the mechanisms that repress retrotransposition in human cells and their links to cancer.

  5. Crossing the LINE toward genomic instability: LINE-1 retrotransposition in cancer

    Directory of Open Access Journals (Sweden)

    Jacqueline R. Kemp

    2015-12-01

    Full Text Available Retrotransposons are repetitive DNA sequences that are positioned throughout the human genome. Retrotransposons are capable of copying themselves and mobilizing new copies to novel genomic locations in a process called retrotransposition. While most retrotransposon sequences in the human genome are incomplete and incapable of mobilization, the LINE-1 retrotransposon, which comprises approximately 17% of the human genome, remains active. The disruption of cellular mechanisms that suppress retrotransposon activity is linked to the generation of aneuploidy, a potential driver of tumor development. When retrotransposons insert into a novel genomic region, they have the potential to disrupt the coding sequence of endogenous genes and alter gene expression, which can lead to deleterious consequences for the organism. Additionally, increased LINE-1 copy numbers provide more chances for recombination events to occur between retrotransposons, which can lead to chromosomal breaks and rearrangements. LINE-1 activity is increased in various cancer cell lines and in patient tissues resected from primary tumors. LINE-1 activity also correlates with increased cancer metastasis. This review aims to give a brief overview of the connections between LINE-1 retrotransposition and the loss of genome stability. We will also discuss the mechanisms that repress retrotransposition in human cells and their links to cancer.

  6. Can metabolomics in addition to genomics add to prognostic and predictive information in breast cancer?

    Science.gov (United States)

    Howell, Anthony

    2010-11-16

    Genomic data from breast cancers provide additional prognostic and predictive information that is beginning to be used for patient management. The question arises whether additional information derived from other 'omic' approaches such as metabolomics can provide additional information. In an article published this month in BMC Cancer, Borgan et al. add metabolomic information to genomic measures in breast tumours and demonstrate, for the first time, that it may be possible to further define subgroups of patients which could be of value clinically. See research article: http://www.biomedcentral.com/1471-2407/10/628.

  7. Integrated proteomic and genomic analysis of colorectal cancer

    Science.gov (United States)

    Investigators who analyzed 95 human colorectal tumor samples have determined how gene alterations identified in previous analyses of the same samples are expressed at the protein level. The integration of proteomic and genomic data, or proteogenomics, pro

  8. Complete Genome Sequence of Helicobacter pylori Strain 29CaP Isolated from a Mexican Patient with Gastric Cancer

    Science.gov (United States)

    Mucito-Varela, Eduardo; Castillo-Rojas, Gonzalo; Cevallos, Miguel A.; Lozano, Luis; Merino, Enrique; López-Leal, Gamaliel

    2016-01-01

    Helicobacter pylori infection is a risk factor for the development of gastric cancer and other gastroduodenal diseases. We report here the complete genome sequence of H. pylori strain 29CaP, isolated from a Mexican patient with gastric cancer. The genomic data analysis revealed a cag-negative H. pylori strain that contains a prophage sequence. PMID:26769924

  9. An Online Atlas for Exploring Spatio-Temporal Patterns of Cancer Mortality (1972-2011) and Incidence (1995-2008) in Taiwan.

    Science.gov (United States)

    Ku, Wen-Yuan; Liaw, Yung-Po; Huang, Jing-Yang; Nfor, Oswald Ndi; Hsu, Shu-Yi; Ko, Pei-Chieh; Lee, Wen-Chung; Chen, Chien-Jen

    2016-05-01

    Public health mapping and Geographical Information Systems (GIS) are already being used to locate the geographical spread of diseases. This study describes the construction of an easy-to-use online atlas of cancer mortality (1972-2011) and incidence (1995-2008) in Taiwan.Two sets of color maps were made based on "age-adjusted mortality by rate" and "age-adjusted mortality by rank." AJAX (Asynchronous JavaScript and XML), JSON (JavaScript Object Notation), and SVG (Scaling Vector Graphic) were used to create the online atlas. Spatio-temporal patterns of cancer mortality and incidence in Taiwan over the period from 1972 to 2011 and from 1995 to 2008.The constructed online atlas contains information on cancer mortality and incidence (http://taiwancancermap.csmu-liawyp.tw/). The common GIS functions include zoom and pan and identity tools. Users can easily customize the maps to explore the spatio-temporal trends of cancer mortality and incidence using different devices (such as personal computers, mobile phone, or pad). This study suggests an easy- to-use, low-cost, and independent platform for exploring cancer incidence and mortality. It is expected to serve as a reference tool for cancer prevention and risk assessment.This online atlas is a cheap and fast tool that integrates various cancer maps. Therefore, it can serve as a powerful tool that allows users to examine and compare spatio-temporal patterns of various maps. Furthermore, it is an-easy-to use tool for updating data and assessing risk factors of cancer in Taiwan.

  10. Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations.

    Science.gov (United States)

    Fehringer, Gordon; Kraft, Peter; Pharoah, Paul D; Eeles, Rosalind A; Chatterjee, Nilanjan; Schumacher, Fredrick R; Schildkraut, Joellen M; Lindström, Sara; Brennan, Paul; Bickeböller, Heike; Houlston, Richard S; Landi, Maria Teresa; Caporaso, Neil; Risch, Angela; Amin Al Olama, Ali; Berndt, Sonja I; Giovannucci, Edward L; Grönberg, Henrik; Kote-Jarai, Zsofia; Ma, Jing; Muir, Kenneth; Stampfer, Meir J; Stevens, Victoria L; Wiklund, Fredrik; Willett, Walter C; Goode, Ellen L; Permuth, Jennifer B; Risch, Harvey A; Reid, Brett M; Bezieau, Stephane; Brenner, Hermann; Chan, Andrew T; Chang-Claude, Jenny; Hudson, Thomas J; Kocarnik, Jonathan K; Newcomb, Polly A; Schoen, Robert E; Slattery, Martha L; White, Emily; Adank, Muriel A; Ahsan, Habibul; Aittomäki, Kristiina; Baglietto, Laura; Blomquist, Carl; Canzian, Federico; Czene, Kamila; Dos-Santos-Silva, Isabel; Eliassen, A Heather; Figueroa, Jonine D; Flesch-Janys, Dieter; Fletcher, Olivia; Garcia-Closas, Montserrat; Gaudet, Mia M; Johnson, Nichola; Hall, Per; Hazra, Aditi; Hein, Rebecca; Hofman, Albert; Hopper, John L; Irwanto, Astrid; Johansson, Mattias; Kaaks, Rudolf; Kibriya, Muhammad G; Lichtner, Peter; Liu, Jianjun; Lund, Eiliv; Makalic, Enes; Meindl, Alfons; Müller-Myhsok, Bertram; Muranen, Taru A; Nevanlinna, Heli; Peeters, Petra H; Peto, Julian; Prentice, Ross L; Rahman, Nazneen; Sanchez, Maria Jose; Schmidt, Daniel F; Schmutzler, Rita K; Southey, Melissa C; Tamimi, Rulla; Travis, Ruth C; Turnbull, Clare; Uitterlinden, Andre G; Wang, Zhaoming; Whittemore, Alice S; Yang, Xiaohong R; Zheng, Wei; Buchanan, Daniel D; Casey, Graham; Conti, David V; Edlund, Christopher K; Gallinger, Steven; Haile, Robert W; Jenkins, Mark; Le Marchand, Loïc; Li, Li; Lindor, Noralene M; Schmit, Stephanie L; Thibodeau, Stephen N; Woods, Michael O; Rafnar, Thorunn; Gudmundsson, Julius; Stacey, Simon N; Stefansson, Kari; Sulem, Patrick; Chen, Y Ann; Tyrer, Jonathan P; Christiani, David C; Wei, Yongyue; Shen, Hongbing; Hu, Zhibin; Shu, Xiao-Ou; Shiraishi, Kouya; Takahashi, Atsushi; Bossé, Yohan; Obeidat, Ma'en; Nickle, David; Timens, Wim; Freedman, Matthew L; Li, Qiyuan; Seminara, Daniela; Chanock, Stephen J; Gong, Jian; Peters, Ulrike; Gruber, Stephen B; Amos, Christopher I; Sellers, Thomas A; Easton, Douglas F; Hunter, David J; Haiman, Christopher A; Henderson, Brian E; Hung, Rayjean J

    2016-09-01

    Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103-14. ©2016 AACR.

  11. Genome-wide transcript profiling reveals novel breast cancer-associated intronic sense RNAs.

    Science.gov (United States)

    Kim, Sang Woo; Fishilevich, Elane; Arango-Argoty, Gustavo; Lin, Yuefeng; Liu, Guodong; Li, Zhihua; Monaghan, A Paula; Nichols, Mark; John, Bino

    2015-01-01

    Non-coding RNAs (ncRNAs) play major roles in development and cancer progression. To identify novel ncRNAs that may identify key pathways in breast cancer development, we performed high-throughput transcript profiling of tumor and normal matched-pair tissue samples. Initial transcriptome profiling using high-density genome-wide tiling arrays revealed changes in over 200 novel candidate genomic regions that map to intronic regions. Sixteen genomic loci were identified that map to the long introns of five key protein-coding genes, CRIM1, EPAS1, ZEB2, RBMS1, and RFX2. Consistent with the known role of the tumor suppressor ZEB2 in the cancer-associated epithelial to mesenchymal transition (EMT), in situ hybridization reveals that the intronic regions deriving from ZEB2 as well as those from RFX2 and EPAS1 are down-regulated in cells of epithelial morphology, suggesting that these regions may be important for maintaining normal epithelial cell morphology. Paired-end deep sequencing analysis reveals a large number of distinct genomic clusters with no coding potential within the introns of these genes. These novel transcripts are only transcribed from the coding strand. A comprehensive search for breast cancer associated genes reveals enrichment for transcribed intronic regions from these loci, pointing to an underappreciated role of introns or mechanisms relating to their biology in EMT and breast cancer.

  12. Genome-wide transcript profiling reveals novel breast cancer-associated intronic sense RNAs.

    Directory of Open Access Journals (Sweden)

    Sang Woo Kim

    Full Text Available Non-coding RNAs (ncRNAs play major roles in development and cancer progression. To identify novel ncRNAs that may identify key pathways in breast cancer development, we performed high-throughput transcript profiling of tumor and normal matched-pair tissue samples. Initial transcriptome profiling using high-density genome-wide tiling arrays revealed changes in over 200 novel candidate genomic regions that map to intronic regions. Sixteen genomic loci were identified that map to the long introns of five key protein-coding genes, CRIM1, EPAS1, ZEB2, RBMS1, and RFX2. Consistent with the known role of the tumor suppressor ZEB2 in the cancer-associated epithelial to mesenchymal transition (EMT, in situ hybridization reveals that the intronic regions deriving from ZEB2 as well as those from RFX2 and EPAS1 are down-regulated in cells of epithelial morphology, suggesting that these regions may be important for maintaining normal epithelial cell morphology. Paired-end deep sequencing analysis reveals a large number of distinct genomic clusters with no coding potential within the introns of these genes. These novel transcripts are only transcribed from the coding strand. A comprehensive search for breast cancer associated genes reveals enrichment for transcribed intronic regions from these loci, pointing to an underappreciated role of introns or mechanisms relating to their biology in EMT and breast cancer.

  13. Detecting the somatic mutations spectrum of Chinese lung cancer by analyzing the whole mitochondrial DNA genomes.

    Science.gov (United States)

    Fang, Yu; Huang, Jie; Zhang, Jing; Wang, Jun; Qiao, Fei; Chen, Hua-Mei; Hong, Zhi-Peng

    2015-02-01

    To detect the somatic mutations and character its spectrum in Chinese lung cancer patients. In this study, we sequenced the whole mitochondrial DNA (mtDNA) genomes for 10 lung cancer patients including the primary cancerous, matched paracancerous normal and distant normal tissues. By analyzing the 30 whole mtDNA genomes, eight somatic mutations were identified from five patients investigated, which were confirmed with the cloning and sequencing of the somatic mutations. Five of the somatic mutations were detected among control region and the rests were found at the coding region. Heterogeneity was the main character of the somatic mutations in Chinese lung cancer patients. Further potential disease-related screening showed that, except the C deletion at position 309 showed AD-weakly associated, most of them were not disease-related. Although the role of aforementioned somatic mutations was unknown, however, considering the relative higher frequency of somatic mutations among the whole mtDNA genomes, it hints that detecting the somatic mutation(s) from the whole mtDNA genomes can serve as a useful tool for the Chinese lung cancer diagnostic to some extent.

  14. Outsmarting cancer: the power of hybrid genomic/proteomic biomarkers to predict drug response.

    Science.gov (United States)

    Rexer, Brent N; Arteaga, Carlos L

    2014-01-01

    A recent study by Niepel and colleagues describes a novel approach to predicting response to targeted anti-cancer therapies. The authors used biochemical profiling of signaling activity in basal and ligand-stimulated states for a panel of receptor and intracellular kinases to develop predictive models of drug sensitivity. In some cases, the response to ligand stimulation predicted drug response better than did target abundance or genomic alterations in the targeted pathway. Furthermore, combining biochemical profiles with genomic information was better at predicting drug response. This work suggests that incorporating biochemical signaling profiles with genomic alterations should provide powerful predictors of response to molecularly targeted therapies.

  15. Tumor Genomic Profiling in Breast Cancer Patients Using Targeted Massively Parallel Sequencing

    Science.gov (United States)

    2015-04-30

    McDonald S, Watson M, Dooling DJ, Ota D, Chang LW, Bose R, Ley TJ, 18 Piwnica-Worms D, Stuart JM, Wilson RK, Mardis ER. Whole- genome analysis informs...AWARD NUMBER: W81XWH-13-1-0032 TITLE: Tumor Genomic Profiling in Breast Cancer Patients Using Targeted Massively Parallel Sequencing PRINCIPAL...THE ABOVE ADDRESS. 1. REPORT DATE I 2. REPORT TYPE 3. DATES COVERED 04-30-2015 Annual 01-01-2014 to 04-30-2015 4. TITLE AND SUBTITLE Tumor genomic

  16. Landscape of somatic mutations in 560 breast cancer whole genome sequences

    Science.gov (United States)

    Nik-Zainal, Serena; Davies, Helen; Staaf, Johan; Ramakrishna, Manasa; Glodzik, Dominik; Zou, Xueqing; Martincorena, Inigo; Alexandrov, Ludmil B.; Martin, Sancha; Wedge, David C.; Van Loo, Peter; Ju, Young Seok; Smid, Marcel; Brinkman, Arie B; Morganella, Sandro; Aure, Miriam R.; Lingjærde, Ole Christian; Langerød, Anita; Ringnér, Markus; Ahn, Sung-Min; Boyault, Sandrine; Brock, Jane E.; Broeks, Annegien; Butler, Adam; Desmedt, Christine; Dirix, Luc; Dronov, Serge; Fatima, Aquila; Foekens, John A.; Gerstung, Moritz; Hooijer, Gerrit KJ; Jang, Se Jin; Jones, David R.; Kim, Hyung-Yong; King, Tari A.; Krishnamurthy, Savitri; Lee, Hee Jin; Lee, Jeong-Yeon; Li, Yilong; McLaren, Stuart; Menzies, Andrew; Mustonen, Ville; O’Meara, Sarah; Pauporté, Iris; Pivot, Xavier; Purdie, Colin A.; Raine, Keiran; Ramakrishnan, Kamna; Rodríguez-González, F. Germán; Romieu, Gilles; Sieuwerts, Anieta M.; Simpson, Peter T; Shepherd, Rebecca; Stebbings, Lucy; Stefansson, Olafur A; Teague, Jon; Tommasi, Stefania; Treilleux, Isabelle; Van den Eynden, Gert G.; Vermeulen, Peter; Vincent-Salomon, Anne; Yates, Lucy; Caldas, Carlos; van’t Veer, Laura; Tutt, Andrew; Knappskog, Stian; Tan, Benita Kiat Tee; Jonkers, Jos; Borg, Åke; Ueno, Naoto T; Sotiriou, Christos; Viari, Alain; Futreal, P. Andrew; Campbell, Peter J; Span, Paul N.; Van Laere, Steven; Lakhani, Sunil R; Eyfjord, Jorunn E.; Thompson, Alastair M.; Birney, Ewan; Stunnenberg, Hendrik G; van de Vijver, Marc J; Martens, John W.M.; Børresen-Dale, Anne-Lise; Richardson, Andrea L.; Kong, Gu; Thomas, Gilles; Stratton, Michael R.

    2016-01-01

    We analysed whole genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. 93 protein-coding cancer genes carried likely driver mutations. Some non-coding regions exhibited high mutation frequencies but most have distinctive structural features probably causing elevated mutation rates and do not harbour driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed 12 base substitution and six rearrangement signatures. Three rearrangement signatures, characterised by tandem duplications or deletions, appear associated with defective homologous recombination based DNA repair: one with deficient BRCA1 function; another with deficient BRCA1 or BRCA2 function; the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operative, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer. PMID:27135926

  17. An open access pilot freely sharing cancer genomic data from participants in Texas.

    Science.gov (United States)

    Becnel, Lauren B; Pereira, Stacey; Drummond, Jennifer A; Gingras, Marie-Claude; Covington, Kyle R; Kovar, Christie L; Doddapaneni, Harsha Vardhan; Hu, Jianhong; Muzny, Donna; McGuire, Amy L; Wheeler, David A; Gibbs, Richard A

    2016-02-16

    Genomic data sharing in cancer has been restricted to aggregate or controlled-access initiatives to protect the privacy of research participants. By limiting access to these data, it has been argued that the autonomy of individuals who decide to participate in data sharing efforts has been superseded and the utility of the data as research and educational tools reduced. In a pilot Open Access (OA) project from the CPRIT-funded Texas Cancer Research Biobank, many Texas cancer patients were willing to openly share genomic data from tumor and normal matched pair specimens. For the first time, genetic data from 7 human cancer cases with matched normal are freely available without requirement for data use agreements nor any major restriction except that end users cannot attempt to re-identify the participants (http://txcrb.org/open.html).

  18. In Remembrance of Robert J. Arceci, M.D., Ph.D. | Office of Cancer Genomics

    Science.gov (United States)

    It is with great sadness and a profound sense of loss that OCG recognizes the untimely passing of Dr. Robert J. Arceci. Dr. Arceci was a co-Principal Investigator for the Acute Myeloid Leukemia (AML) project within the TARGET initiative, which aims to discover novel, more effective treatments for childhood cancers. Dr. Arceci was passionate about the use of cancer genomics to both inform therapeutic approaches in the clinic and expand the field of precision medicine.

  19. Genomic and phenotypic profiles of two Brazilian breast cancer cell lines derived from primary human tumors

    DEFF Research Database (Denmark)

    Corrêa, Natássia C R; Kuasne, Hellen; Faria, Jerusa A Q A

    2013-01-01

    Breast cancer is the most common type of cancer among women worldwide. Research using breast cancer cell lines derived from primary tumors may provide valuable additional knowledge regarding this type of cancer. Therefore, the aim of this study was to investigate the phenotypic profiles of MACL-1...... and MGSO-3, the only Brazilian breast cancer cell lines available for comparative studies. We evaluated the presence of hormone receptors, proliferation, differentiation and stem cell markers, using immunohistochemical staining of the primary tumor, cultured cells and xenografts implanted....... This shift in expression may be due to the selection of an 'establishment' phenotype in vitro. Whole-genome DNA evaluation showed a large amount of copy number alterations (CNAs) in the two cell lines. These findings render MACL-1 and MGSO-3 the first characterized Brazilian breast cancer cell lines...

  20. Global Genomic Analysis of Prostate, Breast and Pancreatic Cancer

    Science.gov (United States)

    2012-10-01

    Gleason grade to assess prognosis of the disease and risk assessment tools such as CAPRA -S (Cancer of the Prostate Risk Assessment Post- Surgical...JF, Carroll PR. The CAPRA -S score: A straightforward tool for improved prediction of outcomes after radical prostatectomy.Cancer. 2011 Nov 15;117(22

  1. Genomic profiling identifies GATA6 as a candidate oncogene amplified in pancreatobiliary cancer.

    Directory of Open Access Journals (Sweden)

    Kevin A Kwei

    2008-05-01

    Full Text Available Pancreatobiliary cancers have among the highest mortality rates of any cancer type. Discovering the full spectrum of molecular genetic alterations may suggest new avenues for therapy. To catalogue genomic alterations, we carried out array-based genomic profiling of 31 exocrine pancreatic cancers and 6 distal bile duct cancers, expanded as xenografts to enrich the tumor cell fraction. We identified numerous focal DNA amplifications and deletions, including in 19% of pancreatobiliary cases gain at cytoband 18q11.2, a locus uncommonly amplified in other tumor types. The smallest shared amplification at 18q11.2 included GATA6, a transcriptional regulator previously linked to normal pancreas development. When amplified, GATA6 was overexpressed at both the mRNA and protein levels, and strong immunostaining was observed in 25 of 54 (46% primary pancreatic cancers compared to 0 of 33 normal pancreas specimens surveyed. GATA6 expression in xenografts was associated with specific microarray gene-expression patterns, enriched for GATA binding sites and mitochondrial oxidative phosphorylation activity. siRNA mediated knockdown of GATA6 in pancreatic cancer cell lines with amplification led to reduced cell proliferation, cell cycle progression, and colony formation. Our findings indicate that GATA6 amplification and overexpression contribute to the oncogenic phenotypes of pancreatic cancer cells, and identify GATA6 as a candidate lineage-specific oncogene in pancreatobiliary cancer, with implications for novel treatment strategies.

  2. Cross-cancer genome-wide analysis of lung, ovary, breast, prostate and colorectal cancer reveals novel pleiotropic associations

    Science.gov (United States)

    Fehringer, Gordon; Kraft, Peter; Pharoah, Paul D.; Eeles, Rosalind A.; Chatterjee, Nilanjan; Schumacher, Fred; Schildkraut, Joellen; Lindström, Sara; Brennan, Paul; Bickeböller, Heike; Houlston, Richard S.; Landi, Maria Teresa; Caporaso, Neil; Risch, Angela; Olama, Ali Amin Al; Berndt, Sonja I; Giovannucci, Edward; Grönberg, Henrik; Kote-Jarai, Zsofia; Ma, Jing; Muir, Kenneth; Stampfer, Meir; Stevens, Victoria L.; Wiklund, Fredrik; Willett, Walter; Goode, Ellen L.; Permuth, Jennifer; Risch, Harvey A.; Reid, Brett M.; Bezieau, Stephane; Brenner, Hermann; Chan, Andrew T.; Chang-Claude, Jenny; Hudson, Thomas J.; Kocarnik, Jonathan K.; Newcomb, Polly A.; Schoen, Robert E.; Slattery, Martha L.; White, Emily; Adank, Muriel A.; Ahsan, Habibul; Aittomäki, Kristiina; Baglietto, Laura; Blomquist, Carl; Canzian, Federico; Czene, Kamila; dos-Santos-Silva, Isabel; Eliassen, A. Heather; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Garcia-Closas, Montserrat; Gaudet, Mia M.; Johnson, Nichola; Hall, Per; Hazra, Aditi; Hein, Rebecca; Hofman, Albert; Hopper, John L.; Irwanto, Astrid; Johansson, Mattias; Kaaks, Rudolf; Kibriya, Muhammad G.; Lichtner, Peter; Liu, Jianjun; Lund, Eiliv; Makalic, Enes; Meindl, Alfons; Müller-Myhsok, Bertram; Muranen, Taru A.; Nevanlinna, Heli; Peeters, Petra H.; Peto, Julian; Prentice, Ross L.; Rahman, Nazneen; Sanchez, Maria Jose; Schmidt, Daniel F.; Schmutzler, Rita K.; Southey, Melissa C.; Tamimi, Rulla; Travis, Ruth C.; Turnbull, Clare; Uitterlinden, Andre G.; Wang, Zhaoming; Whittemore, Alice S.; Yang, Xiaohong R.; Zheng, Wei; Rafnar, Thorunn; Gudmundsson, Julius; Stacey, Simon N.; Stefansson, Kari; Sulem, Patrick; Chen, Y. Ann; Tyrer, Jonathan P.; Christiani, David C.; Wei, Yongyue; Shen, Hongbing; Hu, Zhibin; Shu, Xiao-Ou; Shiraishi, Kouya; Takahashi, Atsushi; Bossé, Yohan; Obeidat, Ma’en; Nickle, David; Timens, Wim; Freedman, Matthew L.; Li, Qiyuan; Seminara, Daniela; Chanock, Stephen J.; Gong, Jian; Peters, Ulrike; Gruber, Stephen B.; Amos, Christopher I.; Sellers, Thomas A.; Easton, Douglas F.; Hunter, David J.; Haiman, Christopher A.; Henderson, Brian E.; Hung, Rayjean J.

    2016-01-01

    Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-staged approach to conduct genome-wide association studies for lung, ovary, breast, prostate and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. PMID:27197191

  3. Genomic and genetic alterations influence the progression of gastric cancer

    Institute of Scientific and Technical Information of China (English)

    Stefania Nobili; Lorenzo Bruno; Ida Landini; Cristina Napoli; Paolo Bechi; Francesco Tonelli; Carlos A Rubio; Enrico Mini; Gabriella Nesi

    2011-01-01

    Gastric cancer is one of the leading causes of cancerrelated deaths worldwide, although the incidence has gradually decreased in many Western countries. Twomain gastric cancer histotypes, intestinal and diffuse, are recognised. Although most of the described genetic alterations have been observed in both types, different genetic pathways have been hypothesized. Genetic and epigenetic events, including 1q loss of heterozygosity (LOH), microsatellite instability and hypermethylation, have mostly been reported in intestinal-type gastric carcinoma and its precursor lesions, whereas 17p LOH, mutation or loss of E-cadherin are more often implicated in the development of diffuse-type gastric cancer.

  4. Clinical genomics information management software linking cancer genome sequence and clinical decisions.

    Science.gov (United States)

    Watt, Stuart; Jiao, Wei; Brown, Andrew M K; Petrocelli, Teresa; Tran, Ben; Zhang, Tong; McPherson, John D; Kamel-Reid, Suzanne; Bedard, Philippe L; Onetto, Nicole; Hudson, Thomas J; Dancey, Janet; Siu, Lillian L; Stein, Lincoln; Ferretti, Vincent

    2013-09-01

    Using sequencing information to guide clinical decision-making requires coordination of a diverse set of people and activities. In clinical genomics, the process typically includes sample acquisition, template preparation, genome data generation, analysis to identify and confirm variant alleles, interpretation of clinical significance, and reporting to clinicians. We describe a software application developed within a clinical genomics study, to support this entire process. The software application tracks patients, samples, genomic results, decisions and reports across the cohort, monitors progress and sends reminders, and works alongside an electronic data capture system for the trial's clinical and genomic data. It incorporates systems to read, store, analyze and consolidate sequencing results from multiple technologies, and provides a curated knowledge base of tumor mutation frequency (from the COSMIC database) annotated with clinical significance and drug sensitivity to generate reports for clinicians. By supporting the entire process, the application provides deep support for clinical decision making, enabling the generation of relevant guidance in reports for verification by an expert panel prior to forwarding to the treating physician.

  5. Genomic Basis of Prostate Cancer Health Disparity Among African American Men

    Science.gov (United States)

    2015-10-01

    Nothing to Report APPENDIX Attached Robust Genomic Predictor of Prostate Cancer Metastasis Alexander Pearlman1, Kinnari Upadhyay1*, Kim Cole1...the International Society of Urological Pathology consensus conference. Am J Surg Pathol 38:1017-22, 2014 15. Cullen J, Rosner IL, Brand TC, et al: A

  6. Genome-wide association study of prostate cancer-specific survival

    DEFF Research Database (Denmark)

    Szulkin, Robert; Karlsson, Robert; Whitington, Thomas

    2015-01-01

    BACKGROUND: Unnecessary intervention and overtreatment of indolent disease are common challenges in clinical management of prostate cancer. Improved tools to distinguish lethal from indolent disease are critical. METHODS: We performed a genome-wide survival analysis of cause-specific death in 24,...

  7. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer

    NARCIS (Netherlands)

    Peifer, Martin; Fernandez-Cuesta, Lynnette; Sos, Martin L.; George, Julie; Seidel, Danila; Kasper, Lawryn H.; Plenker, Dennis; Leenders, Frauke; Sun, Ruping; Zander, Thomas; Menon, Roopika; Koker, Mirjam; Dahmen, Ilona; Mueller, Christian; Di Cerbo, Vincenzo; Schildhaus, Hans-Ulrich; Altmueller, Janine; Baessmann, Ingelore; Becker, Christian; de Wilde, Bram; Vandesompele, Jo; Boehm, Diana; Ansen, Sascha; Gabler, Franziska; Wilkening, Ines; Heynck, Stefanie; Heuckmann, Johannes M.; Lu, Xin; Carter, Scott L.; Cibulskis, Kristian; Banerji, Shantanu; Getz, Gad; Park, Kwon-Sik; Rauh, Daniel; Gruetter, Christian; Fischer, Matthias; Pasqualucci, Laura; Wright, Gavin; Wainer, Zoe; Russell, Prudence; Petersen, Iver; Chen, Yuan; Stoelben, Erich; Ludwig, Corinna; Schnabel, Philipp; Hoffmann, Hans; Muley, Thomas; Brockmann, Michael; Engel-Riedel, Walburga; Muscarella, Lucia A.; Fazio, Vito M.; Groen, Harry; Timens, Wim; Sietsma, Hannie; Thunnissen, Erik; Smit, Egbert; Heideman, Danielle A. M.; Snijders, Peter J. F.; Cappuzzo, Federico; Ligorio, Claudia; Damiani, Stefania; Field, John; Solberg, Steinar; Brustugun, Odd Terje; Lund-Iversen, Marius; Saenger, Joerg; Clement, Joachim H.; Soltermann, Alex; Moch, Holger; Weder, Walter; Solomon, Benjamin; Soria, Jean-Charles; Validire, Pierre; Besse, Benjamin; Brambilla, Elisabeth; Brambilla, Christian; Lantuejoul, Sylvie; Lorimier, Philippe; Schneider, Peter M.; Hallek, Michael; Pao, William; Meyerson, Matthew; Sage, Julien; Shendure, Jay; Schneider, Robert; Buettner, Reinhard; Wolf, Juergen; Nuernberg, Peter; Perner, Sven; Heukamp, Lukas C.; Brindle, Paul K.; Haas, Stefan; Thomas, Roman K.

    2012-01-01

    Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor prognosis(1-3). We sequenced 29 SCLC exomes, 2 genomes and 15 transcriptomes and found an extremely high mutation rate of 7.4 +/- 1 protein-changing mutations per million base pairs. Therefore, we conducted integrated analys

  8. Apoptotic and genomic effects of corilagin on SKOV3 ovarian cancer cell line

    Science.gov (United States)

    Attar, Rukset; Cincin, Zeynep Birsu; Bireller, Elif Sinem; Cakmakoglu, Bedia

    2017-01-01

    Corilagin is a member of the tannin family and has been isolated from traditional Chinese medicinal plants, such as Phyllanthus spp. Corilagin has anti-inflammatory, antioxidative, antiatherogenic, and antihypertensive effects in various experimental models. In this research, we aimed to investigate for the first time whether corilagin had apoptotic and genomic effects in ovarian cancer treatment in the same study. The potential apoptotic of corilagin was investigated using a WST1 cell proliferation test, caspase 3, and mitochondrial membrane potential JC1 assays in a time- and dose-dependent manner. Genomic changes in expression levels against corilagin treatment were measured using an Illumina human HT-12V4 BeadChip microarray. Bioinformatic data analyses were performed using GenomeStudio and Ingenuity Pathway Analysis software. The data of our study demonstrated that there were statistically significant time- and dose-dependent increases in caspase 3 enzymatic activity and loss of mitochondrial membrane potential in line with decreases in cancer cell proliferation. According to gene-ontology analysis, we found that adherens junctions, antigen processing and presentation, and the phosphatidylinositol signaling system were the most statistically significant networks in response to corilagin treatment on SKOV3 cells, in a time- and dose-dependent manner. The apoptotic and genome-wide effects of corilagin on ovarian cancer cells were examined in detail for the first time in the literature. The results of our study suggest that corilagin might have the potential to be used as a new treatment option for epithelial ovarian cancer.

  9. A novel approach for determining cancer genomic breakpoints in the presence of normal DNA.

    Directory of Open Access Journals (Sweden)

    Yu-Tsueng Liu

    Full Text Available CDKN2A (encodes p16(INK4A and p14(ARF deletion, which results in both Rb and p53 inactivation, is the most common chromosomal anomaly in human cancers. To precisely map the deletion breakpoints is important to understanding the molecular mechanism of genomic rearrangement and may also be useful for clinical applications. However, current methods for determining the breakpoint are either of low resolution or require the isolation of relatively pure cancer cells, which can be difficult for clinical samples that are typically contaminated with various amounts of normal host cells. To overcome this hurdle, we have developed a novel approach, designated Primer Approximation Multiplex PCR (PAMP, for enriching breakpoint sequences followed by genomic tiling array hybridization to locate the breakpoints. In a series of proof-of-concept experiments, we were able to identify cancer-derived CDKN2A genomic breakpoints when more than 99.9% of wild type genome was present in a model system. This design can be scaled up with bioinformatics support and can be applied to validate other candidate cancer-associated loci that are revealed by other more systemic but lower throughput assays.

  10. Breast cancer genome and transcriptome integration implicates specific mutational signatures with immune cell infiltration

    NARCIS (Netherlands)

    M. Smid (Marcel); F.G. Rodriguez-Gonzalez (F. German); A.M. Sieuwerts (Anieta); R. Salgado (Roberto); W.J.C. Prager-van der Smissen (Wendy); Vlugt-Daane, M.V.D. (Michelle Van Der); A. van Galen (Anne); S. Nik-Zainal (Serena); J. Staaf (Johan); A.B. Brinkman (Arie B.); M.J. Vijver (Marc ); A.L. Richardson (Andrea); A. Fatima (Aquila); Berentsen, K. (Kim); A. Butler (Adam); S. Martin (Sandra); H. Davies (Helen); J.E.M.A. Debets (Reno); M.E.M.-V. Gelder (Marion E. Meijer-Van); C.H.M. van Deurzen (Carolien); Macgrogan, G. (Gaëtan); Van Den Eynden, G.G.G.M. (Gert G. G. M.); C.A. Purdie (Colin A.); A.M. Thompson (Alastair M.); C. Caldas (Carlos); P.N. Span (Paul); Simpson, P.T. (Peter T.); S. Lakhani (Sunil); S.J. van Laere (Steven); C. Desmedt (Christine); Ringnér, M. (Markus); Tommasi, S. (Stefania); Eyford, J. (Jorunn); A. Broeks (Annegien); A. Vincent-Salomon (Anne); Futreal, P.A. (P. Andrew); S. Knappskog (Stian); King, T. (Tari); G. Thomas (Gilles); Viari, A. (Alain); Langerød, A. (Anita); A.-L. Borresen-Dale (Anne-Lise); E. Birney (Ewan); H. Stunnenberg (Henk); M.R. Stratton (Michael); J.A. Foekens (John); J.W.M. Martens (John)

    2016-01-01

    textabstractA recent comprehensive whole genome analysis of a large breast cancer cohort was used to link known and novel drivers and substitution signatures to the transcriptome of 266 cases. Here, we validate that subtype-specific aberrations show concordant expression changes for, for example, TP

  11. Breast cancer genome and transcriptome integration implicates specific mutational signatures with immune cell infiltration

    NARCIS (Netherlands)

    Smid, M.; Rodriguez-Gonzalez, F.G.; Sieuwerts, A.M.; Salgado, R.; Smissen, W.J. Prager-Van der; Vlugt-Daane, M.V.; Galen, A. van; Nik-Zainal, S.; Staaf, J.; Brinkman, A.B.; Vijver, M.J. van de; Richardson, A.L.; Fatima, A.; Berentsen, K.; Butler, A.; Martin, S.; Davies, H.R.; Debets, R.; Gelder, M.E. Meijer-van; Deurzen, C.H. van; MacGrogan, G.; Eynden, G.G. Van den; Purdie, C.; Thompson, A.M.; Caldas, C.; Span, P.N; Simpson, P.T.; Lakhani, S.R.; Laere, S. van; Desmedt, C.; Ringner, M.; Tommasi, S.; Eyford, J.; Broeks, A.; Vincent-Salomon, A.; Futreal, P.A.; Knappskog, S.; King, T.; Thomas, G; Viari, A.; Langerod, A.; Borresen-Dale, A.L.; Birney, E.; Stunnenberg, H.G.; Stratton, M.; Foekens, J.A.; Martens, J.W.M.

    2016-01-01

    A recent comprehensive whole genome analysis of a large breast cancer cohort was used to link known and novel drivers and substitution signatures to the transcriptome of 266 cases. Here, we validate that subtype-specific aberrations show concordant expression changes for, for example, TP53, PIK3CA,

  12. Integrating proteomic and functional genomic technologies in discovery-driven translational breast cancer research

    DEFF Research Database (Denmark)

    Celis, Julio E; Gromov, Pavel; Gromova, Irina

    2003-01-01

    The application of state-of-the-art proteomics and functional genomics technologies to the study of cancer is rapidly shifting toward the analysis of clinically relevant samples derived from patients, as the ultimate aim of translational research is to bring basic discoveries closer to the bedsid...

  13. Gross genomic damage measured by DNA image cytometry independently predicts gastric cancer patient survival

    NARCIS (Netherlands)

    Belien, J.A.M.; Buffart, T.E.; Gill, A.; Broeckaert, M.A.M.; Quirke, P.; Meijer, G.A.; Grabsch, H.

    2009-01-01

    BACKGROUND: DNA aneuploidy reflects gross genomic changes. It can be measured by flow cytometry (FCM-DNA) or image cytometry (ICM-DNA). In gastric cancer, the prevalence of DNA aneuploidy has been reported to range from 27 to 100%, with conflicting associations with clinicopathological variables. Th

  14. Noncoding Genomics in Gastric Cancer and the Gastric Precancerous Cascade: Pathogenesis and Biomarkers

    Directory of Open Access Journals (Sweden)

    Alejandra Sandoval-Bórquez

    2015-01-01

    Full Text Available Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related death, whose patterns vary among geographical regions and ethnicities. It is a multifactorial disease, and its development depends on infection by Helicobacter pylori (H. pylori and Epstein-Barr virus (EBV, host genetic factors, and environmental factors. The heterogeneity of the disease has begun to be unraveled by a comprehensive mutational evaluation of primary tumors. The low-abundance of mutations suggests that other mechanisms participate in the evolution of the disease, such as those found through analyses of noncoding genomics. Noncoding genomics includes single nucleotide polymorphisms (SNPs, regulation of gene expression through DNA methylation of promoter sites, miRNAs, other noncoding RNAs in regulatory regions, and other topics. These processes and molecules ultimately control gene expression. Potential biomarkers are appearing from analyses of noncoding genomics. This review focuses on noncoding genomics and potential biomarkers in the context of gastric cancer and the gastric precancerous cascade.

  15. Chromothripsis is a common mechanism driving genomic rearrangements in primary and metastatic colorectal cancer

    NARCIS (Netherlands)

    Kloosterman, W.P.; Hoogstraat, M.; Paling, O.; Tavakoli-Yaraki, M.; Renkens, I.; Vermaat, J.E.; van Roosmalen, M.; van Lieshout, S.; Nijman, I.J.; Roessingh, W.; Van't Slot, R.; van de Belt, J.; Guryev, V.; Koudijs, M.J.; Voest, E.E.; Cuppen, E.

    2011-01-01

    ABSTRACT: BACKGROUND: Structural rearrangements form a major class of somatic variation in cancer genomes. Local chromosome shattering, termed chromothripsis, is a mechanism proposed to be the cause of clustered chromosomal rearrangements and was recently described to occur in a small percentage of

  16. Chromothripsis is a common mechanism driving genomic rearrangements in primary and metastatic colorectal cancer

    NARCIS (Netherlands)

    Kloosterman, W.P.; Hoogstraat, M.; Paling, O.; Tavakoli-Yaraki, M.; Renkens, I.; Vermaat, J.S.; Roosmalen, van M.J.; Lieshout, van S.; Nijman, I.J.; Roessingh, W.; Slot, van 't R.; Belt, van de J.

    2011-01-01

    Background - Structural rearrangements form a major class of somatic variation in cancer genomes. Local chromosome shattering, termed chromothripsis, is a mechanism proposed to be the cause of clustered chromosomal rearrangements and was recently described to occur in a small percentage of tumors. T

  17. Mitochondrial Genome Deletion for Detection of Prostate Cancer — EDRN Public Portal

    Science.gov (United States)

    The Prostate Core Mitomic Test™ is based upon a 3.4 kb mitochondrial genome deletion (3.4 mtdelta) that was identified through PCR analysis of frozen prostate cancer samples. In cancer research it has been found that deletions in mitochondrial DNA can correlate with cellular changes that indicate development of cancer. This deletion includes the terminal 22 bases of MT-ND4L, all of MT-ND4, 3 tRNAs (histidine, serine 2, and leucine 2), and all except the terminal 24 bases of MT-ND5.

  18. Data Mining Approaches for Genomic Biomarker Development: Applications Using Drug Screening Data from the Cancer Genome Project and the Cancer Cell Line Encyclopedia.

    Science.gov (United States)

    Covell, David G

    2015-01-01

    Developing reliable biomarkers of tumor cell drug sensitivity and resistance can guide hypothesis-driven basic science research and influence pre-therapy clinical decisions. A popular strategy for developing biomarkers uses characterizations of human tumor samples against a range of cancer drug responses that correlate with genomic change; developed largely from the efforts of the Cancer Cell Line Encyclopedia (CCLE) and Sanger Cancer Genome Project (CGP). The purpose of this study is to provide an independent analysis of this data that aims to vet existing and add novel perspectives to biomarker discoveries and applications. Existing and alternative data mining and statistical methods will be used to a) evaluate drug responses of compounds with similar mechanism of action (MOA), b) examine measures of gene expression (GE), copy number (CN) and mutation status (MUT) biomarkers, combined with gene set enrichment analysis (GSEA), for hypothesizing biological processes important for drug response, c) conduct global comparisons of GE, CN and MUT as biomarkers across all drugs screened in the CGP dataset, and d) assess the positive predictive power of CGP-derived GE biomarkers as predictors of drug response in CCLE tumor cells. The perspectives derived from individual and global examinations of GEs, MUTs and CNs confirm existing and reveal unique and shared roles for these biomarkers in tumor cell drug sensitivity and resistance. Applications of CGP-derived genomic biomarkers to predict the drug response of CCLE tumor cells finds a highly significant ROC, with a positive predictive power of 0.78. The results of this study expand the available data mining and analysis methods for genomic biomarker development and provide additional support for using biomarkers to guide hypothesis-driven basic science research and pre-therapy clinical decisions.

  19. Data Mining Approaches for Genomic Biomarker Development: Applications Using Drug Screening Data from the Cancer Genome Project and the Cancer Cell Line Encyclopedia.

    Directory of Open Access Journals (Sweden)

    David G Covell

    Full Text Available Developing reliable biomarkers of tumor cell drug sensitivity and resistance can guide hypothesis-driven basic science research and influence pre-therapy clinical decisions. A popular strategy for developing biomarkers uses characterizations of human tumor samples against a range of cancer drug responses that correlate with genomic change; developed largely from the efforts of the Cancer Cell Line Encyclopedia (CCLE and Sanger Cancer Genome Project (CGP. The purpose of this study is to provide an independent analysis of this data that aims to vet existing and add novel perspectives to biomarker discoveries and applications. Existing and alternative data mining and statistical methods will be used to a evaluate drug responses of compounds with similar mechanism of action (MOA, b examine measures of gene expression (GE, copy number (CN and mutation status (MUT biomarkers, combined with gene set enrichment analysis (GSEA, for hypothesizing biological processes important for drug response, c conduct global comparisons of GE, CN and MUT as biomarkers across all drugs screened in the CGP dataset, and d assess the positive predictive power of CGP-derived GE biomarkers as predictors of drug response in CCLE tumor cells. The perspectives derived from individual and global examinations of GEs, MUTs and CNs confirm existing and reveal unique and shared roles for these biomarkers in tumor cell drug sensitivity and resistance. Applications of CGP-derived genomic biomarkers to predict the drug response of CCLE tumor cells finds a highly significant ROC, with a positive predictive power of 0.78. The results of this study expand the available data mining and analysis methods for genomic biomarker development and provide additional support for using biomarkers to guide hypothesis-driven basic science research and pre-therapy clinical decisions.

  20. Organoids as Models for Neoplastic Transformation | Office of Cancer Genomics

    Science.gov (United States)

    Cancer models strive to recapitulate the incredible diversity inherent in human tumors. A key challenge in accurate tumor modeling lies in capturing the panoply of homo- and heterotypic cellular interactions within the context of a three-dimensional tissue microenvironment. To address this challenge, researchers have developed organotypic cancer models (organoids) that combine the 3D architecture of in vivo tissues with the experimental facility of 2D cell lines.

  1. Evaluation of atlas-based auto-segmentation software in prostate cancer patients

    Energy Technology Data Exchange (ETDEWEB)

    Greenham, Stuart, E-mail: stuart.greenham@ncahs.health.nsw.gov.au [Department of Radiation Oncology, North Coast Cancer Institute, Coffs Harbour Health Campus, Coffs Harbour, New South Wales (Australia); Dean, Jenna [North Coast Cancer Institute, Port Macquarie Health Campus, Port Macquarie, New South Wales (Australia); Fu, Cheuk Kuen Kenneth [North Coast Cancer Institute, Lismore Health Campus, Lismore, New South Wales (Australia); Goman, Joanne [Department of Radiation Oncology, Calvary Mater Newcastle, Newcastle, New South Wales (Australia); Mulligan, Jeremy [North Coast Cancer Institute, Port Macquarie Health Campus, Port Macquarie, New South Wales (Australia); Tune, Deanna [Department of Radiation Oncology, North Coast Cancer Institute, Coffs Harbour Health Campus, Coffs Harbour, New South Wales (Australia); Sampson, David [North Coast Cancer Institute, Lismore Health Campus, Lismore, New South Wales (Australia); Westhuyzen, Justin [Department of Radiation Oncology, North Coast Cancer Institute, Coffs Harbour Health Campus, Coffs Harbour, New South Wales (Australia); McKay, Michael [North Coast Cancer Institute, Lismore Health Campus, Lismore, New South Wales (Australia); Department of Radiation Oncology, North Coast Cancer Institute, Coffs Harbour Health Campus, Coffs Harbour, New South Wales (Australia)

    2014-09-15

    The performance and limitations of an atlas-based auto-segmentation software package (ABAS; Elekta Inc.) was evaluated using male pelvic anatomy as the area of interest. Contours from 10 prostate patients were selected to create atlases in ABAS. The contoured regions of interest were created manually to align with published guidelines and included the prostate, bladder, rectum, femoral heads and external patient contour. Twenty-four clinically treated prostate patients were auto-contoured using a randomised selection of two, four, six, eight or ten atlases. The concordance between the manually drawn and computer-generated contours were evaluated statistically using Pearson's product–moment correlation coefficient (r) and clinically in a validated qualitative evaluation. In the latter evaluation, six radiation therapists classified the degree of agreement for each structure using seven clinically appropriate categories. The ABAS software generated clinically acceptable contours for the bladder, rectum, femoral heads and external patient contour. For these structures, ABAS-generated volumes were highly correlated with ‘as treated’ volumes, manually drawn; for four atlases, for example, bladder r = 0.988 (P < 0.001), rectum r = 0.739 (P < 0.001) and left femoral head r = 0.560 (P < 0.001). Poorest results were seen for the prostate (r = 0.401, P < 0.05) (four atlases); however this was attributed to the comparison prostate volume being contoured on magnetic resonance imaging (MRI) rather than computed tomography (CT) data. For all structures, increasing the number of atlases did not consistently improve accuracy. ABAS-generated contours are clinically useful for a range of structures in the male pelvis. Clinically appropriate volumes were created, but editing of some contours was inevitably required. The ideal number of atlases to improve generated automatic contours is yet to be determined.

  2. [Genomic Tests as Predictors of Breast Cancer Patients Prognosis].

    Science.gov (United States)

    Bielčiková, Z; Petruželka, L

    2016-01-01

    Hormonal dependent breast cancer is a heterogeneous disease from a molecular and clinical perspective. The relapse risk of early breast cancer patients treated with adjuvant hormonal therapy varies. Validated predictive markers concerning adjuvant cytotoxic treatment are still lacking in ER+/ HER2-  breast cancer, which has a good prognosis in general. This can lead to the inefficient chemotherapy indication. Molecular classification of breast cancer reports evidence about the heterogeneity of hormonal dependent breast cancer and its stratification to different groups with different characteristics. Multigene assays work on the molecular level, and their aim is to provide patients risk stratification and therapy efficacy prediction. The position of multigene assays in clinical practice is not stabile yet. Non uniform level of evidence connected to patients prognosis interpretations and difficult comparison of tests are the key problems, which prevent their wide clinical use. The article is a summary of some of the most important multigene assays in breast cancer and their current position in oncology practice.

  3. Gastric cancers of Western European and African patients show different patterns of genomic instability

    Directory of Open Access Journals (Sweden)

    Mulder Chris JJ

    2011-01-01

    Full Text Available Abstract Background Infection with H. pylori is important in the etiology of gastric cancer. Gastric cancer is infrequent in Africa, despite high frequencies of H. pylori infection, referred to as the African enigma. Variation in environmental and host factors influencing gastric cancer risk between different populations have been reported but little is known about the biological differences between gastric cancers from different geographic locations. We aim to study genomic instability patterns of gastric cancers obtained from patients from United Kingdom (UK and South Africa (SA, in an attempt to support the African enigma hypothesis at the biological level. Methods DNA was isolated from 67 gastric adenocarcinomas, 33 UK patients, 9 Caucasian SA patients and 25 native SA patients. Microsatellite instability and chromosomal instability were analyzed by PCR and microarray comparative genomic hybridization, respectively. Data was analyzed by supervised univariate and multivariate analyses as well as unsupervised hierarchical cluster analysis. Results Tumors from Caucasian and native SA patients showed significantly more microsatellite instable tumors (p Conclusions Gastric cancers from SA and UK patients show differences in genetic instability patterns, indicating possible different biological mechanisms in patients from different geographical origin. This is of future clinical relevance for stratification of gastric cancer therapy.

  4. Commentary on Almassalha et al., "The Greater Genomic Landscape: The Heterogeneous Evolution of Cancer".

    Science.gov (United States)

    Lynch, Henry T; Rendell, Marc; Shaw, Trudy G; Silberstein, Peter; Ngo, Binh T

    2016-10-01

    In this issue of Cancer Research, Almassalha and colleagues have proposed a new concept of the development of malignancy, that of the greater genomic landscape. They propose a stressor-related exploration of intracellular genomic sites as a response mechanism. This process can express sites with beneficial or deleterious effects, among them those that promote cell proliferation. They point out that their conception is broader, although certainly inclusive, of the process of gene induction. The authors view the physical process of chromatin reorganization as central to the exploration of the genomic landscape. Accordingly, they advocate the development of agents to limit chromatin structural modification as a chemotherapeutic approach in cancer. We found their theory relevant to understand the phenotypic heterogeneity of malignancy, particularly in familial cancer syndromes. For example, the familial atypical multiple mole melanoma (FAMMM) syndrome, related to a gene mutation, is characterized by a diversity of melanocytic lesions, only some of which become malignant melanoma. This new conceptualization can do much to increase understanding of the diversity of malignancy in families with hereditary cancer. Cancer Res; 76(19); 5602-4. ©2016 AACR.

  5. Acetylation Reader Proteins: Linking Acetylation Signaling to Genome Maintenance and Cancer.

    Science.gov (United States)

    Gong, Fade; Chiu, Li-Ya; Miller, Kyle M

    2016-09-01

    Chromatin-based DNA damage response (DDR) pathways are fundamental for preventing genome and epigenome instability, which are prevalent in cancer. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) catalyze the addition and removal of acetyl groups on lysine residues, a post-translational modification important for the DDR. Acetylation can alter chromatin structure as well as function by providing binding signals for reader proteins containing acetyl-lysine recognition domains, including the bromodomain (BRD). Acetylation dynamics occur upon DNA damage in part to regulate chromatin and BRD protein interactions that mediate key DDR activities. In cancer, DDR and acetylation pathways are often mutated or abnormally expressed. DNA damaging agents and drugs targeting epigenetic regulators, including HATs, HDACs, and BRD proteins, are used or are being developed to treat cancer. Here, we discuss how histone acetylation pathways, with a focus on acetylation reader proteins, promote genome stability and the DDR. We analyze how acetylation signaling impacts the DDR in the context of cancer and its treatments. Understanding the relationship between epigenetic regulators, the DDR, and chromatin is integral for obtaining a mechanistic understanding of genome and epigenome maintenance pathways, information that can be leveraged for targeting acetylation signaling, and/or the DDR to treat diseases, including cancer.

  6. Integrated analysis of copy number variation and genome-wide expression profiling in colorectal cancer tissues.

    Science.gov (United States)

    Ali Hassan, Nur Zarina; Mokhtar, Norfilza Mohd; Kok Sin, Teow; Mohamed Rose, Isa; Sagap, Ismail; Harun, Roslan; Jamal, Rahman

    2014-01-01

    Integrative analyses of multiple genomic datasets for selected samples can provide better insight into the overall data and can enhance our knowledge of cancer. The objective of this study was to elucidate the association between copy number variation (CNV) and gene expression in colorectal cancer (CRC) samples and their corresponding non-cancerous tissues. Sixty-four paired CRC samples from the same patients were subjected to CNV profiling using the Illumina HumanOmni1-Quad assay, and validation was performed using multiplex ligation probe amplification method. Genome-wide expression profiling was performed on 15 paired samples from the same group of patients using the Affymetrix Human Gene 1.0 ST array. Significant genes obtained from both array results were then overlapped. To identify molecular pathways, the data were mapped to the KEGG database. Whole genome CNV analysis that compared primary tumor and non-cancerous epithelium revealed gains in 1638 genes and losses in 36 genes. Significant gains were mostly found in chromosome 20 at position 20q12 with a frequency of 45.31% in tumor samples. Examples of genes that were associated at this cytoband were PTPRT, EMILIN3 and CHD6. The highest number of losses was detected at chromosome 8, position 8p23.2 with 17.19% occurrence in all tumor samples. Among the genes found at this cytoband were CSMD1 and DLC1. Genome-wide expression profiling showed 709 genes to be up-regulated and 699 genes to be down-regulated in CRC compared to non-cancerous samples. Integration of these two datasets identified 56 overlapping genes, which were located in chromosomes 8, 20 and 22. MLPA confirmed that the CRC samples had the highest gains in chromosome 20 compared to the reference samples. Interpretation of the CNV data in the context of the transcriptome via integrative analyses may provide more in-depth knowledge of the genomic landscape of CRC.

  7. Integrated analysis of copy number variation and genome-wide expression profiling in colorectal cancer tissues.

    Directory of Open Access Journals (Sweden)

    Nur Zarina Ali Hassan

    Full Text Available Integrative analyses of multiple genomic datasets for selected samples can provide better insight into the overall data and can enhance our knowledge of cancer. The objective of this study was to elucidate the association between copy number variation (CNV and gene expression in colorectal cancer (CRC samples and their corresponding non-cancerous tissues. Sixty-four paired CRC samples from the same patients were subjected to CNV profiling using the Illumina HumanOmni1-Quad assay, and validation was performed using multiplex ligation probe amplification method. Genome-wide expression profiling was performed on 15 paired samples from the same group of patients using the Affymetrix Human Gene 1.0 ST array. Significant genes obtained from both array results were then overlapped. To identify molecular pathways, the data were mapped to the KEGG database. Whole genome CNV analysis that compared primary tumor and non-cancerous epithelium revealed gains in 1638 genes and losses in 36 genes. Significant gains were mostly found in chromosome 20 at position 20q12 with a frequency of 45.31% in tumor samples. Examples of genes that were associated at this cytoband were PTPRT, EMILIN3 and CHD6. The highest number of losses was detected at chromosome 8, position 8p23.2 with 17.19% occurrence in all tumor samples. Among the genes found at this cytoband were CSMD1 and DLC1. Genome-wide expression profiling showed 709 genes to be up-regulated and 699 genes to be down-regulated in CRC compared to non-cancerous samples. Integration of these two datasets identified 56 overlapping genes, which were located in chromosomes 8, 20 and 22. MLPA confirmed that the CRC samples had the highest gains in chromosome 20 compared to the reference samples. Interpretation of the CNV data in the context of the transcriptome via integrative analyses may provide more in-depth knowledge of the genomic landscape of CRC.

  8. Identification of Variant-Specific Functions of PIK3CA by Rapid Phenotyping of Rare Mutations | Office of Cancer Genomics

    Science.gov (United States)

    Large-scale sequencing efforts are uncovering the complexity of cancer genomes, which are composed of causal "driver" mutations that promote tumor progression along with many more pathologically neutral "passenger" events. The majority of mutations, both in known cancer drivers and uncharacterized genes, are generally of low occurrence, highlighting the need to functionally annotate the long tail of infrequent mutations present in heterogeneous cancers.

  9. Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia.

    NARCIS (Netherlands)

    Lan, Q.; Hsiung, C.A.; Matsuo, K.; Hong, Y.C.; Seow, A.; Wang, Z.; Hosgood, H.D.; Chen, K.; Wang, J.C.; Chatterjee, N.; Hu, W.; Wong, M.P.; Zheng, W.; Caporaso, N.; Park, J.Y.; Chen, C.J.; Kim, Y.H.; Kim, Y.T.; Landi, M.T.; Shen, H.; Lawrence, C.; Burdett, L.; Yeager, M.; Yuenger, J.; Jacobs, K.B.; Chang, I.S.; Mitsudomi, T.; Kim, H.N.; Chang, G.C.; Bassig, B.A.; Tucker, M.; Wei, F.; Yin, Y.; Wu, C.; An, S.J.; Qian, B.; Lee, V.H.; Lu, D.; Liu, J.; Jeon, H.S.; Hsiao, C.F.; Sung, J.S.; Kim, J.H.; Gao, Y.T.; Tsai, Y.H.; Jung, Y.J.; Guo, H.; Hu, Z.; Hutchinson, A.; Wang, W.C.; Klein, R.; Chung, C.C.; Oh, I.J.; Chen, K.Y.; Berndt, S.I.; He, X.; Wu, W.; Chang, J.; Zhang, X.C.; Huang, M.S.; Zheng, H.; Wang, J.; Zhao, X.; Li, Y.; Choi, J.E.; Su, W.C.; Park, K.H.; Sung, S.W.; Shu, X.O.; Chen, Y.M.; Liu, L.; Kang, C.H.; Hu, L.; Chen, C.H.; Pao, W.; Kim, Y.C.; Yang, T.Y.; Xu, J.; Guan, P.; Tan, W.; Su, J.; Wang, C.L.; Li, H.; Sihoe, A.D.; Zhao, Z.; Chen, Y.; Choi, Y.Y.; Hung, J.Y.; Kim, J.S.; Yoon, H.I.; Cai, Q.; Lin, C.C.; Park, I.K.; Xu, P.; Dong, J.; Kim, C.; He, Q; Perng, R.P.; Kohno, T.; Kweon, S.S.; Chen, C.Y.; Vermeulen, R.; Wu, J.; Lim, W.Y.; Chen, K.C.; Chow, W.H.; Ji, B.T.; Chan, J.K.; Chu, M.; Li, Y.J.; Yokota, J.; Li, J.; Chen, H.; Xiang, Y.B.; Yu, C.J.; Kunitoh, H.; Wu, G.; Jin, L.; Lo, Y.L.; Shiraishi, K.; Chen, Y.H.; Lin, H.C.; Wu, T.; WU, Y.; Yang, P.C.; Zhou, B.; Shin, M.H.; Fraumeni, J.F.; Lin, D.; Chanock, S.J.; Rothman, N.

    2012-01-01

    To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland Ch

  10. The importance of p53 pathway genetics in inherited and somatic cancer genomes.

    Science.gov (United States)

    Stracquadanio, Giovanni; Wang, Xuting; Wallace, Marsha D; Grawenda, Anna M; Zhang, Ping; Hewitt, Juliet; Zeron-Medina, Jorge; Castro-Giner, Francesc; Tomlinson, Ian P; Goding, Colin R; Cygan, Kamil J; Fairbrother, William G; Thomas, Laurent F; Sætrom, Pål; Gemignani, Federica; Landi, Stefano; Schuster-Böckler, Benjamin; Bell, Douglas A; Bond, Gareth L

    2016-04-01

    Decades of research have shown that mutations in the p53 stress response pathway affect the incidence of diverse cancers more than mutations in other pathways. However, most evidence is limited to somatic mutations and rare inherited mutations. Using newly abundant genomic data, we demonstrate that commonly inherited genetic variants in the p53 pathway also affect the incidence of a broad range of cancers more than variants in other pathways. The cancer-associated single nucleotide polymorphisms (SNPs) of the p53 pathway have strikingly similar genetic characteristics to well-studied p53 pathway cancer-causing somatic mutations. Our results enable insights into p53-mediated tumour suppression in humans and into p53 pathway-based cancer surveillance and treatment strategies.

  11. Figure 2 from Integrative Genomics Viewer: Visualizing Big Data | Office of Cancer Genomics

    Science.gov (United States)

    Grouping and sorting genomic data in IGV. The IGV user interface displaying 202 glioblastoma samples from TCGA. Samples are grouped by tumor subtype (second annotation column) and data type (first annotation column) and sorted by copy number of the EGFR locus (middle column). Adapted from Figure 1; Robinson et al. 2011

  12. Figure 4 from Integrative Genomics Viewer: Visualizing Big Data | Office of Cancer Genomics

    Science.gov (United States)

    Gene-list view of genomic data. The gene-list view allows users to compare data across a set of loci. The data in this figure includes copy number, mutation, and clinical data from 202 glioblastoma samples from TCGA. Adapted from Figure 7; Thorvaldsdottir H et al. 2012

  13. Figure 5 from Integrative Genomics Viewer: Visualizing Big Data | Office of Cancer Genomics

    Science.gov (United States)

    Split-Screen View. The split-screen view is useful for exploring relationships of genomic features that are independent of chromosomal location. Color is used here to indicate mate pairs that map to different chromosomes, chromosomes 1 and 6, suggesting a translocation event. Adapted from Figure 8; Thorvaldsdottir H et al. 2012

  14. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

    DEFF Research Database (Denmark)

    Gusev, Alexander; Shi, Huwenbo; Kichaev, Gleb

    2016-01-01

    Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with c...

  15. Centrosome Dysfunction Contributes To Chromosome Instability, Chromoanagenesis And Genome Reprograming In Cancer.

    Directory of Open Access Journals (Sweden)

    German A Pihan

    2013-11-01

    Full Text Available The unique ability of centrosomes to nucleate and organize microtubules makes them unrivaled conductors of important interphase processes, such as intracellular payload traffic, cell polarity, cell locomotion, and organization of the immunologic synapse. But it is in mitosis that centrosomes loom large, for they orchestrate, with clockmaker’s precision, the assembly and functioning of the mitotic spindle, ensuring the equal partitioning of the replicated genome into daughter cells. Centrosome dysfunction is inextricably linked to aneuploidy and chromosome instability, both hallmarks of cancer cells. Several aspects of centrosome function in normal and cancer cells have been molecularly characterized during the last two decades, greatly enhancing our mechanistic understanding of this tiny organelle. Whether centrosome defects alone can cause cancer, remains unanswered. Until recently, the aggregate of the evidence had suggested that centrosome dysfunction, by deregulating the fidelity of chromosome segregation, promotes and accelerates the characteristic Darwinian evolution of the cancer genome enabled by increased mutational load and/or decreased DNA repair. Very recent experimental work has shown that missegreated chromosomes resulting from centrosome dysfunction may experience extensive DNA damage, suggesting additional dimensions to the role of centrosomes in cancer. Centrosome dysfunction is particularly prevalent in tumors in which the genome has undergone extensive structural rearrangements and chromosome domain reshuffling. Ongoing gene reshuffling reprograms the genome for continuous growth, survival, and evasion of the immune system. Manipulation of molecular networks controlling centrosome function may soon become a viable target for specific therapeutic intervention in cancer, particularly since normal cells, which lack centrosome alterations, may be spared the toxicity of such therapies.

  16. A comprehensive catalogue of somatic mutations in cancer genomes.

    Science.gov (United States)

    Friedberg, Errol C

    2010-04-04

    This Hot Topics contribution considers two recently published papers that demonstrate the utility of advanced DNA sequencing technologies for identifying classes of mutations other than base substitutions. Data are presented from genome analyses of immortalized cell lines derived from a malignant melanoma and a small cell carcinoma of the lung. Among other observations the studies suggest the operation of novel DNA repair mechanisms or modes.

  17. Systematic identification of genomic markers of drug sensitivity in cancer cells.

    Science.gov (United States)

    Garnett, Mathew J; Edelman, Elena J; Heidorn, Sonja J; Greenman, Chris D; Dastur, Anahita; Lau, King Wai; Greninger, Patricia; Thompson, I Richard; Luo, Xi; Soares, Jorge; Liu, Qingsong; Iorio, Francesco; Surdez, Didier; Chen, Li; Milano, Randy J; Bignell, Graham R; Tam, Ah T; Davies, Helen; Stevenson, Jesse A; Barthorpe, Syd; Lutz, Stephen R; Kogera, Fiona; Lawrence, Karl; McLaren-Douglas, Anne; Mitropoulos, Xeni; Mironenko, Tatiana; Thi, Helen; Richardson, Laura; Zhou, Wenjun; Jewitt, Frances; Zhang, Tinghu; O'Brien, Patrick; Boisvert, Jessica L; Price, Stacey; Hur, Wooyoung; Yang, Wanjuan; Deng, Xianming; Butler, Adam; Choi, Hwan Geun; Chang, Jae Won; Baselga, Jose; Stamenkovic, Ivan; Engelman, Jeffrey A; Sharma, Sreenath V; Delattre, Olivier; Saez-Rodriguez, Julio; Gray, Nathanael S; Settleman, Jeffrey; Futreal, P Andrew; Haber, Daniel A; Stratton, Michael R; Ramaswamy, Sridhar; McDermott, Ultan; Benes, Cyril H

    2012-03-28

    Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.

  18. POSSIBLE REASONS FOR TP53 ACCUMULATION IN NASO- PHARYNGEAL CARCINOMA USING ATLAS HUMAN CANCER cDNA EXPRESSION ARRAY

    Institute of Scientific and Technical Information of China (English)

    李虹; 韩为农; 张玲; 冯湘玲; 姚开泰

    2002-01-01

    Objective: To compare gene expression profiles of nasopharyngeal carcinoma (NPC) tissue with that of control tissue by cDNA Array and to discuss possible reasons of TP53 accumulation in NPC tissue. Methods: (1) hybridization of Atlas Human Cancer cDNA Expression Array 7742-1; (2) analysis of Atlas Arrays using Atlasimage 1.01a; (3) verification of results of array by RT-PCR; (4) verification of protein expression alterations by immuno- histochemistry. Results: (1) Of 588 tumor-related genes, 134 genes were upregulated, 88 downregulated; (2) Of 32 TP53-regulated genes, 13 genes were shown differential expression, 11 upregulated, 2 downregulated; (3) ATM and JNK2 were upregulated; (4) mRNA expression of ubiquitin-conjugating enzyme E2 (M74524) and ubiquitin- conjugating enzyme E2 (L22005) has no evident changes; Conclusion: (1) TP53 dysfunction exists in NPC tissues; (2) ATM and JNK might be the important causes of TP53 accumulation.

  19. Comprehensive genomic sequencing and the molecular profiles of clinically advanced breast cancer.

    Science.gov (United States)

    Ross, Jeffrey S; Gay, Laurie M

    2017-02-01

    Targeting specific mutations that have arisen within a tumour is a promising means of increasing the efficacy of treatments, and breast cancer is no exception to this new paradigm of personalised medicine. Traditional DNA sequencing methods used to characterise clinical cancer specimens and impact treatment decisions are highly sensitive, but are often limited in their scope to known mutational hot spots. Next-generation sequencing (NGS) technologies can also test for these well-known hot spots, as well as identifying insertions and deletions, copy number changes such as ERBB2 (HER2) gene amplification, and a wide array of fusion or rearrangement events. By rapidly analysing many genes in parallel, NGS technologies can make efficient use of precious biopsy material. Comprehensive genomic profiling (CGP) by NGS can reveal targetable, clinically relevant genomic alterations that can stratify tumours by predicted sensitivity to a variety of therapies, including HER2- or MTOR-targeted therapies, immunotherapies, and other kinase inhibitors. Many clinically relevant genomic alterations would not be identified by IHC or hotspot testing, but can be detected by NGS. In addition to the most common breast carcinoma subtypes, rare subtypes analysed with CGP also harbour clinically relevant genomic alterations that can potentially direct therapy selection, illustrating that CGP is a powerful tool for guiding treatment across all breast cancer subtypes.

  20. Integrated functional, gene expression and genomic analysis for the identification of cancer targets.

    Directory of Open Access Journals (Sweden)

    Elizabeth Iorns

    Full Text Available The majority of new drug approvals for cancer are based on existing therapeutic targets. One approach to the identification of novel targets is to perform high-throughput RNA interference (RNAi cellular viability screens. We describe a novel approach combining RNAi screening in multiple cell lines with gene expression and genomic profiling to identify novel cancer targets. We performed parallel RNAi screens in multiple cancer cell lines to identify genes that are essential for viability in some cell lines but not others, suggesting that these genes constitute key drivers of cellular survival in specific cancer cells. This approach was verified by the identification of PIK3CA, silencing of which was selectively lethal to the MCF7 cell line, which harbours an activating oncogenic PIK3CA mutation. We combined our functional RNAi approach with gene expression and genomic analysis, allowing the identification of several novel kinases, including WEE1, that are essential for viability only in cell lines that have an elevated level of expression of this kinase. Furthermore, we identified a subset of breast tumours that highly express WEE1 suggesting that WEE1 could be a novel therapeutic target in breast cancer. In conclusion, this strategy represents a novel and effective strategy for the identification of functionally important therapeutic targets in cancer.

  1. Protein-Protein Interactions (PPI) reagents: | Office of Cancer Genomics

    Science.gov (United States)

    The CTD2 Center at Emory University has a library of genes used to study protein-protein interactions in mammalian cells. These genes are cloned in different mammalian expression vectors. A list of available cancer-associated genes can be accessed below.

  2. Protein-Protein Interaction Reagents | Office of Cancer Genomics

    Science.gov (United States)

    The CTD2 Center at Emory University has a library of genes used to study protein-protein interactions in mammalian cells. These genes are cloned in different mammalian expression vectors. A list of available cancer-associated genes can be accessed below. Emory_CTD^2_PPI_Reagents.xlsx Contact: Haian Fu

  3. MuSiC: identifying mutational significance in cancer genomes.

    Science.gov (United States)

    Dees, Nathan D; Zhang, Qunyuan; Kandoth, Cyriac; Wendl, Michael C; Schierding, William; Koboldt, Daniel C; Mooney, Thomas B; Callaway, Matthew B; Dooling, David; Mardis, Elaine R; Wilson, Richard K; Ding, Li

    2012-08-01

    Massively parallel sequencing technology and the associated rapidly decreasing sequencing costs have enabled systemic analyses of somatic mutations in large cohorts of cancer cases. Here we introduce a comprehensive mutational analysis pipeline that uses standardized sequence-based inputs along with multiple types of clinical data to establish correlations among mutation sites, affected genes and pathways, and to ultimately separate the commonly abundant passenger mutations from the truly significant events. In other words, we aim to determine the Mutational Significance in Cancer (MuSiC) for these large data sets. The integration of analytical operations in the MuSiC framework is widely applicable to a broad set of tumor types and offers the benefits of automation as well as standardization. Herein, we describe the computational structure and statistical underpinnings of the MuSiC pipeline and demonstrate its performance using 316 ovarian cancer samples from the TCGA ovarian cancer project. MuSiC correctly confirms many expected results, and identifies several potentially novel avenues for discovery.

  4. Genomic and transcriptomic plasticity in treatment-naive ovarian cancer

    NARCIS (Netherlands)

    Hoogstraat, Marlous; de Pagter, Mirjam S; Cirkel, Geert A; van Roosmalen, Markus J; Harkins, Timothy T; Duran, Karen; Kreeftmeijer, Jennifer; Renkens, Ivo; Witteveen, Petronella O; Lee, Clarence C; Nijman, Isaac J; Guy, Tanisha; van 't Slot, Ruben; Jonges, Trudy N; Lolkema, Martijn P; Koudijs, Marco J; Zweemer, Ronald P; Voest, Emile E; Cuppen, Edwin; Kloosterman, Wigard P

    2014-01-01

    Intra-tumor heterogeneity is a hallmark of many cancers and may lead to therapy resistance or interfere with personalized treatment strategies. Here, we combined topographic mapping of somatic breakpoints and transcriptional profiling to probe intra-tumor heterogeneity of treatment-naïve stage IIIC/

  5. Genomic Alterations in Liquid Biopsies from Patients with Bladder Cancer

    DEFF Research Database (Denmark)

    Birkenkamp-Demtröder, Karin; Nordentoft, Iver Kristiansen; Christensen, Emil;

    2016-01-01

    Background: At least half of the patients diagnosed with non–muscle-invasive bladder cancer (NMIBC) experience recurrence and approximately 15% will develop progression to muscle invasive or metastatic disease. Biomarkers for disease surveillance are urgently needed. Objective: Development of ass...

  6. Integration of genomics and histology revises diagnosis and enables effective therapy of refractory cancer of unknown primary with PDL1 amplification.

    Science.gov (United States)

    Gröschel, Stefan; Bommer, Martin; Hutter, Barbara; Budczies, Jan; Bonekamp, David; Heining, Christoph; Horak, Peter; Fröhlich, Martina; Uhrig, Sebastian; Hübschmann, Daniel; Geörg, Christina; Richter, Daniela; Pfarr, Nicole; Pfütze, Katrin; Wolf, Stephan; Schirmacher, Peter; Jäger, Dirk; von Kalle, Christof; Brors, Benedikt; Glimm, Hanno; Weichert, Wilko; Stenzinger, Albrecht; Fröhling, Stefan

    2016-11-01

    Identification of the tissue of origin in cancer of unknown primary (CUP) poses a diagnostic challenge and is critical for directing site-specific therapy. Currently, clinical decision-making in patients with CUP primarily relies on histopathology and clinical features. Comprehensive molecular profiling has the potential to contribute to diagnostic categorization and, most importantly, guide CUP therapy through identification of actionable lesions. We here report the case of an advanced-stage malignancy initially mimicking poorly differentiated soft-tissue sarcoma that did not respond to multiagent chemotherapy. Molecular profiling within a clinical whole-exome and transcriptome sequencing program revealed a heterozygous, highly amplified KRAS G12S mutation, compound-heterozygous TP53 mutation/deletion, high mutational load, and focal high-level amplification of Chromosomes 9p (including PDL1 [CD274] and JAK2) and 10p (including GATA3). Integrated analysis of molecular data and histopathology provided a rationale for immune checkpoint inhibitor (ICI) therapy with pembrolizumab, which resulted in rapid clinical improvement and a lasting partial remission. Histopathological analyses ruled out sarcoma and established the diagnosis of a poorly differentiated adenocarcinoma. Although neither histopathology nor molecular data were able to pinpoint the tissue of origin, our analyses established several differential diagnoses including triple-negative breast cancer (TNBC). We analyzed 157 TNBC samples from The Cancer Genome Atlas, revealing PDL1 copy number gains coinciding with excessive PDL1 mRNA expression in 24% of cases. Collectively, these results illustrate the impact of multidimensional tumor profiling in cases with nondescript histology and immunophenotype, show the predictive potential of PDL1 amplification for immune checkpoint inhibitors (ICIs), and suggest a targeted therapeutic strategy in Chromosome 9p24.1/PDL1-amplified cancers.

  7. Five endometrial cancer risk loci identified through genome-wide association analysis.

    Science.gov (United States)

    Cheng, Timothy H T; Thompson, Deborah J; O'Mara, Tracy A; Painter, Jodie N; Glubb, Dylan M; Flach, Susanne; Lewis, Annabelle; French, Juliet D; Freeman-Mills, Luke; Church, David; Gorman, Maggie; Martin, Lynn; Hodgson, Shirley; Webb, Penelope M; Attia, John; Holliday, Elizabeth G; McEvoy, Mark; Scott, Rodney J; Henders, Anjali K; Martin, Nicholas G; Montgomery, Grant W; Nyholt, Dale R; Ahmed, Shahana; Healey, Catherine S; Shah, Mitul; Dennis, Joe; Fasching, Peter A; Beckmann, Matthias W; Hein, Alexander; Ekici, Arif B; Hall, Per; Czene, Kamila; Darabi, Hatef; Li, Jingmei; Dörk, Thilo; Dürst, Matthias; Hillemanns, Peter; Runnebaum, Ingo; Amant, Frederic; Schrauwen, Stefanie; Zhao, Hui; Lambrechts, Diether; Depreeuw, Jeroen; Dowdy, Sean C; Goode, Ellen L; Fridley, Brooke L; Winham, Stacey J; Njølstad, Tormund S; Salvesen, Helga B; Trovik, Jone; Werner, Henrica M J; Ashton, Katie; Otton, Geoffrey; Proietto, Tony; Liu, Tao; Mints, Miriam; Tham, Emma; Li, Mulin Jun; Yip, Shun H; Wang, Junwen; Bolla, Manjeet K; Michailidou, Kyriaki; Wang, Qin; Tyrer, Jonathan P; Dunlop, Malcolm; Houlston, Richard; Palles, Claire; Hopper, John L; Peto, Julian; Swerdlow, Anthony J; Burwinkel, Barbara; Brenner, Hermann; Meindl, Alfons; Brauch, Hiltrud; Lindblom, Annika; Chang-Claude, Jenny; Couch, Fergus J; Giles, Graham G; Kristensen, Vessela N; Cox, Angela; Cunningham, Julie M; Pharoah, Paul D P; Dunning, Alison M; Edwards, Stacey L; Easton, Douglas F; Tomlinson, Ian; Spurdle, Amanda B

    2016-06-01

    We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r(2) = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.

  8. Genome-wide association study identifies multiple loci associated with bladder cancer risk

    Science.gov (United States)

    Figueroa, Jonine D.; Ye, Yuanqing; Siddiq, Afshan; Garcia-Closas, Montserrat; Chatterjee, Nilanjan; Prokunina-Olsson, Ludmila; Cortessis, Victoria K.; Kooperberg, Charles; Cussenot, Olivier; Benhamou, Simone; Prescott, Jennifer; Porru, Stefano; Dinney, Colin P.; Malats, Núria; Baris, Dalsu; Purdue, Mark; Jacobs, Eric J.; Albanes, Demetrius; Wang, Zhaoming; Deng, Xiang; Chung, Charles C.; Tang, Wei; Bas Bueno-de-Mesquita, H.; Trichopoulos, Dimitrios; Ljungberg, Börje; Clavel-Chapelon, Françoise; Weiderpass, Elisabete; Krogh, Vittorio; Dorronsoro, Miren; Travis, Ruth; Tjønneland, Anne; Brenan, Paul; Chang-Claude, Jenny; Riboli, Elio; Conti, David; Gago-Dominguez, Manuela; Stern, Mariana C.; Pike, Malcolm C.; Van Den Berg, David; Yuan, Jian-Min; Hohensee, Chancellor; Rodabough, Rebecca; Cancel-Tassin, Geraldine; Roupret, Morgan; Comperat, Eva; Chen, Constance; De Vivo, Immaculata; Giovannucci, Edward; Hunter, David J.; Kraft, Peter; Lindstrom, Sara; Carta, Angela; Pavanello, Sofia; Arici, Cecilia; Mastrangelo, Giuseppe; Kamat, Ashish M.; Lerner, Seth P.; Barton Grossman, H.; Lin, Jie; Gu, Jian; Pu, Xia; Hutchinson, Amy; Burdette, Laurie; Wheeler, William; Kogevinas, Manolis; Tardón, Adonina; Serra, Consol; Carrato, Alfredo; García-Closas, Reina; Lloreta, Josep; Schwenn, Molly; Karagas, Margaret R.; Johnson, Alison; Schned, Alan; Armenti, Karla R.; Hosain, G.M.; Andriole, Gerald; Grubb, Robert; Black, Amanda; Ryan Diver, W.; Gapstur, Susan M.; Weinstein, Stephanie J.; Virtamo, Jarmo; Haiman, Chris A.; Landi, Maria T.; Caporaso, Neil; Fraumeni, Joseph F.; Vineis, Paolo; Wu, Xifeng; Silverman, Debra T.; Chanock, Stephen; Rothman, Nathaniel

    2014-01-01

    Candidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 × 10−5 was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 × 10−9) and rs907611 on 11p15.5 (P = 4.11 × 10−8). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 × 10−7) and rs4510656 on 6p22.3 (P = 6.98 × 10−7); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis. PMID:24163127

  9. Clonal expansion and linear genome evolution through breast cancer progression from pre-invasive stages to asynchronous metastasis

    DEFF Research Database (Denmark)

    Krøigård, Anne Bruun; Larsen, Martin Jakob; Lænkholm, Anne Vibeke;

    2015-01-01

    Evolution of the breast cancer genome from pre-invasive stages to asynchronous metastasis is complex and mostly unexplored, but highly demanded as it may provide novel markers for and mechanistic insights in cancer progression. The increasing use of personalized therapy of breast cancer necessita......Evolution of the breast cancer genome from pre-invasive stages to asynchronous metastasis is complex and mostly unexplored, but highly demanded as it may provide novel markers for and mechanistic insights in cancer progression. The increasing use of personalized therapy of breast cancer...... progression from one breast cancer patient, including two different regions of Ductal Carcinoma In Situ (DCIS), primary tumor and an asynchronous metastasis. We identify a remarkable landscape of somatic mutations, retained throughout breast cancer progression and with new mutational events emerging at each...

  10. Genomic DNA copy-number alterations of the let-7 family in human cancers.

    Directory of Open Access Journals (Sweden)

    Yanling Wang

    Full Text Available In human cancer, expression of the let-7 family is significantly reduced, and this is associated with shorter survival times in patients. However, the mechanisms leading to let-7 downregulation in cancer are still largely unclear. Since an alteration in copy-number is one of the causes of gene deregulation in cancer, we examined copy number alterations of the let-7 family in 2,969 cancer specimens from a high-resolution SNP array dataset. We found that there was a reduction in the copy number of let-7 genes in a cancer-type specific manner. Importantly, focal deletion of four let-7 family members was found in three cancer types: medulloblastoma (let-7a-2 and let-7e, breast cancer (let-7a-2, and ovarian cancer (let-7a-3/let-7b. For example, the genomic locus harboring let-7a-3/let-7b was deleted in 44% of the specimens from ovarian cancer patients. We also found a positive correlation between the copy number of let-7b and mature let-7b expression in ovarian cancer. Finally, we showed that restoration of let-7b expression dramatically reduced ovarian tumor growth in vitro and in vivo. Our results indicate that copy number deletion is an important mechanism leading to the downregulation of expression of specific let-7 family members in medulloblastoma, breast, and ovarian cancers. Restoration of let-7 expression in tumor cells could provide a novel therapeutic strategy for the treatment of cancer.

  11. Dynamics of genomic clones in breast cancer patient xenografts at single cell resolution

    Science.gov (United States)

    Eirew, Peter; Steif, Adi; Khattra, Jaswinder; Ha, Gavin; Yap, Damian; Farahani, Hossein; Gelmon, Karen; Chia, Stephen; Mar, Colin; Wan, Adrian; Laks, Emma; Biele, Justina; Shumansky, Karey; Rosner, Jamie; McPherson, Andrew; Nielsen, Cydney; Roth, Andrew J. L.; Lefebvre, Calvin; Bashashati, Ali; de Souza, Camila; Siu, Celia; Aniba, Radhouane; Brimhall, Jazmine; Oloumi, Arusha; Osako, Tomo; Bruna, Alejandra; Sandoval, Jose; Algara, Teresa; Greenwood, Wendy; Leung, Kaston; Cheng, Hongwei; Xue, Hui; Wang, Yuzhuo; Lin, Dong; Mungall, Andrew J.; Moore, Richard; Zhao, Yongjun; Lorette, Julie; Nguyen, Long; Huntsman, David; Eaves, Connie J.; Hansen, Carl; Marra, Marco A.; Caldas, Carlos; Shah, Sohrab P.; Aparicio, Samuel

    2016-01-01

    Human cancers, including breast cancers, are comprised of clones differing in mutation content. Clones evolve dynamically in space and time following principles of Darwinian evolution1,2, underpinning important emergent features such as drug resistance and metastasis3–7. Human breast cancer xenoengraftment is used as a means of capturing and studying tumour biology, and breast tumour xenografts are generally assumed to be reasonable models of the originating tumours8–10. However the consequences and reproducibility of engraftment and propagation on the genomic clonal architecture of tumours has not been systematically examined at single cell resolution. Here we show by both deep genome and single cell sequencing methods, the clonal dynamics of initial engraftment and subsequent serial propagation of primary and metastatic human breast cancers in immunodeficient mice. In all 15 cases examined, clonal selection on engraftment was observed in both primary and metastatic breast tumours, varying in degree from extreme selective engraftment of minor (<5% of starting population) clones to moderate, polyclonal engraftment. Furthermore, ongoing clonal dynamics during serial passaging is a feature of tumours experiencing modest initial selection. Through single cell sequencing, we show that major mutation clusters estimated from tumour population sequencing relate predictably to the most abundant clonal genotypes, even in clonally complex and rapidly evolving cases. Finally, we show that similar clonal expansion patterns can emerge in independent grafts of the same starting tumour population, indicating that genomic aberrations can be reproducible determinants of evolutionary trajectories. Our results show that measurement of genomically defined clonal population dynamics will be highly informative for functional studies utilizing patient-derived breast cancer xenoengraftment. PMID:25470049

  12. Genomic profiling of inflammatory breast cancer: a review.

    Science.gov (United States)

    Bertucci, François; Finetti, Pascal; Vermeulen, Peter; Van Dam, Peter; Dirix, Luc; Birnbaum, Daniel; Viens, Patrice; Van Laere, Steven

    2014-10-01

    Inflammatory breast cancer (IBC) is a rare but aggressive form of breast cancer. Despite efforts in the past decade to delineate the molecular biology of IBC by applying high-throughput molecular profiling technologies to clinical samples, IBC remains insufficiently characterized. The reasons for that include limited sizes of the study population, heterogeneity with respect to the composition of the IBC and non-IBC control groups and technological differences across studies. In 2008, the World IBC Consortium was founded to foster collaboration between research groups focusing on IBC. One of the initial projects was to redefine the molecular profile of IBC using an unprecedented number of samples and search for gene signatures associated with survival and response to neo-adjuvant chemotherapy. Here, we provide an overview of all the molecular profiling studies that have been performed on IBC clinical samples to date.

  13. Unique Genomic Alterations in Prostate Cancers in African American Men

    Science.gov (United States)

    2015-12-01

    with MNX1 mRNA in AA PCa by Pearson Product Moment. Correlation coefficient and p-value are shown. 13 Subtask 6: Validation of key gene...associated with aggressive pathological features (high Gleason score , seminal vesicle invasion and extracapsular extension). Figure 6. Expression of...was seen in stromal tissues. C, D. Weak expression of MNX1 mRNA in prostate cancer cells (arrowheads). Subtask 4: Correlate expression

  14. Identification of chromosome aberrations in sporadic microsatellite stable and unstable colorectal cancers using array comparative genomic hybridization

    DEFF Research Database (Denmark)

    Jensen, Thomas Dyrsø; Li, Jian; Wang, Kai;

    2011-01-01

    Colorectal cancer (CRC) is one of the most common cancers in Denmark and in the western world in general, and the prognosis is generally poor. According to the traditional molecular classification of sporadic colorectal cancer, microsatellite stable (MSS)/chromosome unstable (CIN) colorectal...... cancers constitute approximately 85% of sporadic cases, whereas microsatellite unstable (MSI) cases constitute the remaining 15%. In this study, we used array comparative genomic hybridization (aCGH) to identify genomic hotspot regions that harbor recurrent copy number changes. The study material...

  15. A genome-wide association study of upper aerodigestive tract cancers conducted within the INHANCE consortium.

    Directory of Open Access Journals (Sweden)

    James D McKay

    2011-03-01

    Full Text Available Genome-wide association studies (GWAS have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p ≤ 5 × 10⁻⁷. Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10⁻⁸ located near DNA repair related genes HEL308 and FAM175A (or Abraxas and a 12q24 variant (rs4767364, p =2 × 10⁻⁸ located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2 gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 × 10⁻⁸; rs1229984-ADH1B, p = 7 × 10⁻⁹; and rs698-ADH1C, p = 0.02. These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.

  16. A genome-wide association study of upper aerodigestive tract cancers conducted within the INHANCE consortium.

    LENUS (Irish Health Repository)

    McKay, James D

    2011-03-01

    Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p ≤ 5 × 10⁻⁷). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10⁻⁸) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p =2 × 10⁻⁸) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 × 10⁻⁸); rs1229984-ADH1B, p = 7 × 10⁻⁹; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.

  17. Genome-wide interaction study of smoking and bladder cancer risk

    Science.gov (United States)

    Figueroa, Jonine D.; Han, Summer S.; Garcia-Closas, Montserrat; Baris, Dalsu; Jacobs, Eric J.; Kogevinas, Manolis; Schwenn, Molly; Malats, Nuria; Johnson, Alison; Purdue, Mark P.; Caporaso, Neil; Landi, Maria Teresa; Prokunina-Olsson, Ludmila; Wang, Zhaoming; Hutchinson, Amy; Burdette, Laurie; Wheeler, William; Vineis, Paolo; Siddiq, Afshan; Cortessis, Victoria K.; Kooperberg, Charles; Cussenot, Olivier; Benhamou, Simone; Prescott, Jennifer; Porru, Stefano; Bueno-de-Mesquita, H.Bas; Trichopoulos, Dimitrios; Ljungberg, Börje; Clavel-Chapelon, Françoise; Weiderpass, Elisabete; Krogh, Vittorio; Dorronsoro, Miren; Travis, Ruth; Tjønneland, Anne; Brenan, Paul; Chang-Claude, Jenny; Riboli, Elio; Conti, David; Gago-Dominguez, Manuela; Stern, Mariana C.; Pike, Malcolm C.; Van Den Berg, David; Yuan, Jian-Min; Hohensee, Chancellor; Rodabough, Rebecca; Cancel-Tassin, Geraldine; Roupret, Morgan; Comperat, Eva; Chen, Constance; De Vivo, Immaculata; Giovannucci, Edward; Hunter, David J.; Kraft, Peter; Lindstrom, Sara; Carta, Angela; Pavanello, Sofia; Arici, Cecilia; Mastrangelo, Giuseppe; Karagas, Margaret R.; Schned, Alan; Armenti, Karla R.; Hosain, G.M.Monawar; Haiman, Chris A.; Fraumeni, Joseph F.; Chanock, Stephen J.; Chatterjee, Nilanjan; Rothman, Nathaniel; Silverman, Debra T.

    2014-01-01

    Bladder cancer is a complex disease with known environmental and genetic risk factors. We performed a genome-wide interaction study (GWAS) of smoking and bladder cancer risk based on primary scan data from 3002 cases and 4411 controls from the National Cancer Institute Bladder Cancer GWAS. Alternative methods were used to evaluate both additive and multiplicative interactions between individual single nucleotide polymorphisms (SNPs) and smoking exposure. SNPs with interaction P values < 5 × 10− 5 were evaluated further in an independent dataset of 2422 bladder cancer cases and 5751 controls. We identified 10 SNPs that showed association in a consistent manner with the initial dataset and in the combined dataset, providing evidence of interaction with tobacco use. Further, two of these novel SNPs showed strong evidence of association with bladder cancer in tobacco use subgroups that approached genome-wide significance. Specifically, rs1711973 (FOXF2) on 6p25.3 was a susceptibility SNP for never smokers [combined odds ratio (OR) = 1.34, 95% confidence interval (CI) = 1.20–1.50, P value = 5.18 × 10− 7]; and rs12216499 (RSPH3-TAGAP-EZR) on 6q25.3 was a susceptibility SNP for ever smokers (combined OR = 0.75, 95% CI = 0.67–0.84, P value = 6.35 × 10− 7). In our analysis of smoking and bladder cancer, the tests for multiplicative interaction seemed to more commonly identify susceptibility loci with associations in never smokers, whereas the additive interaction analysis identified more loci with associations among smokers—including the known smoking and NAT2 acetylation interaction. Our findings provide additional evidence of gene–environment interactions for tobacco and bladder cancer. PMID:24662972

  18. Insights into pancreatic cancer etiology from pathway analysis of genome-wide association study data.

    Directory of Open Access Journals (Sweden)

    Peng Wei

    Full Text Available Pancreatic cancer is the fourth leading cause of cancer death in the U.S. and the etiology of this highly lethal disease has not been well defined. To identify genetic susceptibility factors for pancreatic cancer, we conducted pathway analysis of genome-wide association study (GWAS data in 3,141 pancreatic cancer patients and 3,367 controls with European ancestry.Using the gene set ridge regression in association studies (GRASS method, we analyzed 197 pathways identified from the Kyoto Encyclopedia of Genes and Genomes database. We used the logistic kernel machine (LKM test to identify major contributing genes to each pathway. We conducted functional enrichment analysis of the most significant genes (P<0.01 using the Database for Annotation, Visualization, and Integrated Discovery (DAVID.Two pathways were significantly associated with risk of pancreatic cancer after adjusting for multiple comparisons (P<0.00025 and in replication testing: neuroactive ligand-receptor interaction, (Ps<0.00002, and the olfactory transduction pathway (P = 0.0001. LKM test identified four genes that were significantly associated with risk of pancreatic cancer after Bonferroni correction (P<1×10(-5: ABO, HNF1A, OR13C4, and SHH. Functional enrichment analysis using DAVID consistently found the G protein-coupled receptor signaling pathway (including both neuroactive ligand-receptor interaction and olfactory transduction pathways to be the most significant pathway for pancreatic cancer risk in this study population.These novel findings provide new perspectives on genetic susceptibility to and molecular mechanisms of pancreatic cancer.

  19. The genomic landscape of cutaneous melanoma.

    Science.gov (United States)

    Zhang, Tongwu; Dutton-Regester, Ken; Brown, Kevin M; Hayward, Nicholas K

    2016-05-01

    Somatic mutation analysis of melanoma has been performed at the single gene level extensively over the past several decades. This has provided considerable insight into the critical pathways controlling melanoma initiation and progression. During the last 5 yr, next-generation sequencing (NGS) has enabled even more comprehensive mutational screening at the level of multigene panels, exomes and genomes. These studies have uncovered many new and unexpected players in melanoma development. The recent landmark study from The Cancer Genome Atlas (TCGA) consortium describing the genomic architecture of 333 cutaneous melanomas provides the largest and broadest analysis to date on the somatic aberrations underlying melanoma genesis. It thus seems timely to review the mutational landscape of melanoma and highlight the key genes and cellular pathways that appear to drive this cancer.

  20. NMD Microarray Analysis for Rapid Genome-Wide Screen of Mutated Genes in Cancer

    Directory of Open Access Journals (Sweden)

    Maija Wolf

    2005-01-01

    Full Text Available Gene mutations play a critical role in cancer development and progression, and their identification offers possibilities for accurate diagnostics and therapeutic targeting. Finding genes undergoing mutations is challenging and slow, even in the post-genomic era. A new approach was recently developed by Noensie and Dietz to prioritize and focus the search, making use of nonsense-mediated mRNA decay (NMD inhibition and microarray analysis (NMD microarrays in the identification of transcripts containing nonsense mutations. We combined NMD microarrays with array-based CGH (comparative genomic hybridization in order to identify inactivation of tumor suppressor genes in cancer. Such a “mutatomics” screening of prostate cancer cell lines led to the identification of inactivating mutations in the EPHB2 gene. Up to 8% of metastatic uncultured prostate cancers also showed mutations of this gene whose loss of function may confer loss of tissue architecture. NMD microarray analysis could turn out to be a powerful research method to identify novel mutated genes in cancer cell lines, providing targets that could then be further investigated for their clinical relevance and therapeutic potential.

  1. BaalChIP: Bayesian analysis of allele-specific transcription factor binding in cancer genomes.

    Science.gov (United States)

    de Santiago, Ines; Liu, Wei; Yuan, Ke; O'Reilly, Martin; Chilamakuri, Chandra Sekhar Reddy; Ponder, Bruce A J; Meyer, Kerstin B; Markowetz, Florian

    2017-02-24

    Allele-specific measurements of transcription factor binding from ChIP-seq data are key to dissecting the allelic effects of non-coding variants and their contribution to phenotypic diversity. However, most methods of detecting an allelic imbalance assume diploid genomes. This assumption severely limits their applicability to cancer samples with frequent DNA copy-number changes. Here we present a Bayesian statistical approach called BaalChIP to correct for the effect of background allele frequency on the observed ChIP-seq read counts. BaalChIP allows the joint analysis of multiple ChIP-seq samples across a single variant and outperforms competing approaches in simulations. Using 548 ENCODE ChIP-seq and six targeted FAIRE-seq samples, we show that BaalChIP effectively corrects allele-specific analysis for copy-number variation and increases the power to detect putative cis-acting regulatory variants in cancer genomes.

  2. Identifying anti-growth factors for human cancer cell lines through genome-scale metabolic modeling

    DEFF Research Database (Denmark)

    Ghaffari, Pouyan; Mardinoglu, Adil; Asplund, Anna

    2015-01-01

    Human cancer cell lines are used as important model systems to study molecular mechanisms associated with tumor growth, hereunder how genomic and biological heterogeneity found in primary tumors affect cellular phenotypes. We reconstructed Genome scale metabolic models (GEMs) for eleven cell lines...... based on RNA-Seq data and validated the functionality of these models with data from metabolite profiling. We used cell line-specific GEMs to analyze the differences in the metabolism of cancer cell lines, and to explore the heterogeneous expression of the metabolic subsystems. Furthermore, we predicted...... antimetabolites using two cell lines with different phenotypic origins, and found that it is effective in inhibiting the growth of these cell lines. Using immunohistochemistry, we also showed high or moderate expression levels of proteins targeted by the validated antimetabolite. Identified anti-growth factors...

  3. Transmissible [corrected] dog cancer genome reveals the origin and history of an ancient cell lineage.

    Science.gov (United States)

    Murchison, Elizabeth P; Wedge, David C; Alexandrov, Ludmil B; Fu, Beiyuan; Martincorena, Inigo; Ning, Zemin; Tubio, Jose M C; Werner, Emma I; Allen, Jan; De Nardi, Andrigo Barboza; Donelan, Edward M; Marino, Gabriele; Fassati, Ariberto; Campbell, Peter J; Yang, Fengtang; Burt, Austin; Weiss, Robin A; Stratton, Michael R

    2014-01-24

    Canine transmissible venereal tumor (CTVT) is the oldest known somatic cell lineage. It is a transmissible cancer that propagates naturally in dogs. We sequenced the genomes of two CTVT tumors and found that CTVT has acquired 1.9 million somatic substitution mutations and bears evidence of exposure to ultraviolet light. CTVT is remarkably stable and lacks subclonal heterogeneity despite thousands of rearrangements, copy-number changes, and retrotransposon insertions. More than 10,000 genes carry nonsynonymous variants, and 646 genes have been lost. CTVT first arose in a dog with low genomic heterozygosity that may have lived about 11,000 years ago. The cancer spawned by this individual dispersed across continents about 500 years ago. Our results provide a genetic identikit of an ancient dog and demonstrate the robustness of mammalian somatic cells to survive for millennia despite a massive mutation burden.

  4. Ectopic expression of cancer/testis antigen SSX2 induces DNA damage and promotes genomic instability

    DEFF Research Database (Denmark)

    Greve, Katrine Buch Vidén; Lindgreen, Jonas; Terp, Mikkel Green

    2015-01-01

    replication stress translates into mitotic defects and genomic instability. Arrest of cell growth and induction of DNA double-strand breaks was also observed in MCF7 breast cancer cells in response to SSX2 expression. Additionally, MCF7 cells with ectopic SSX2 expression demonstrated typical signs......SSX cancer/testis antigens are frequently expressed in melanoma tumors and represent attractive targets for immunotherapy, but their role in melanoma tumorigenesis has remained elusive. Here, we investigated the cellular effects of SSX2 expression. In A375 melanoma cells, SSX2 expression resulted...... of SSX2 expression in melanoma cell lines demonstrated that SSX2 supports the growth of melanoma cells. Our results reveal two important phenotypes of ectopic SSX2 expression that may drive/support tumorigenesis: First, immediate induction of genomic instability, and second, long-term support of tumor...

  5. Genome-based versus gene-based theory of cancer: Possible implications for clinical practice

    Indian Academy of Sciences (India)

    Nataša Todorović-Raković

    2011-09-01

    The current state in oncology research indicates that the attempts to explain such complex process as cancerogenesis by a single or several genetic mutations were not successful enough. On the other hand, chromosomal/genomic instability – almost universal features of malignant tumours which influence a global pattern of gene expression and, subsequently, many oncogenic pathways – were often disregarded and considered nonessential to clinical application. However, a new arising field of system biology including ‘new forms’ of genome diversity such as copy number variations (CNV) and high-throughput oncogene mutation profiling now reveal all the complexity of cancer and provide the final explanation of the oncogenic pathways, based on stochastic (onco)genomic variation rather than on (onco)genic concepts.

  6. An improved method for detecting and delineating genomic regions with altered gene expression in cancer

    OpenAIRE

    2008-01-01

    Genomic regions with altered gene expression are a characteristic feature of cancer cells. We present a novel method for identifying such regions in gene expression maps. This method is based on total variation minimization, a classical signal restoration technique. In systematic evaluations, we show that our method combines top-notch detection performance with an ability to delineate relevant regions without excessive over-segmentation, making it a significant advance over existing methods. ...

  7. Comprehensive long-span paired-end-tag mapping reveals characteristic patterns of structural variations in epithelial cancer genomes.

    Science.gov (United States)

    Hillmer, Axel M; Yao, Fei; Inaki, Koichiro; Lee, Wah Heng; Ariyaratne, Pramila N; Teo, Audrey S M; Woo, Xing Yi; Zhang, Zhenshui; Zhao, Hao; Ukil, Leena; Chen, Jieqi P; Zhu, Feng; So, Jimmy B Y; Salto-Tellez, Manuel; Poh, Wan Ting; Zawack, Kelson F B; Nagarajan, Niranjan; Gao, Song; Li, Guoliang; Kumar, Vikrant; Lim, Hui Ping J; Sia, Yee Yen; Chan, Chee Seng; Leong, See Ting; Neo, Say Chuan; Choi, Poh Sum D; Thoreau, Hervé; Tan, Patrick B O; Shahab, Atif; Ruan, Xiaoan; Bergh, Jonas; Hall, Per; Cacheux-Rataboul, Valère; Wei, Chia-Lin; Yeoh, Khay Guan; Sung, Wing-Kin; Bourque, Guillaume; Liu, Edison T; Ruan, Yijun

    2011-05-01

    Somatic genome rearrangements are thought to play important roles in cancer development. We optimized a long-span paired-end-tag (PET) sequencing approach using 10-Kb genomic DNA inserts to study human genome structural variations (SVs). The use of a 10-Kb insert size allows the identification of breakpoints within repetitive or homology-containing regions of a few kilobases in size and results in a higher physical coverage compared with small insert libraries with the same sequencing effort. We have applied this approach to comprehensively characterize the SVs of 15 cancer and two noncancer genomes and used a filtering approach to strongly enrich for somatic SVs in the cancer genomes. Our analyses revealed that most inversions, deletions, and insertions are germ-line SVs, whereas tandem duplications, unpaired inversions, interchromosomal translocations, and complex rearrangements are over-represented among somatic rearrangements in cancer genomes. We demonstrate that the quantitative and connective nature of DNA-PET data is precise in delineating the genealogy of complex rearrangement events, we observe signatures that are compatible with breakage-fusion-bridge cycles, and we discover that large duplications are among the initial rearrangements that trigger genome instability for extensive amplification in epithelial cancers.

  8. European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene

    NARCIS (Netherlands)

    Rafnar, T.; Vermeulen, H.H.M.; Sulem, P.; Thorleifsson, G.; Aben, K.K.H.; Witjes, J.A.; Grotenhuis, A.J.; Verhaegh, G.W.C.T.; Hulsbergen- van de Kaa, C.A.; Besenbacher, S.; Gudbjartsson, D.; Stacey, S.N.; Gudmundsson, J.; Johannsdottir, H.; Bjarnason, H.; Zanon, C.; Helgadottir, H.; Jonasson, J.G.; Tryggvadottir, L.; Jonsson, E.; Geirsson, G.; Nikulasson, S.; Petursdottir, V.; Bishop, D.T.; Chung-Sak, S.; Choudhury, A.; Elliott, F.; Barrett, J.H.; Knowles, M.A.; Verdier, P. de; Ryk, C.; Lindblom, A.; Rudnai, P.; Gurzau, E.; Koppova, K.; Vineis, P.; Polidoro, S.; Guarrera, S.; Sacerdote, C.; Panadero, A.; Sanz-Velez, J.I.; Sanchez, M.; Valdivia, G.; Garcia-Prats, M.D.; Hengstler, J.G.; Selinski, S.; Gerullis, H.; Ovsiannikov, D.; Khezri, A.; Aminsharifi, A.; Malekzadeh, M.; Berg, L.H. van den; Ophoff, R.A.; Veldink, J.H.; Zeegers, M.P.; Kellen, E.; Fostinelli, J.; Andreoli, D.; Arici, C.; Porru, S.; Buntinx, F.; Ghaderi, A.; Golka, K.; Mayordomo, J.I.; Matullo, G.; Kumar, R.; Steineck, G.; Kiltie, A.E.; Kong, A.; Thorsteinsdottir, U.; Stefansson, K.; Kiemeney, L.A.L.M.

    2011-01-01

    Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European G

  9. 1-Mb resolution array-based comparative genomic hybridization using a BAC clone set optimized for cancer gene analysis

    NARCIS (Netherlands)

    Greshock, J; Naylor, TL; Margolin, A; Diskin, S; Cleaver, SH; Futreal, PA; deJong, PJ; Zhao, SY; Liebman, M; Weber, BL

    2004-01-01

    Array-based comparative genomic hybridization (aCGH) is a recently developed tool for genome-wide determination of DNA copy number alterations. This technology has tremendous potential for disease-gene discovery in cancer and developmental disorders as well as numerous other applications. However, w

  10. Epidemiological studies of esophageal cancer in the era of genome-wide association studies

    Institute of Scientific and Technical Information of China (English)

    An-Hui; Wang; Yuan; Liu; Bo; Wang; Yi-Xuan; He; Ye-Xian; Fang; Yong-Ping; Yan

    2014-01-01

    Esophageal cancer(EC) caused about 395000 deaths in 2010. China has the most cases of EC and EC is the fourth leading cause of cancer death in China. Esophageal squamous cell carcinoma(ESCC) is the predominant histologic type(90%-95%), while the incidence of esophageal adenocarcinoma(EAC) remains extremely low in China. Traditional epidemiological studies have revealed that environmental carcinogens are risk factors for EC. Molecular epidemiological studies revealed that susceptibility to EC is influenced by both environmental and genetic risk factors. Of all the risk factors for EC, some are associated with the risk of ESCC and others with the risk of EAC. However, the details and mechanisms of risk factors involved in the process for EC are unclear. The advanced methods and techniques used in human genome studies bring a great opportunity for researchers to explore and identify the details of those risk factors or susceptibility genes involved inthe process of EC. Human genome epidemiology is a new branch of epidemiology, which leads the epidemiology study from the molecular epidemiology era to the era of genome wide association studies(GWAS). Here we review the epidemiological studies of EC(especially ESCC) in the era of GWAS, and provide an overview of the general risk factors and those genomic variants(genes, SNPs, miRNAs, proteins) involved in the process of ESCC.

  11. Transcription Restores DNA Repair to Heterochromatin, Determining Regional Mutation Rates in Cancer Genomes

    Directory of Open Access Journals (Sweden)

    Christina L. Zheng

    2014-11-01

    Full Text Available Somatic mutations in cancer are more frequent in heterochromatic and late-replicating regions of the genome. We report that regional disparities in mutation density are virtually abolished within transcriptionally silent genomic regions of cutaneous squamous cell carcinomas (cSCCs arising in an XPC−/− background. XPC−/− cells lack global genome nucleotide excision repair (GG-NER, thus establishing differential access of DNA repair machinery within chromatin-rich regions of the genome as the primary cause for the regional disparity. Strikingly, we find that increasing levels of transcription reduce mutation prevalence on both strands of gene bodies embedded within H3K9me3-dense regions, and only to those levels observed in H3K9me3-sparse regions, also in an XPC-dependent manner. Therefore, transcription appears to reduce mutation prevalence specifically by relieving the constraints imposed by chromatin structure on DNA repair. We model this relationship among transcription, chromatin state, and DNA repair, revealing a new, personalized determinant of cancer risk.

  12. A novel genomic alteration of LSAMP associates with aggressive prostate cancer in African American men

    Directory of Open Access Journals (Sweden)

    Gyorgy Petrovics

    2015-12-01

    Full Text Available Evaluation of cancer genomes in global context is of great interest in light of changing ethnic distribution of the world population. We focused our study on men of African ancestry because of their disproportionately higher rate of prostate cancer (CaP incidence and mortality. We present a systematic whole genome analyses, revealing alterations that differentiate African American (AA and Caucasian American (CA CaP genomes. We discovered a recurrent deletion on chromosome 3q13.31 centering on the LSAMP locus that was prevalent in tumors from AA men (cumulative analyses of 435 patients: whole genome sequence, 14; FISH evaluations, 101; and SNP array, 320 patients. Notably, carriers of this deletion experienced more rapid disease progression. In contrast, PTEN and ERG common driver alterations in CaP were significantly lower in AA prostate tumors compared to prostate tumors from CA. Moreover, the frequency of inter-chromosomal rearrangements was significantly higher in AA than CA tumors. These findings reveal differentially distributed somatic mutations in CaP across ancestral groups, which have implications for precision medicine strategies.

  13. Clonal expansion and linear genome evolution through breast cancer progression from pre-invasive stages to asynchronous metastasis

    DEFF Research Database (Denmark)

    Krøigård, Anne Bruun; Larsen, Martin Jakob; Lænkholm, Anne Vibeke

    step. Our data, contrary to the proposed model of early dissemination of metastatic cells and parallel progression of primary tumors and metastases, provide evidence of linear progression of breast cancer with relatively late dissemination from the primary tumor. The genomic discordance between......Evolution of the breast cancer genome from pre-invasive stages to asynchronous metastasis is complex and mostly unexplored, but highly demanded as it may provide novel markers for and mechanistic insights in cancer progression. The increasing use of personalized therapy of breast cancer...... necessitates knowledge of the degree of genomic concordance between different steps of malignant progression as primary tumors often are used as surrogates of systemic disease. Based on exome sequencing we performed copy number profiling and point mutation detection on successive steps of breast cancer...

  14. Clonal expansion and linear genome evolution through breast cancer progression from pre-invasive stages to asynchronous metastasis

    DEFF Research Database (Denmark)

    Krøigård, Anne Bruun; Larsen, Martin Jakob; Lænkholm, Anne Vibeke

    2015-01-01

    step. Our data, contrary to the proposed model of early dissemination of metastatic cells and parallel progression of primary tumors and metastases, provide evidence of linear progression of breast cancer with relatively late dissemination from the primary tumor. The genomic discordance between......Evolution of the breast cancer genome from pre-invasive stages to asynchronous metastasis is complex and mostly unexplored, but highly demanded as it may provide novel markers for and mechanistic insights in cancer progression. The increasing use of personalized therapy of breast cancer...... necessitates knowledge of the degree of genomic concordance between different steps of malignant progression as primary tumors often are used as surrogates of systemic disease. Based on exome sequencing we performed copy number profiling and point mutation detection on successive steps of breast cancer...

  15. Comparative genomic analysis of primary tumors and metastases in breast cancer.

    Science.gov (United States)

    Bertucci, François; Finetti, Pascal; Guille, Arnaud; Adélaïde, José; Garnier, Séverine; Carbuccia, Nadine; Monneur, Audrey; Charafe-Jauffret, Emmanuelle; Goncalves, Anthony; Viens, Patrice; Birnbaum, Daniel; Chaffanet, Max

    2016-05-10

    Personalized medicine uses genomic information for selecting therapy in patients with metastatic cancer. An issue is the optimal tissue source (primary tumor or metastasis) for testing. We compared the DNA copy number and mutational profiles of primary breast cancers and paired metastases from 23 patients using whole-genome array-comparative genomic hybridization and next-generation sequencing of 365 "cancer-associated" genes. Primary tumors and metastases harbored copy number alterations (CNAs) and mutations common in breast cancer and showed concordant profiles. The global concordance regarding CNAs was shown by clustering and correlation matrix, which showed that each metastasis correlated more strongly with its paired tumor than with other samples. Genes with recurrent amplifications in breast cancer showed 100% (ERBB2, FGFR1), 96% (CCND1), and 88% (MYC) concordance for the amplified/non-amplified status. Among all samples, 499 mutations were identified, including 39 recurrent (AKT1, ERBB2, PIK3CA, TP53) and 460 non-recurrent variants. The tumors/metastases concordance of variants was 75%, higher for recurrent (92%) than for non-recurrent (73%) variants. Further mutational discordance came from very different variant allele frequencies for some variants. We showed that the chosen targeted therapy in two clinical trials of personalized medicine would be concordant in all but one patient (96%) when based on the molecular profiling of tumor and paired metastasis. Our results suggest that the genotyping of primary tumor may be acceptable to guide systemic treatment if the metastatic sample is not obtainable. However, given the rare but potentially relevant divergences for some actionable driver genes, the profiling of metastatic sample is recommended.

  16. Identification of novel targets for breast cancer by exploring gene switches on a genome scale

    Directory of Open Access Journals (Sweden)

    Wu Ming

    2011-11-01

    Full Text Available Abstract Background An important feature that emerges from analyzing gene regulatory networks is the "switch-like behavior" or "bistability", a dynamic feature of a particular gene to preferentially toggle between two steady-states. The state of gene switches plays pivotal roles in cell fate decision, but identifying switches has been difficult. Therefore a challenge confronting the field is to be able to systematically identify gene switches. Results We propose a top-down mining approach to exploring gene switches on a genome-scale level. Theoretical analysis, proof-of-concept examples, and experimental studies demonstrate the ability of our mining approach to identify bistable genes by sampling across a variety of different conditions. Applying the approach to human breast cancer data identified genes that show bimodality within the cancer samples, such as estrogen receptor (ER and ERBB2, as well as genes that show bimodality between cancer and non-cancer samples, where tumor-associated calcium signal transducer 2 (TACSTD2 is uncovered. We further suggest a likely transcription factor that regulates TACSTD2. Conclusions Our mining approach demonstrates that one can capitalize on genome-wide expression profiling to capture dynamic properties of a complex network. To the best of our knowledge, this is the first attempt in applying mining approaches to explore gene switches on a genome-scale, and the identification of TACSTD2 demonstrates that single cell-level bistability can be predicted from microarray data. Experimental confirmation of the computational results suggest TACSTD2 could be a potential biomarker and attractive candidate for drug therapy against both ER+ and ER- subtypes of breast cancer, including the triple negative subtype.

  17. The impact of vitamin D in breast cancer: genomics, pathways, metabolism

    Directory of Open Access Journals (Sweden)

    Carmen Judith Narvaez

    2014-06-01

    Full Text Available Nuclear receptors exert profound effects on mammary gland physiology and have complex roles in the etiology of breast cancer. In addition to receptors for classic steroid hormones such as estrogen and progesterone, the nuclear vitamin D receptor (VDR interacts with its ligand 1α,25(OH2D3 to modulate the normal mammary epithelial cell genome and subsequent phenotype. Observational studies suggest that vitamin D deficiency is common in breast cancer patients and that low vitamin D status enhances the risk for disease development or progression. Genomic profiling has characterized many 1α,25(OH2D3 responsive targets in normal mammary cells and in breast cancers, providing insight into the molecular actions of 1α,25(OH2D3 and the VDR in regulation of cell cycle, apoptosis and differentiation. New areas of emphasis include regulation of tumor metabolism and innate immune responses. However, the role of VDR in individual cell types (ie epithelial, adipose, fibroblast, endotelial, immune of normal and tumor tissues remains to be clarified. Furthermore, the mechanisms by which VDR integrates signaling between diverse cell types and controls soluble signals and paracrine pathways in the tissue/tumor microenvironment remain to be defined. Model systems of carcinogenesis have provided evidence that both VDR expression and 1α,25(OH2D3 actions change with transformation but clinical data regarding vitamin D responsiveness of established tumors is limited and inconclusive. Because breast cancer is heterogeneous, analysis of VDR actions in specific molecular subtypes of the disease may help to clarify the conflicting data. The expanded use of genomic, proteomic and metabolomic approaches on a diverse array of in vitro and in vivo model systems is clearly warranted to comprehensively understand the nework of vitamin D regulated pathways in the context of breast cancer.

  18. Genomic Testing and Therapies for Breast Cancer in Clinical Practice

    Science.gov (United States)

    Haas, Jennifer S.; Phillips, Kathryn A.; Liang, Su-Ying; Hassett, Michael J.; Keohane, Carol; Elkin, Elena B.; Armstrong, Joanne; Toscano, Michele

    2011-01-01

    Purpose: Given the likely proliferation of targeted testing and treatment strategies for cancer, a better understanding of the utilization patterns of human epidermal growth factor receptor 2 (HER2) testing and trastuzumab and newer gene expression profiling (GEP) for risk stratification and chemotherapy decision making are important. Study Design: Cross-sectional. Methods: We performed a medical record review of women age 35 to 65 years diagnosed between 2006 and 2007 with invasive localized breast cancer, identified using claims from a large national health plan (N = 775). Results: Almost all women received HER2 testing (96.9%), and 24.9% of women with an accepted indication received GEP. Unexplained socioeconomic differences in GEP use were apparent after adjusting for age and clinical characteristics; specifically, GEP use increased with income. For example, those in the lowest income category (< $40,000) were less likely than those with an income of $125,000 or more to receive GEP (odds ratio, 0.34; 95% CI, 0.16 to 0.73). A majority of women (57.7%) with HER2-positive disease received trastuzumab; among these women, differences in age and clinical characteristics were not apparent, although surprisingly, those in the lowest income category were more likely than those in the high-income category to receive trastuzumab (P = .02). Among women who did not have a positive HER2 test, 3.9% still received trastuzumab. Receipt of adjuvant chemotherapy increased as GEP score indicated greater risk of recurrence. Conclusion: Identifying and eliminating unnecessary variation in the use of these expensive tests and treatments should be part of quality improvement and efficiency programs. PMID:21886507

  19. The Naked Mole Rat Genome Resource: facilitating analyses of cancer and longevity-related adaptations

    Science.gov (United States)

    Keane, Michael; Craig, Thomas; Alföldi, Jessica; Berlin, Aaron M.; Johnson, Jeremy; Seluanov, Andrei; Gorbunova, Vera; Di Palma, Federica; Lindblad-Toh, Kerstin; Church, George M.; de Magalhães, João Pedro

    2014-01-01

    Motivation: The naked mole rat (Heterocephalus glaber) is an exceptionally long-lived and cancer-resistant rodent native to East Africa. Although its genome was previously sequenced, here we report a new assembly sequenced by us with substantially higher N50 values for scaffolds and contigs. Results: We analyzed the annotation of this new improved assembly and identified candidate genomic adaptations which may have contributed to the evolution of the naked mole rat’s extraordinary traits, including in regions of p53, and the hyaluronan receptors CD44 and HMMR (RHAMM). Furthermore, we developed a freely available web portal, the Naked Mole Rat Genome Resource (http://www.naked-mole-rat.org), featuring the data and results of our analysis, to assist researchers interested in the genome and genes of the naked mole rat, and also to facilitate further studies on this fascinating species. Availability and implementation: The Naked Mole Rat Genome Resource is freely available online at http://www.naked-mole-rat.org. This resource is open source and the source code is available at https://github.com/maglab/naked-mole-rat-portal. Contact: jp@senescence.info PMID:25172923

  20. Genomic and oncoproteomic advances in detection and treatment of colorectal cancer.

    LENUS (Irish Health Repository)

    McHugh, Seamus M

    2012-02-01

    AIMS: We will examine the latest advances in genomic and proteomic laboratory technology. Through an extensive literature review we aim to critically appraise those studies which have utilized these latest technologies and ascertain their potential to identify clinically useful biomarkers. METHODS: An extensive review of the literature was carried out in both online medical journals and through the Royal College of Surgeons in Ireland library. RESULTS: Laboratory technology has advanced in the fields of genomics and oncoproteomics. Gene expression profiling with DNA microarray technology has allowed us to begin genetic profiling of colorectal cancer tissue. The response to chemotherapy can differ amongst individual tumors. For the first time researchers have begun to isolate and identify the genes responsible. New laboratory techniques allow us to isolate proteins preferentially expressed in colorectal cancer tissue. This could potentially lead to identification of a clinically useful protein biomarker in colorectal cancer screening and treatment. CONCLUSION: If a set of discriminating genes could be used for characterization and prediction of chemotherapeutic response, an individualized tailored therapeutic regime could become the standard of care for those undergoing systemic treatment for colorectal cancer. New laboratory techniques of protein identification may eventually allow identification of a clinically useful biomarker that could be used for screening and treatment. At present however, both expression of different gene signatures and isolation of various protein peaks has been limited by study size. Independent multi-centre correlation of results with larger sample sizes is needed to allow translation into clinical practice.

  1. Five endometrial cancer risk loci identified through genome-wide association analysis

    Science.gov (United States)

    O’Mara, Tracy A; Painter, Jodie N; Glubb, Dylan M; Flach, Susanne; Lewis, Annabelle; French, Juliet D; Freeman-Mills, Luke; Church, David; Gorman, Maggie; Martin, Lynn; Hodgson, Shirley; Webb, Penelope M; Attia, John; Holliday, Elizabeth G; McEvoy, Mark; Scott, Rodney J; Henders, Anjali K; Martin, Nicholas G; Montgomery, Grant W; Nyholt, Dale R; Ahmed, Shahana; Healey, Catherine S; Shah, Mitul; Dennis, Joe; Fasching, Peter A; Beckmann, Matthias W; Hein, Alexander; Ekici, Arif B; Hall, Per; Czene, Kamila; Darabi, Hatef; Li, Jingmei; Dörk, Thilo; Dürst, Matthias; Hillemanns, Peter; Runnebaum, Ingo; Amant, Frederic; Schrauwen, Stefanie; Zhao, Hui; Lambrechts, Diether; Depreeuw, Jeroen; Dowdy, Sean C; Goode, Ellen L; Fridley, Brooke L; Winham, Stacey J; Njølstad, Tormund S; Salvesen, Helga B; Trovik, Jone; Werner, Henrica MJ; Ashton, Katie; Otton, Geoffrey; Proietto, Tony; Liu, Tao; Mints, Miriam; Tham, Emma; Consortium, CHIBCHA; Jun Li, Mulin; Yip, Shun H; Wang, Junwen; Bolla, Manjeet K; Michailidou, Kyriaki; Wang, Qin; Tyrer, Jonathan P; Dunlop, Malcolm; Houlston, Richard; Palles, Claire; Hopper, John L; Peto, Julian; Swerdlow, Anthony J; Burwinkel, Barbara; Brenner, Hermann; Meindl, Alfons; Brauch, Hiltrud; Lindblom, Annika; Chang-Claude, Jenny; Couch, Fergus J; Giles, Graham G; Kristensen, Vessela N; Cox, Angela; Cunningham, Julie M; Pharoah, Paul D P; Dunning, Alison M; Edwards, Stacey L; Easton, Douglas F; Tomlinson, Ian; Spurdle, Amanda B

    2016-01-01

    We conducted a meta-analysis of three endometrial cancer GWAS and two replication phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five novel risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1 near SIVA1). A second independent 8q24.21 signal (rs17232730) was found. Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r2=0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103-T endometrial cancer protective allele suppressed gene expression in vitro suggesting that regulation of KLF5 expression, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer. PMID:27135401

  2. Genomic and oncoproteomic advances in detection and treatment of colorectal cancer.

    LENUS (Irish Health Repository)

    McHugh, Seamus M

    2009-01-01

    AIMS: We will examine the latest advances in genomic and proteomic laboratory technology. Through an extensive literature review we aim to critically appraise those studies which have utilized these latest technologies and ascertain their potential to identify clinically useful biomarkers. METHODS: An extensive review of the literature was carried out in both online medical journals and through the Royal College of Surgeons in Ireland library. RESULTS: Laboratory technology has advanced in the fields of genomics and oncoproteomics. Gene expression profiling with DNA microarray technology has allowed us to begin genetic profiling of colorectal cancer tissue. The response to chemotherapy can differ amongst individual tumors. For the first time researchers have begun to isolate and identify the genes responsible. New laboratory techniques allow us to isolate proteins preferentially expressed in colorectal cancer tissue. This could potentially lead to identification of a clinically useful protein biomarker in colorectal cancer screening and treatment. CONCLUSION: If a set of discriminating genes could be used for characterization and prediction of chemotherapeutic response, an individualized tailored therapeutic regime could become the standard of care for those undergoing systemic treatment for colorectal cancer. New laboratory techniques of protein identification may eventually allow identification of a clinically useful biomarker that could be used for screening and treatment. At present however, both expression of different gene signatures and isolation of various protein peaks has been limited by study size. Independent multi-centre correlation of results with larger sample sizes is needed to allow translation into clinical practice.

  3. Capturing Genomic Evolution of Lung Cancers through Liquid Biopsy for Circulating Tumor DNA

    Directory of Open Access Journals (Sweden)

    Michael Offin

    2017-01-01

    Full Text Available Genetic sequencing of malignancies has become increasingly important to uncover therapeutic targets and capture the tumor’s dynamic changes to drug sensitivity and resistance through genomic evolution. In lung cancers, the current standard of tissue biopsy at the time of diagnosis and progression is not always feasible or practical and may underestimate intratumoral heterogeneity. Technological advances in genetic sequencing have enabled the use of circulating tumor DNA (ctDNA analysis to obtain information on both targetable mutations and capturing real-time Darwinian evolution of tumor clones and drug resistance mechanisms under selective therapeutic pressure. The ability to analyze ctDNA from plasma, CSF, or urine enables a comprehensive view of cancers as systemic diseases and captures intratumoral heterogeneity. Here, we describe these recent advances in the setting of lung cancers and advocate for further research and the incorporation of ctDNA analysis in clinical trials of targeted therapies. By capturing genomic evolution in a noninvasive manner, liquid biopsy for ctDNA analysis could accelerate therapeutic discovery and deliver the next leap forward in precision medicine for patients with lung cancers and other solid tumors.

  4. Extending pathways and processes using molecular interaction networks to analyse cancer genome data

    Directory of Open Access Journals (Sweden)

    Krasnogor Natalio

    2010-12-01

    Full Text Available Abstract Background Cellular processes and pathways, whose deregulation may contribute to the development of cancers, are often represented as cascades of proteins transmitting a signal from the cell surface to the nucleus. However, recent functional genomic experiments have identified thousands of interactions for the signalling canonical proteins, challenging the traditional view of pathways as independent functional entities. Combining information from pathway databases and interaction networks obtained from functional genomic experiments is therefore a promising strategy to obtain more robust pathway and process representations, facilitating the study of cancer-related pathways. Results We present a methodology for extending pre-defined protein sets representing cellular pathways and processes by mapping them onto a protein-protein interaction network, and extending them to include densely interconnected interaction partners. The added proteins display distinctive network topological features and molecular function annotations, and can be proposed as putative new components, and/or as regulators of the communication between the different cellular processes. Finally, these extended pathways and processes are used to analyse their enrichment in pancreatic mutated genes. Significant associations between mutated genes and certain processes are identified, enabling an analysis of the influence of previously non-annotated cancer mutated genes. Conclusions The proposed method for extending cellular pathways helps to explain the functions of cancer mutated genes by exploiting the synergies of canonical knowledge and large-scale interaction data.

  5. Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers

    NARCIS (Netherlands)

    Wang, Xianshu; Pankratz, V. Shane; Fredericksen, Zachary; Tarrell, Robert; Karaus, Mary; McGuffog, Lesley; Pharaoh, Paul D. P.; Ponder, Bruce A. J.; Dunning, Alison M.; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Sinilnikova, Olga M.; Stoppa-Lyonnet, Dominique; Mazoyer, Sylvie; Houdayer, Claude; Hogervorst, Frans B. L.; Hooning, Maartje J.; Ligtenberg, Marjolijn J.; Spurdle, Amanda; Chenevix-Trench, Georgia; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Singer, Christian F.; Gschwantler-Kaulich, Daphne; Dressler, Catherina; Fink, Anneliese; Szabo, Csilla I.; Zikan, Michal; Foretova, Lenka; Claes, Kathleen; Thomas, Gilles; Hoover, Robert N.; Hunter, David J.; Chanock, Stephen J.; Easton, Douglas F.; Antoniou, Antonis C.; Couch, Fergus J.

    2010-01-01

    Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Since these risk modifiers were originally identified as genetic risk factors for breast cancer in genome-wide association studies (GWASs), additio

  6. Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers.

    NARCIS (Netherlands)

    Wang, X.; Pankratz, V.S.; Fredericksen, Z.; Tarrell, R.; Karaus, M.; McGuffog, L.; Pharaoh, P.D.; Ponder, B.A.J.; Dunning, A.M.; Peock, S.; Cook, M.; Oliver, C.; Frost, D.; Sinilnikova, O.M.; Stoppa-Lyonnet, D.; Mazoyer, S.; Houdayer, C.; Hogervorst, F.B.L.; Hooning, M.J.; Ligtenberg, M.J.L.; Spurdle, A.; Chenevix-Trench, G.; Schmutzler, R.K.; Wappenschmidt, B.; Engel, C.; Meindl, A.; Domchek, S.M.; Nathanson, K.L.; Rebbeck, T.R.; Singer, C.F.; Gschwantler-Kaulich, D.; Dressler, C.; Fink, A.; Szabo, C.I.; Zikan, M.; Foretova, L.; Claes, K.; Thomas, G.; Hoover, R.N.; Hunter, D.J.; Chanock, S.J.; Easton, D.F.; Antoniou, A.C.; Couch, F.J.

    2010-01-01

    Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Since these risk modifiers were originally identified as genetic risk factors for breast cancer in genome-wide association studies (GWASs), additio

  7. Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

    DEFF Research Database (Denmark)

    Kar, Siddhartha P; Beesley, Jonathan; Amin Al Olama, Ali

    2016-01-01

    UNLABELLED: Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349...

  8. Identification and Targeting of Tyrosine Kinase Activity in Prostate Cancer Initiation, Progression, and Metastasis

    Science.gov (United States)

    2013-12-01

    25. Anonymous; Cancer Genome Atlas Network (2012) Comprehensive molecular por- traits of human breast tumours. Nature 490(7418):61–70. 26. Rubbi L, et...phosphorylation site localization using phosphoRS. J Proteome Res 10, 5354 (Dec 2, 2011). 56. J. A. Vizcaino, R. G. Cote , A. Csordas, J. A. Dianes

  9. GWAS meets TCGA to illuminate mechanisms of cancer predisposition.

    Science.gov (United States)

    Kim, Hyun Seok; Minna, John D; White, Michael A

    2013-01-31

    Genome-wide association studies (GWASs) have unraveled a large number of cancer risk alleles. Understanding how these allelic variants predispose to disease is a major bottleneck confronting translational application. In this issue, Li and colleagues combine GWASs with The Cancer Genome Atlas (TCGA) to disambiguate the contributions of germline and somatic variants to tumorigenic gene expression programs. They find that close to half of the known risk alleles for estrogen receptor (ER)-positive breast cancer are expression quantitative trait loci (eQTLs) acting upon major determinants of gene expression in tumors.

  10. Tapping CD4 T cells for cancer immunotherapy: the choice of personalized genomics.

    Science.gov (United States)

    Zanetti, Maurizio

    2015-03-01

    Cellular immune responses that protect against tumors typically have been attributed to CD8 T cells. However, CD4 T cells also play a central role. It was shown recently that, in a patient with metastatic cholangiocarcinoma, CD4 T cells specific for a peptide from a mutated region of ERBB2IP could arrest tumor progression. This and other recent findings highlight new opportunities for CD4 T cells in cancer immunotherapy. In this article, I discuss the role and regulation of CD4 T cells in response to tumor Ags. Emphasis is placed on the types of Ags and mechanisms that elicit tumor-protective responses. I discuss the advantages and drawbacks of cancer immunotherapy through personalized genomics. These considerations should help to guide the design of next-generation therapeutic cancer vaccines.

  11. Genome-wide association study for ovarian cancer susceptibility using pooled DNA

    DEFF Research Database (Denmark)

    Lu, Yi; Chen, Xiaoqing; Beesley, Jonathan;

    2012-01-01

    Recent Genome-Wide Association Studies (GWAS) have identified four low-penetrance ovarian cancer susceptibility loci. We hypothesized that further moderate- or low-penetrance variants exist among the subset of single-nucleotide polymorphisms (SNPs) not well tagged by the genotyping arrays used...... in a much larger stage 2 set of 4,651 cases and 6,966 controls from the Ovarian Cancer Association Consortium. Given that most of the top 20 SNPs from pooling were validated in the same samples by individual genotyping, the lack of replication is likely to be due to the relatively small sample size in our...... stage 1 GWAS rather than due to problems with the pooling approach. We conclude that there are unlikely to be any moderate or large effects on ovarian cancer risk untagged by less dense arrays. However, our study lacked power to make clear statements on the existence of hitherto untagged small...

  12. Genome-wide association study of colorectal cancer identifies six new susceptibility loci

    Science.gov (United States)

    Schumacher, Fredrick R.; Schmit, Stephanie L.; Jiao, Shuo; Edlund, Christopher K.; Wang, Hansong; Zhang, Ben; Hsu, Li; Huang, Shu-Chen; Fischer, Christopher P.; Harju, John F.; Idos, Gregory E.; Lejbkowicz, Flavio; Manion, Frank J.; McDonnell, Kevin; McNeil, Caroline E.; Melas, Marilena; Rennert, Hedy S.; Shi, Wei; Thomas, Duncan C.; Van Den Berg, David J.; Hutter, Carolyn M.; Aragaki, Aaron K.; Butterbach, Katja; Caan, Bette J.; Carlson, Christopher S.; Chanock, Stephen J.; Curtis, Keith R.; Fuchs, Charles S.; Gala, Manish; Giovannucci, Edward L.; Gogarten, Stephanie M.; Hayes, Richard B.; Henderson, Brian; Hunter, David J.; Jackson, Rebecca D.; Kolonel, Laurence N.; Kooperberg, Charles; Küry, Sébastien; LaCroix, Andrea; Laurie, Cathy C.; Laurie, Cecelia A.; Lemire, Mathieu; Levine, David; Ma, Jing; Makar, Karen W.; Qu, Conghui; Taverna, Darin; Ulrich, Cornelia M.; Wu, Kana; Kono, Suminori; West, Dee W.; Berndt, Sonja I.; Bezieau, Stéphane; Brenner, Hermann; Campbell, Peter T.; Chan, Andrew T.; Chang-Claude, Jenny; Coetzee, Gerhard A.; Conti, David V.; Duggan, David; Figueiredo, Jane C.; Fortini, Barbara K.; Gallinger, Steven J.; Gauderman, W. James; Giles, Graham; Green, Roger; Haile, Robert; Harrison, Tabitha A.; Hoffmeister, Michael; Hopper, John L.; Hudson, Thomas J.; Jacobs, Eric; Iwasaki, Motoki; Jee, Sun Ha; Jenkins, Mark; Jia, Wei-Hua; Joshi, Amit; Li, Li; Lindor, Noralene M.; Matsuo, Keitaro; Moreno, Victor; Mukherjee, Bhramar; Newcomb, Polly A.; Potter, John D.; Raskin, Leon; Rennert, Gad; Rosse, Stephanie; Severi, Gianluca; Schoen, Robert E.; Seminara, Daniela; Shu, Xiao-Ou; Slattery, Martha L.; Tsugane, Shoichiro; White, Emily; Xiang, Yong-Bing; Zanke, Brent W.; Zheng, Wei; Le Marchand, Loic; Casey, Graham; Gruber, Stephen B.; Peters, Ulrike

    2016-01-01

    Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P<5.0E-08. These findings provide additional insight into the underlying biological mechanisms of colorectal cancer and demonstrate the scientific value of large consortia-based genetic epidemiology studies. PMID:26151821

  13. Pathway analysis of bladder cancer genome-wide association study identifies novel pathways involved in bladder cancer development

    Science.gov (United States)

    Chen, Meng; Rothman, Nathaniel; Ye, Yuanqing; Gu, Jian; Scheet, Paul A.; Huang, Maosheng; Chang, David W.; Dinney, Colin P.; Silverman, Debra T.; Figueroa, Jonine D.; Chanock, Stephen J.; Wu, Xifeng

    2016-01-01

    Genome-wide association studies (GWAS) are designed to identify individual regions associated with cancer risk, but only explain a small fraction of the inherited variability. Alternative approach analyzing genetic variants within biological pathways has been proposed to discover networks of susceptibility genes with additional effects. The gene set enrichment analysis (GSEA) may complement and expand traditional GWAS analysis to identify novel genes and pathways associated with bladder cancer risk. We selected three GSEA methods: Gen-Gen, Aligator, and the SNP Ratio Test to evaluate cellular signaling pathways involved in bladder cancer susceptibility in a Texas GWAS population. The candidate genetic polymorphisms from the significant pathway selected by GSEA were validated in an independent NCI GWAS. We identified 18 novel pathways (P < 0.05) significantly associated with bladder cancer risk. Five of the most promising pathways (P ≤ 0.001 in any of the three GSEA methods) among the 18 pathways included two cell cycle pathways and neural cell adhesion molecule (NCAM), platelet-derived growth factor (PDGF), and unfolded protein response pathways. We validated the candidate polymorphisms in the NCI GWAS and found variants of RAPGEF1, SKP1, HERPUD1, CACNB2, CACNA1C, CACNA1S, COL4A2, SRC, and CACNA1C were associated with bladder cancer risk. Two CCNE1 variants, rs8102137 and rs997669, from cell cycle pathways showed the strongest associations; the CCNE1 signal at 19q12 has already been reported in previous GWAS. These findings offer additional etiologic insights highlighting the specific genes and pathways associated with bladder cancer development. GSEA may be a complementary tool to GWAS to identify additional loci of cancer susceptibility.

  14. A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2

    DEFF Research Database (Denmark)

    Song, Honglin; Ramus, Susan J; Tyrer, Jonathan

    2009-01-01

    Epithelial ovarian cancer has a major heritable component, but the known susceptibility genes explain less than half the excess familial risk. We performed a genome-wide association study (GWAS) to identify common ovarian cancer susceptibility alleles. We evaluated 507,094 SNPs genotyped in 1,817...

  15. A novel genomic alteration of LSAMP associates with aggressive prostate cancer in African American men

    DEFF Research Database (Denmark)

    Petrovics, Gyorgy; Li, Hua; Stümpel, Tanja;

    2015-01-01

    Evaluation of cancer genomes in global context is of great interest in light of changing ethnic distribution of the world population. We focused our study on men of African ancestry because of their disproportionately higher rate of prostate cancer (CaP) incidence and mortality. We present a syst...

  16. Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA

    DEFF Research Database (Denmark)

    Earp, Madalene A; Kelemen, Linda E; Magliocco, Anthony M

    2014-01-01

    Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by...

  17. Differential pathway dependency discovery associated with drug response across cancer cell lines. | Office of Cancer Genomics

    Science.gov (United States)

    The effort to personalize treatment plans for cancer patients involves the identification of drug treatments that can effectively target the disease while minimizing the likelihood of adverse reactions. In this study, the gene-expression profile of 810 cancer cell lines and their response data to 368 small molecules from the Cancer Therapeutics Research Portal (CTRP) are analyzed to identify pathways with significant rewiring between genes, or differential gene dependency, between sensitive and non-sensitive cell lines.

  18. Use of genome-wide association studies for cancer research and drug repositioning.

    Directory of Open Access Journals (Sweden)

    Jizhun Zhang

    Full Text Available Although genome-wide association studies have identified many risk loci associated with colorectal cancer, the molecular basis of these associations are still unclear. We aimed to infer biological insights and highlight candidate genes of interest within GWAS risk loci. We used an in silico pipeline based on functional annotation, quantitative trait loci mapping of cis-acting gene, PubMed text-mining, protein-protein interaction studies, genetic overlaps with cancer somatic mutations and knockout mouse phenotypes, and functional enrichment analysis to prioritize the candidate genes at the colorectal cancer risk loci. Based on these analyses, we observed that these genes were the targets of approved therapies for colorectal cancer, and suggested that drugs approved for other indications may be repurposed for the treatment of colorectal cancer. This study highlights the use of publicly available data as a cost effective solution to derive biological insights, and provides an empirical evidence that the molecular basis of colorectal cancer can provide important leads for the discovery of new drugs.

  19. Use of Whole Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics Clinic

    Directory of Open Access Journals (Sweden)

    Samantha B. Foley

    2015-01-01

    Full Text Available Despite the potential of whole-genome sequencing (WGS to improve patient diagnosis and care, the empirical value of WGS in the cancer genetics clinic is unknown. We performed WGS on members of two cohorts of cancer genetics patients: those with BRCA1/2 mutations (n = 176 and those without (n = 82. Initial analysis of potentially pathogenic variants (PPVs, defined as nonsynonymous variants with allele frequency < 1% in ESP6500 in 163 clinically-relevant genes suggested that WGS will provide useful clinical results. This is despite the fact that a majority of PPVs were novel missense variants likely to be classified as variants of unknown significance (VUS. Furthermore, previously reported pathogenic missense variants did not always associate with their predicted diseases in our patients. This suggests that the clinical use of WGS will require large-scale efforts to consolidate WGS and patient data to improve accuracy of interpretation of rare variants. While loss-of-function (LoF variants represented only a small fraction of PPVs, WGS identified additional cancer risk LoF PPVs in patients with known BRCA1/2 mutations and led to cancer risk diagnoses in 21% of non-BRCA cancer genetics patients after expanding our analysis to 3209 ClinVar genes. These data illustrate how WGS can be used to improve our ability to discover patients' cancer genetic risks.

  20. Genome-wide DNA methylation modified by soy phytoestrogens: role for epigenetic therapeutics in prostate cancer?

    Science.gov (United States)

    Karsli-Ceppioglu, Seher; Ngollo, Marjolaine; Adjakly, Mawussi; Dagdemir, Aslihan; Judes, Gaëlle; Lebert, André; Boiteux, Jean-Paul; Penault-LLorca, Frédérique; Bignon, Yves-Jean; Guy, Laurent; Bernard-Gallon, Dominique

    2015-04-01

    In prostate cancer, DNA methylation is significantly associated with tumor initiation, progression, and metastasis. Previous studies have suggested that soy phytoestrogens might regulate DNA methylation at individual candidate gene loci and that they play a crucial role as potential therapeutic agents for prostate cancer. The purpose of our study was to examine the modulation effects of phytoestrogens on a genome-wide scale in regards to DNA methylation in prostate cancer. Prostate cancer cell lines DU-145 and LNCaP were treated with 40 μM of genistein and 110 μM of daidzein. DNMT inhibitor 5-azacytidine (2 μM) and the methylating agent budesonide (2 μM) were used to compare their demethylation/methylation effects with phytoestrogens. The regulatory effects of phytoestrogens on DNA methylation were analyzed by using a methyl-DNA immunoprecipitation method coupled with Human DNA Methylation Microarrays (MeDIP-chip). We observed that the methylation profiles of 58 genes were altered by genistein and daidzein treatments in DU-145 and LNCaP prostate cancer cells. In addition, the methylation frequencies of the MAD1L1, TRAF7, KDM4B, and hTERT genes were remarkably modified by genistein treatment. Our results suggest that the modulation effects of phytoestrogens on DNA methylation essentially lead to inhibition of cell growth and induction of apoptosis. Genome-wide methylation profiling reported here suggests that epigenetic regulation mechanisms and, by extension, epigenetics-driven novel therapeutic candidates warrant further consideration in future "omics" studies of prostate cancer.

  1. Lessons learned from the application of whole-genome analysis to the treatment of patients with advanced cancers.

    Science.gov (United States)

    Laskin, Janessa; Jones, Steven; Aparicio, Samuel; Chia, Stephen; Ch'ng, Carolyn; Deyell, Rebecca; Eirew, Peter; Fok, Alexandra; Gelmon, Karen; Ho, Cheryl; Huntsman, David; Jones, Martin; Kasaian, Katayoon; Karsan, Aly; Leelakumari, Sreeja; Li, Yvonne; Lim, Howard; Ma, Yussanne; Mar, Colin; Martin, Monty; Moore, Richard; Mungall, Andrew; Mungall, Karen; Pleasance, Erin; Rassekh, S Rod; Renouf, Daniel; Shen, Yaoqing; Schein, Jacqueline; Schrader, Kasmintan; Sun, Sophie; Tinker, Anna; Zhao, Eric; Yip, Stephen; Marra, Marco A

    2015-10-01

    Given the success of targeted agents in specific populations it is expected that some degree of molecular biomarker testing will become standard of care for many, if not all, cancers. To facilitate this, cancer centers worldwide are experimenting with targeted "panel" sequencing of selected mutations. Recent advances in genomic technology enable the generation of genome-scale data sets for individual patients. Recognizing the risk, inherent in panel sequencing, of failing to detect meaningful somatic alterations, we sought to establish processes to integrate data from whole-genome analysis (WGA) into routine cancer care. Between June 2012 and August 2014, 100 adult patients with incurable cancers consented to participate in the Personalized OncoGenomics (POG) study. Fresh tumor and blood samples were obtained and used for whole-genome and RNA sequencing. Computational approaches were used to identify candidate driver mutations, genes, and pathways. Diagnostic and drug information were then sought based on these candidate "drivers." Reports were generated and discussed weekly in a multidisciplinary team setting. Other multidisciplinary working groups were assembled to establish guidelines on the interpretation, communication, and integration of individual genomic findings into patient care. Of 78 patients for whom WGA was possible, results were considered actionable in 55 cases. In 23 of these 55 cases, the patients received treatments motivated by WGA. Our experience indicates that a multidisciplinary team of clinicians and scientists can implement a paradigm in which WGA is integrated into the care of late stage cancer patients to inform systemic therapy decisions.

  2. Frontiers in cancer epidemiology: a challenge to the research community from the Epidemiology and Genomics Research Program at the National Cancer Institute.

    Science.gov (United States)

    Khoury, Muin J; Freedman, Andrew N; Gillanders, Elizabeth M; Harvey, Chinonye E; Kaefer, Christie; Reid, Britt C; Rogers, Scott; Schully, Sheri D; Seminara, Daniela; Verma, Mukesh

    2012-07-01

    The Epidemiology and Genomics Research Program (EGRP) at the National Cancer Institute (NCI) is developing scientific priorities for cancer epidemiology research in the next decade. We would like to engage the research community and other stakeholders in a planning effort that will include a workshop in December 2012 to help shape new foci for cancer epidemiology research. To facilitate the process of defining the future of cancer epidemiology, we invite the research community to join in an ongoing web-based conversation at http://blog-epi.grants.cancer.gov/ to develop priorities and the next generation of high-impact studies.

  3. Alternate estrogen receptors promote invasion of inflammatory breast cancer cells via non-genomic signaling.

    Directory of Open Access Journals (Sweden)

    Kazufumi Ohshiro

    Full Text Available Although Inflammatory Breast Cancer (IBC is a rare and an aggressive type of locally advanced breast cancer with a generally worst prognosis, little work has been done in identifying the status of non-genomic signaling in the invasiveness of IBC. The present study was performed to explore the status of non-genomic signaling as affected by various estrogenic and anti-estrogenic agents in IBC cell lines SUM149 and SUM190. We have identified the presence of estrogen receptor α (ERα variant, ERα36 in SUM149 and SUM190 cells. This variant as well as ERβ was present in a substantial concentration in IBC cells. The treatment with estradiol (E2, anti-estrogenic agents 4-hydroxytamoxifen and ICI 182780, ERβ specific ligand DPN and GPR30 agonist G1 led to a rapid activation of p-ERK1/2, suggesting the involvement of ERα36, ERβ and GPR30 in the non-genomic signaling pathway in these cells. We also found a substantial increase in the cell migration and invasiveness of SUM149 cells upon the treatment with these ligands. Both basal and ligand-induced migration and invasiveness of SUM149 cells were drastically reduced in the presence of MEK inhibitor U0126, implicating that the phosphorylation of ERK1/2 by MEK is involved in the observed motility and invasiveness of IBC cells. We also provide evidence for the upregulation of p-ERK1/2 through immunostaining in IBC patient samples. These findings suggest a role of non-genomic signaling through the activation of p-ERK1/2 in the hormonal dependence of IBC by a combination of estrogen receptors. These findings only explain the failure of traditional anti-estrogen therapies in ER-positive IBC which induces the non-genomic signaling, but also opens newer avenues for design of modified therapies targeting these estrogen receptors.

  4. Whole genome sequence analysis suggests intratumoral heterogeneity in dissemination of breast cancer to lymph nodes.

    Directory of Open Access Journals (Sweden)

    Kevin Blighe

    Full Text Available BACKGROUND: Intratumoral heterogeneity may help drive resistance to targeted therapies in cancer. In breast cancer, the presence of nodal metastases is a key indicator of poorer overall survival. The aim of this study was to identify somatic genetic alterations in early dissemination of breast cancer by whole genome next generation sequencing (NGS of a primary breast tumor, a matched locally-involved axillary lymph node and healthy normal DNA from blood. METHODS: Whole genome NGS was performed on 12 µg (range 11.1-13.3 µg of DNA isolated from fresh-frozen primary breast tumor, axillary lymph node and peripheral blood following the DNA nanoball sequencing protocol. Single nucleotide variants, insertions, deletions, and substitutions were identified through a bioinformatic pipeline and compared to CIN25, a key set of genes associated with tumor metastasis. RESULTS: Whole genome sequencing revealed overlapping variants between the tumor and node, but also variants that were unique to each. Novel mutations unique to the node included those found in two CIN25 targets, TGIF2 and CCNB2, which are related to transcription cyclin activity and chromosomal stability, respectively, and a unique frameshift in PDS5B, which is required for accurate sister chromatid segregation during cell division. We also identified dominant clonal variants that progressed from tumor to node, including SNVs in TP53 and ARAP3, which mediates rearrangements to the cytoskeleton and cell shape, and an insertion in TOP2A, the expression of which is significantly associated with tumor proliferation and can segregate breast cancers by outcome. CONCLUSION: This case study provides preliminary evidence that primary tumor and early nodal metastasis have largely overlapping somatic genetic alterations. There were very few mutations unique to the involved node. However, significant conclusions regarding early dissemination needs analysis of a larger number of patient samples.

  5. The genomic analysis of lactic acidosis and acidosis response in human cancers.

    Directory of Open Access Journals (Sweden)

    Julia Ling-Yu Chen

    2008-12-01

    Full Text Available The tumor microenvironment has a significant impact on tumor development. Two important determinants in this environment are hypoxia and lactic acidosis. Although lactic acidosis has long been recognized as an important factor in cancer, relatively little is known about how cells respond to lactic acidosis and how that response relates to cancer phenotypes. We develop genome-scale gene expression studies to dissect transcriptional responses of primary human mammary epithelial cells to lactic acidosis and hypoxia in vitro and to explore how they are linked to clinical tumor phenotypes in vivo. The resulting experimental signatures of responses to lactic acidosis and hypoxia are evaluated in a heterogeneous set of breast cancer datasets. A strong lactic acidosis response signature identifies a subgroup of low-risk breast cancer patients having distinct metabolic profiles suggestive of a preference for aerobic respiration. The association of lactic acidosis response with good survival outcomes may relate to the role of lactic acidosis in directing energy generation toward aerobic respiration and utilization of other energy sources via inhibition of glycolysis. This "inhibition of glycolysis" phenotype in tumors is likely caused by the repression of glycolysis gene expression and Akt inhibition. Our study presents a genomic evaluation of the prognostic information of a lactic acidosis response independent of the hypoxic response. Our results identify causal roles of lactic acidosis in metabolic reprogramming, and the direct functional consequence of lactic acidosis pathway activity on cellular responses and tumor development. The study also demonstrates the utility of genomic analysis that maps expression-based findings from in vitro experiments to human samples to assess links to in vivo clinical phenotypes.

  6. Whole-genome sequencing analysis of phenotypic heterogeneity and anticipation in Li–Fraumeni cancer predisposition syndrome

    OpenAIRE

    Ariffin, Hany; Hainaut,Pierre; Puzio-Kuter, Anna; Choong, Soo Sin; Chan, Adelyne Sue Li; Tolkunov, Denis; Rajagopal, Gunaretnam; Kang, Wenfeng; Lim, Leon Li Wen; Krishnan, Shekhar; Chen, Kok-Siong; Achatz, Maria Isabel; Karsa, Mawar; Shamsani, Jannah; Levine, Arnold J.

    2014-01-01

    Germ-line mutation in the tumor suppressor TP53 causes Li–Fraumeni syndrome (LFS), a complex predisposition to multiple cancers. Types of cancers and ages at diagnosis vary among subjects and families, with apparent genetic anticipation: i.e., earlier cancer onset with successive generations. It has been proposed that anticipation is caused by accumulation of copy-number variations (CNV) in a context of TP53 haploinsufficiency. Using genome/exome sequencing, we found no evidence of increased ...

  7. Recurrent genomic gains in preinvasive lesions as a biomarker of risk for lung cancer.

    Directory of Open Access Journals (Sweden)

    Pierre P Massion

    Full Text Available Lung carcinoma development is accompanied by field changes that may have diagnostic significance. We have previously shown the importance of chromosomal aneusomy in lung cancer progression. Here, we tested whether genomic gains in six specific loci, TP63 on 3q28, EGFR on 7p12, MYC on 8q24, 5p15.2, and centromeric regions for chromosomes 3 (CEP3 and 6 (CEP6, may provide further value in the prediction of lung cancer. Bronchial biopsy specimens were obtained by LIFE bronchoscopy from 70 subjects (27 with prevalent lung cancers and 43 individuals without lung cancer. Twenty six biopsies were read as moderate dysplasia, 21 as severe dysplasia and 23 as carcinoma in situ (CIS. Four-micron paraffin sections were submitted to a 4-target FISH assay (LAVysion, Abbott Molecular and reprobed for TP63 and CEP 3 sequences. Spot counts were obtained in 30-50 nuclei per specimen for each probe. Increased gene copy number in 4 of the 6 probes was associated with increased risk of being diagnosed with lung cancer both in unadjusted analyses (odds ratio = 11, p<0.05 and adjusted for histology grade (odds ratio = 17, p<0.05. The most informative 4 probes were TP63, MYC, CEP3 and CEP6. The combination of these 4 probes offered a sensitivity of 82% for lung cancer and a specificity of 58%. These results indicate that specific cytogenetic alterations present in preinvasive lung lesions are closely associated with the diagnosis of lung cancer and may therefore have value in assessing lung cancer risk.

  8. Delineation of target volumes and organs at risk in adjuvant radiotherapy of early breast cancer: National guidelines and contouring atlas by the Danish Breast Cancer Cooperative Group

    Energy Technology Data Exchange (ETDEWEB)

    Nielsen, Mette H. [Dept. of Oncology, Odense Univ. Hospital, Odense (Denmark)], E-mail: mette.m.nielsen@ouh.regionsyddanmark.dk; Berg, Martin [Dept. of Medical Physics, Hospital of Vejle, Vejle (Denmark); Pedersen, Anders N. [Dept. of Oncology, Rigshospitalet, Copenhagen (Denmark)] [and others

    2013-05-15

    During the past decade planning of adjuvant radiotherapy (RT) of early breast cancer has changed from two-dimensional (2D) to 3D conformal techniques. In the planning computerised tomography (CT) scan both the targets for RT and the organs at risk (OARs) are visualised, enabling an increased focus on target dose coverage and homogeneity with only minimal dose to the OARs. To ensure uniform RT in the national prospective trials of the Danish Breast Cancer Cooperative Group (DBCG), a national consensus for the delineation of clinical target volumes (CTVs) and OARs was required. Material and methods. A CT scan of a breast cancer patient after surgical breast conservation and axillary lymph node (LN) dissection was used for delineation. During multiple dummy-runs seven experienced radiation oncologists contoured all CTVs and OARs of interest in adjuvant breast RT. Two meetings were held in the DBCG Radiotherapy Committee to discuss the contouring and to approve a fi nal consensus. The Dice similarity coefficient (DSC) was used to evaluate the delineation agreement before and after the consensus. Results. The consensus delineations of CTVs and OARs are available online and a table is presented with a contouring description of the individual volumes. The consensus provides recommendations for target delineation in a standard patient both in case of breast conservation or mastectomy. Before the consensus, the average value of the DSC was modest for most volumes, but high for the breast CTV and the heart. After the consensus, the DSC increased for all volumes. Conclusion. The DBCG has provided the fi rst national guidelines and a contouring atlas of CTVs and OARs definition for RT of early breast cancer. The DSC is a useful tool in quantifying the effect of the introduction of guidelines indicating improved inter-delineator agreement. This consensus will be used by the DBCG in our prospective trials.

  9. Genomic Analysis of Uterine Lavage Fluid Detects Early Endometrial Cancers and Reveals a Prevalent Landscape of Driver Mutations in Women without Histopathologic Evidence of Cancer: A Prospective Cross-Sectional Study

    Science.gov (United States)

    Camacho, Sandra Catalina; Schumacher, Cassie A.; Irish, Jonathan C.; Harkins, Timothy T.; Belfer, Rachel; Kalir, Tamara; Reva, Boris; Dottino, Peter; Martignetti, John A.

    2016-01-01

    Background Endometrial cancer is the most common gynecologic malignancy, and its incidence and associated mortality are increasing. Despite the immediate need to detect these cancers at an earlier stage, there is no effective screening methodology or protocol for endometrial cancer. The comprehensive, genomics-based analysis of endometrial cancer by The Cancer Genome Atlas (TCGA) revealed many of the molecular defects that define this cancer. Based on these cancer genome results, and in a prospective study, we hypothesized that the use of ultra-deep, targeted gene sequencing could detect somatic mutations in uterine lavage fluid obtained from women undergoing hysteroscopy as a means of molecular screening and diagnosis. Methods and Findings Uterine lavage and paired blood samples were collected and analyzed from 107 consecutive patients who were undergoing hysteroscopy and curettage for diagnostic evaluation from this single-institution study. The lavage fluid was separated into cellular and acellular fractions by centrifugation. Cellular and cell-free DNA (cfDNA) were isolated from each lavage. Two targeted next-generation sequencing (NGS) gene panels, one composed of 56 genes and the other of 12 genes, were used for ultra-deep sequencing. To rule out potential NGS-based errors, orthogonal mutation validation was performed using digital PCR and Sanger sequencing. Seven patients were diagnosed with endometrial cancer based on classic histopathologic analysis. Six of these patients had stage IA cancer, and one of these cancers was only detectable as a microscopic focus within a polyp. All seven patients were found to have significant cancer-associated gene mutations in both cell pellet and cfDNA fractions. In the four patients in whom adequate tumor sample was available, all tumor mutations above a specific allele fraction were present in the uterine lavage DNA samples. Mutations originally only detected in lavage fluid fractions were later confirmed to be present

  10. Genome-wide analysis of alternative transcripts in human breast cancer

    Science.gov (United States)

    Wen, Ji; Toomer, Kevin H.

    2016-01-01

    Transcript variants play a critical role in diversifying gene expression. Alternative splicing is a major mechanism for generating transcript variants. A number of genes have been implicated in breast cancer pathogenesis with their aberrant expression of alternative transcripts. In this study, we performed genome-wide analyses of transcript variant expression in breast cancer. With RNA-Seq data from 105 patients, we characterized the transcriptome of breast tumors, by pairwise comparison of gene expression in the breast tumor versus matched healthy tissue from each patient. We identified 2839 genes, ~10 % of protein-coding genes in the human genome, that had differential expression of transcript variants between tumors and healthy tissues. The validity of the computational analysis was confirmed by quantitative RT-PCR assessment of transcript variant expression from four top candidate genes. The alternative transcript profiling led to classification of breast cancer into two subgroups and yielded a novel molecular signature that could be prognostic of patients’ tumor burden and survival. We uncovered nine splicing factors (FOX2, MBNL1, QKI, PTBP1, ELAVL1, HNRNPC, KHDRBS1, SFRS2, and TIAR) that were involved in aberrant splicing in breast cancer. Network analyses for the coordinative patterns of transcript variant expression identified twelve “hub” genes that differentiated the cancerous and normal transcriptomes. Dysregulated expression of alternative transcripts may reveal novel biomarkers for tumor development. It may also suggest new therapeutic targets, such as the “hub” genes identified through the network analyses of transcript variant expression, or splicing factors implicated in the formation of the tumor transcriptome. PMID:25913416

  11. Comparison of mortality and incidence cancer risk and models of genomic instability: the Techa River cohort

    Energy Technology Data Exchange (ETDEWEB)

    Eidemueller, Markus; Jacob, Peter [Helmholtz Zentrum Muenchen, Institut fuer Strahlenschutz, Neuherberg (Germany); Ostroumova, Zhenia; Krestinina, Ludmila; Akleyev, Alexander [Urals Research Center for Radiation Medicine, Chelyabinsk (Russian Federation)

    2009-07-01

    Solid cancer mortality and incidence risk after radiation exposure in the Techa River Cohort in the Southern Urals region of Russia is analyzed. Residents along the Techa River received protracted exposure in the 1950s due to the releases of radioactive materials from the Mayak plutonium complex. The analysis is performed within the framework of the biologically based two-stage clonal expansion (TSCE) model and with excess relative risk models. TSCE models including effects of radiation-induced genomic instability are applied to the data and it is found that the best description of the radiation risk is achieved with the same model of genomic instability both for the mortality and incidence cohort. By a direct comparison of the cancer risk in both cohorts it is shown how the mortality and incidence rates and excess relative risk can be related. The TSCE parameters, that describe effective biological time scales in the process of cancer development, turn out to be similar for the mortality and incidence data sets.

  12. Breast cancer risk among Swedish hemangioma patients and possible consequences of radiation-induced genomic instability

    Energy Technology Data Exchange (ETDEWEB)

    Eidemueller, Markus, E-mail: markus.eidemueller@helmholtz-muenchen.de [Helmholtz Zentrum Muenchen, Institute of Radiation Protection, 85764 Neuherberg (Germany); Holmberg, Erik [Department of Oncology, Sahlgrenska University Hospital, SE-413 45 Goeteborg (Sweden); Jacob, Peter [Helmholtz Zentrum Muenchen, Institute of Radiation Protection, 85764 Neuherberg (Germany); Lundell, Marie [Department of Medical Physics, Radiumhemmet, Karolinska University Hospital, SE-171 76 Stockholm (Sweden); Karlsson, Per [Department of Oncology, Sahlgrenska University Hospital, SE-413 45 Goeteborg (Sweden)

    2009-10-02

    Breast cancer incidence among 17,158 female Swedish hemangioma patients was analyzed with empirical excess relative risk models and with a biologically-based model of carcinogenesis. The patients were treated in infancy mainly by external application of radium-226. The mean and median absorbed doses to the breast were 0.29 and 0.04 Gy, and a total of 678 breast cancer cases have been observed. Both models agree very well in the risk estimates with an excess relative risk and excess absolute risk at the age of 50 years, about the mean age of breast cancer incidence, of 0.25 Gy{sup -1}(95% CI 0.14; 0.37) and 30.7 (10{sup 5}BYRGy){sup -1} (95% CI 16.9; 42.8), respectively. Models incorporating effects of radiation-induced genomic instability were developed and applied to the hemangioma cohort. The biologically-based description of the radiation risk was significantly improved with a model of genomic instability at an early stage of carcinogenesis.

  13. Structural variation discovery in the cancer genome using next generation sequencing: Computational solutions and perspectives

    Science.gov (United States)

    Liu, Biao; Conroy, Jeffrey M.; Morrison, Carl D.; Odunsi, Adekunle O.; Qin, Maochun; Wei, Lei; Trump, Donald L.; Johnson, Candace S.; Liu, Song; Wang, Jianmin

    2015-01-01

    Somatic Structural Variations (SVs) are a complex collection of chromosomal mutations that could directly contribute to carcinogenesis. Next Generation Sequencing (NGS) technology has emerged as the primary means of interrogating the SVs of the cancer genome in recent investigations. Sophisticated computational methods are required to accurately identify the SV events and delineate their breakpoints from the massive amounts of reads generated by a NGS experiment. In this review, we provide an overview of current analytic tools used for SV detection in NGS-based cancer studies. We summarize the features of common SV groups and the primary types of NGS signatures that can be used in SV detection methods. We discuss the principles and key similarities and differences of existing computational programs and comment on unresolved issues related to this research field. The aim of this article is to provide a practical guide of relevant concepts, computational methods, software tools and important factors for analyzing and interpreting NGS data for the detection of SVs in the cancer genome. PMID:25849937

  14. Prediction of cancer cell sensitivity to natural products based on genomic and chemical properties

    Directory of Open Access Journals (Sweden)

    Zhenyu Yue

    2015-11-01

    Full Text Available Natural products play a significant role in cancer chemotherapy. They are likely to provide many lead structures, which can be used as templates for the construction of novel drugs with enhanced antitumor activity. Traditional research approaches studied structure-activity relationship of natural products and obtained key structural properties, such as chemical bond or group, with the purpose of ascertaining their effect on a single cell line or a single tissue type. Here, for the first time, we develop a machine learning method to comprehensively predict natural products responses against a panel of cancer cell lines based on both the gene expression and the chemical properties of natural products. The results on two datasets, training set and independent test set, show that this proposed method yields significantly better prediction accuracy. In addition, we also demonstrate the predictive power of our proposed method by modeling the cancer cell sensitivity to two natural products, Curcumin and Resveratrol, which indicate that our method can effectively predict the response of cancer cell lines to these two natural products. Taken together, the method will facilitate the identification of natural products as cancer therapies and the development of precision medicine by linking the features of patient genomes to natural product sensitivity.

  15. Genome-wide association study of pancreatic cancer in Japanese population.

    Directory of Open Access Journals (Sweden)

    Siew-Kee Low

    Full Text Available Pancreatic cancer shows very poor prognosis and is the fifth leading cause of cancer death in Japan. Previous studies indicated some genetic factors contributing to the development and progression of pancreatic cancer; however, there are limited reports for common genetic variants to be associated with this disease, especially in the Asian population. We have conducted a genome-wide association study (GWAS using 991 invasive pancreatic ductal adenocarcinoma cases and 5,209 controls, and identified three loci showing significant association (P-value<5x10(-7 with susceptibility to pancreatic cancer. The SNPs that showed significant association carried estimated odds ratios of 1.29, 1.32, and 3.73 with 95% confidence intervals of 1.17-1.43, 1.19-1.47, and 2.24-6.21; P-value of 3.30x10(-7, 3.30x10(-7, and 4.41x10(-7; located on chromosomes 6p25.3, 12p11.21 and 7q36.2, respectively. These associated SNPs are located within linkage disequilibrium blocks containing genes that have been implicated some roles in the oncogenesis of pancreatic cancer.

  16. Prediction of cancer cell sensitivity to natural products based on genomic and chemical properties.

    Science.gov (United States)

    Yue, Zhenyu; Zhang, Wenna; Lu, Yongming; Yang, Qiaoyue; Ding, Qiuying; Xia, Junfeng; Chen, Yan

    2015-01-01

    Natural products play a significant role in cancer chemotherapy. They are likely to provide many lead structures, which can be used as templates for the construction of novel drugs with enhanced antitumor activity. Traditional research approaches studied structure-activity relationship of natural products and obtained key structural properties, such as chemical bond or group, with the purpose of ascertaining their effect on a single cell line or a single tissue type. Here, for the first time, we develop a machine learning method to comprehensively predict natural products responses against a panel of cancer cell lines based on both the gene expression and the chemical properties of natural products. The results on two datasets, training set and independent test set, show that this proposed method yields significantly better prediction accuracy. In addition, we also demonstrate the predictive power of our proposed method by modeling the cancer cell sensitivity to two natural products, Curcumin and Resveratrol, which indicate that our method can effectively predict the response of cancer cell lines to these two natural products. Taken together, the method will facilitate the identification of natural products as cancer therapies and the development of precision medicine by linking the features of patient genomes to natural product sensitivity.

  17. Copy number analysis identifies novel interactions between genomic loci in ovarian cancer.

    Directory of Open Access Journals (Sweden)

    Kylie L Gorringe

    Full Text Available Ovarian cancer is a heterogeneous disease displaying complex genomic alterations, and consequently, it has been difficult to determine the most relevant copy number alterations with the scale of studies to date. We obtained genome-wide copy number alteration (CNA data from four different SNP array platforms, with a final data set of 398 ovarian tumours, mostly of the serous histological subtype. Frequent CNA aberrations targeted many thousands of genes. However, high-level amplicons and homozygous deletions enabled filtering of this list to the most relevant. The large data set enabled refinement of minimal regions and identification of rare amplicons such as at 1p34 and 20q11. We performed a novel co-occurrence analysis to assess cooperation and exclusivity of CNAs and analysed their relationship to patient outcome. Positive associations were identified between gains on 19 and 20q, gain of 20q and loss of X, and between several regions of loss, particularly 17q. We found weak correlations of CNA at genomic loci such as 19q12 with clinical outcome. We also assessed genomic instability measures and found a correlation of the number of higher amplitude gains with poorer overall survival. By assembling the largest collection of ovarian copy number data to date, we have been able to identify the most frequent aberrations and their interactions.

  18. Copy number analysis identifies novel interactions between genomic loci in ovarian cancer.

    Science.gov (United States)

    Gorringe, Kylie L; George, Joshy; Anglesio, Michael S; Ramakrishna, Manasa; Etemadmoghadam, Dariush; Cowin, Prue; Sridhar, Anita; Williams, Louise H; Boyle, Samantha E; Yanaihara, Nozomu; Okamoto, Aikou; Urashima, Mitsuyoshi; Smyth, Gordon K; Campbell, Ian G; Bowtell, David D L

    2010-09-10

    Ovarian cancer is a heterogeneous disease displaying complex genomic alterations, and consequently, it has been difficult to determine the most relevant copy number alterations with the scale of studies to date. We obtained genome-wide copy number alteration (CNA) data from four different SNP array platforms, with a final data set of 398 ovarian tumours, mostly of the serous histological subtype. Frequent CNA aberrations targeted many thousands of genes. However, high-level amplicons and homozygous deletions enabled filtering of this list to the most relevant. The large data set enabled refinement of minimal regions and identification of rare amplicons such as at 1p34 and 20q11. We performed a novel co-occurrence analysis to assess cooperation and exclusivity of CNAs and analysed their relationship to patient outcome. Positive associations were identified between gains on 19 and 20q, gain of 20q and loss of X, and between several regions of loss, particularly 17q. We found weak correlations of CNA at genomic loci such as 19q12 with clinical outcome. We also assessed genomic instability measures and found a correlation of the number of higher amplitude gains with poorer overall survival. By assembling the largest collection of ovarian copy number data to date, we have been able to identify the most frequent aberrations and their interactions.

  19. Genome remodelling in a basal-like breast cancer metastasis and xenograft.

    Science.gov (United States)

    Ding, Li; Ellis, Matthew J; Li, Shunqiang; Larson, David E; Chen, Ken; Wallis, John W; Harris, Christopher C; McLellan, Michael D; Fulton, Robert S; Fulton, Lucinda L; Abbott, Rachel M; Hoog, Jeremy; Dooling, David J; Koboldt, Daniel C; Schmidt, Heather; Kalicki, Joelle; Zhang, Qunyuan; Chen, Lei; Lin, Ling; Wendl, Michael C; McMichael, Joshua F; Magrini, Vincent J; Cook, Lisa; McGrath, Sean D; Vickery, Tammi L; Appelbaum, Elizabeth; Deschryver, Katherine; Davies, Sherri; Guintoli, Therese; Lin, Li; Crowder, Robert; Tao, Yu; Snider, Jacqueline E; Smith, Scott M; Dukes, Adam F; Sanderson, Gabriel E; Pohl, Craig S; Delehaunty, Kim D; Fronick, Catrina C; Pape, Kimberley A; Reed, Jerry S; Robinson, Jody S; Hodges, Jennifer S; Schierding, William; Dees, Nathan D; Shen, Dong; Locke, Devin P; Wiechert, Madeline E; Eldred, James M; Peck, Josh B; Oberkfell, Benjamin J; Lolofie, Justin T; Du, Feiyu; Hawkins, Amy E; O'Laughlin, Michelle D; Bernard, Kelly E; Cunningham, Mark; Elliott, Glendoria; Mason, Mark D; Thompson, Dominic M; Ivanovich, Jennifer L; Goodfellow, Paul J; Perou, Charles M; Weinstock, George M; Aft, Rebecca; Watson, Mark; Ley, Timothy J; Wilson, Richard K; Mardis, Elaine R

    2010-04-15

    Massively parallel DNA sequencing technologies provide an unprecedented ability to screen entire genomes for genetic changes associated with tumour progression. Here we describe the genomic analyses of four DNA samples from an African-American patient with basal-like breast cancer: peripheral blood, the primary tumour, a brain metastasis and a xenograft derived from the primary tumour. The metastasis contained two de novo mutations and a large deletion not present in the primary tumour, and was significantly enriched for 20 shared mutations. The xenograft retained all primary tumour mutations and displayed a mutation enrichment pattern that resembled the metastasis. Two overlapping large deletions, encompassing CTNNA1, were present in all three tumour samples. The differential mutation frequencies and structural variation patterns in metastasis and xenograft compared with the primary tumour indicate that secondary tumours may arise from a minority of cells within the primary tumour.

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  15. File list: Oth.Prs.05.AllAg.Prostate_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Prs.05.AllAg.Prostate_cancer hg19 TFs and others Prostate Prostate cancer SRX50...X502065,SRX502055,SRX502069 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Prs.05.AllAg.Prostate_cancer.bed ...

  16. File list: ALL.Brs.50.AllAg.Breast_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Brs.50.AllAg.Breast_cancer hg19 All antigens Breast Breast cancer SRX186804,SRX...SRX186809,SRX186818,SRX186827,SRX186829,SRX186830 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/ALL.Brs.50.AllAg.Breast_cancer.bed ...

  17. File list: InP.Prs.20.AllAg.Prostate_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Prs.20.AllAg.Prostate_cancer hg19 Input control Prostate Prostate cancer SRX861...688,SRX861689,SRX861686 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/InP.Prs.20.AllAg.Prostate_cancer.bed ...

  18. File list: InP.Dig.50.AllAg.Colon_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Dig.50.AllAg.Colon_cancer hg19 Input control Digestive tract Colon cancer SRX12...155774,SRX124693,SRX124698 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/InP.Dig.50.AllAg.Colon_cancer.bed ...

  19. File list: Oth.Brs.05.AllAg.Breast_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Brs.05.AllAg.Breast_cancer hg19 TFs and others Breast Breast cancer SRX186804,S... http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Brs.05.AllAg.Breast_cancer.bed ...

  20. File list: Unc.Dig.50.AllAg.Colon_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Unc.Dig.50.AllAg.Colon_cancer hg19 Unclassified Digestive tract Colon cancer SRX115...0169,SRX1150170,SRX124703 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Unc.Dig.50.AllAg.Colon_cancer.bed ...

  1. File list: Oth.Prs.10.AllAg.Prostate_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Prs.10.AllAg.Prostate_cancer_cells hg19 TFs and others Prostate Prostate cancer... cells SRX022578,SRX022577 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Prs.10.AllAg.Prostate_cancer_cells.bed ...

  2. File list: ALL.Prs.50.AllAg.Prostate_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Prs.50.AllAg.Prostate_cancer hg19 All antigens Prostate Prostate cancer SRX5020...02062,SRX861679,SRX861684,SRX861685,SRX861681,SRX861678 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/ALL.Prs.50.AllAg.Prostate_cancer.bed ...

  3. File list: ALL.Brs.05.AllAg.Breast_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Brs.05.AllAg.Breast_cancer hg19 All antigens Breast Breast cancer SRX186799,SRX...SRX186817,SRX186826,SRX186812,SRX186820,SRX186823 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/ALL.Brs.05.AllAg.Breast_cancer.bed ...

  4. File list: InP.Prs.50.AllAg.Prostate_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Prs.50.AllAg.Prostate_cancer hg19 Input control Prostate Prostate cancer SRX861...688,SRX861686,SRX861689 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/InP.Prs.50.AllAg.Prostate_cancer.bed ...

  5. File list: Oth.Pan.05.AllAg.Pancreatic_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Pan.05.AllAg.Pancreatic_cancer_cells mm9 TFs and others Pancreas Pancreatic cancer... cells SRX174586,SRX174585 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Oth.Pan.05.AllAg.Pancreatic_cancer_cells.bed ...

  6. File list: InP.Dig.10.AllAg.Colon_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Dig.10.AllAg.Colon_cancer hg19 Input control Digestive tract Colon cancer SRX12...155774,SRX625671,SRX155777 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/InP.Dig.10.AllAg.Colon_cancer.bed ...

  7. File list: InP.Prs.10.AllAg.Prostate_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Prs.10.AllAg.Prostate_cancer hg19 Input control Prostate Prostate cancer SRX861...688,SRX861689,SRX861686 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/InP.Prs.10.AllAg.Prostate_cancer.bed ...

  8. File list: ALL.Brs.10.AllAg.Breast_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Brs.10.AllAg.Breast_cancer hg19 All antigens Breast Breast cancer SRX186799,SRX...SRX186812,SRX186826,SRX186820,SRX186817,SRX186823 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/ALL.Brs.10.AllAg.Breast_cancer.bed ...

  9. File list: InP.Prs.05.AllAg.Prostate_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Prs.05.AllAg.Prostate_cancer hg19 Input control Prostate Prostate cancer SRX861...688,SRX861689,SRX861686 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/InP.Prs.05.AllAg.Prostate_cancer.bed ...

  10. File list: Unc.Dig.05.AllAg.Colon_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Unc.Dig.05.AllAg.Colon_cancer hg19 Unclassified Digestive tract Colon cancer SRX115...0169,SRX1150170,SRX124703 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Unc.Dig.05.AllAg.Colon_cancer.bed ...

  11. File list: Oth.Dig.20.AllAg.Colon_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Dig.20.AllAg.Colon_cancer hg19 TFs and others Digestive tract Colon cancer SRX1...55772,SRX155773,SRX155775,SRX155776 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Dig.20.AllAg.Colon_cancer.bed ...

  12. File list: Oth.Dig.10.AllAg.Colon_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Dig.10.AllAg.Colon_cancer hg19 TFs and others Digestive tract Colon cancer SRX1...55772,SRX155775,SRX155773,SRX155776 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Dig.10.AllAg.Colon_cancer.bed ...

  13. File list: Oth.Prs.10.AllAg.Prostate_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Prs.10.AllAg.Prostate_cancer hg19 TFs and others Prostate Prostate cancer SRX50...X502065,SRX502059,SRX502055 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Prs.10.AllAg.Prostate_cancer.bed ...

  14. File list: His.Prs.20.AllAg.Prostate_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.Prs.20.AllAg.Prostate_cancer_cells hg19 Histone Prostate Prostate cancer cells ...SRX022579,SRX022581,SRX022580 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/His.Prs.20.AllAg.Prostate_cancer_cells.bed ...

  15. File list: Unc.Dig.10.AllAg.Colon_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Unc.Dig.10.AllAg.Colon_cancer hg19 Unclassified Digestive tract Colon cancer SRX115...0169,SRX124703,SRX1150170 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Unc.Dig.10.AllAg.Colon_cancer.bed ...

  16. File list: Pol.Prs.10.AllAg.Prostate_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Pol.Prs.10.AllAg.Prostate_cancer_cells hg19 RNA polymerase Prostate Prostate cancer... cells SRX022582 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Pol.Prs.10.AllAg.Prostate_cancer_cells.bed ...

  17. File list: Oth.Brs.20.AllAg.Breast_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Brs.20.AllAg.Breast_cancer hg19 TFs and others Breast Breast cancer SRX186804,S... http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Brs.20.AllAg.Breast_cancer.bed ...

  18. File list: Oth.Dig.05.AllAg.Colon_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Dig.05.AllAg.Colon_cancer hg19 TFs and others Digestive tract Colon cancer SRX1...55772,SRX155773,SRX155775,SRX155776 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Dig.05.AllAg.Colon_cancer.bed ...

  19. File list: InP.Dig.20.AllAg.Colon_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Dig.20.AllAg.Colon_cancer hg19 Input control Digestive tract Colon cancer SRX12...124693,SRX124697,SRX124698 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/InP.Dig.20.AllAg.Colon_cancer.bed ...

  20. File list: InP.Dig.05.AllAg.Colon_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Dig.05.AllAg.Colon_cancer hg19 Input control Digestive tract Colon cancer SRX12...124693,SRX124695,SRX124694 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/InP.Dig.05.AllAg.Colon_cancer.bed ...

  1. File list: Oth.Dig.50.AllAg.Colon_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Dig.50.AllAg.Colon_cancer hg19 TFs and others Digestive tract Colon cancer SRX1...55772,SRX155775,SRX155773,SRX155776 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Dig.50.AllAg.Colon_cancer.bed ...

  2. File list: ALL.Brs.20.AllAg.Breast_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Brs.20.AllAg.Breast_cancer hg19 All antigens Breast Breast cancer SRX186804,SRX...SRX186823,SRX186817,SRX186820,SRX186832,SRX186829 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/ALL.Brs.20.AllAg.Breast_cancer.bed ...

  3. File list: Oth.Brs.10.AllAg.Breast_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Brs.10.AllAg.Breast_cancer hg19 TFs and others Breast Breast cancer SRX186804,S... http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Brs.10.AllAg.Breast_cancer.bed ...

  4. File list: Oth.Brs.50.AllAg.Breast_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Brs.50.AllAg.Breast_cancer hg19 TFs and others Breast Breast cancer SRX186804,S... http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Brs.50.AllAg.Breast_cancer.bed ...

  5. File list: Unc.Dig.20.AllAg.Colon_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Unc.Dig.20.AllAg.Colon_cancer hg19 Unclassified Digestive tract Colon cancer SRX115...0169,SRX1150170,SRX124703 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Unc.Dig.20.AllAg.Colon_cancer.bed ...

  6. File list: ALL.Prs.10.AllAg.Prostate_cancer [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Prs.10.AllAg.Prostate_cancer hg19 All antigens Prostate Prostate cancer SRX5020...61686,SRX502069,SRX502057,SRX502065,SRX502059,SRX502055 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/ALL.Prs.10.AllAg.Prostate_cancer.bed ...

  7. File list: His.Prs.05.AllAg.Prostate_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.Prs.05.AllAg.Prostate_cancer_cells hg19 Histone Prostate Prostate cancer cells ...SRX022581,SRX022579,SRX022580 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/His.Prs.05.AllAg.Prostate_cancer_cells.bed ...

  8. File list: Oth.Prs.50.AllAg.Prostate_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Prs.50.AllAg.Prostate_cancer_cells hg19 TFs and others Prostate Prostate cancer... cells SRX022577,SRX022578 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Prs.50.AllAg.Prostate_cancer_cells.bed ...

  9. File list: Unc.Prs.20.AllAg.Prostate_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Unc.Prs.20.AllAg.Prostate_cancer_cells hg19 Unclassified Prostate Prostate cancer c...ells http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Unc.Prs.20.AllAg.Prostate_cancer_cells.bed ...

  10. File list: Oth.Prs.20.AllAg.Prostate_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Prs.20.AllAg.Prostate_cancer_cells hg19 TFs and others Prostate Prostate cancer... cells SRX022578,SRX022577 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Prs.20.AllAg.Prostate_cancer_cells.bed ...

  11. File list: Oth.Brs.20.AllAg.Breast_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Brs.20.AllAg.Breast_cancer_cells hg19 TFs and others Breast Breast cancer cells... SRX155767,SRX155769,SRX155766,SRX155770 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Brs.20.AllAg.Breast_cancer_cells.bed ...

  12. File list: Oth.Brs.05.AllAg.Breast_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Brs.05.AllAg.Breast_cancer_cells hg19 TFs and others Breast Breast cancer cells... SRX155766,SRX155769,SRX155770,SRX155767 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Brs.05.AllAg.Breast_cancer_cells.bed ...

  13. File list: His.Brs.05.AllAg.Breast_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.Brs.05.AllAg.Breast_cancer_cells hg19 Histone Breast Breast cancer cells SRX102...3529,SRX1023530 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/His.Brs.05.AllAg.Breast_cancer_cells.bed ...

  14. File list: His.Brs.50.AllAg.Breast_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.Brs.50.AllAg.Breast_cancer_cells hg19 Histone Breast Breast cancer cells SRX102...3529,SRX1023530 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/His.Brs.50.AllAg.Breast_cancer_cells.bed ...

  15. File list: Unc.Brs.20.AllAg.Breast_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Unc.Brs.20.AllAg.Breast_cancer_cells hg19 Unclassified Breast Breast cancer cells h...ttp://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Unc.Brs.20.AllAg.Breast_cancer_cells.bed ...

  16. File list: ALL.Brs.10.AllAg.Breast_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Brs.10.AllAg.Breast_cancer_cells hg19 All antigens Breast Breast cancer cells S...71,SRX155768,ERX210206,ERX210207,SRX155770,SRX155769 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/ALL.Brs.10.AllAg.Breast_cancer_cells.bed ...

  17. File list: Oth.Brs.50.AllAg.Breast_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Brs.50.AllAg.Breast_cancer_cells hg19 TFs and others Breast Breast cancer cells... SRX155769,SRX155766,SRX155767,SRX155770 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Brs.50.AllAg.Breast_cancer_cells.bed ...

  18. File list: Oth.Brs.10.AllAg.Breast_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Brs.10.AllAg.Breast_cancer_cells hg19 TFs and others Breast Breast cancer cells... SRX155766,SRX155767,SRX155770,SRX155769 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Brs.10.AllAg.Breast_cancer_cells.bed ...

  19. File list: Unc.Brs.50.AllAg.Breast_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Unc.Brs.50.AllAg.Breast_cancer_cells hg19 Unclassified Breast Breast cancer cells h...ttp://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Unc.Brs.50.AllAg.Breast_cancer_cells.bed ...

  20. File list: DNS.Brs.50.AllAg.Breast_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available DNS.Brs.50.AllAg.Breast_cancer_cells hg19 DNase-seq Breast Breast cancer cells http...://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/DNS.Brs.50.AllAg.Breast_cancer_cells.bed ...

  1. File list: ALL.Brs.20.AllAg.Breast_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Brs.20.AllAg.Breast_cancer_cells hg19 All antigens Breast Breast cancer cells S...68,SRX155769,SRX155766,SRX155770,ERX210212,SRX155771 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/ALL.Brs.20.AllAg.Breast_cancer_cells.bed ...

  2. File list: His.Brs.10.AllAg.Breast_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.Brs.10.AllAg.Breast_cancer_cells hg19 Histone Breast Breast cancer cells SRX102...3529,SRX1023530 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/His.Brs.10.AllAg.Breast_cancer_cells.bed ...

  3. File list: Pol.Brs.50.AllAg.Breast_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Pol.Brs.50.AllAg.Breast_cancer_cells hg19 RNA polymerase Breast Breast cancer cells... http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Pol.Brs.50.AllAg.Breast_cancer_cells.bed ...

  4. File list: Unc.Brs.10.AllAg.Breast_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Unc.Brs.10.AllAg.Breast_cancer_cells hg19 Unclassified Breast Breast cancer cells h...ttp://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Unc.Brs.10.AllAg.Breast_cancer_cells.bed ...

  5. File list: His.Brs.20.AllAg.Breast_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.Brs.20.AllAg.Breast_cancer_cells hg19 Histone Breast Breast cancer cells SRX102...3529,SRX1023530 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/His.Brs.20.AllAg.Breast_cancer_cells.bed ...

  6. File list: ALL.Brs.05.AllAg.Breast_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Brs.05.AllAg.Breast_cancer_cells hg19 All antigens Breast Breast cancer cells S...69,SRX155770,SRX155767,ERX210207,SRX155771,SRX155768 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/ALL.Brs.05.AllAg.Breast_cancer_cells.bed ...

  7. File list: Pol.Brs.05.AllAg.Breast_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Pol.Brs.05.AllAg.Breast_cancer_cells hg19 RNA polymerase Breast Breast cancer cells... http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Pol.Brs.05.AllAg.Breast_cancer_cells.bed ...

  8. File list: DNS.Brs.05.AllAg.Breast_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available DNS.Brs.05.AllAg.Breast_cancer_cells hg19 DNase-seq Breast Breast cancer cells http...://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/DNS.Brs.05.AllAg.Breast_cancer_cells.bed ...

  9. File list: Pol.Brs.20.AllAg.Breast_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Pol.Brs.20.AllAg.Breast_cancer_cells hg19 RNA polymerase Breast Breast cancer cells... http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Pol.Brs.20.AllAg.Breast_cancer_cells.bed ...

  10. File list: Pol.Brs.10.AllAg.Breast_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Pol.Brs.10.AllAg.Breast_cancer_cells hg19 RNA polymerase Breast Breast cancer cells... http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Pol.Brs.10.AllAg.Breast_cancer_cells.bed ...

  11. File list: ALL.Brs.50.AllAg.Breast_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Brs.50.AllAg.Breast_cancer_cells hg19 All antigens Breast Breast cancer cells S...66,SRX155767,SRX155770,ERX210209,ERX210208,ERX210212 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/ALL.Brs.50.AllAg.Breast_cancer_cells.bed ...

  12. The genomic landscape of response to EGFR blockade in colorectal cancer.

    Science.gov (United States)

    Bertotti, Andrea; Papp, Eniko; Jones, Siân; Adleff, Vilmos; Anagnostou, Valsamo; Lupo, Barbara; Sausen, Mark; Phallen, Jillian; Hruban, Carolyn A; Tokheim, Collin; Niknafs, Noushin; Nesselbush, Monica; Lytle, Karli; Sassi, Francesco; Cottino, Francesca; Migliardi, Giorgia; Zanella, Eugenia R; Ribero, Dario; Russolillo, Nadia; Mellano, Alfredo; Muratore, Andrea; Paraluppi, Gianluca; Salizzoni, Mauro; Marsoni, Silvia; Kragh, Michael; Lantto, Johan; Cassingena, Andrea; Li, Qing Kay; Karchin, Rachel; Scharpf, Robert; Sartore-Bianchi, Andrea; Siena, Salvatore; Diaz, Luis A; Trusolino, Livio; Velculescu, Victor E

    2015-10-08

    Colorectal cancer is the third most common cancer worldwide, with 1.2 million patients diagnosed annually. In late-stage colorectal cancer, the most commonly used targeted therapies are the monoclonal antibodies cetuximab and panitumumab, which prevent epidermal growth factor receptor (EGFR) activation. Recent studies have identified alterations in KRAS and other genes as likely mechanisms of primary and secondary resistance to anti-EGFR antibody therapy. Despite these efforts, additional mechanisms of resistance to EGFR blockade are thought to be present in colorectal cancer and little is known about determinants of sensitivity to this therapy. To examine the effect of somatic genetic changes in colorectal cancer on response to anti-EGFR antibody therapy, here we perform complete exome sequence and copy number analyses of 129 patient-derived tumour grafts and targeted genomic analyses of 55 patient tumours, all of which were KRAS wild-type. We analysed the response of tumours to anti-EGFR antibody blockade in tumour graft models and in clinical settings and functionally linked therapeutic responses to mutational data. In addition to previously identified genes, we detected mutations in ERBB2, EGFR, FGFR1, PDGFRA, and MAP2K1 as potential mechanisms of primary resistance to this therapy. Novel alterations in the ectodomain of EGFR were identified in patients with acquired resistance to EGFR blockade. Amplifications and sequence changes in the tyrosine kinase receptor adaptor gene IRS2 were identified in tumours with increased sensitivity to anti-EGFR therapy. Therapeutic resistance to EGFR blockade could be overcome in tumour graft models through combinatorial therapies targeting actionable genes. These analyses provide a systematic approach to evaluating response to targeted therapies in human cancer, highlight new mechanisms of responsiveness to anti-EGFR therapies, and delineate new avenues for intervention in managing colorectal cancer.

  13. Colorectal Cancer and the Human Gut Microbiome: Reproducibility with Whole-Genome Shotgun Sequencing.

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    Emily Vogtmann

    Full Text Available Accumulating evidence indicates that the gut microbiota affects colorectal cancer development, but previous studies have varied in population, technical methods, and associations with cancer. Understanding these variations is needed for comparisons and for potential pooling across studies. Therefore, we performed whole-genome shotgun sequencing on fecal samples from 52 pre-treatment colorectal cancer cases and 52 matched controls from Washington, DC. We compared findings from a previously published 16S rRNA study to the metagenomics-derived taxonomy within the same population. In addition, metagenome-predicted genes, modules, and pathways in the Washington, DC cases and controls were compared to cases and controls recruited in France whose specimens were processed using the same platform. Associations between the presence of fecal Fusobacteria, Fusobacterium, and Porphyromonas with colorectal cancer detected by 16S rRNA were reproduced by metagenomics, whereas higher relative abundance of Clostridia in cancer cases based on 16S rRNA was merely borderline based on metagenomics. This demonstrated that within the same sample set, most, but not all taxonomic associations were seen with both methods. Considering significant cancer associations with the relative abundance of genes, modules, and pathways in a recently published French metagenomics dataset, statistically significant associations in the Washington, DC population were detected for four out of 10 genes, three out of nine modules, and seven out of 17 pathways. In total, colorectal cancer status in the Washington, DC study was associated with 39% of the metagenome-predicted genes, modules, and pathways identified in the French study. More within and between population comparisons are needed to identify sources of variation and disease associations that can be reproduced despite these variations. Future studies should have larger sample sizes or pool data across studies to have sufficient

  14. Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer.

    Science.gov (United States)

    Lesseur, Corina; Diergaarde, Brenda; Olshan, Andrew F; Wünsch-Filho, Victor; Ness, Andrew R; Liu, Geoffrey; Lacko, Martin; Eluf-Neto, José; Franceschi, Silvia; Lagiou, Pagona; Macfarlane, Gary J; Richiardi, Lorenzo; Boccia, Stefania; Polesel, Jerry; Kjaerheim, Kristina; Zaridze, David; Johansson, Mattias; Menezes, Ana M; Curado, Maria Paula; Robinson, Max; Ahrens, Wolfgang; Canova, Cristina; Znaor, Ariana; Castellsagué, Xavier; Conway, David I; Holcátová, Ivana; Mates, Dana; Vilensky, Marta; Healy, Claire M; Szeszenia-Dąbrowska, Neonila; Fabiánová, Eleonóra; Lissowska, Jolanta; Grandis, Jennifer R; Weissler, Mark C; Tajara, Eloiza H; Nunes, Fabio D; de Carvalho, Marcos B; Thomas, Steve; Hung, Rayjean J; Peters, Wilbert H M; Herrero, Rolando; Cadoni, Gabriella; Bueno-de-Mesquita, H Bas; Steffen, Annika; Agudo, Antonio; Shangina, Oxana; Xiao, Xiangjun; Gaborieau, Valérie; Chabrier, Amélie; Anantharaman, Devasena; Boffetta, Paolo; Amos, Christopher I; McKay, James D; Brennan, Paul

    2016-12-01

    We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly associated loci (P < 5 × 10(-8)), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2-TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer-related loci-9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region, and classical HLA allele imputation showed a protective association with the class II haplotype HLA-DRB1*1301-HLA-DQA1*0103-HLA-DQB1*0603 (odds ratio (OR) = 0.59, P = 2.7 × 10(-9)). Stratified analyses on a subgroup of oropharyngeal cases with information available on human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR = 0.23, P = 1.6 × 10(-6)) than in HPV-negative (OR = 0.75, P = 0.16) cancers.

  15. Specific genomic aberrations in primary colorectal cancer are associated with liver metastases

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    Wessels Lodewyk F

    2010-12-01

    Full Text Available Abstract Background Accurate staging of colorectal cancer (CRC with clinicopathological parameters is important for predicting prognosis and guiding treatment but provides no information about organ site of metastases. Patterns of genomic aberrations in primary colorectal tumors may reveal a chromosomal signature for organ specific metastases. Methods Array Comparative Genomic Hybridization (aCGH was employed to asses DNA copy number changes in primary colorectal tumors of three distinctive patient groups. This included formalin-fixed, paraffin-embedded tissue of patients who developed liver metastases (LM; n = 36, metastases (PM; n = 37 and a group that remained metastases-free (M0; n = 25. A novel statistical method for identifying recurrent copy number changes, KC-SMART, was used to find specific locations of genomic aberrations specific for various groups. We created a classifier for organ specific metastases based on the aCGH data using Prediction Analysis for Microarrays (PAM. Results Specifically in the tumors of primary CRC patients who subsequently developed liver metastasis, KC-SMART analysis identified genomic aberrations on chromosome 20q. LM-PAM, a shrunken centroids classifier for liver metastases occurrence, was able to distinguish the LM group from the other groups (M0&PM with 80% accuracy (78% sensitivity and 86% specificity. The classification is predominantly based on chromosome 20q aberrations. Conclusion Liver specific CRC metastases may be predicted with a high accuracy based on specific genomic aberrations in the primary CRC tumor. The ability to predict the site of metastases is important for improvement of personalized patient management.

  16. High-resolution comparative genomic hybridization of inflammatory breast cancer and identification of candidate genes.

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    Ismahane Bekhouche

    Full Text Available BACKGROUND: Inflammatory breast cancer (IBC is an aggressive form of BC poorly defined at the molecular level. We compared the molecular portraits of 63 IBC and 134 non-IBC (nIBC clinical samples. METHODOLOGY/FINDINGS: Genomic imbalances of 49 IBCs and 124 nIBCs were determined using high-resolution array-comparative genomic hybridization, and mRNA expression profiles of 197 samples using whole-genome microarrays. Genomic profiles of IBCs were as heterogeneous as those of nIBCs, and globally relatively close. However, IBCs showed more frequent "complex" patterns and a higher percentage of genes with CNAs per sample. The number of altered regions was similar in both types, although some regions were altered more frequently and/or with higher amplitude in IBCs. Many genes were similarly altered in both types; however, more genes displayed recurrent amplifications in IBCs. The percentage of genes whose mRNA expression correlated with CNAs was similar in both types for the gained genes, but ∼7-fold lower in IBCs for the lost genes. Integrated analysis identified 24 potential candidate IBC-specific genes. Their combined expression accurately distinguished IBCs and nIBCS in an independent validation set, and retained an independent prognostic value in a series of 1,781 nIBCs, reinforcing the hypothesis for a link with IBC aggressiveness. Consistent with the hyperproliferative and invasive phenotype of IBC these genes are notably involved in protein translation, cell cycle, RNA processing and transcription, metabolism, and cell migration. CONCLUSIONS: Our results suggest a higher genomic instability of IBC. We established the first repertory of DNA copy number alterations in this tumor, and provided a list of genes that may contribute to its aggressiveness and represent novel therapeutic targets.

  17. Biosemiotic Entropy of the Genome: Mutations and Epigenetic Imbalances Resulting in Cancer

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    Samuel S. Shepard

    2013-01-01

    Full Text Available Biosemiotic entropy involves the deterioration of biological sign systems. The genome is a coded sign system that is connected to phenotypic outputs through the interpretive functions of the tRNA/ribosome machinery. This symbolic sign system (semiosis at the core of all biology has been termed “biosemiosis”. Layers of biosemiosis and cellular information management are analogous in varying degrees to the semiotics of computer programming, spoken, and written human languages. Biosemiotic entropy — an error or deviation from a healthy state — results from errors in copying functional information (mutations and errors in the appropriate context or quantity of gene expression (epigenetic imbalance. The concept of biosemiotic entropy is a deeply imbedded assumption in the study of cancer biology. Cells have a homeostatic, preprogrammed, ideal or healthy state that is rooted in genomics, strictly orchestrated by epigenetic regulation, and maintained by DNA repair mechanisms. Cancer is an eminent illustration of biosemiotic entropy, in which the corrosion of genetic information via substitutions, deletions, insertions, fusions, and aberrant regulation results in malignant phenotypes. However, little attention has been given to explicitly outlining the paradigm of biosemiotic entropy in the context of cancer. Herein we distill semiotic theory (from the familiar and well understood spheres of human language and computer code to draw analogies useful for understanding the operation of biological semiosis at the genetic level. We propose that the myriad checkpoints, error correcting mechanisms, and immunities are all systems whose primary role is to defend against the constant pressure of biosemiotic entropy, which malignancy must shut down in order to achieve advanced stages. In lieu of the narrower tumor suppressor/oncogene model, characterization of oncogenesis into the biosemiotic framework of sign, index, or object entropy may allow for more

  18. Translating genomics: cancer genetics, public health and the making of the (de)molecularised body in Cuba and Brazil.

    Science.gov (United States)

    Gibbon, Sahra

    2016-01-01

    This article examines how cancer genetics has emerged as a focus for research and healthcare in Cuba and Brazil. Drawing on ethnographic research undertaken in community genetics clinics and cancer genetics services, the article examines how the knowledge and technologies associated with this novel area of healthcare are translated and put to work by researchers, health professionals, patients and their families in these two contexts. It illuminates the comparative similarities and differences in how cancer genetics is emerging in relation to transnational research priorities, the history and contemporary politics of public health and embodied vulnerability to cancer that reconfigures the scope and meaning of genomics as "personalised" medicine.

  19. The Art and Science of Thyroid Surgery in the Age of Genomics: 100 years after Theodor Kocher

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    Seza Gulec

    2017-02-01

    Full Text Available Cancer is a disorder of the genome. The thyroid cancer genome is being decoded. Recent studies have identified a mutation or a genetic alteration in 95% of thyroid cancers. The National Cancer Institute initiated the Cancer Genome Atlas project in 2006 to catalogue genetic mutations associated with cancer, using genome sequencing and bioinformatics. The project has expanded to carry out genomic characterization and sequence analysis of thyroid cancer. The concept of risk stratification based on traditional parameters will soon vacate their role for clear molecular markers of non-invasive/focal, invasive/metastatic and systemic stages/phases of neoplastic disorder. A refined classification scheme based on genomics and its phenotypic expressions will accurately reflect the biologic differences between the different morphologic definitions we use today. Tumor differentiation/de-differentiation, and clinical behavior of an individual cancer will be defined by molecular markers, in addition to standard morpho-pathology. Empiricism in science of medicine and surgery has acquired a new method for testing the appropriate treatment for individual patients; that is molecular pathology, governed by genomics. The technology is present and rapidly evolving. The surgeons will determine the extent of interventions with molecular evidence and guidance.

  20. The Art and Science of Thyroid Surgery in the Age of Genomics: 100 years after Theodor Kocher

    Science.gov (United States)

    Gulec, Seza

    2017-01-01

    Cancer is a disorder of the genome. The thyroid cancer genome is being decoded. Recent studies have identified a mutation or a genetic alteration in 95% of thyroid cancers. The National Cancer Institute initiated the Cancer Genome Atlas project in 2006 to catalogue genetic mutations associated with cancer, using genome sequencing and bioinformatics. The project has expanded to carry out genomic characterization and sequence analysis of thyroid cancer. The concept of risk stratification based on traditional parameters will soon vacate their role for clear molecular markers of non-invasive/focal, invasive/metastatic and systemic stages/phases of neoplastic disorder. A refined classification scheme based on genomics and its phenotypic expressions will accurately reflect the biologic differences between the different morphologic definitions we use today. Tumor differentiation/de-differentiation, and clinical behavior of an individual cancer will be defined by molecular markers, in addition to standard morpho-pathology. Empiricism in science of medicine and surgery has acquired a new method for testing the appropriate treatment for individual patients; that is molecular pathology, governed by genomics. The technology is present and rapidly evolving. The surgeons will determine the extent of interventions with molecular evidence and guidance. PMID:28117284

  1. Large genomic rearrangement of BRCA1 and BRCA2 genes in familial breast cancer patients in Korea.

    Science.gov (United States)

    Cho, Ja Young; Cho, Dae-Yeon; Ahn, Sei Hyun; Choi, Su-Youn; Shin, Inkyung; Park, Hyun Gyu; Lee, Jong Won; Kim, Hee Jeong; Yu, Jong Han; Ko, Beom Seok; Ku, Bo Kyung; Son, Byung Ho

    2014-06-01

    We screened large genomic rearrangements of the BRCA1 and BRCA2 genes in Korean, familial breast cancer patients. Multiplex ligation-dependent probe amplification assay was used to identify BRCA1 and BRCA2 genomic rearrangements in 226 Korean familial breast cancer patients with risk factors for BRCA1 and BRCA2 mutations, who previously tested negative for point mutations in the two genes. We identified only one large deletion (c.4186-1593_4676-1465del) in BRCA1. No large rearrangements were found in BRCA2. Our result indicates that large genomic rearrangement in the BRCA1 and BRCA2 genes does not seem like a major determinant of breast cancer susceptibility in the Korean population. A large-scale study needs to validate our result in Korea.

  2. Genome-wide association study identifies novel breast cancer susceptibility loci

    Science.gov (United States)

    Easton, Douglas F.; Pooley, Karen A.; Dunning, Alison M.; Pharoah, Paul D. P.; Thompson, Deborah; Ballinger, Dennis G.; Struewing, Jeffery P.; Morrison, Jonathan; Field, Helen; Luben, Robert; Wareham, Nicholas; Ahmed, Shahana; Healey, Catherine S.; Bowman, Richard; Meyer, Kerstin B.; Haiman, Christopher A.; Kolonel, Laurence K.; Henderson, Brian E.; Marchand, Loic Le; Brennan, Paul; Sangrajrang, Suleeporn; Gaborieau, Valerie; Odefrey, Fabrice; Shen, Chen-Yang; Wu, Pei-Ei; Wang, Hui-Chun; Eccles, Diana; Evans, D. Gareth; Peto, Julian; Fletcher, Olivia; Johnson, Nichola; Seal, Sheila; Stratton, Michael R.; Rahman, Nazneen; Chenevix-Trench, Georgia; Bojesen, Stig E.; Nordestgaard, Børge G.; Axelsson, Christen K.; Garcia-Closas, Montserrat; Brinton, Louise; Chanock, Stephen; Lissowska, Jolanta; Peplonska, Beata; Nevanlinna, Heli; Fagerholm, Rainer; Eerola, Hannaleena; Kang, Daehee; Yoo, Keun-Young; Noh, Dong-Young; Ahn, Sei-Hyun; Hunter, David J.; Hankinson, Susan E.; Cox, David G.; Hall, Per; Wedren, Sara; Liu, Jianjun; Low, Yen-Ling; Bogdanova, Natalia; Schürmann, Peter; Dörk, Thilo; Tollenaar, Rob A. E. M.; Jacobi, Catharina E.; Devilee, Peter; Klijn, Jan G. M.; Sigurdson, Alice J.; Doody, Michele M.; Alexander, Bruce H.; Zhang, Jinghui; Cox, Angela; Brock, Ian W.; MacPherson, Gordon; Reed, Malcolm W. R.; Couch, Fergus J.; Goode, Ellen L.; Olson, Janet E.; Meijers-Heijboer, Hanne; van den Ouweland, Ans; Uitterlinden, André; Rivadeneira, Fernando; Milne, Roger L.; Ribas, Gloria; Gonzalez-Neira, Anna; Benitez, Javier; Hopper, John L.; McCredie, Margaret; Southey, Melissa; Giles, Graham G.; Schroen, Chris; Justenhoven, Christina; Brauch, Hiltrud; Hamann, Ute; Ko, Yon-Dschun; Spurdle, Amanda B.; Beesley, Jonathan; Chen, Xiaoqing; Mannermaa, Arto; Kosma, Veli-Matti; Kataja, Vesa; Hartikainen, Jaana; Day, Nicholas E.; Cox, David R.; Ponder, Bruce A. J.; Luccarini, Craig; Conroy, Don; Shah, Mitul; Munday, Hannah; Jordan, Clare; Perkins, Barbara; West, Judy; Redman, Karen; Driver, Kristy; Aghmesheh, Morteza; Amor, David; Andrews, Lesley; Antill, Yoland; Armes, Jane; Armitage, Shane; Arnold, Leanne; Balleine, Rosemary; Begley, Glenn; Beilby, John; Bennett, Ian; Bennett, Barbara; Berry, Geoffrey; Blackburn, Anneke; Brennan, Meagan; Brown, Melissa; Buckley, Michael; Burke, Jo; Butow, Phyllis; Byron, Keith; Callen, David; Campbell, Ian; Chenevix-Trench, Georgia; Clarke, Christine; Colley, Alison; Cotton, Dick; Cui, Jisheng; Culling, Bronwyn; Cummings, Margaret; Dawson, Sarah-Jane; Dixon, Joanne; Dobrovic, Alexander; Dudding, Tracy; Edkins, Ted; Eisenbruch, Maurice; Farshid, Gelareh; Fawcett, Susan; Field, Michael; Firgaira, Frank; Fleming, Jean; Forbes, John; Friedlander, Michael; Gaff, Clara; Gardner, Mac; Gattas, Mike; George, Peter; Giles, Graham; Gill, Grantley; Goldblatt, Jack; Greening, Sian; Grist, Scott; Haan, Eric; Harris, Marion; Hart, Stewart; Hayward, Nick; Hopper, John; Humphrey, Evelyn; Jenkins, Mark; Jones, Alison; Kefford, Rick; Kirk, Judy; Kollias, James; Kovalenko, Sergey; Lakhani, Sunil; Leary, Jennifer; Lim, Jacqueline; Lindeman, Geoff; Lipton, Lara; Lobb, Liz; Maclurcan, Mariette; Mann, Graham; Marsh, Deborah; McCredie, Margaret; McKay, Michael; McLachlan, Sue Anne; Meiser, Bettina; Milne, Roger; Mitchell, Gillian; Newman, Beth; O'Loughlin, Imelda; Osborne, Richard; Peters, Lester; Phillips, Kelly; Price, Melanie; Reeve, Jeanne; Reeve, Tony; Richards, Robert; Rinehart, Gina; Robinson, Bridget; Rudzki, Barney; Salisbury, Elizabeth; Sambrook, Joe; Saunders, Christobel; Scott, Clare; Scott, Elizabeth; Scott, Rodney; Seshadri, Ram; Shelling, Andrew; Southey, Melissa; Spurdle, Amanda; Suthers, Graeme; Taylor, Donna; Tennant, Christopher; Thorne, Heather; Townshend, Sharron; Tucker, Kathy; Tyler, Janet; Venter, Deon; Visvader, Jane; Walpole, Ian; Ward, Robin; Waring, Paul; Warner, Bev; Warren, Graham; Watson, Elizabeth; Williams, Rachael; Wilson, Judy; Winship, Ingrid; Young, Mary Ann; Bowtell, David; Green, Adele; deFazio, Anna; Chenevix-Trench, Georgia; Gertig, Dorota; Webb, Penny

    2009-01-01

    Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2>0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P<10−7). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P<0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach. PMID:17529967

  3. Degradation of the cancer genomic DNA deaminase APOBEC3B by SIV Vif.

    Science.gov (United States)

    Land, Allison M; Wang, Jiayi; Law, Emily K; Aberle, Ryan; Kirmaier, Andrea; Krupp, Annabel; Johnson, Welkin E; Harris, Reuben S

    2015-11-24

    APOBEC3B is a newly identified source of mutation in many cancers, including breast, head/neck, lung, bladder, cervical, and ovarian. APOBEC3B is a member of the APOBEC3 family of enzymes that deaminate DNA cytosine to produce the pro-mutagenic lesion, uracil. Several APOBEC3 family members function to restrict virus replication. For instance, APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H combine to restrict HIV-1 in human lymphocytes. HIV-1 counteracts these APOBEC3s with the viral protein Vif, which targets the relevant APOBEC3s for proteasomal degradation. While APOBEC3B does not restrict HIV-1 and is not targeted by HIV-1 Vif in CD4-positive T cells, we asked whether related lentiviral Vif proteins could degrade APOBEC3B. Interestingly, several SIV Vif proteins are capable of promoting APOBEC3B degradation, with SIVmac239 Vif proving the most potent. This likely occurs through the canonical polyubiquitination mechanism as APOBEC3B protein levels are restored by MG132 treatment and by altering a conserved E3 ligase-binding motif. We further show that SIVmac239 Vif can prevent APOBEC3B mediated geno/cytotoxicity and degrade endogenous APOBEC3B in several cancer cell lines. Our data indicate that the APOBEC3B degradation potential of SIV Vif is an effective tool for neutralizing the cancer genomic DNA deaminase APOBEC3B. Further optimization of this natural APOBEC3 antagonist may benefit cancer therapy.

  4. Pathway analysis for genome-wide association study of lung cancer in Han Chinese population.

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    Ruyang Zhang

    Full Text Available Genome-wide association studies (GWAS have identified a number of genetic variants associated with lung cancer risk. However, these loci explain only a small fraction of lung cancer hereditability and other variants with weak effect may be lost in the GWAS approach due to the stringent significance level after multiple comparison correction. In this study, in order to identify important pathways involving the lung carcinogenesis, we performed a two-stage pathway analysis in GWAS of lung cancer in Han Chinese using gene set enrichment analysis (GSEA method. Predefined pathways by BioCarta and KEGG databases were systematically evaluated on Nanjing study (Discovery stage: 1,473 cases and 1,962 controls and the suggestive pathways were further to be validated in Beijing study (Replication stage: 858 cases and 1,115 controls. We found that four pathways (achPathway, metPathway, At1rPathway and rac1Pathway were consistently significant in both studies and the P values for combined dataset were 0.012, 0.010, 0.022 and 0.005 respectively. These results were stable after sensitivity analysis based on gene definition and gene overlaps between pathways. These findings may provide new insights into the etiology of lung cancer.

  5. Isolation and bioinformatics analysis of differentially methylated genomic fragments in human gastric cancer

    Institute of Scientific and Technical Information of China (English)

    Ai-Jun Liao; Qi Su; Xun Wang; Bin Zeng; Wei Shi

    2008-01-01

    AIM:To isolate and analyze the DNA sequences which are methylated differentially between gastric cancer and normal gastric mucosa.METHODS:The differentially methylated DNA sequences between gastric cancer and normal gastric mucosa were isolated by methylation-sensitive representational difference analysis (MS-RDA).Similarities between the separated fragments and the human genomic DNA were analyzed with Basic Local Alignment Search Tool (BLAST).RESULTS:Three differentially methylated DNA sequences were obtained,two of which have been accepted by GenBank.The accession numbers are AY887106 and AY887107.AY887107 was highly similar to the 11th exon of LOC440683 (98%),3'end of LOC440887 (99%),and promoter and exon regions of DRD5 (94%).AY887106 was consistent (98%) with a CpG island in ribosomal RNA isolated from colorectal cancer by Minoru Toyota in 1999.CONCLUSION:The methylation degree is different between gastric cancer and normal gastric mucosa.The differentially methylated DNA sequences can be isolated effectively by MS-RDA.

  6. Epigenetic mechanisms and cancer: an interface between the environment and the genome.

    Science.gov (United States)

    Herceg, Zdenko; Vaissière, Thomas

    2011-07-01

    Although epidemiological studies support the role of environment in a wide range of human cancers, the precise mechanisms by which environmental exposures promote cancer development and progression remain poorly understood. Environmental factors have been proposed to promote the development of malignancies by eliciting epigenetic changes; however, it is only with recent advances in epigenetics and epigenomics that target genes and the mechanisms underlying environmental influences are beginning to be elucidated. Because epigenetic mechanisms may function as an interface between environmental factors and the genome, deregulation of the epigenome by environmental stressors is likely to disrupt different cellular processes and contribute to cancer risk. In addition, the early appearance and ubiquity of epigenetic changes in virtually all steps of tumor development and progression in most, if not all, human neoplasms, make them attractive targets for biomarker discovery and targeted prevention. At the cellular level, aberrant epigenetic changes associated with environmental exposures may deregulate key cellular processes (including transcriptional control, DNA repair, cell cycle control, and carcinogen detoxification), which can be further modulated by environmental stressors, thus defining not only the phenotype of the disease but also potential biomarkers. This review summarizes recent progress in our understanding of the epigenetic mechanisms through which environmental factors may promote tumor development, with a particular focus on human lung cancer.

  7. Genome-wide analysis of the homeobox C6 transcriptional network in prostate cancer.

    Science.gov (United States)

    McCabe, Colleen D; Spyropoulos, Demetri D; Martin, David; Moreno, Carlos S

    2008-03-15

    Homeobox transcription factors are developmentally regulated genes that play crucial roles in tissue patterning. Homeobox C6 (HOXC6) is overexpressed in prostate cancers and correlated with cancer progression, but the downstream targets of HOXC6 are largely unknown. We have performed genome-wide localization analysis to identify promoters bound by HOXC6 in prostate cancer cells. This analysis identified 468 reproducibly bound promoters whose associated genes are involved in functions such as cell proliferation and apoptosis. We have complemented these data with expression profiling of prostates from mice with homozygous disruption of the Hoxc6 gene to identify 31 direct regulatory target genes of HOXC6. We show that HOXC6 directly regulates expression of bone morphogenic protein 7, fibroblast growth factor receptor 2, insulin-like growth factor binding protein 3, and platelet-derived growth factor receptor alpha (PDGFRA) in prostate cells and indirectly influences the Notch and Wnt signaling pathways in vivo. We further show that inhibition of PDGFRA reduces proliferation of prostate cancer cells, and that overexpression of HOXC6 can overcome the effects of PDGFRA inhibition. HOXC6 regulates genes with both oncogenic and tumor suppressor activities as well as several genes such as CD44 that are important for prostate branching morphogenesis and metastasis to the bone microenvironment.

  8. An arranged marriage for precision medicine: hypoxia and genomic assays in localized prostate cancer radiotherapy.

    Science.gov (United States)

    Bristow, R G; Berlin, A; Dal Pra, A

    2014-03-01

    Prostate cancer (CaP) is the most commonly diagnosed malignancy in males in the Western world with one in six males diagnosed in their lifetime. Current clinical prognostication groupings use pathologic Gleason score, pre-treatment prostatic-specific antigen and Union for International Cancer Control-TNM staging to place patients with localized CaP into low-, intermediate- and high-risk categories. These categories represent an increasing risk of biochemical failure and CaP-specific mortality rates, they also reflect the need for increasing treatment intensity and justification for increased side effects. In this article, we point out that 30-50% of patients will still fail image-guided radiotherapy or surgery despite the judicious use of clinical risk categories owing to interpatient heterogeneity in treatment response. To improve treatment individualization, better predictors of prognosis and radiotherapy treatment response are needed to triage patients to bespoke and intensified CaP treatment protocols. These should include the use of pre-treatment genomic tests based on DNA or RNA indices and/or assays that reflect cancer metabolism, such as hypoxia assays, to define patient-specific CaP progression and aggression. More importantly, it is argued that these novel prognostic assays could be even more useful if combined together to drive forward precision cancer medicine for localized CaP.

  9. Genome-wide association studies identify four ER negative–specific breast cancer risk loci

    Science.gov (United States)

    Garcia-Closas, Montserrat; Couch, Fergus J; Lindstrom, Sara; Michailidou, Kyriaki; Schmidt, Marjanka K; Brook, Mark N; orr, Nick; Rhie, Suhn Kyong; Riboli, Elio; Feigelson, Heather s; Le Marchand, Loic; Buring, Julie E; Eccles, Diana; Miron, Penelope; Fasching, Peter A; Brauch, Hiltrud; Chang-Claude, Jenny; Carpenter, Jane; Godwin, Andrew K; Nevanlinna, Heli; Giles, Graham G; Cox, Angela; Hopper, John L; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Dicks, Ed; Howat, Will J; Schoof, Nils; Bojesen, Stig E; Lambrechts, Diether; Broeks, Annegien; Andrulis, Irene L; Guénel, Pascal; Burwinkel, Barbara; Sawyer, Elinor J; Hollestelle, Antoinette; Fletcher, Olivia; Winqvist, Robert; Brenner, Hermann; Mannermaa, Arto; Hamann, Ute; Meindl, Alfons; Lindblom, Annika; Zheng, Wei; Devillee, Peter; Goldberg, Mark S; Lubinski, Jan; Kristensen, Vessela; Swerdlow, Anthony; Anton-Culver, Hoda; Dörk, Thilo; Muir, Kenneth; Matsuo, Keitaro; Wu, Anna H; Radice, Paolo; Teo, Soo Hwang; Shu, Xiao-Ou; Blot, William; Kang, Daehee; Hartman, Mikael; Sangrajrang, Suleeporn; Shen, Chen-Yang; Southey, Melissa C; Park, Daniel J; Hammet, Fleur; Stone, Jennifer; Veer, Laura J Van’t; Rutgers, Emiel J; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Peto, Julian; Schrauder, Michael G; Ekici, Arif B; Beckmann, Matthias W; Silva, Isabel dos Santos; Johnson, Nichola; Warren, Helen; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Marme, Federick; Schneeweiss, Andreas; Sohn, Christof; Truong, Therese; Laurent-Puig, Pierre; Kerbrat, Pierre; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Milne, Roger L; Perez, Jose Ignacio Arias; Menéndez, Primitiva; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Lichtner, Peter; Lochmann, Magdalena; Justenhoven, Christina; Ko, Yon-Dschun; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Greco, Dario; Heikkinen, Tuomas; Ito, Hidemi; Iwata, Hiroji; Yatabe, Yasushi; Antonenkova, Natalia N; Margolin, Sara; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Balleine, Rosemary; Tseng, Chiu-Chen; Van Den Berg, David; Stram, Daniel O; Neven, Patrick; Dieudonné, Anne-Sophie; Leunen, Karin; Rudolph, Anja; Nickels, Stefan; Flesch-Janys, Dieter; Peterlongo, Paolo; Peissel, Bernard; Bernard, Loris; Olson, Janet E; Wang, Xianshu; Stevens, Kristen; Severi, Gianluca; Baglietto, Laura; Mclean, Catriona; Coetzee, Gerhard A; Feng, Ye; Henderson, Brian E; Schumacher, Fredrick; Bogdanova, Natalia V; Labrèche, France; Dumont, Martine; Yip, Cheng Har; Taib, Nur Aishah Mohd; Cheng, Ching-Yu; Shrubsole, Martha; Long, Jirong; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; knight, Julia A; Glendon, Gord; Mulligan, Anna Marie; Tollenaar, Robertus A E M; Seynaeve, Caroline M; Kriege, Mieke; Hooning, Maartje J; Van den Ouweland, Ans M W; Van Deurzen, Carolien H M; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Balasubramanian, Sabapathy P; Cross, Simon S; Reed, Malcolm W R; Signorello, Lisa; Cai, Qiuyin; Shah, Mitul; Miao, Hui; Chan, Ching Wan; Chia, Kee Seng; Jakubowska, Anna; Jaworska, Katarzyna; Durda, Katarzyna; Hsiung, Chia-Ni; Wu, Pei-Ei; Yu, Jyh-Cherng; Ashworth, Alan; Jones, Michael; Tessier, Daniel C; González-Neira, Anna; Pita, Guillermo; Alonso, M Rosario; Vincent, Daniel; Bacot, Francois; Ambrosone, Christine B; Bandera, Elisa V; John, Esther M; Chen, Gary K; Hu, Jennifer J; Rodriguez-gil, Jorge L; Bernstein, Leslie; Press, Michael F; Ziegler, Regina G; Millikan, Robert M; Deming-Halverson, Sandra L; Nyante, Sarah; Ingles, Sue A; Waisfisz, Quinten; Tsimiklis, Helen; Makalic, Enes; Schmidt, Daniel; Bui, Minh; Gibson, Lorna; Müller-Myhsok, Bertram; Schmutzler, Rita K; Hein, Rebecca; Dahmen, Norbert; Beckmann, Lars; Aaltonen, Kirsimari; Czene, Kamila; Irwanto, Astrid; Liu, Jianjun; Turnbull, Clare; Rahman, Nazneen; Meijers-Heijboer, Hanne; Uitterlinden, Andre G; Rivadeneira, Fernando; Olswold, Curtis; Slager, Susan; Pilarski, Robert; Ademuyiwa, Foluso; Konstantopoulou, Irene; Martin, Nicholas G; Montgomery, Grant W; Slamon, Dennis J; Rauh, Claudia; Lux, Michael P; Jud, Sebastian M; Bruning, Thomas; Weaver, Joellen; Sharma, Priyanka; Pathak, Harsh; Tapper, Will; Gerty, Sue; Durcan, Lorraine; Trichopoulos, Dimitrios; Tumino, Rosario; Peeters, Petra H; Kaaks, Rudolf; Campa, Daniele; Canzian, Federico; Weiderpass, Elisabete; Johansson, Mattias; Khaw, Kay-Tee; Travis, Ruth; Clavel-Chapelon, Françoise; Kolonel, Laurence N; Chen, Constance; Beck, Andy; Hankinson, Susan E; Berg, Christine D; Hoover, Robert N; Lissowska, Jolanta; Figueroa, Jonine D

    2013-01-01

    Estrogen receptor (ER)-negative tumors represent 20–30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry1. The etiology2 and clinical behavior3 of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition4. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10−12 and LGR6, P = 1.4 × 10−8), 2p24.1 (P = 4.6 × 10−8) and 16q12.2 (FTO, P = 4.0 × 10−8), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers. PMID:23535733

  10. The state of genomic health care and cancer. Are we going two steps forward and one step backward?

    Science.gov (United States)

    Greco, Karen E; Mahon, Suzanne M

    2011-01-01

    As the application of genomic information and technology crosses the horizon of health care into our everyday lives, expanding genomic knowledge continues to affect how health care services are defined and delivered. Genomic discoveries have led to enhanced clinical capabilities to predict susceptibility to common diseases and conditions such as cancer, diabetes, cardiovascular disease, and Alzheimer's disease. Hundreds of genetic tests are now available that can identify individuals who carry one or more gene mutations that increase their risk of developing cancer or other common diseases. Increased availability and direct-to-consumer marketing of genetic testing is moving genetic testing away from trained genetics health professionals and into the hands of primary care providers and consumers. Genetic tests available on the Internet are being directly marketed to individuals, who can order these tests and receive a report of their risk for numerous health conditions and diseases. Health care providers are expected to interpret these test results, evaluate their accuracy, address the psychosocial consequences of those distressed by receiving their results, and translate genomic information into effective care. However, as we move two steps forward, we are also moving one step backward because many health care providers are unprepared for this genomic revolution. A number of international education, practice, and policy efforts are underway to address the challenges health care providers face in providing competent genomic health care in the context of unprecedented access to information, technology, and global communication. Efforts to integrate standard of care guidelines into electronic medical records increases health care providers' access to information for individuals at risk fo or diagnosed with a genomic condition. Development of genomic competencie for health care providers has led to increased genomic content in academic pro grams. These and other

  11. Distribution Atlas of Proliferating Bone Marrow in Non-Small Cell Lung Cancer Patients Measured by FLT-PET/CT Imaging, With Potential Applicability in Radiation Therapy Planning

    Energy Technology Data Exchange (ETDEWEB)

    Campbell, Belinda A., E-mail: Belinda.Campbell@petermac.org [Department of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne (Australia); Callahan, Jason [Centre for Molecular Imaging, Peter MacCallum Cancer Centre, East Melbourne (Australia); Bressel, Mathias [Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, East Melbourne (Australia); Simoens, Nathalie [Centre for Molecular Imaging, Peter MacCallum Cancer Centre, East Melbourne (Australia); Everitt, Sarah [Radiotherapy Services, Peter MacCallum Cancer Centre, East Melbourne (Australia); Hofman, Michael S.; Hicks, Rodney J. [Centre for Molecular Imaging, Peter MacCallum Cancer Centre, East Melbourne (Australia); Burbury, Kate [Department of Haematology, Peter MacCallum Cancer Centre, East Melbourne (Australia); MacManus, Michael [Department of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne (Australia)

    2015-08-01

    Purpose: Proliferating bone marrow is exquisitely sensitive to ionizing radiation. Knowledge of its distribution could improve radiation therapy planning to minimize unnecessary marrow exposure and avoid consequential prolonged myelosuppression. [18F]-Fluoro-3-deoxy-3-L-fluorothymidine (FLT)–positron emission tomography (PET) is a novel imaging modality that provides detailed quantitative images of proliferating tissues, including bone marrow. We used FLT-PET imaging in cancer patients to produce an atlas of marrow distribution with potential clinical utility. Methods and Materials: The FLT-PET and fused CT scans of eligible patients with non-small cell lung cancer (no distant metastases, no prior cytotoxic exposure, no hematologic disorders) were reviewed. The proportions of skeletal FLT activity in 10 predefined bony regions were determined and compared according to age, sex, and recent smoking status. Results: Fifty-one patients were studied: 67% male; median age 68 (range, 31-87) years; 8% never smokers; 70% no smoking in the preceding 3 months. Significant differences in marrow distribution occurred between sex and age groups. No effect was detected from smoking in the preceding 3 months. Using the mean percentages of FLT uptake per body region, we created an atlas of the distribution of functional bone marrow in 4 subgroups defined by sex and age. Conclusions: This atlas has potential utility for estimating the distribution of active marrow in adult cancer patients to guide radiation therapy planning. However, because of interindividual variation it should be used with caution when radiation therapy risks ablating large proportions of active marrow; in such cases, individual FLT-PET scans may be required.

  12. Molecular profiling of indolent human prostate cancer:tackling technical challenges to achieve high-fidelity genome-wide data

    Institute of Scientific and Technical Information of China (English)

    Thomas A. Dunn; Helen L. Fedor; Angelo M. De Marzo; Jun Luo

    2012-01-01

    The contemporary problem of prostate cancer overtreatment can be partially attributed to the diagnosis of potentially indolent prostate cancers that pose low risk to aged men,and lack of sufficiently accurate risk stratification methods to reliably seek out men with indolent diseases.Since progressive acquisition and accumulation of genomic alterations,both genetic and epigenetic,is a defining feature of all human cancers at different stages of disease progression,it is hypothesized that RNA and DNA alterations characteristic of indolent prostate tumors may be different from those previously characterized in the setting of clinically significant prostate cancer.Approaches capable of detecting such alterations on a genome-wide level are the most promising.Such analysis may uncover molecular events defining early initiating stages along the natural history of prostate cancer progression,and ultimately lead to rational development of risk stratification methods for identification of men who can safely forego treatment.However,defining and characterizing indolent prostate cancer in a clinically relevant context remains a challenge,particularly when genome-wide approaches are employed to profile formalin-fixed paraffin-embedded (FFPE) tissue specimens.Here,we provide the conceptual basis underlying the importance of understanding indolent prostate cancer from molecular profiling studies,identify the key hurdles in sample acquisition and variables that affect molecular data derived from FFPE tissues,and highlight recent progresses in efforts to address these technical challenges.

  13. MicroRNA Machinery Genes as Novel Biomarkers for Cancer.

    Science.gov (United States)

    Huang, Jing-Tao; Wang, Jin; Srivastava, Vibhuti; Sen, Subrata; Liu, Song-Mei

    2014-01-01

    MicroRNAs (miRNAs) directly and indirectly affect tumorigenesis. To be able to perform their myriad roles, miRNA machinery genes, such as Drosha, DGCR8, Dicer1, XPO5, TRBP, and AGO2, must generate precise miRNAs. These genes have specific expression patterns, protein-binding partners, and biochemical capabilities in different cancers. Our preliminary analysis of data from The Cancer Genome Atlas consortium on multiple types of cancer revealed significant alterations in these miRNA machinery genes. Here, we review their biological structures and functions with an eye toward understanding how they could serve as cancer biomarkers.

  14. Tumor Mutation Burden Forecasts Outcome in Ovarian Cancer with BRCA1 or BRCA2 Mutations

    DEFF Research Database (Denmark)

    Birkbak, Nicolai Juul; Kochupurakkal, Bose; Gonzalez-Izarzugaza, Jose Maria;

    2013-01-01

    Background: Increased number of single nucleotide substitutions is seen in breast and ovarian cancer genomes carrying disease-associated mutations in BRCA1 or BRCA2. The significance of these genome-wide mutations is unknown. We hypothesize genome-wide mutation burden mirrors deficiencies in DNA...... repair and is associated with treatment outcome in ovarian cancer. Methods and Results: The total number of synonymous and non-synonymous exome mutations (Nmut), and the presence of germline or somatic mutation in BRCA1 or BRCA2 (mBRCA) were extracted from whole-exome sequences of high-grade serous...... ovarian cancers from The Cancer Genome Atlas (TCGA). Cox regression and Kaplan-Meier methods were used to correlate Nmut with chemotherapy response and outcome. Higher Nmut correlated with a better response to chemotherapy after surgery. In patients with mBRCA-associated cancer, low Nmut was associated...

  15. A comprehensive analysis of genome-wide association studies to identify prostate cancer susceptibility loci for the Romanian population.

    Science.gov (United States)

    Rădăvoi, George Daniel; Pricop, Cătălin; Jinga, Viorel; Mateş, Dana; Rădoi, Viorica Elena; Jinga, Mariana; Ursu, Radu Ioan; Bratu, Ovidiu Gabriel; Mischianu, Dan Liviu Dorel; Iordache, Paul

    2016-01-01

    The aim of this study is to examine a large dataset of single nucleotide polymorphism known to be associated with prostate cancer from previous genome-wide association studies and create a dataset of single nucleotide polymorphisms that can be used in replication studies for the Romanian population. This study will define a list of markers showing a significant association with this phenotype. We propose the results of this study as a starting point for any Romanian genome-wide association studies researching the genetic susceptibility for prostate cancer.

  16. Possible role of the WDR3 gene on genome stability in thyroid cancer patients.

    Directory of Open Access Journals (Sweden)

    Wilser Andrés García-Quispes

    Full Text Available The role of the WDR3 gene on genomic instability has been evaluated in a group of 115 differentiated thyroid cancer (DTC patients. Genomic instability has been measured according to the response of peripheral blood lymphocytes to ionizing radiation (0.5 Gy. The response has been measured with the micronucleus (MN test evaluating the frequency of binucleated cells with MN (BNMN, both before and after the irradiation. No differences between genotypes, for the BNMN frequencies previous the irradiation, were observed. Nevertheless significant decreases in DNA damage after irradiation were observed in individuals carrying the variant alleles for each of the three genotyped SNPs: rs3754127 [-8.85 (-15.01 to -2.70, P<0.01]; rs3765501 [-8.98 (-15.61 to -2.36, P<0.01]; rs4658973 [-8.70 (-14.94 to -2.46, P<0.01]. These values correspond to those obtained assuming a dominant model. This study shows for the first time that WDR3 can modulate genome stability.

  17. TP53 Variations in Human Cancers: New Lessons from the IARC TP53 Database and Genomics Data.

    Science.gov (United States)

    Bouaoun, Liacine; Sonkin, Dmitriy; Ardin, Maude; Hollstein, Monica; Byrnes, Graham; Zavadil, Jiri; Olivier, Magali

    2016-09-01

    TP53 gene mutations are one of the most frequent somatic events in cancer. The IARC TP53 Database (http://p53.iarc.fr) is a popular resource that compiles occurrence and phenotype data on TP53 germline and somatic variations linked to human cancer. The deluge of data coming from cancer genomic studies generates new data on TP53 variations and attracts a growing number of database users for the interpretation of TP53 variants. Here, we present the current contents and functionalities of the IARC TP53 Database and perform a systematic analysis of TP53 somatic mutation data extracted from this database and from genomic data repositories. This analysis showed that IARC has more TP53 somatic mutation data than genomic repositories (29,000 vs. 4,000). However, the more complete screening achieved by genomic studies highlighted some overlooked facts about TP53 mutations, such as the presence of a significant number of mutations occurring outside the DNA-binding domain in specific cancer types. We also provide an update on TP53 inherited variants including the ones that should be considered as neutral frequent variations. We thus provide an update of current knowledge on TP53 variations in human cancer as well as inform users on the efficient use of the IARC TP53 Database.

  18. Genomic gain of the PRL-3 gene may represent poor prognosis of primary colorectal cancer, and associate with liver metastasis.

    Science.gov (United States)

    Nakayama, N; Yamashita, K; Tanaka, T; Kawamata, H; Ooki, A; Sato, T; Nakamura, T; Watanabe, M

    2016-01-01

    PRL-3 genomic copy number is increased in colorectal cancer (CRC), and PRL-3 expression is closely associated with lymph node and liver metastasis of CRC. However, the clinical significance of PRL-3 genomic gain for CRC remains obscure. Here, PRL-3 genomic status in 109 primary CRC tumors and in 44 CRC tumors that had metastasized to the liver, was quantified using real time PCR. Association of PRL-3 genomic status with clinicopathological factors and prognosis was assessed in detail. PRL-3 genomic gain was identified in 31 primary CRC (27.4 %) and was more frequently seen in stage III than in stage II (p = 0.025). Among the clinicopathological factors assessed, PRL-3 genomic gain was significantly associated with poorly differentiated histology (p = 0.0039). Moreover, CRC patients with PRL-3 genomic gain exhibited poorer prognosis than those with no gain in stage II-IV CRC (p = 0.017). PRL-3 genomic gain was identified in 18 (41 %) of the liver metastasis tumors, and this frequency of gain was significantly increased as compared to that of the corresponding primary CRCs (11 %) (p = 0.001). Our findings suggested that PRL-3 genomic gain may represent an aggressive phenotype of primary CRC, and may associate with liver metastasis.

  19. Anatomy atlases.

    Science.gov (United States)

    Rosse, C

    1999-01-01

    Anatomy atlases are unlike other knowledge sources in the health sciences in that they communicate knowledge through annotated images without the support of narrative text. An analysis of the knowledge component represented by images and the history of anatomy atlases suggest some distinctions that should be made between atlas and textbook illustrations. Textbook and atlas should synergistically promote the generation of a mental model of anatomy. The objective of such a model is to support anatomical reasoning and thereby replace memorization of anatomical facts. Criteria are suggested for selecting anatomy texts and atlases that complement one another, and the advantages and disadvantages of hard copy and computer-based anatomy atlases are considered.

  20. Loss of FOXA1 Drives Sexually Dimorphic Changes in Urothelial Differentiation and Is an Independent Predictor of Poor Prognosis in Bladder Cancer

    DEFF Research Database (Denmark)

    Reddy, Opal L; Cates, Justin M; Gellert, Lan L;

    2015-01-01

    We previously found loss of forkhead box A1 (FOXA1) expression to be associated with aggressive urothelial carcinoma of the bladder, as well as increased tumor proliferation and invasion. These initial findings were substantiated by The Cancer Genome Atlas, which identified FOXA1 mutations...

  1. A genome assembly-integrated dog 1 Mb BAC microarray: a cytogenetic resource for canine cancer studies and comparative genomic analysis.

    Science.gov (United States)

    Thomas, R; Duke, S E; Karlsson, E K; Evans, A; Ellis, P; Lindblad-Toh, K; Langford, C F; Breen, M

    2008-01-01

    Molecular cytogenetic studies have been instrumental in defining the nature of numerical and structural chromosome changes in human cancers, but their significance remains to be fully understood. The emergence of high quality genome assemblies for several model organisms provides exciting opportunities to develop novel genome-integrated molecular cytogenetic resources that now permit a comparative approach to evaluating the relevance of tumor-associated chromosome aberrations, both within and between species. We have used the dog genome sequence assembly to identify a framework panel of 2,097 bacterial artificial chromosome (BAC) clones, selected at intervals of approximately one megabase. Each clone has been evaluated by multicolor fluorescence in situ hybridization (FISH) to confirm its unique cytogenetic location in concordance with its reported position in the genome assembly, providing new information on the organization of the dog genome. This panel of BAC clones also represents a powerful cytogenetic resource with numerous potential applications. We have used the clone set to develop a genome-wide microarray for comparative genomic hybridization (aCGH) analysis, and demonstrate its application in detection of tumor-associated DNA copy number aberrations (CNAs) including single copy deletions and amplifications, regional aneuploidy and whole chromosome aneuploidy. We also show how individual clones selected from the BAC panel can be used as FISH probes in direct evaluation of tumor karyotypes, to verify and explore CNAs detected using aCGH analysis. This cytogenetically validated, genome integrated BAC clone panel has enormous potential for aiding gene discovery through a comparative approach to molecular oncology.

  2. Alternative splicing and differential gene expression in colon cancer detected by a whole genome exon array

    Directory of Open Access Journals (Sweden)

    Sugnet Charles

    2006-12-01

    Full Text Available Abstract Background Alternative splicing is a mechanism for increasing protein diversity by excluding or including exons during post-transcriptional processing. Alternatively spliced proteins are particularly relevant in oncology since they may contribute to the etiology of cancer, provide selective drug targets, or serve as a marker set for cancer diagnosis. While conventional identification of splice variants generally targets individual genes, we present here a new exon-centric array (GeneChip Human Exon 1.0 ST that allows genome-wide identification of differential splice variation, and concurrently provides a flexible and inclusive analysis of gene expression. Results We analyzed 20 paired tumor-normal colon cancer samples using a microarray designed to detect over one million putative exons that can be virtually assembled into potential gene-level transcripts according to various levels of prior supporting evidence. Analysis of high confidence (empirically supported transcripts identified 160 differentially expressed genes, with 42 genes occupying a network impacting cell proliferation and another twenty nine genes with unknown functions. A more speculative analysis, including transcripts based solely on computational prediction, produced another 160 differentially expressed genes, three-fourths of which have no previous annotation. We also present a comparison of gene signal estimations from the Exon 1.0 ST and the U133 Plus 2.0 arrays. Novel splicing events were predicted by experimental algorithms that compare the relative contribution of each exon to the cognate transcript intensity in each tissue. The resulting candidate splice variants were validated with RT-PCR. We found nine genes that were differentially spliced between colon tumors and normal colon tissues, several of which have not been previously implicated in cancer. Top scoring candidates from our analysis were also found to substantially overlap with EST-based bioinformatic

  3. DNA Damage Follows Repair Factor Depletion and Portends Genome Variation in Cancer Cells after Pore Migration.

    Science.gov (United States)

    Irianto, Jerome; Xia, Yuntao; Pfeifer, Charlotte R; Athirasala, Avathamsa; Ji, Jiazheng; Alvey, Cory; Tewari, Manu; Bennett, Rachel R; Harding, Shane M; Liu, Andrea J; Greenberg, Roger A; Discher, Dennis E

    2017-01-23

    Migration through micron-size constrictions has been seen to rupture the nucleus, release nuclear-localized GFP, and cause localized accumulations of ectopic 53BP1-a DNA repair protein. Here, constricted migration of two human cancer cell types and primary mesenchymal stem cells (MSCs) increases DNA breaks throughout the nucleoplasm as assessed by endogenous damage markers and by electrophoretic "comet" measurements. Migration also causes multiple DNA repair proteins to segregate away from DNA, with cytoplasmic mis-localization sustained for many hours as is relevant to delayed repair. Partial knockdown of repair factors that also regulate chromosome copy numbers is seen to increase DNA breaks in U2OS osteosarcoma cells without affecting migration and with nucleoplasmic patterns of damage similar to constricted migration. Such depletion also causes aberrant levels of DNA. Migration-induced nuclear damage is nonetheless reversible for wild-type and sub-cloned U2OS cells, except for lasting genomic differences between stable clones as revealed by DNA arrays and sequencing. Gains and losses of hundreds of megabases in many chromosomes are typical of the changes and heterogeneity in bone cancer. Phenotypic differences that arise from constricted migration of U2OS clones are further illustrated by a clone with a highly elongated and stable MSC-like shape that depends on microtubule assembly downstream of the transcription factor GATA4. Such changes are consistent with reversion to a more stem-like state upstream of cancerous osteoblastic cells. Migration-induced genomic instability can thus associate with heritable changes.

  4. Genome network medicine: innovation to overcome huge challenges in cancer therapy.

    Science.gov (United States)

    Roukos, Dimitrios H

    2014-01-01

    The post-ENCODE era shapes now a new biomedical research direction for understanding transcriptional and signaling networks driving gene expression and core cellular processes such as cell fate, survival, and apoptosis. Over the past half century, the Francis Crick 'central dogma' of single n gene/protein-phenotype (trait/disease) has defined biology, human physiology, disease, diagnostics, and drugs discovery. However, the ENCODE project and several other genomic studies using high-throughput sequencing technologies, computational strategies, and imaging techniques to visualize regulatory networks, provide evidence that transcriptional process and gene expression are regulated by highly complex dynamic molecular and signaling networks. This Focus article describes the linear experimentation-based limitations of diagnostics and therapeutics to cure advanced cancer and the need to move on from reductionist to network-based approaches. With evident a wide genomic heterogeneity, the power and challenges of next-generation sequencing (NGS) technologies to identify a patient's personal mutational landscape for tailoring the best target drugs in the individual patient are discussed. However, the available drugs are not capable of targeting aberrant signaling networks and research on functional transcriptional heterogeneity and functional genome organization is poorly understood. Therefore, the future clinical genome network medicine aiming at overcoming multiple problems in the new fields of regulatory DNA mapping, noncoding RNA, enhancer RNAs, and dynamic complexity of transcriptional circuitry are also discussed expecting in new innovation technology and strong appreciation of clinical data and evidence-based medicine. The problematic and potential solutions in the discovery of next-generation, molecular, and signaling circuitry-based biomarkers and drugs are explored.

  5. Genome-wide search for gene-gene interactions in colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Shuo Jiao

    Full Text Available Genome-wide association studies (GWAS have successfully identified a number of single-nucleotide polymorphisms (SNPs associated with colorectal cancer (CRC risk. However, these susceptibility loci known today explain only a small fraction of the genetic risk. Gene-gene interaction (GxG is considered to be one source of the missing heritability. To address this, we performed a genome-wide search for pair-wise GxG associated with CRC risk using 8,380 cases and 10,558 controls in the discovery phase and 2,527 cases and 2,658 controls in the replication phase. We developed a simple, but powerful method for testing interaction, which we term the Average Risk Due to Interaction (ARDI. With this method, we conducted a genome-wide search to identify SNPs showing evidence for GxG with previously identified CRC susceptibility loci from 14 independent regions. We also conducted a genome-wide search for GxG using the marginal association screening and examining interaction among SNPs that pass the screening threshold (p<10(-4. For the known locus rs10795668 (10p14, we found an interacting SNP rs367615 (5q21 with replication p = 0.01 and combined p = 4.19×10(-8. Among the top marginal SNPs after LD pruning (n = 163, we identified an interaction between rs1571218 (20p12.3 and rs10879357 (12q21.1 (nominal combined p = 2.51×10(-6; Bonferroni adjusted p = 0.03. Our study represents the first comprehensive search for GxG in CRC, and our results may provide new insight into the genetic etiology of CRC.

  6. Understanding Cancer Prognosis

    Medline Plus

    Full Text Available ... Effects of Childhood Cancer Treatment Pediatric Supportive Care Unusual Cancers of Childhood Treatment Childhood Cancer Genomics Study ... Genomics Causes of Cancer Diagnosis Prevention Screening & Early Detection Treatment Cancer & Public Health Cancer Health Disparities Childhood ...

  7. Understanding Cancer Prognosis

    Medline Plus

    Full Text Available ... Partners & Collaborators Spotlight on Scientists Research Areas Cancer Biology Cancer Genomics Causes of Cancer Diagnosis Prevention Screening & ... Collaborators Spotlight on Scientists NCI Research Areas Cancer Biology Cancer Genomics Causes of Cancer Diagnosis Prevention Screening & ...

  8. A genome-wide map of aberrantly expressed chromosomal islands in colorectal cancer

    Directory of Open Access Journals (Sweden)

    Castanos-Velez Esmeralda

    2006-09-01

    Full Text Available Abstract Background Cancer development is accompanied by genetic phenomena like deletion and amplification of chromosome parts or alterations of chromatin structure. It is expected that these mechanisms have a strong effect on regional gene expression. Results We investigated genome-wide gene expression in colorectal carcinoma (CRC and normal epithelial tissues from 25 patients using oligonucleotide arrays. This allowed us to identify 81 distinct chromosomal islands with aberrant gene expression. Of these, 38 islands show a gain in expression and 43 a loss of expression. In total, 7.892 genes (25.3% of all human genes are located in aberrantly expressed islands. Many chromosomal regions that are linked to hereditary colorectal cancer show deregulated expression. Also, many known tumor genes localize to chromosomal islands of misregulated expression in CRC. Conclusion An extensive comparison with published CGH data suggests that chromosomal regions known for frequent deletions in colon cancer tend to show reduced expression. In contrast, regions that are often amplified in colorectal tumors exhibit heterogeneous expression patterns: even show a decrease of mRNA expression. Because for several islands of deregulated expression chromosomal aberrations have never been observed, we speculate that additional mechanisms (like abnormal states of regional chromatin also have a substantial impact on the formation of co-expression islands in colorectal carcinoma.

  9. Genome-wide association study identifies new prostate cancer susceptibility loci

    Science.gov (United States)

    Schumacher, Fredrick R.; Berndt, Sonja I.; Siddiq, Afshan; Jacobs, Kevin B.; Wang, Zhaoming; Lindstrom, Sara; Stevens, Victoria L.; Chen, Constance; Mondul, Alison M.; Travis, Ruth C.; Stram, Daniel O.; Eeles, Rosalind A.; Easton, Douglas F.; Giles, Graham; Hopper, John L.; Neal, David E.; Hamdy, Freddie C.; Donovan, Jenny L.; Muir, Kenneth; Al Olama, Ali Amin; Kote-Jarai, Zsofia; Guy, Michelle; Severi, Gianluca; Grönberg, Henrik; Isaacs, William B.; Karlsson, Robert; Wiklund, Fredrik; Xu, Jianfeng; Allen, Naomi E.; Andriole, Gerald L.; Barricarte, Aurelio; Boeing, Heiner; Bas Bueno-de-Mesquita, H.; Crawford, E. David; Diver, W. Ryan; Gonzalez, Carlos A.; Gaziano, J. Michael; Giovannucci, Edward L.; Johansson, Mattias; Le Marchand, Loic; Ma, Jing; Sieri, Sabina; Stattin, Pär; Stampfer, Meir J.; Tjonneland, Anne; Vineis, Paolo; Virtamo, Jarmo; Vogel, Ulla; Weinstein, Stephanie J.; Yeager, Meredith; Thun, Michael J.; Kolonel, Laurence N.; Henderson, Brian E.; Albanes, Demetrius; Hayes, Richard B.; Spencer Feigelson, Heather; Riboli, Elio; Hunter, David J.; Chanock, Stephen J.; Haiman, Christopher A.; Kraft, Peter

    2011-01-01

    Prostate cancer (PrCa) is the most common non-skin cancer diagnosed among males in developed countries and the second leading cause of cancer mortality, yet little is known regarding its etiology and factors that influence clinical outcome. Genome-wide association studies (GWAS) of PrCa have identified at least 30 distinct loci associated with small differences in risk. We conducted a GWAS in 2782 advanced PrCa cases (Gleason grade ≥ 8 or tumor stage C/D) and 4458 controls with 571 243 single nucleotide polymorphisms (SNPs). Based on in silico replication of 4679 SNPs (Stage 1, P < 0.02) in two published GWAS with 7358 PrCa cases and 6732 controls, we identified a new susceptibility locus associated with overall PrCa risk at 2q37.3 (rs2292884, P= 4.3 × 10−8). We also confirmed a locus suggested by an earlier GWAS at 12q13 (rs902774, P= 8.6 × 10−9). The estimated per-allele odds ratios for these loci (1.14 for rs2292884 and 1.17 for rs902774) did not differ between advanced and non-advanced PrCa (case-only test for heterogeneity P= 0.72 and P= 0.61, respectively). Further studies will be needed to assess whether these or other loci are differentially associated with PrCa subtypes. PMID:21743057

  10. A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci

    Science.gov (United States)

    Rothman, Nathaniel; Garcia-Closas, Montserrat; Chatterjee, Nilanjan; Malats, Nuria; Wu, Xifeng; Figueroa, Jonine; Real, Francisco X; Van Den Berg, David; Matullo, Giuseppe; Baris, Dalsu; Thun, Michael; Kiemeney, Lambertus A; Vineis, Paolo; De Vivo, Immaculata; Albanes, Demetrius; Purdue, Mark P; Rafnar, Thorunn; Hildebrandt, Michelle A T; Kiltie, Anne E; Cussenot, Olivier; Golka, Klaus; Kumar, Rajiv; Taylor, Jack A; Mayordomo, Jose I; Jacobs, Kevin B; Kogevinas, Manolis; Hutchinson, Amy; Wang, Zhaoming; Fu, Yi-Ping; Prokunina-Olsson, Ludmila; Burdette, Laurie; Yeager, Meredith; Wheeler, William; Tardón, Adonina; Serra, Consol; Carrato, Alfredo; García-Closas, Reina; Lloreta, Josep; Johnson, Alison; Schwenn, Molly; Karagas, Margaret R; Schned, Alan; Andriole, Gerald; Grubb, Robert; Black, Amanda; Jacobs, Eric J; Diver, W Ryan; Gapstur, Susan M; Weinstein, Stephanie J; Virtamo, Jarmo; Cortessis, Victoria K; Gago-Dominguez, Manuela; Pike, Malcolm C; Stern, Mariana C; Yuan, Jian-Min; Hunter, David; McGrath, Monica; Dinney, Colin P; Czerniak, Bogdan; Chen, Meng; Yang, Hushan; Vermeulen, Sita H; Aben, Katja K; Witjes, J Alfred; Makkinje, Remco R; Sulem, Patrick; Besenbacher, Soren; Stefansson, Kari; Riboli, Elio; Brennan, Paul; Panico, Salvatore; Navarro, Carmen; Allen, Naomi E; Bueno-de-Mesquita, H Bas; Trichopoulos, Dimitrios; Caporaso, Neil; Landi, Maria Teresa; Canzian, Federico; Ljungberg, Borje; Tjonneland, Anne; Clavel-Chapelon, Francoise; Bishop, David T; Teo, Mark T W; Knowles, Margaret A; Guarrera, Simonetta; Polidoro, Silvia; Ricceri, Fulvio; Sacerdote, Carlotta; Allione, Alessandra; Cancel-Tassin, Geraldine; Selinski, Silvia; Hengstler, Jan G; Dietrich, Holger; Fletcher, Tony; Rudnai, Peter; Gurzau, Eugen; Koppova, Kvetoslava; Bolick, Sophia C E; Godfrey, Ashley; Xu, Zongli; Sanz-Velez, José I; García-Prats, María D; Sanchez, Manuel; Valdivia, Gabriel; Porru, Stefano; Benhamou, Simone; Hoover, Robert N; Fraumeni, Joseph F; Silverman, Debra T; Chanock, Stephen J

    2010-01-01

    We conducted a multi-stage, genome-wide association study (GWAS) of bladder cancer with a primary scan of 589,299 single nucleotide polymorphisms (SNPs) in 3,532 cases and 5,120 controls of European descent (5 studies) followed by a replication strategy, which included 8,381 cases and 48,275 controls (16 studies). In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1; rs1014971, (P=8×10−12) maps to a non-genic region of chromosome 22q13.1; rs8102137 (P=2×10−11) on 19q12 maps to CCNE1; and rs11892031 (P=1×10−7) maps to the UGT1A cluster on 2q37.1. We confirmed four previous GWAS associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P=4×10−11) and a tag SNP for NAT2 acetylation status (P=4×10−11), as well as demonstrated smoking interactions with both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into mechanisms of carcinogenesis. PMID:20972438

  11. Non-Genomic Actions of the Androgen Receptor in Prostate Cancer

    Science.gov (United States)

    Leung, Jacky K.; Sadar, Marianne D.

    2017-01-01

    Androgen receptor (AR) is a validated drug target for prostate cancer based on its role in proliferation, survival, and metastases of prostate cancer cells. Unfortunately, despite recent improvements to androgen deprivation therapy and the advent of better antiandrogens with a superior affinity for the AR ligand-binding domain (LBD), most patients with recurrent disease will eventually develop lethal metastatic castration-resistant prostate cancer (CRPC). Expression of constitutively active AR splice variants that lack the LBD contribute toward therapeutic resistance by bypassing androgen blockade and antiandrogens. In the canonical pathway, binding of androgen to AR LBD triggers the release of AR from molecular chaperones which enable conformational changes and protein–protein interactions to facilitate its nuclear translocation where it regulates the expression of target genes. However, preceding AR function in the nucleus, initial binding of androgen to AR LBD in the cytoplasm may already initiate signal transduction pathways to modulate cellular proliferation and migration. In this article, we review the significance of signal transduction pathways activated by rapid, non-genomic signaling of the AR during the progression to metastatic CRPC and put into perspective the implications for current and novel therapies that target different domains of AR.

  12. Using Generalized Equivalent Uniform Dose Atlases to Combine and Analyze Prospective Dosimetric and Radiation Pneumonitis Data From 2 Non-Small Cell Lung Cancer Dose Escalation Protocols

    Energy Technology Data Exchange (ETDEWEB)

    Liu Fan; Yorke, Ellen D. [Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Belderbos, Jose S.A.; Borst, Gerben R. [The Netherlands Cancer Institute, Antoni Van Leeuwenhoek Hospital, Amsterdam (Netherlands); Rosenzweig, Kenneth E. [Mount Sinai School of Medicine, New York, New York (United States); Lebesque, Joos V. [The Netherlands Cancer Institute, Antoni Van Leeuwenhoek Hospital, Amsterdam (Netherlands); Jackson, Andrew, E-mail: jacksona@mskcc.org [Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York (United States)

    2013-01-01

    Purpose: To demonstrate the use of generalized equivalent uniform dose (gEUD) atlas for data pooling in radiation pneumonitis (RP) modeling, to determine the dependence of RP on gEUD, to study the consistency between data sets, and to verify the increased statistical power of the combination. Methods and Materials: Patients enrolled in prospective phase I/II dose escalation studies of radiation therapy of non-small cell lung cancer at Memorial Sloan-Kettering Cancer Center (MSKCC) (78 pts) and the Netherlands Cancer Institute (NKI) (86 pts) were included; 10 (13%) and 14 (17%) experienced RP requiring steroids (RPS) within 6 months after treatment. gEUD was calculated from dose-volume histograms. Atlases for each data set were created using 1-Gy steps from exact gEUDs and RPS data. The Lyman-Kutcher-Burman model was fit to the atlas and exact gEUD data. Heterogeneity and inconsistency statistics for the fitted parameters were computed. gEUD maps of the probability of RPS rate {>=}20% were plotted. Results: The 2 data sets were homogeneous and consistent. The best fit values of the volume effect parameter a were small, with upper 95% confidence limit around 1.0 in the joint data. The likelihood profiles around the best fit a values were flat in all cases, making determination of the best fit a weak. All confidence intervals (CIs) were narrower in the joint than in the individual data sets. The minimum P value for correlations of gEUD with RPS in the joint data was .002, compared with P=.01 and .05 for MSKCC and NKI data sets, respectively. gEUD maps showed that at small a, RPS risk increases with gEUD. Conclusions: The atlas can be used to combine gEUD and RPS information from different institutions and model gEUD dependence of RPS. RPS has a large volume effect with the mean dose model barely included in the 95% CI. Data pooling increased statistical power.

  13. Cancer 2015”: A Prospective, Population-Based Cancer Cohort—Phase 1: Feasibility of Genomics-Guided Precision Medicine in the Clinic

    Directory of Open Access Journals (Sweden)

    John P. Parisot

    2015-10-01

    Full Text Available “Cancer 2015” is a longitudinal and prospective cohort. It is a phased study whose aim was to pilot recruiting 1000 patients during phase 1 to establish the feasibility of providing a population-based genomics cohort. Newly diagnosed adult patients with solid cancers, with residual tumour material for molecular genomics testing, were recruited into the cohort for the collection of a dataset containing clinical, molecular pathology, health resource use and outcomes data. 1685 patients have been recruited over almost 3 years from five hospitals. Thirty-two percent are aged between 61–70 years old, with a median age of 63 years. Diagnostic tumour samples were obtained for 90% of these patients for multiple parallel sequencing. Patients identified with somatic mutations of potentially “actionable” variants represented almost 10% of those tumours sequenced, while 42% of the cohort had no mutations identified. These genomic data were annotated with information such as cancer site, stage, morphology, treatment and patient outcomes and health resource use and cost. This cohort has delivered its main objective of establishing an upscalable genomics cohort within a clinical setting and in phase 2 aims to develop a protocol for how genomics testing can be used in real-time clinical decision-making, providing evidence on the value of precision medicine to clinical practice.

  14. KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer. | Office of Cancer Genomics

    Science.gov (United States)

    Inhibitors that target the receptor tyrosine kinase (RTK)/Ras/mitogen-activated protein kinase (MAPK) pathway have led to clinical responses in lung and other cancers, but some patients fail to respond and in those that do resistance inevitably occurs (Balak et al., 2006; Kosaka et al., 2006; Rudin et al., 2013; Wagle et al., 2011). To understand intrinsic and acquired resistance to inhibition of MAPK signaling, we performed CRISPR-Cas9 gene deletion screens in the setting of BRAF, MEK, EGFR, and ALK inhibition.

  15. Comparison of 6q25 Breast Cancer Hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC)

    NARCIS (Netherlands)

    Hein, Rebecca; Maranian, Melanie; Hopper, John L.; Kapuscinski, Miroslaw K.; Southey, Melissa C.; Park, Daniel J.; Schmidt, Marjanka K.; Broeks, Annegien; Hogervorst, Frans B. L.; Bueno-de-Mesquit, H. Bas; Muir, Kenneth R.; Lophatananon, Artitaya; Rattanamongkongul, Suthee; Puttawibul, Puttisak; Fasching, Peter A.; Hein, Alexander; Ekici, Arif B.; Beckmann, Matthias W.; Fletcher, Olivia; Johnson, Nichola; Silva, Isabel dos Santos; Peto, Julian; Sawyer, Elinor; Tomlinson, Ian; Kerin, Michael; Miller, Nicola; Marmee, Frederick; Schneeweiss, Andreas; Sohn, Christof; Burwinkel, Barbara; Guenel, Pascal; Cordina-Duverger, Emilie; Menegaux, Florence; Truong, Therese; Bojesen, Stig E.; Nordestgaard, Borge G.; Flyger, Henrik; Milne, Roger L.; Arias Perez, Jose Ignacio; Pilar Zamora, M.; Benitez, Javier; Anton-Culver, Hoda; Ziogas, Argyrios; Bernstein, Leslie; Clarke, Christina A.; Brenner, Hermann; Mueller, Heiko; Arndt, Volker; Stegmaier, Christa; Rahman, Nazneen; Seal, Sheila; Turnbull, Clare; Renwick, Anthony; Meindl, Alfons; Schott, Sarah; Bartram, Claus R.; Schmutzler, Rita K.; Brauch, Hiltrud; Hamann, Ute; Ko, Yon-Dschun; Wang-Gohrke, Shan; Doerk, Thilo; Schuermann, Peter; Karstens, Johann H.; Hillemanns, Peter; Nevanlinna, Heli; Heikkinen, Tuomas; Aittomaki, Kristiina; Blomqvist, Carl; Bogdanova, Natalia V.; Zalutsky, Iosif V.; Antonenkova, Natalia N.; Bermisheva, Marina; Prokovieva, Darya; Farahtdinova, Albina; Khusnutdinova, Elza; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana; Chen, Xiaoqing; Beesley, Jonathan; Lambrechts, Diether; Zhao, Hui; Neven, Patrick; Wildiers, Hans; Nickels, Stefan; Flesch-Janys, Dieter; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Barile, Monica; Couch, Fergus J.; Olson, Janet E.; Wang, Xianshu; Fredericksen, Zachary; Giles, Graham G.; Baglietto, Laura; McLean, Catriona A.; Severi, Gianluca; Offit, Kenneth; Robson, Mark; Gaudet, Mia M.; Vijai, Joseph; Alnaes, Grethe Grenaker; Kristensen, Vessela; Borresen-Dale, Anne-Lise; John, Esther M.; Miron, Alexander; Winqvist, Robert; Pylkas, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Mulligan, Anna Marie; Figueroa, Jonine D.; Garcia-Closas, Montserrat; Lissowska, Jolanta; Sherman, Mark E.; Hooning, Maartje; Martens, John W. M.; Seynaeve, Caroline; Collee, Margriet; Hall, Per; Humpreys, Keith; Czene, Kamila; Liu, Jianjun; Cox, Angela; Brock, Ian W.; Cross, Simon S.; Reed, Malcolm W. R.; Ahmed, Shahana; Ghoussaini, Maya; Pharoah, Paul D. P.; Kang, Daehee; Yoo, Keun-Young; Noh, Dong-Young; Jakubowska, Anna; Jaworska, Katarzyna; Durda, Katarzyna; Zlowocka, Elzbieta; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Shen, Chen-Yang; Yu, Jyh-Cherng; Hsu, Huan-Ming; Hou, Ming-Feng; Orr, Nick; Schoemaker, Minouk; Ashworth, Alan; Swerdlow, Anthony; Trentham-Dietz, Amy; Newcomb, Polly A.; Titus, Linda; Egan, Kathleen M.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Humphreys, Manjeet K.; Morrison, Jonathan; Chang-Claude, Jenny; Easton, Douglas F.; Dunning, Alison M.

    2012-01-01

    The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europea

  16. Large scale digital atlases in neuroscience

    Science.gov (United States)

    Hawrylycz, M.; Feng, D.; Lau, C.; Kuan, C.; Miller, J.; Dang, C.; Ng, L.

    2014-03-01

    Imaging in neuroscience has revolutionized our current understanding of brain structure, architecture and increasingly its function. Many characteristics of morphology, cell type, and neuronal circuitry have been elucidated through methods of neuroimaging. Combining this data in a meaningful, standardized, and accessible manner is the scope and goal of the digital brain atlas. Digital brain atlases are used today in neuroscience to characterize the spatial organization of neuronal structures, for planning and guidance during neurosurgery, and as a reference for interpreting other data modalities such as gene expression and connectivity data. The field of digital atlases is extensive and in addition to atlases of the human includes high quality brain atlases of the mouse, rat, rhesus macaque, and other model organisms. Using techniques based on histology, structural and functional magnetic resonance imaging as well as gene expression data, modern digital atlases use probabilistic and multimodal techniques, as well as sophisticated visualization software to form an integrated product. Toward this goal, brain atlases form a common coordinate framework for summarizing, accessing, and organizing this knowledge and will undoubtedly remain a key technology in neuroscience in the future. Since the development of its flagship project of a genome wide image-based atlas of the mouse brain, the Allen Institute for Brain Science has used imaging as a primary data modality for many of its large scale atlas projects. We present an overview of Allen Institute digital atlases in neuroscience, with a focus on the challenges and opportunities for image processing and computation.

  17. A time for atlases and atlases for time

    Directory of Open Access Journals (Sweden)

    Yoav Livneh

    2010-02-01

    Full Text Available Advances in neuroanatomy and computational power are leading to the construction of new digital brain atlases. Atlases are rising as indispensable tools for comparing anatomical data as well as being stimulators of new hypotheses and experimental designs. Brain atlases describe nervous systems which are inherently plastic and variable. Thus, the levels of brain plasticity and stereotypy would be important to evaluate as limiting factors in the context of static brain atlases. In this review, we discuss the extent of structural changes which neurons undergo over time, and how these changes would impact the static nature of atlases. We describe the anatomical stereotypy between neurons of the same type, highlighting the differences between invertebrates and vertebrates. We review some recent experimental advances in our understanding of anatomical dynamics in adult neural circuits, and how these are modulated by the organism’s experience. In this respect, we discuss some analogies between brain atlases and the sequenced genome and the emerging epigenome. We argue that variability and plasticity of neurons are substantially high, and should thus be considered as integral features of high-resolution digital brain atlases.

  18. Genome-wide association study yields variants at 20p12.2 that associate with urinary bladder cancer

    NARCIS (Netherlands)

    Rafnar, T.; Sulem, P.; Thorleifsson, G.; Vermeulen, S.; Helgason, H.; Saemundsdottir, J.; Gudjonsson, S.A.; Sigurdsson, A.; Stacey, S.N.; Gudmundsson, J.; Johannsdottir, H.; Alexiusdottir, K.; Petursdottir, V.; Nikulasson, S.; Geirsson, G.; Jonsson, T.; Aben, K.K.H.; Grotenhuis, A.J.; Verhaegh, G.W.C.T.; Dudek, A.M.D.; Witjes, J.A.; Heijden, A.G. van der; Vrieling, A.; Galesloot, T.E.; Juan, A. de; Panadero, A.; Rivera, F.; Hurst, C.; Bishop, D.T.; Sak, S.C.; Choudhury, A.; Teo, M.T.; Arici, C.; Carta, A.; Toninelli, E.; Verdier, P. de; Rudnai, P.; Gurzau, E; Koppova, K.; Keur, K.A. van der; Lurkin, I.; Goossens, M.; Kellen, E.; Guarrera, S.; Russo, A.; Critelli, R.; Sacerdote, C.; Vineis, P.; Krucker, C.; Zeegers, M.P.; Gerullis, H.; Ovsiannikov, D.; Volkert, F.; Hengstler, J.G.; Selinski, S.; Magnusson, O.T.; Masson, G.; Kong, A.; Gudbjartsson, D.; Lindblom, A.; Zwarthoff, E.; Porru, S.; Golka, K.; Buntinx, F.; Matullo, G.; Kumar, R.; Mayordomo, J.I.; Steineck, D.G.; Kiltie, A.E.; Jonsson, E.; Radvanyi, F.; Knowles, M.A.; Thorsteinsdottir, U.; Kiemeney, B.; Stefansson, K.

    2014-01-01

    Genome-wide association studies (GWAS) of urinary bladder cancer (UBC) have yielded common variants at 12 loci that associate with risk of the disease. We report here the results of a GWAS of UBC including 1670 UBC cases and 90 180 controls, followed by replication analysis in additional 5266 UBC ca

  19. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

    NARCIS (Netherlands)

    Michailidou, Kyriaki; Beesley, Jonathan; Lindstrom, Sara; Canisius, Sander; Dennis, Joe; Lush, Michael J.; Maranian, Mel J.; Bolla, Manjeet K.; Wang, Qin; Shah, Mitul; Perkins, Barbara J.; Czene, Kamila; Eriksson, Mikael; Darabi, Hatef; Brand, Judith S.; Bojesen, Stig E.; Nordestgaard, Borge G.; Flyger, Henrik; Nielsen, Sune F.; Rahman, Nazneen; Turnbull, Clare; Fletcher, Olivia; Peto, Julian; Gibson, Lorna; dos-Santos-Silva, Isabel; Chang-Claude, Jenny; Flesch-Janys, Dieter; Rudolph, Anja; Eilber, Ursula; Behrens, Sabine; Nevanlinna, Heli; Muranen, Taru A.; Aittomaki, Kristiina; Blomqvist, Carl; Khan, Sofia; Aaltonen, Kirsimari; Ahsan, Habibul; Kibriya, Muhammad G.; Whittemore, Alice S.; John, Esther M.; Malone, Kathleen E.; Gammon, Marilie D.; Santella, Regina M.; Ursin, Giske; Makalic, Enes; Schmidt, Daniel F.; Casey, Graham; Hunter, David J.; Gapstur, Susan M.; Gaudet, Mia M.; Diver, W. Ryan; Haiman, Christopher A.; Schumacher, Fredrick; Henderson, Brian E.; Le Marchand, Loic; Berg, Christine D.; Chanock, Stephen J.; Figueroa, Jonine; Hoover, Robert N.; Lambrechts, Diether; Neven, Patrick; Wildiers, Hans; van Limbergen, Erik; Schmidt, Marjanka K.; Broeks, Annegien; Verhoef, Senno; Cornelissen, Sten; Couch, Fergus J.; Olson, Janet E.; Hallberg, Emily; Vachon, Celine; Waisfisz, Quinten; Meijers-Heijboer, Hanne; Adank, Muriel A.; van der Luijt, Rob B.; Li, Jingmei; Liu, Jianjun; Humphreys, Keith; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K.; Yoo, Keun-Young; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Tajima, Kazuo; Guenel, Pascal; Truong, Therese; Mulot, Claire; Sanchez, Marie; Burwinkel, Barbara; Marme, Frederik; Surowy, Harald; Sohn, Christof; Wu, Anna H.; Tseng, Chiu-chen; Van den Berg, David; Stram, Daniel O.; Gonzalez-Neira, Anna; Benitez, Javier; Zamora, M. Pilar; Arias Perez, Jose Ignacio; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Cox, Angela; Cross, Simon S.; Reed, Malcolm W. R.; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Mulligan, Anna Marie; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Lindblom, Annika; Margolin, Sara; Teo, Soo Hwang; Yip, Cheng Har; Taib, Nur Aishah Mohd; Tan, Gie-Hooi; Hooning, Maartje J.; Hollestelle, Antoinette; Martens, John W. M.; Collee, J. Margriet; Blot, William; Signorello, Lisa B.; Cai, Qiuyin; Hopper, John L.; Southey, Melissa C.; Tsimiklis, Helen; Apicella, Carmel; Shen, Chen-Yang; Hsiung, Chia-Ni; Wu, Pei-Ei; Hou, Ming-Feng; Kristensen, Vessela N.; Nord, Silje; Alnaes, Grethe I. Grenaker; Giles, Graham G.; Milne, Roger L.; McLean, Catriona; Canzian, Federico; Trichopoulos, Dimitrios; Peeters, Petra; Lund, Eiliv; Sund, Malin; Khaw, Kay-Tee; Gunter, Marc J.; Palli, Domenico; Mortensen, Lotte Maxild; Dossus, Laure; Huerta, Jose-Maria; Meindl, Alfons; Schmutzler, Rita K.; Sutter, Christian; Yang, Rongxi; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Hartman, Mikael; Miao, Hui; Chia, Kee Seng; Chan, Ching Wan; Fasching, Peter A.; Hein, Alexander; Beckmann, Matthias W.; Haeberle, Lothar; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Ashworth, Alan; Orr, Nick; Schoemaker, Minouk J.; Swerdlow, Anthony J.; Brinton, Louise; Garcia-Closas, Montserrat; Zheng, Wei; Halverson, Sandra L.; Shrubsole, Martha; Long, Jirong; Goldberg, Mark S.; Labreche, France; Dumont, Martine; Winqvist, Robert; Pylkas, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Brauch, Hiltrud; Hamann, Ute; Bruening, Thomas; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Bernard, Loris; Bogdanova, Natalia V.; Doerk, Thilo; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Devilee, Peter; Tollenaar, Robert A. E. M.; Seynaeve, Caroline; Van Asperen, Christi J.; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Huzarski, Tomasz; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; Mckay, James; Slager, Susan; Toland, Amanda E.; Ambrosone, Christine B.; Yannoukakos, Drakoulis; Kabisch, Maria; Torres, Diana; Neuhausen, Susan L.; Anton-Culver, Hoda; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Healey, Catherine S.; Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois; Pita, Guillermo; Rosario Alonso, M.; Alvarez, Nuria; Herrero, Daniel; Simard, Jacques; Pharoah, Paul P. D. P.; Kraft, Peter; Dunning, Alison M.; Chenevix-Trench, Georgia; Hall, Per; Easton, Douglas F.

    2015-01-01

    Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining similar to 14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising

  20. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

    NARCIS (Netherlands)

    K. Michailidou (Kyriaki); J. Beesley (Jonathan); S. Lindstrom (Stephen); S. Canisius (Sander); J. Dennis (Joe); M. Lush (Michael); M. Maranian (Melanie); M.K. Bolla (Manjeet); Q. Wang (Qing); M. Shah (Mitul); B. Perkins (Barbara); K. Czene (Kamila); M. Eriksson (Mikael); H. Darabi (Hatef); J.S. Brand (Judith S.); S.E. Bojesen (Stig); B.G. Nordestgaard (Børge); H. Flyger (Henrik); S.F. Nielsen (Sune); N. Rahman (Nazneen); C. Turnbull (Clare); O. Fletcher (Olivia); J. Peto (Julian); L.J. Gibson (Lorna); I. dos Santos Silva (Isabel); J. Chang-Claude (Jenny); D. Flesch-Janys (Dieter); A. Rudolph (Anja); U. Eilber (Ursula); T.W. Behrens (Timothy); H. Nevanlinna (Heli); T.A. Muranen (Taru); K. Aittomäki (Kristiina); C. Blomqvist (Carl); S. Khan (Sofia); K. Aaltonen (Kirsimari); H. Ahsan (Habibul); M.G. Kibriya (Muhammad); A.S. Whittemore (Alice S.); E.M. John (Esther M.); K.E. Malone (Kathleen E.); M.D. Gammon (Marilie); R.M. Santella (Regina M.); G. Ursin (Giske); E. Makalic (Enes); D.F. Schmidt (Daniel); G. Casey (Graham); D.J. Hunter (David J.); S.M. Gapstur (Susan M.); M.M. Gaudet (Mia); W.R. Diver (Ryan); C.A. Haiman (Christopher A.); F.R. Schumacher (Fredrick); B.E. Henderson (Brian); L. Le Marchand (Loic); C.D. Berg (Christine); S.J. Chanock (Stephen); J.D. Figueroa (Jonine); R.N. Hoover (Robert N.); D. Lambrechts (Diether); P. Neven (Patrick); H. Wildiers (Hans); E. van Limbergen (Erik); M.K. Schmidt (Marjanka); A. Broeks (Annegien); S. Verhoef; S. Cornelissen (Sten); F.J. Couch (Fergus); J.E. Olson (Janet); B. Hallberg (Boubou); C. Vachon (Celine); Q. Waisfisz (Quinten); E.J. Meijers-Heijboer (Hanne); M.A. Adank (Muriel); R.B. van der Luijt (Rob); J. Li (Jingmei); J. Liu (Jianjun); M.K. Humphreys (Manjeet); D. Kang (Daehee); J.-Y. Choi (Ji-Yeob); S.K. Park (Sue K.); K.Y. Yoo; K. Matsuo (Keitaro); H. Ito (Hidemi); H. Iwata (Hiroji); K. Tajima (Kazuo); P. Guénel (Pascal); T. Truong (Thérèse); C. Mulot (Claire); M. Sanchez (Marie); B. Burwinkel (Barbara); F. Marme (Federick); H. Surowy (Harald); C. Sohn (Christof); A.H. Wu (Anna H); C.-C. Tseng (Chiu-chen); D. Van Den Berg (David); D.O. Stram (Daniel O.); A. González-Neira (Anna); J. Benítez (Javier); M.P. Zamora (Pilar); J.I.A. Perez (Jose Ignacio Arias); X.-O. Shu (Xiao-Ou); W. Lu (Wei); Y. Gao; H. Cai (Hui); A. Cox (Angela); S.S. Cross (Simon); M.W.R. Reed (Malcolm); I.L. Andrulis (Irene); J.A. Knight (Julia); G. Glendon (Gord); A.-M. Mulligan (Anna-Marie); E.J. Sawyer (Elinor); I.P. Tomlinson (Ian); M. Kerin (Michael); N. Miller (Nicola); A. Lindblom (Annika); S. Margolin (Sara); S.H. Teo (Soo Hwang); C.H. Yip (Cheng Har); N.A.M. Taib (Nur Aishah Mohd); G.-H. Tan (Gie-Hooi); M.J. Hooning (Maartje); A. Hollestelle (Antoinette); J.W.M. Martens (John); J. Margriet Collée; W.J. Blot (William); L.B. Signorello (Lisa B.); Q. Cai (Qiuyin); J. Hopper (John); M.C. Southey (Melissa); H. Tsimiklis (Helen); C. Apicella (Carmel); C-Y. Shen (Chen-Yang); C.-N. Hsiung (Chia-Ni); P.-E. Wu (Pei-Ei); M.-F. Hou (Ming-Feng); V. Kristensen (Vessela); S. Nord (Silje); G.G. Alnæs (Grethe Grenaker); G.G. Giles (Graham G.); R.L. Milne (Roger); C.A. McLean (Catriona Ann); F. Canzian (Federico); D. Trichopoulos (Dimitrios); P.H.M. Peeters; E. Lund (Eiliv); R. Sund (Reijo); K.T. Khaw; M.J. Gunter (Marc J.); D. Palli (Domenico); L.M. Mortensen (Lotte Maxild); L. Dossus (Laure); J.-M. Huerta (Jose-Maria); A. Meindl (Alfons); R.K. Schmutzler (Rita); C. Sutter (Christian); R. Yang (Rongxi); K. Muir (Kenneth); A. Lophatananon (Artitaya); S. Stewart-Brown (Sarah); P. Siriwanarangsan (Pornthep); J.M. Hartman (Joost); X. Miao; K.S. Chia (Kee Seng); C.W. Chan (Ching Wan); P.A. Fasching (Peter); R. Hein (Rebecca); M.W. Beckmann (Matthias W.); L. Haeberle (Lothar); H. Brenner (Hermann); A.K. Dieffenbach (Aida Karina); V. Arndt (Volker); C. Stegmaier (Christa); A. Ashworth (Alan); N. Orr (Nick); M. Schoemaker (Minouk); A.J. Swerdlow (Anthony ); L.A. Brinton (Louise); M. García-Closas (Montserrat); W. Zheng (Wei); S.L. Halverson (Sandra L.); M. Shrubsole (Martha); J. Long (Jirong); M.S. Goldberg (Mark); F. Labrèche (France); M. Dumont (Martine); R. Winqvist (Robert); K. Pykäs (Katri); A. Jukkola-Vuorinen (Arja); M. Grip (Mervi); H. Brauch (Hiltrud); U. Hamann (Ute); T. Brüning (Thomas); P. Radice (Paolo); P. Peterlongo (Paolo); S. Manoukian (Siranoush); L. Bernard (Loris); N.V. Bogdanova (Natalia); T. Dörk (Thilo); A. Mannermaa (Arto); V. Kataja (Vesa); V-M. Kosma (Veli-Matti); J.M. Hartikainen (J.); P. Devilee (Peter); R.A.E.M. Tollenaar (Rob); C.M. Seynaeve (Caroline); C.J. van Asperen (Christi); A. Jakubowska (Anna); J. Lubinski (Jan); K. Jaworska (Katarzyna); T. Huzarski (Tomasz); S. Sangrajrang (Suleeporn); V. Gaborieau (Valerie); P. Brennan (Paul); J.D. McKay (James); S. Slager (Susan); A.E. Toland (Amanda); C.B. Ambrosone (Christine B.); D. Yannoukakos (Drakoulis); M. Kabisch (Maria); D. Torres (Diana); S.L. Neuhausen (Susan); H. Anton-Culver (Hoda); C. Luccarini (Craig); C. Baynes (Caroline); S. Ahmed (Shahana); S. Healey (Sue); D.C. Tessier (Daniel C.); D. Vincent (Daniel); F. Bacot (Francois); G. Pita (G.); M.R. Alonso (M Rosario); N. Álvarez (Nuria); D. Herrero (Daniel); J. Simard (Jacques); P.P.D.P. Pharoah (Paul P.D.P.); P. Kraft (Peter); A.M. Dunning (Alison); G. Chenevix-Trench (Georgia); P. Hall (Per); D.F. Easton (Douglas)

    2015-01-01

    textabstractGenome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprisi

  1. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

    DEFF Research Database (Denmark)

    Michailidou, Kyriaki; Beesley, Jonathan; Lindstrom, Sara

    2015-01-01

    Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748...

  2. ATLAS: Adjuvant Tamoxifen Longer Against Shorter

    Science.gov (United States)

    1998-09-01

    tamoxifen duration in early breast cancer Davies C Peto R Gray R 3rd Portuguese -Brazilian Mastology Congress - Recife, Brazil November 1996 ATLAS: An...van Leeuwenhoek Huis Oficina ATLAS (Espana) Inst. Portugues de Oncologia Antoninlvan Leeuwenhoek HuisCEPSS - FPT Av. Bissaia Barreto Plesmanlaan 121

  3. Genome-wide Meta-analyses of Breast, Ovarian and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by At Least Two Cancer Types

    Science.gov (United States)

    Kar, Siddhartha P.; Beesley, Jonathan; Al Olama, Ali Amin; Michailidou, Kyriaki; Tyrer, Jonathan; Kote-Jarai, ZSofia; Lawrenson, Kate; Lindstrom, Sara; Ramus, Susan J.; Thompson, Deborah J.; Kibel, Adam S.; Dansonka-Mieszkowska, Agnieszka; Michael, Agnieszka; Dieffenbach, Aida K.; Gentry-Maharaj, Aleksandra; Whittemore, Alice S.; Wolk, Alicja; Monteiro, Alvaro; Peixoto, Ana; Kierzek, Andrzej; Cox, Angela; Rudolph, Anja; Gonzalez-Neira, Anna; Wu, Anna H.; Lindblom, Annika; Swerdlow, Anthony; Ziogas, Argyrios; Ekici, Arif B.; Burwinkel, Barbara; Karlan, Beth Y.; Nordestgaard, Børge G.; Blomqvist, Carl; Phelan, Catherine; McLean, Catriona; Pearce, Celeste Leigh; Vachon, Celine; Cybulski, Cezary; Slavov, Chavdar; Stegmaier, Christa; Maier, Christiane; Ambrosone, Christine B.; Høgdall, Claus K.; Teerlink, Craig C.; Kang, Daehee; Tessier, Daniel C.; Schaid, Daniel J.; Stram, Daniel O.; Cramer, Daniel W.; Neal, David E.; Eccles, Diana; Flesch-Janys, Dieter; Velez Edwards, Digna R.; Wokozorczyk, Dominika; Levine, Douglas A.; Yannoukakos, Drakoulis; Sawyer, Elinor J.; Bandera, Elisa V.; Poole, Elizabeth M.; Goode, Ellen L.; Khusnutdinova, Elza; Høgdall, Estrid; Song, Fengju; Bruinsma, Fiona; Heitz, Florian; Modugno, Francesmary; Hamdy, Freddie C.; Wiklund, Fredrik; Giles, Graham G.; Olsson, Håkan; Wildiers, Hans; Ulmer, Hans-Ulrich; Pandha, Hardev; Risch, Harvey A.; Darabi, Hatef; Salvesen, Helga B.; Nevanlinna, Heli; Gronberg, Henrik; Brenner, Hermann; Brauch, Hiltrud; Anton-Culver, Hoda; Song, Honglin; Lim, Hui-Yi; McNeish, Iain; Campbell, Ian; Vergote, Ignace; Gronwald, Jacek; Lubiński, Jan; Stanford, Janet L.; Benítez, Javier; Doherty, Jennifer A.; Permuth, Jennifer B.; Chang-Claude, Jenny; Donovan, Jenny L.; Dennis, Joe; Schildkraut, Joellen M.; Schleutker, Johanna; Hopper, John L.; Kupryjanczyk, Jolanta; Park, Jong Y.; Figueroa, Jonine; Clements, Judith A.; Knight, Julia A.; Peto, Julian; Cunningham, Julie M.; Pow-Sang, Julio; Batra, Jyotsna; Czene, Kamila; Lu, Karen H.; Herkommer, Kathleen; Khaw, Kay-Tee; Matsuo, Keitaro; Muir, Kenneth; Offitt, Kenneth; Chen, Kexin; Moysich, Kirsten B.; Aittomäki, Kristiina; Odunsi, Kunle; Kiemeney, Lambertus A.; Massuger, Leon F.A.G.; Fitzgerald, Liesel M.; Cook, Linda S.; Cannon-Albright, Lisa; Hooning, Maartje J.; Pike, Malcolm C.; Bolla, Manjeet K.; Luedeke, Manuel; Teixeira, Manuel R.; Goodman, Marc T.; Schmidt, Marjanka K.; Riggan, Marjorie; Aly, Markus; Rossing, Mary Anne; Beckmann, Matthias W.; Moisse, Matthieu; Sanderson, Maureen; Southey, Melissa C.; Jones, Michael; Lush, Michael; Hildebrandt, Michelle A. T.; Hou, Ming-Feng; Schoemaker, Minouk J.; Garcia-Closas, Montserrat; Bogdanova, Natalia; Rahman, Nazneen; Le, Nhu D.; Orr, Nick; Wentzensen, Nicolas; Pashayan, Nora; Peterlongo, Paolo; Guénel, Pascal; Brennan, Paul; Paulo, Paula; Webb, Penelope M.; Broberg, Per; Fasching, Peter A.; Devilee, Peter; Wang, Qin; Cai, Qiuyin; Li, Qiyuan; Kaneva, Radka; Butzow, Ralf; Kopperud, Reidun Kristin; Schmutzler, Rita K.; Stephenson, Robert A.; MacInnis, Robert J.; Hoover, Robert N.; Winqvist, Robert; Ness, Roberta; Milne, Roger L.; Travis, Ruth C.; Benlloch, Sara; Olson, Sara H.; McDonnell, Shannon K.; Tworoger, Shelley S.; Maia, Sofia; Berndt, Sonja; Lee, Soo Chin; Teo, Soo-Hwang; Thibodeau, Stephen N.; Bojesen, Stig E.; Gapstur, Susan M.; Kjær, Susanne Krüger; Pejovic, Tanja; Tammela, Teuvo L.J.; Dörk, Thilo; Brüning, Thomas; Wahlfors, Tiina; Key, Tim J.; Edwards, Todd L.; Menon, Usha; Hamann, Ute; Mitev, Vanio; Kosma, Veli-Matti; Setiawan, Veronica Wendy; Kristensen, Vessela; Arndt, Volker; Vogel, Walther; Zheng, Wei; Sieh, Weiva; Blot, William J.; Kluzniak, Wojciech; Shu, Xiao-Ou; Gao, Yu-Tang; Schumacher, Fredrick; Freedman, Matthew L.; Berchuck, Andrew; Dunning, Alison M.; Simard, Jacques; Haiman, Christopher A.; Spurdle, Amanda; Sellers, Thomas A.; Hunter, David J.; Henderson, Brian E.; Kraft, Peter; Chanock, Stephen J.; Couch, Fergus J.; Hall, Per; Gayther, Simon A.; Easton, Douglas F.; Chenevix-Trench, Georgia; Eeles, Rosalind; Pharoah, Paul D.P.; Lambrechts, Diether

    2016-01-01

    Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10−8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10−5 in the three-cancer meta-analysis. PMID:27432226

  4. Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer

    DEFF Research Database (Denmark)

    Weischenfeldt, Joachim; Simon, Ronald; Feuerbach, Lars;

    2013-01-01

    comparative assessments with seven elderly-onset PCA genomes. Remarkable age-related differences in structural rearrangement (SR) formation became evident, suggesting distinct disease pathomechanisms. Whereas EO-PCAs harbored a prevalence of balanced SRs, with a specific abundance of androgen-regulated ETS......Early-onset prostate cancer (EO-PCA) represents the earliest clinical manifestation of prostate cancer. To compare the genomic alteration landscapes of EO-PCA with "classical" (elderly-onset) PCA, we performed deep sequencing-based genomics analyses in 11 tumors diagnosed at young age, and pursued...... gene fusions including TMPRSS2:ERG, elderly-onset PCAs displayed primarily non-androgen-associated SRs. Data from a validation cohort of > 10,000 patients showed age-dependent androgen receptor levels and a prevalence of SRs affecting androgen-regulated genes, further substantiating the activity...

  5. Genomic instability and cellular stress in organ biopsies and peripheral blood lymphocytes from patients with colorectal cancer and predisposing pathologies

    Science.gov (United States)

    Lombardi, Sara; Fuoco, Ilenia; di Fluri, Giorgia; Costa, Francesco; Ricchiuti, Angelo; Biondi, Graziano; Nardini, Vincenzo; Scarpato, Roberto

    2015-01-01

    Inflammatory bowel disease (IBD) and polyps, are common colorectal pathologies in western society and are risk factors for development of colorectal cancer (CRC). Genomic instability is a cancer hallmark and is connected to changes in chromosomal structure, often caused by double strand break formation (DSB), and aneuploidy. Cellular stress, may contribute to genomic instability. In colorectal biopsies and peripheral blood lymphocytes of patients with IBD, polyps and CRC, we evaluated 1) genomic instability using the γH2AX assay as marker of DSB and micronuclei in mononuclear lymphocytes kept under cytodieresis inhibition, and 2) cellular stress through expression and cellular localization of glutathione-S-transferase omega 1 (GSTO1). Colon biopsies showed γH2AX increase starting from polyps, while lymphocytes already from IBD. Micronuclei frequency began to rise in lymphocytes of subjects with polyps, suggesting a systemic genomic instability condition. Colorectal tissues lost GSTO1 expression but increased nuclear localization with pathology progression. Lymphocytes did not change GSTO1 expression and localization until CRC formation, where enzyme expression was increased. We propose that the growing genomic instability found in our patients is connected with the alteration of cellular environment. Evaluation of genomic damage and cellular stress in colorectal pathologies may facilitate prevention and management of CRC. PMID:26046795

  6. Advances in targeted and immunobased therapies for colorectal cancer in the genomic era

    Directory of Open Access Journals (Sweden)

    Seow HF

    2016-03-01

    Full Text Available Heng Fong Seow,1 Wai Kien Yip,1 Theodora Fifis2 1Immunology Unit, Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia; 2Department of Surgery, University of Melbourne, Melbourne, Australia Abstract: Targeted therapies require information on specific defective signaling pathways or mutations. Advances in genomic technologies and cell biology have led to identification of new therapeutic targets associated with signal-transduction pathways. Survival times of patients with colorectal cancer (CRC can be extended with combinations of conventional cytotoxic agents and targeted therapies. Targeting EGFR- and VEGFR-signaling systems has been the major focus for treatment of metastatic CRC. However, there are still limitations in their clinical application, and new and better drug combinations are needed. This review provides information on EGFR and VEGF inhibitors, new therapeutic agents in the pipeline targeting EGFR and VEGFR pathways, and those targeting other signal-transduction pathways, such as MET, IGF1R, MEK, PI3K, Wnt, Notch, Hedgehog, and death-receptor signaling pathways for treatment of metastatic CRC. Additionally, multitargeted approaches in combination therapies targeting negative-feedback loops, compensatory networks, and cross talk between pathways are highlighted. Then, immunobased strategies to enhance antitumor immunity using specific monoclonal antibodies, such as the immune-checkpoint inhibitors anti-CTLA4 and anti-PD1, as well as the challenges that need to be overcome for increased efficacy of targeted therapies, including drug resistance, predictive markers of response, tumor subtypes, and cancer stem cells, are covered. The review concludes with a brief insight into the applications of next-generation sequencing, expression profiling for tumor subtyping, and the exciting progress made in in silico predictive analysis in the development of a prescription strategy for

  7. Paired ductal carcinoma in situ and invasive breast cancer lesions in the D-loop of the mitochondrial genome indicate a cancerization field effect.

    Science.gov (United States)

    Maggrah, Andrea; Robinson, Kerry; Creed, Jennifer; Wittock, Roy; Gehman, Ken; Gehman, Teresa; Brown, Helen; Harbottle, Andrew; Froberg, M Kent; Klein, Daniel; Reguly, Brian; Parr, Ryan

    2013-01-01

    Alterations in the mitochondrial genome have been chronicled in most solid tumors, including breast cancer. The intent of this paper is to compare and document somatic mitochondrial D-loop mutations in paired samples of ductal carcinoma in situ (DCIS) and invasive breast cancer (IBC) indicating a potential breast ductal epithelial cancerization field effect. Paired samples of these histopathologies were laser-captured microdissected (LCM) from biopsy, lumpectomy, and mastectomy tissues. Blood samples were collected as germplasm control references. For each patient, hypervariable region 1 (HV1) in the D-loop portion of the mitochondrial genome (mtGenome) was sequenced for all 3 clinical samples. Specific parallel somatic heteroplasmic alterations between these histopathologies, particularly at sites 16189, 16223, 16224, 16270, and 16291, suggest the presence of an epithelial, mitochondrial cancerization field effect. These results indicate that further characterization of the mutational pathway of DCIS and IBC may help establish the invasive potential of DCIS. Moreover, this paper indicates that biofluids with low cellularity, such as nipple aspirate fluid and/or ductal lavage, warrant further investigation as early and minimally invasive detection mediums of a cancerization field effect within breast tissue.

  8. Paired Ductal Carcinoma In Situ and Invasive Breast Cancer Lesions in the D-Loop of the Mitochondrial Genome Indicate a Cancerization Field Effect

    Directory of Open Access Journals (Sweden)

    Andrea Maggrah

    2013-01-01

    Full Text Available Alterations in the mitochondrial genome have been chronicled in most solid tumors, including breast cancer. The intent of this paper is to compare and document somatic mitochondrial D-loop mutations in paired samples of ductal carcinoma in situ (DCIS and invasive breast cancer (IBC indicating a potential breast ductal epithelial cancerization field effect. Paired samples of these histopathologies were laser-captured microdissected (LCM from biopsy, lumpectomy, and mastectomy tissues. Blood samples were collected as germplasm control references. For each patient, hypervariable region 1 (HV1 in the D-loop portion of the mitochondrial genome (mtGenome was sequenced for all 3 clinical samples. Specific parallel somatic heteroplasmic alterations between these histopathologies, particularly at sites 16189, 16223, 16224, 16270, and 16291, suggest the presence of an epithelial, mitochondrial cancerization field effect. These results indicate that further characterization of the mutational pathway of DCIS and IBC may help establish the invasive potential of DCIS. Moreover, this paper indicates that biofluids with low cellularity, such as nipple aspirate fluid and/or ductal lavage, warrant further investigation as early and minimally invasive detection mediums of a cancerization field effect within breast tissue.

  9. A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer.

    Science.gov (United States)

    Gudmundsson, Julius; Sulem, Patrick; Gudbjartsson, Daniel F; Masson, Gisli; Agnarsson, Bjarni A; Benediktsdottir, Kristrun R; Sigurdsson, Asgeir; Magnusson, Olafur Th; Gudjonsson, Sigurjon A; Magnusdottir, Droplaug N; Johannsdottir, Hrefna; Helgadottir, Hafdis Th; Stacey, Simon N; Jonasdottir, Adalbjorg; Olafsdottir, Stefania B; Thorleifsson, Gudmar; Jonasson, Jon G; Tryggvadottir, Laufey; Navarrete, Sebastian; Fuertes, Fernando; Helfand, Brian T; Hu, Qiaoyan; Csiki, Irma E; Mates, Ioan N; Jinga, Viorel; Aben, Katja K H; van Oort, Inge M; Vermeulen, Sita H; Donovan, Jenny L; Hamdy, Freddy C; Ng, Chi-Fai; Chiu, Peter K F; Lau, Kin-Mang; Ng, Maggie C Y; Gulcher, Jeffrey R; Kong, Augustine; Catalona, William J; Mayordomo, Jose I; Einarsson, Gudmundur V; Barkardottir, Rosa B; Jonsson, Eirikur; Mates, Dana; Neal, David E; Kiemeney, Lambertus A; Thorsteinsdottir, Unnur; Rafnar, Thorunn; Stefansson, Kari

    2012-12-01

    In Western countries, prostate cancer is the most prevalent cancer of men and one of the leading causes of cancer-related death in men. Several genome-wide association studies have yielded numerous common variants conferring risk of prostate cancer. Here, we analyzed 32.5 million variants discovered by whole-genome sequencing 1,795 Icelanders. We identified a new low-frequency variant at 8q24 associated with prostate cancer in European populations, rs188140481[A] (odds ratio (OR) = 2.90; P(combined) = 6.2 × 10(-34)), with an average risk allele frequency in controls of 0.54%. This variant is only very weakly correlated (r(2) ≤ 0.06) with previously reported risk variants at 8q24, and its association remains significant after adjustment for all known risk-associated variants. Carriers of rs188140481[A] were diagnosed with prostate cancer 1.26 years younger than non-carriers (P = 0.0059). We also report results for a previously described HOXB13 variant (rs138213197[T]), confirming it as a prostate cancer risk variant in populations from across Europe.

  10. Genomic structure of the human BCCIP gene and its expression in cancer.

    Science.gov (United States)

    Meng, Xiangbing; Liu, Jingmei; Shen, Zhiyuan

    2003-01-02

    Human BCCIPalpha (Tok-1alpha) is a BRCA2 and CDKN1A (Cip1, p21) interacting protein. Our previous studies have showed that overexpression of BCCIPalpha inhibits the growth of certain tumor cells [Oncogene 20 (2001) 336]. In this study, we report the genomic structure of the human BCCIP gene, which contains nine exons. Alternative splicing of the 3'-terminal exons produces two isoforms of BCCIP transcripts, BCCIPalpha and BCCIPbeta. The BCCIP gene is flanked by two genes that are transcribed in the opposite orientation of the BCCIP gene. It lies head-to-head and shares a bi-directional promoter with the uroporphyrinogen III synthase (UROS) gene. The last three exons of BCCIP gene overlap the 3'-terminal seven exons of a DEAD/H helicase-like gene (DDX32). Using a matched normal/tumor cDNA array, we identified a reduced expression of BCCIP in kidney tumor, suggesting a role of BCCIP in cancer etiology.

  11. An Integrated Genome-Wide Systems Genetics Screen for Breast Cancer Metastasis Susceptibility Genes.

    Directory of Open Access Journals (Sweden)

    Ling Bai

    2016-04-01

    Full Text Available Metastasis remains the primary cause of patient morbidity and mortality in solid tumors and is due to the action of a large number of tumor-autonomous and non-autonomous factors. Here we report the results of a genome-wide integrated strategy to identify novel metastasis susceptibility candidate genes and molecular pathways in breast cancer metastasis. This analysis implicates a number of transcriptional regulators and suggests cell-mediated immunity is an important determinant. Moreover, the analysis identified novel or FDA-approved drugs as potentially useful for anti-metastatic therapy. Further explorations implementing this strategy may therefore provide a variety of information for clinical applications in the control and treatment of advanced neoplastic disease.

  12. Genomic hallmarks of genes involved in chromosomal translocations in hematological cancer.

    Directory of Open Access Journals (Sweden)

    Mikhail Shugay

    Full Text Available Reciprocal chromosomal translocations (RCTs leading to the formation of fusion genes are important drivers of hematological cancers. Although the general requirements for breakage and fusion are fairly well understood, quantitative support for a general mechanism of RCT formation is still lacking. The aim of this paper is to analyze available high-throughput datasets with computational and robust statistical methods, in order to identify genomic hallmarks of translocation partner genes (TPGs. Our results show that fusion genes are generally overexpressed due to increased promoter activity of 5' TPGs and to more stable 3'-UTR regions of 3' TPGs. Furthermore, expression profiling of 5' TPGs and of interaction partners of 3' TPGs indicates that these features can help to explain tissue specificity of hematological translocations. Analysis of protein domains retained in fusion proteins shows that the co-occurrence of specific domain combinations is non-random and that distinct functional classes of fusion proteins tend to be associated with different components of the gene fusion network. This indicates that the configuration of fusion proteins plays an important role in determining which 5' and 3' TPGs will combine in specific fusion genes. It is generally accepted that chromosomal proximity in the nucleus can explain the specific pairing of 5' and 3' TPGS and the recurrence of hematological translocations. Using recently available data for chromosomal contact probabilities (Hi-C we show that TPGs are preferentially located in early replicated regions and occupy distinct clusters in the nucleus. However, our data suggest that, in general, nuclear position of TPGs in hematological cancers explains neither TPG pairing nor clinical frequency. Taken together, our results support a model in which genomic features related to regulation of expression and replication timing determine the set of candidate genes more likely to be translocated in

  13. Microsatellite genotyping reveals a signature in breast cancer exomes.

    Science.gov (United States)

    McIver, L J; Fonville, N C; Karunasena, E; Garner, H R

    2014-06-01

    Genomic instability at microsatellite loci is a hallmark of many cancers, including breast cancer. However, much of the genomic variation and many of the hereditary components responsible for breast cancer remain undetected. We hypothesized that variation at microsatellites could provide additional genomic markers for breast cancer risk assessment. A total of 1,345 germline and tumor DNA samples from individuals diagnosed with breast cancer, exome sequenced as part of The Cancer Genome Atlas, were analyzed for microsatellite variation. The comparison group for our analysis, representing healthy individuals, consisted of 249 females which were exome sequenced as part of the 1,000 Genomes Project. We applied our microsatellite-based genotyping pipeline to identify 55 microsatellite loci that can distinguish between the germline of individuals diagnosed with breast cancer and healthy individuals with a sensitivity of 88.4 % and a specificity of 77.1 %. Further, we identified additional microsatellite loci that are potentially useful for distinguishing between breast cancer subtypes, revealing a possible fifth subtype. These findings are of clinical interest as possible risk diagnostics and reveal genes that may be of potential therapeutic value, including genes previously not associated with breast cancer.

  14. Genetic profiles of gastroesophageal cancer: combined analysis using expression array and tiling array--comparative genomic hybridization

    DEFF Research Database (Denmark)

    Isinger-Ekstrand, Anna; Johansson, Jan; Ohlsson, Mattias

    2010-01-01

    We aimed to characterize the genomic profiles of adenocarcinomas in the gastroesophageal junction in relation to cancers in the esophagus and the stomach. Profiles of gains/losses as well as gene expression profiles were obtained from 27 gastroesophageal adenocarcinomas by means of 32k high......15, 13q34, and 12q13, whereas different profiles with gains at 5p15, 7p22, 2q35, and 13q34 characterized gastric cancers. CDK6 and EGFR were identified as putative target genes in cancers of the esophagus and the gastroesophageal junction, with upregulation in one quarter of the tumors. Gains....../losses and gene expression profiles show strong similarity between cancers in the distal esophagus and the gastroesophageal junction with frequent upregulation of CDK6 and EGFR, whereas gastric cancer displays distinct genetic changes. These data suggest that molecular diagnostics and targeted therapies can...

  15. Integrated genome and transcriptome sequencing identifies a novel form of hybrid and aggressive prostate cancer.

    Science.gov (United States)

    Wu, Chunxiao; Wyatt, Alexander W; Lapuk, Anna V; McPherson, Andrew; McConeghy, Brian J; Bell, Robert H; Anderson, Shawn; Haegert, Anne; Brahmbhatt, Sonal; Shukin, Robert; Mo, Fan; Li, Estelle; Fazli, Ladan; Hurtado-Coll, Antonio; Jones, Edward C; Butterfield, Yaron S; Hach, Faraz; Hormozdiari, Fereydoun; Hajirasouliha, Iman; Boutros, Paul C; Bristow, Robert G; Jones, Steven Jm; Hirst, Martin; Marra, Marco A; Maher, Christopher A; Chinnaiyan, Arul M; Sahinalp, S Cenk; Gleave, Martin E; Volik, Stanislav V; Collins, Colin C

    2012-05-01

    Next-generation sequencing is making sequence-based molecular pathology and personalized oncology viable. We selected an individual initially diagnosed with conventional but aggressive prostate adenocarcinoma and sequenced the genome and transcriptome from primary and metastatic tissues collected prior to hormone therapy. The histology-pathology and copy number profiles were remarkably homogeneous, yet it was possible to propose the quadrant of the prostate tumour that likely seeded the metastatic diaspora. Despite a homogeneous cell type, our transcriptome analysis revealed signatures of both luminal and neuroendocrine cell types. Remarkably, the repertoire of expressed but apparently private gene fusions, including C15orf21:MYC, recapitulated this biology. We hypothesize that the amplification and over-expression of the stem cell gene MSI2 may have contributed to the stable hybrid cellular identity. This hybrid luminal-neuroendocrine tumour appears to represent a novel and highly aggressive case of prostate cancer with unique biological features and, conceivably, a propensity for rapid progression to castrate-resistance. Overall, this work highlights the importance of integrated analyses of genome, exome and transcriptome sequences for basic tumour biology, sequence-based molecular pathology and personalized oncology.

  16. Bloom syndrome, genomic instability and cancer: the SOS-like hypothesis.

    Science.gov (United States)

    Amor-Guéret, Mounira

    2006-05-08

    Bloom syndrome (BS) displays one of the strongest known correlations between chromosomal instability and an increased risk of malignancy at an early age. The prevention of genomic instability and cancer depends on a complex network of pathways induced in response to DNA damage and stalled replication forks, including cell-cycle checkpoints, DNA repair, and apoptosis. Several studies have demonstrated that BLM is involved in the cellular response to DNA damage and stalled replication forks. BLM interacts physically and functionally with several proteins involved in the maintenance of genome integrity and BLM is redistributed and/or phosphorylated in response to several genotoxic stresses. The data concerning the relationship between BLM and these cellular pathways are summarized and the role of BLM in the rescue of arrested replication forks is discussed. Moreover, I speculate that BLM deficiency is lethal, and that BLM-deficient cells escaping apoptotic death do so by constitutively inducing a bacterial SOS-like response including the induction of alternative replication pathway(s) dependent on recombination, contributing to the mutator and hyper-Rec phenotypes characteristic of BS cells. This mechanism may be dependent on the RAD51 gene family, and involved in carcinogenesis in the general population.

  17. European American stratification in ovarian cancer case control data: the utility of genome-wide data for inferring ancestry.

    Directory of Open Access Journals (Sweden)

    Paola Raska

    Full Text Available We investigated the ability of several principal components analysis (PCA-based strategies to detect and control for population stratification using data from a multi-center study of epithelial ovarian cancer among women of European-American ethnicity. These include a correction based on an ancestry informative markers (AIMs panel designed to capture European ancestral variation and corrections utilizing un-thinned genome-wide SNP data; case-control samples were drawn from four geographically distinct North-American sites. The AIMs-only and genome-wide first principal components (PC1 both corresponded to the previously described North or Northwest-Southeast axis of European variation. We found that the genome-wide PCA captured this primary dimension of variation more precisely and identified additional axes of genome-wide variation of relevance to epithelial ovarian cancer. Associations evident between the genome-wide PCs and study site corroborate North American immigration history and suggest that undiscovered dimensions of variation lie within Northern Europe. The structure captured by the genome-wide PCA was also found within control individuals and did not reflect the case-control variation present in the data. The genome-wide PCA highlighted three regions of local LD, corresponding to the lactase (LCT gene on chromosome 2, the human leukocyte antigen system (HLA on chromosome 6 and to a common inversion polymorphism on chromosome 8. These features did not compromise the efficacy of PCs from this analysis for ancestry control. This study concludes that although AIMs panels are a cost-effective way of capturing population structure, genome-wide data should preferably be used when available.

  18. Tiling array-CGH for the assessment of genomic similarities among synchronous unilateral and bilateral invasive breast cancer tumor pairs

    Directory of Open Access Journals (Sweden)

    Ringnér Markus

    2008-07-01

    Full Text Available Abstract Background Today, no objective criteria exist to differentiate between individual primary tumors and intra- or intermammary dissemination respectively, in patients diagnosed with two or more synchronous breast cancers. To elucidate whether these tumors most likely arise through clonal expansion, or whether they represent individual primary tumors is of tumor biological interest and may have clinical implications. In this respect, high resolution genomic profiling may provide a more reliable approach than conventional histopathological and tumor biological factors. Methods 32 K tiling microarray-based comparative genomic hybridization (aCGH was used to explore the genomic similarities among synchronous unilateral and bilateral invasive breast cancer tumor pairs, and was compared with histopathological and tumor biological parameters. Results Based on global copy number profiles and unsupervised hierarchical clustering, five of ten (p = 1.9 × 10-5 unilateral tumor pairs displayed similar genomic profiles within the pair, while only one of eight bilateral tumor pairs (p = 0.29 displayed pair-wise genomic similarities. DNA index, histological type and presence of vessel invasion correlated with the genomic analyses. Conclusion Synchronous unilateral tumor pairs are often genomically similar, while synchronous bilateral tumors most often represent individual primary tumors. However, two independent unilateral primary tumors can develop synchronously and contralateral tumor spread can occur. The presence of an intraductal component is not informative when establishing the independence of two tumors, while vessel invasion, the presence of which was found in clustering tumor pairs but not in tumor pairs that did not cluster together, supports the clustering outcome. Our data suggest that genomically similar unilateral tumor pairs may represent a more aggressive disease that requires the addition of more severe treatment modalities, and

  19. Analysis of segmental duplications, mouse genome synteny and recurrent cancer-associated amplicons in human chromosome 6p21-p12.

    Science.gov (United States)

    Martin, J W; Yoshimoto, M; Ludkovski, O; Thorner, P S; Zielenska, M; Squire, J A; Nuin, P A S

    2010-06-01

    It has been proposed that regions of microhomology in the human genome could facilitate genomic rearrangements, copy number transitions, and rapid genomic change during tumor progression. To investigate this idea, this study examines the role of repetitive sequence elements, and corresponding syntenic mouse genomic features, in targeting cancer-associated genomic instability of specific regions of the human genome. Automated database-mining algorithms designed to search for frequent copy number transitions and genomic breakpoints were applied to 2 publicly-available online databases and revealed that 6p21-p12 is one of the regions of the human genome most frequently involved in tumor-specific alterations. In these analyses, 6p21-p12 exhibited the highest frequency of genomic amplification in osteosarcomas. Analysis of repetitive elements in regions of homology between human chromosome 6p and the syntenic regions of the mouse genome revealed a strong association between the location of segmental duplications greater than 5 kilobase-pairs and the position of discontinuities at the end of the syntenic region. The presence of clusters of segmental duplications flanking these syntenic regions also correlated with a high frequency of amplification and genomic alteration. Collectively, the experimental findings, in silico analyses, and comparative genomic studies presented here suggest that segmental duplications may facilitate cancer-associated copy number transitions and rearrangements at chromosome 6p21-p12. This process may involve homology-dependent DNA recombination and/or repair, which may also contribute towards the overall plasticity of the human genome.

  20. Breast cancer genome and transcriptome integration implicates specific mutational signatures with immune cell infiltration.

    Science.gov (United States)

    Smid, Marcel; Rodríguez-González, F Germán; Sieuwerts, Anieta M; Salgado, Roberto; Prager-Van der Smissen, Wendy J C; Vlugt-Daane, Michelle van der; van Galen, Anne; Nik-Zainal, Serena; Staaf, Johan; Brinkman, Arie B; van de Vijver, Marc J; Richardson, Andrea L; Fatima, Aquila; Berentsen, Kim; Butler, Adam; Martin, Sancha; Davies, Helen R; Debets, Reno; Gelder, Marion E Meijer-Van; van Deurzen, Carolien H M; MacGrogan, Gaëtan; Van den Eynden, Gert G G M; Purdie, Colin; Thompson, Alastair M; Caldas, Carlos; Span, Paul N; Simpson, Peter T; Lakhani, Sunil R; Van Laere, Steven; Desmedt, Christine; Ringnér, Markus; Tommasi, Stefania; Eyford, Jorunn; Broeks, Annegien; Vincent-Salomon, Anne; Futreal, P Andrew; Knappskog, Stian; King, Tari; Thomas, Gilles; Viari, Alain; Langerød, Anita; Børresen-Dale, Anne-Lise; Birney, Ewan; Stunnenberg, Hendrik G; Stratton, Mike; Foekens, John A; Martens, John W M

    2016-09-26

    A recent comprehensive whole genome analysis of a large breast cancer cohort was used to link known and novel drivers and substitution signatures to the transcriptome of 266 cases. Here, we validate that subtype-specific aberrations show concordant expression changes for, for example, TP53, PIK3CA, PTEN, CCND1 and CDH1. We find that CCND3 expression levels do not correlate with amplification, while increased GATA3 expression in mutant GATA3 cancers suggests GATA3 is an oncogene. In luminal cases the total number of substitutions, irrespective of type, associates with cell cycle gene expression and adverse outcome, whereas the number of mutations of signatures 3 and 13 associates with immune-response specific gene expression, increased numbers of tumour-infiltrating lymphocytes and better outcome. Thus, while earlier reports imply that the sheer number of somatic aberrations could trigger an immune-response, our data suggests that substitutions of a particular type are more effective in doing so than others.

  1. Genome-wide transcriptional effects of the anti-cancer agent camptothecin.

    Directory of Open Access Journals (Sweden)

    Artur Veloso

    Full Text Available The anti-cancer drug camptothecin inhibits replication and transcription by trapping DNA topoisomerase I (Top1 covalently to DNA in a "cleavable complex". To examine the effects of camptothecin on RNA synthesis genome-wide we used Bru-Seq and show that camptothecin treatment primarily affected transcription elongation. We also observed that camptothecin increased RNA reads past transcription termination sites as well as at enhancer elements. Following removal of camptothecin, transcription spread as a wave from the 5'-end of genes with no recovery of transcription apparent from RNA polymerases stalled in the body of genes. As a result, camptothecin preferentially inhibited the expression of large genes such as proto-oncogenes, and anti-apoptotic genes while smaller ribosomal protein genes, pro-apoptotic genes and p53 target genes showed relative higher expression. Cockayne syndrome group B fibroblasts (CS-B, which are defective in transcription-coupled repair (TCR, showed an RNA synthesis recovery profile similar to normal fibroblasts suggesting that TCR is not involved in the repair of or RNA synthesis recovery from transcription-blocking Top1 lesions. These findings of the effects of camptothecin on transcription have important implications for its anti-cancer activities and may aid in the design of improved combinatorial treatments involving Top1 poisons.

  2. Whole-genome sequencing analysis of phenotypic heterogeneity and anticipation in Li-Fraumeni cancer predisposition syndrome.

    Science.gov (United States)

    Ariffin, Hany; Hainaut, Pierre; Puzio-Kuter, Anna; Choong, Soo Sin; Chan, Adelyne Sue Li; Tolkunov, Denis; Rajagopal, Gunaretnam; Kang, Wenfeng; Lim, Leon Li Wen; Krishnan, Shekhar; Chen, Kok-Siong; Achatz, Maria Isabel; Karsa, Mawar; Shamsani, Jannah; Levine, Arnold J; Chan, Chang S

    2014-10-28

    The Li-Fraumeni syndrome (LFS) and its variant form (LFL) is a familial predisposition to multiple forms of childhood, adolescent, and adult cancers associated with germ-line mutation in the TP53 tumor suppressor gene. Individual disparities in tumor patterns are compounded by acceleration of cancer onset with successive generations. It has been suggested that this apparent anticipation pattern may result from germ-line genomic instability in TP53 mutation carriers, causing increased DNA copy-number variations (CNVs) with successive generations. To address the genetic basis of phenotypic disparities of LFS/LFL, we performed whole-genome sequencing (WGS) of 13 subjects from two generations of an LFS kindred. Neither de novo CNV nor significant difference in total CNV was detected in relation with successive generations or with age at cancer onset. These observations were consistent with an experimental mouse model system showing that trp53 deficiency in the germ line of father or mother did not increase CNV occurrence in the offspring. On the other hand, individual records on 1,771 TP53 mutation carriers from 294 pedigrees were compiled to assess genetic anticipation patterns (International Agency for Research on Cancer TP53 database). No strictly defined anticipation pattern was observed. Rather, in multigeneration families, cancer onset was delayed in older compared with recent generations. These observations support an alternative model for apparent anticipation in which rare variants from noncarrier parents may attenuate constitutive resistance to tumorigenesis in the offspring of TP53 mutation carriers with late cancer onset.

  3. Somatic mutations throughout the entire mitochondrial genome are associated with elevated PSA levels in prostate cancer patients.

    Science.gov (United States)

    Kloss-Brandstätter, Anita; Schäfer, Georg; Erhart, Gertraud; Hüttenhofer, Alexander; Coassin, Stefan; Seifarth, Christof; Summerer, Monika; Bektic, Jasmin; Klocker, Helmut; Kronenberg, Florian

    2010-12-10

    The genetic etiology of prostate cancer, the most common form of male cancer in western countries, is complex and the interplay of disease genes with environmental factors is far from being understood. Studies on somatic mitochondrial DNA (mtDNA) mutations have become an important aspect of cancer research because these mutations might have functional consequences and/or might serve as biosensors for tumor detection and progression. We sequenced the entire mitochondrial genome (16,569 bp) from 30 prospectively collected pairs of macrodissected cancerous and benign cells from prostate cancer patients and compared their genetic variability. Given recent concerns regarding the authenticity of newly discovered mtDNA mutations, we implemented a high-quality procedure for mtDNA whole-genome sequencing. In addition, the mitochondrial genes MT-CO2, MT-CO3, MT-ATP6, and MT-ND6 were sequenced in further 35 paired samples from prostate cancer patients. We identified a total of 41 somatic mutations in 22 out of 30 patients: the majority of these mutations have not previously been observed in the human phylogeny. The presence of somatic mutations in transfer RNAs (tRNAs) was found to be associated with elevated PSA levels (14.25 ± 5.44 versus 7.15 ± 4.32 ng/ml; p = 0.004). The level and degree of heteroplasmy increased with increasing tumor activity. In summary, somatic mutations in the mitochondrial genome are frequent events in prostate cancer. Mutations mapping to mitochondrial tRNAs, ribosomal RNAs, and protein coding genes might impair processes that occur within the mitochondrial compartment (e.g., transcription, RNA processing, and translation) and might finally affect oxidative phosphorylation.

  4. Contouring Guidelines for the Axillary Lymph Nodes for the Delivery of Radiation Therapy in Breast Cancer: Evaluation of the RTOG Breast Cancer Atlas

    Energy Technology Data Exchange (ETDEWEB)

    Gentile, Michelle S. [Department of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois (United States); Usman, Asad A.; Neuschler, Erin I. [Department of Radiology, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois (United States); Sathiaseelan, Vythialinga; Hayes, John P. [Department of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois (United States); Small, William, E-mail: WMSMALL@lumc.edu [Department of Radiation Oncology, Loyola University, Chicago, Illinois (United States)

    2015-10-01

    Purpose: The purpose of this study was to identify the axillary lymph nodes on pretreatment diagnostic computed tomography (CT) of the chest to determine their position relative to the anatomic axillary borders as defined by the Radiation Therapy Oncology Group (RTOG) breast cancer atlas for radiation therapy planning. Methods and Materials: Pretreatment diagnostic CT chest scans available for 30 breast cancer patients with clinically involved lymph nodes were fused with simulation CT. Contouring of axillary levels I, II, and III according to the RTOG guidelines was performed. Measurements were made from the area of distal tumor to the anatomic borders in 6 dimensions for each level. Results: Of the 30 patients, 100%, 93%, and 37% had clinical involvement of levels I, II, and III, respectively. The mean number of lymph nodes dissected was 13.6. The mean size of the largest lymph node was 2.4 cm. Extracapsular extension was seen in 23% of patients. In 97% of patients, an aspect of the involved lymph node lay outside of the anatomic border of a level. In 80% and 83% of patients, tumor extension was seen outside the cranial (1.78 ± 1.0 cm; range, 0.28-3.58 cm) and anterior (1.27 ± 0.92 cm; range, 0.24-3.58 cm) borders of level I, respectively. In 80% of patients, tumor extension was seen outside the caudal border of level II (1.36 ± 1.0 cm, range, 0.27-3.86 cm), and 0% to 33% of patients had tumor extension outside the remaining borders of all levels. Conclusions: To cover 95% of lymph nodes at the cranial and anterior borders of level I, an additional clinical target volume margin of 3.78 cm and 3.11 cm, respectively, is necessary. The RTOG guidelines may be insufficient for coverage of axillary disease in patients with clinical nodal involvement who are undergoing neoadjuvant chemotherapy, incomplete axillary dissection, or treatment with intensity modulated radiation therapy. In patients with pretreatment diagnostic CT chest scans, fusion with