WorldWideScience

Sample records for cancer genome anatomy

  1. 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.

  2. 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.

  3. Anatomy of a Cancer Treatment Scam

    Medline Plus

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  4. Anatomy of a Cancer Treatment Scam

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  5. Anatomy of a Cancer Treatment Scam

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  6. Anatomy of a Cancer Treatment Scam

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  8. Anatomy of a Cancer Treatment Scam

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  9. 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...

  10. The teleost anatomy ontology: anatomical representation for the genomics age.

    Science.gov (United States)

    Dahdul, Wasila M; Lundberg, John G; Midford, Peter E; Balhoff, James P; Lapp, Hilmar; Vision, Todd J; Haendel, Melissa A; Westerfield, Monte; Mabee, Paula M

    2010-07-01

    The rich knowledge of morphological variation among organisms reported in the systematic literature has remained in free-text format, impractical for use in large-scale synthetic phylogenetic work. This noncomputable format has also precluded linkage to the large knowledgebase of genomic, genetic, developmental, and phenotype data in model organism databases. We have undertaken an effort to prototype a curated, ontology-based evolutionary morphology database that maps to these genetic databases (http://kb.phenoscape.org) to facilitate investigation into the mechanistic basis and evolution of phenotypic diversity. Among the first requirements in establishing this database was the development of a multispecies anatomy ontology with the goal of capturing anatomical data in a systematic and computable manner. An ontology is a formal representation of a set of concepts with defined relationships between those concepts. Multispecies anatomy ontologies in particular are an efficient way to represent the diversity of morphological structures in a clade of organisms, but they present challenges in their development relative to single-species anatomy ontologies. Here, we describe the Teleost Anatomy Ontology (TAO), a multispecies anatomy ontology for teleost fishes derived from the Zebrafish Anatomical Ontology (ZFA) for the purpose of annotating varying morphological features across species. To facilitate interoperability with other anatomy ontologies, TAO uses the Common Anatomy Reference Ontology as a template for its upper level nodes, and TAO and ZFA are synchronized, with zebrafish terms specified as subtypes of teleost terms. We found that the details of ontology architecture have ramifications for querying, and we present general challenges in developing a multispecies anatomy ontology, including refinement of definitions, taxon-specific relationships among terms, and representation of taxonomically variable developmental pathways. PMID:20547776

  11. A transcriptome anatomy of human colorectal cancers

    International Nuclear Information System (INIS)

    Accumulating databases in human genome research have enabled integrated genome-wide study on complicated diseases such as cancers. A practical approach is to mine a global transcriptome profile of disease from public database. New concepts of these diseases might emerge by landscaping this profile. In this study, we clustered human colorectal normal mucosa (N), inflammatory bowel disease (IBD), adenoma (A) and cancer (T) related expression sequence tags (EST) into UniGenes via an in-house GetUni software package and analyzed the transcriptome overview of these libraries by GOTree Machine (GOTM). Additionally, we downloaded UniGene based cDNA libraries of colon and analyzed them by Xprofiler to cross validate the efficiency of GetUni. Semi-quantitative RT-PCR was used to validate the expression of β-catenin and. 7 novel genes in colorectal cancers. The efficiency of GetUni was successfully validated by Xprofiler and RT-PCR. Genes in library N, IBD and A were all found in library T. A total of 14,879 genes were identified with 2,355 of them having at least 2 transcripts. Differences in gene enrichment among these libraries were statistically significant in 50 signal transduction pathways and Pfam protein domains by GOTM analysis P < 0.01 Hypergeometric Test). Genes in two metabolic pathways, ribosome and glycolysis, were more enriched in the expression profiles of A and IBD than in N and T. Seven transmembrane receptor superfamily genes were typically abundant in cancers. Colorectal cancers are genetically heterogeneous. Transcription variants are common in them. Aberrations of ribosome and glycolysis pathway might be early indicators of precursor lesions in colon cancers. The electronic gene expression profile could be used to highlight the integral molecular events in colorectal cancers

  12. Center for Cancer Genomics | Office of Cancer Genomics

    Science.gov (United States)

    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

  13. Genomic Data Commons | Office of Cancer Genomics

    Science.gov (United States)

    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. Anatomy & Physiology

    Science.gov (United States)

    ... Surveillance Modules » Anatomy & Physiology Cancer Registration & Surveillance Modules Anatomy & Physiology Intro to the Human Body Body Functions & Life Process Anatomical Terminology Review ...

  15. The Cancer Genome Atlas ovarian cancer analysis

    Science.gov (United States)

    An analysis of genomic changes in ovarian cancer has provided the most comprehensive and integrated view of cancer genes for any cancer type to date. Ovarian serous adenocarcinoma tumors from 500 patients were examined by The Cancer Genome Atlas (TCGA) Re

  16. Collaborators | Office of Cancer Genomics

    Science.gov (United States)

    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.

  17. Anatomy of a Cancer Treatment Scam

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  18. Anatomy of a Cancer Treatment Scam

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  20. Anatomy of a Cancer Treatment Scam

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  1. Evolution of the cancer genome

    OpenAIRE

    Yates, Lucy R.; Campbell, Peter J

    2012-01-01

    The advent of massively parallel sequencing technologies has allowed the characterization of cancer genomes at an unprecedented resolution. Investigation of the mutational landscape of tumours is providing new insights into cancer genome evolution, laying bare the interplay of somatic mutation, adaptation of clones to their environment and natural selection. These studies have demonstrated the extent of the heterogeneity of cancer genomes, have allowed inferences to be made about the forces t...

  2. 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:

  3. Genomic Datasets for Cancer Research

    Science.gov (United States)

    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.

  4. Genomics: Drugs, diabetes and cancer

    OpenAIRE

    Birnbaum, Morris J.; Shaw, Reuben J

    2011-01-01

    Variation in a genomic region that contains the cancer-a ssociated gene ATM affects a patient’s response to the diabetes drug metformin. Two experts discuss the implications for understanding diabetes and the link to cancer.

  5. Contact | Office of Cancer Genomics

    Science.gov (United States)

    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*

  6. Epigenomics Reveals a Functional Genome Anatomy and a New Approach to Common Disease

    OpenAIRE

    Feinberg, Andrew P

    2010-01-01

    Standfirst header Epigenomics provides the functional context of genome sequence, analogous to the functional anatomy of the human body provided by Vesalius a half millennium ago. Much of what appear to be inconclusive genetic data for common disease could therefore become meaningful in an epigenomic context.

  7. 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

  8. 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.

  9. The mouse–human anatomy ontology mapping project

    OpenAIRE

    Hayamizu, Terry F.; de Coronado, Sherri; Fragoso, Gilberto; Sioutos, Nicholas; Kadin, James A.; Ringwald, Martin

    2012-01-01

    The overall objective of the Mouse–Human Anatomy Project (MHAP) was to facilitate the mapping and harmonization of anatomical terms used for mouse and human models by Mouse Genome Informatics (MGI) and the National Cancer Institute (NCI). The anatomy resources designated for this study were the Adult Mouse Anatomy (MA) ontology and the set of anatomy concepts contained in the NCI Thesaurus (NCIt). Several methods and software tools were identified and evaluated, then used to conduct an in-dep...

  10. 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.

  11. International network of cancer genome projects.

    OpenAIRE

    Aretz, Axel; Bernabé, Rosa R.; Eerola, Iiro; Hemsley, Fiona M.; Jennings, Jennifer L.; Kerr, David; Klatt, Peter; Kolar, Patrik; Lane, David P; Laplace, Frank; Nettekoven, Gerd; Remacle, Jacques; WATANABE, Koichi; Yuen, Matthew M. F.; Knoppers, Bartha M.

    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, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeut...

  12. Clinical Implications of the Cancer Genome

    OpenAIRE

    MacConaill, Laura E; Garraway, Levi A

    2010-01-01

    Cancer is a disease of the genome. Most tumors harbor a constellation of structural genomic alterations that may dictate their clinical behavior and treatment response. Whereas elucidating the nature and importance of these genomic alterations has been the goal of cancer biologists for several decades, ongoing global genome characterization efforts are revolutionizing both tumor biology and the optimal paradigm for cancer treatment at an unprecedented scope. The pace of advance has been empow...

  13. Integration of genomics in cancer care

    DEFF Research Database (Denmark)

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

    2013-01-01

    PURPOSE: The article aims to introduce nurses to how genetics-genomics is currently integrated into cancer care from prevention to treatment and influencing oncology nursing practice. ORGANIZING CONSTRUCT: An overview of genetics-genomics is described as it relates to cancer etiology, hereditary...... 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......: Rapidly developing advances in genetics-genomics are changing all aspects of cancer care, with implications for nursing practice. CLINICAL RELEVANCE: Nurses can educate cancer patients and their families about genetic-genomic advances and advocate for use of evidence-based genetic-genomic practice...

  14. 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 ...

  15. 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.

  16. Genomic tumor evolution of breast cancer.

    Science.gov (United States)

    Sato, Fumiaki; Saji, Shigehira; Toi, Masakazu

    2016-01-01

    Owing to recent technical development of comprehensive genome-wide analysis such as next generation sequencing, deep biological insights of breast cancer have been revealed. Information of genomic mutations and rearrangements in patients' tumors is indispensable to understand the mechanism in carcinogenesis, progression, metastasis, and resistance to systemic treatment of breast cancer. To date, comprehensive genomic analyses illustrate not only base substitution patterns and lists of driver mutations and key rearrangements, but also a manner of tumor evolution. Breast cancer genome is dynamically changing and evolving during cancer development course from non-invasive disease via invasive primary tumor to metastatic tumor, and during treatment exposure. The accumulation pattern of base substitution and genomic rearrangement looks gradual and punctuated, respectively, in analogy with contrasting theories for evolution manner of species, Darwin's phyletic gradualism, and Eldredge and Gould's "punctuated equilibrium". Liquid biopsy is a non-invasive method to detect the genomic evolution of breast cancer. Genomic mutation patterns in circulating tumor cells and circulating cell-free tumor DNA represent those of tumors existing in patient body. Liquid biopsy methods are now under development for future application to clinical practice of cancer treatment. In this article, latest knowledge regarding breast cancer genome, especially in terms of 'tumor evolution', is summarized. PMID:25998191

  17. Functional genomics and cancer drug target discovery.

    Science.gov (United States)

    Moody, Susan E; Boehm, Jesse S; Barbie, David A; Hahn, William C

    2010-06-01

    The recent development of technologies for whole-genome sequencing, copy number analysis and expression profiling enables the generation of comprehensive descriptions of cancer genomes. However, although the structural analysis and expression profiling of tumors and cancer cell lines can allow the identification of candidate molecules that are altered in the malignant state, functional analyses are necessary to confirm such genes as oncogenes or tumor suppressors. Moreover, recent research suggests that tumor cells also depend on synthetic lethal targets, which are not mutated or amplified in cancer genomes; functional genomics screening can facilitate the discovery of such targets. This review provides an overview of the tools available for the study of functional genomics, and discusses recent research involving the use of these tools to identify potential novel drug targets in cancer. PMID:20521217

  18. Characterizing the cancer genome in lung adenocarcinoma

    OpenAIRE

    Weir, Barbara A.; Woo, Michele S.; Getz, Gad; Perner, Sven; Ding, Li; Beroukhim, Rameen; Lin, William M.; Province, Michael A; Kraja, Aldi; Johnson, Laura A.; Shah, Kinjal; Sato, Mitsuo; Thomas, Roman K.; Barletta, Justine A; Borecki, Ingrid B

    2007-01-01

    Somatic alterations in cellular DNA underlie almost all human cancers1. The prospect of targeted therapies2 and the development of high-resolution, genome-wide approaches3–8 are now spurring systematic efforts to characterize cancer genomes. Here we report a large-scale project to characterize copy-number alterations in primary lung adenocarcinomas. By analysis of a large collection of tumors (n = 371) using dense single nucleotide polymorphism arrays, we identify a total of 57 significantly ...

  19. 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.

  20. 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.

  1. Genomic Biomarkers for Breast Cancer Risk.

    Science.gov (United States)

    Walsh, Michael F; Nathanson, Katherine L; Couch, Fergus J; Offit, Kenneth

    2016-01-01

    Clinical risk assessment for cancer predisposition includes a three-generation pedigree and physical examination to identify inherited syndromes. Additionally genetic and genomic biomarkers may identify individuals with a constitutional basis for their disease that may not be evident clinically. Genomic biomarker testing may detect molecular variations in single genes, panels of genes, or entire genomes. The strength of evidence for the association of a genomic biomarker with disease risk may be weak or strong. The factors contributing to clinical validity and utility of genomic biomarkers include functional laboratory analyses and genetic epidemiologic evidence. Genomic biomarkers may be further classified as low, moderate or highly penetrant based on the likelihood of disease. Genomic biomarkers for breast cancer are comprised of rare highly penetrant mutations of genes such as BRCA1 or BRCA2, moderately penetrant mutations of genes such as CHEK2, as well as more common genomic variants, including single nucleotide polymorphisms, associated with modest effect sizes. When applied in the context of appropriate counseling and interpretation, identification of genomic biomarkers of inherited risk for breast cancer may decrease morbidity and mortality, allow for definitive prevention through assisted reproduction, and serve as a guide to targeted therapy . PMID:26987529

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

    International Nuclear Information System (INIS)

    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

  3. Cancer Genome Atlas Pan-cancer Analysis Project

    OpenAIRE

    Zhang, Kun; Wang, Hong

    2015-01-01

    Cancer can exhibit different forms depending on the site of origin, cell types, the different forms of genetic mutations which also affect cancer therapeutic effect. Although many genes have been demonstrated to change a direct result of the change in phenotype, however, many cancers lineage complex molecular mechanisms are still not fully elucidated. Therefore, The Cancer Genome Atlas (TCGA) Research Network analyzed a large human tumors, in order to find the molecular changes in DNA, RNA, p...

  4. CTD² Publication Guidelines | Office of Cancer Genomics

    Science.gov (United States)

    The Cancer Target Discovery and Development (CTD2) Network is a “community resource project” supported by the National Cancer Institute’s Office of Cancer Genomics. Members of the Network release data to the broader research community by depositing data into NCI-supported or public databases. Data deposition is NOT equivalent to publishing in a peer-reviewed journal. Unless there is a manuscript associated with a dataset, the Network considers data to be formally unpublished.

  5. 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.

  6. Cancer Genome Atlas Pan-cancer Analysis Project

    Directory of Open Access Journals (Sweden)

    Kun ZHANG

    2015-04-01

    Full Text Available Cancer can exhibit different forms depending on the site of origin, cell types, the different forms of genetic mutations which also affect cancer therapeutic effect. Although many genes have been demonstrated to change a direct result of the change in phenotype, however, many cancers lineage complex molecular mechanisms are still not fully elucidated. Therefore, The Cancer Genome Atlas (TCGA Research Network analyzed a large human tumors, in order to find the molecular changes in DNA, RNA, protein and epigenetic level, The results contain a wealth of data provides us with an opportunity for common, personality and new ideas throughout the cancer lineages form a whole description. Pan-cancer genome program first compares the 12 kinds of cancer types. Analysis of different tumor molecular changes and their functions, will tell us how effective treatment method is applied to a similar phenotype of the tumor.

  7. [Cancer Genome Atlas Pan-cancer Analysis Project].

    Science.gov (United States)

    Zhang, Kun; Wang, Hong

    2015-04-01

    Cancer can exhibit different forms depending on the site of origin, cell types, the different forms of genetic mutations which also affect cancer therapeutic effect. Although many genes have been demonstrated to change a direct result of the change in phenotype, however, many cancers lineage complex molecular mechanisms are still not fully elucidated. Therefore, The Cancer Genome Atlas (TCGA) Research Network analyzed a large human tumors, in order to find the molecular changes in DNA, RNA, protein and epigenetic level, The results contain a wealth of data provides us with an opportunity for common, personality and new ideas throughout the cancer lineages form a whole description. Pan-cancer genome program first compares the 12 kinds of cancer types. Analysis of different tumor molecular changes and their functions, will tell us how effective treatment method is applied to a similar phenotype of the tumor. PMID:25936886

  8. The genomics and genetics of endometrial cancer

    Directory of Open Access Journals (Sweden)

    Bell DW

    2012-03-01

    Full Text Available Andrea J O’Hara,  Daphne W Bell National Human Genome Research Institute, Cancer Genetics Branch, National Institutes of Health, Bethesda, MD, USAAbstract: Most sporadic endometrial cancers (ECs can be histologically classified as endometrioid, serous, or clear cell. Each histotype has a distinct natural history, clinical behavior, and genetic etiology. Endometrioid ECs have an overall favorable prognosis. They are typified by high frequency genomic alterations affecting PIK3CA, PIK3R1, PTEN, KRAS, FGFR2, ARID1A (BAF250a, and CTNNB1 (β-catenin, as well as epigenetic silencing of MLH1 resulting in microsatellite instability. Serous and clear cell ECs are clinically aggressive tumors that are rare at presentation but account for a disproportionate fraction of all endometrial cancer deaths. Serous ECs tend to be aneuploid and are typified by frequent genomic alterations affecting TP53 (p53, PPP2R1A, HER-2/ERBB2, PIK3CA, and PTEN; additionally, they display dysregulation of E-cadherin, p16, cyclin E, and BAF250a. The genetic etiology of clear cell ECs resembles that of serous ECs, but it remains relatively poorly defined. A detailed discussion of the characteristic patterns of genomic alterations that distinguish the three major histotypes of endometrial cancer is reviewed herein.Keywords: endometrial, cancer, genomics, genetics, sporadic

  9. 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

  10. 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.

  11. 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.

  12. 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.

  13. 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

  14. Dr. Marco Marra: Pioneer and Visionary in Cancer Genomics Research | Office of Cancer Genomics

    Science.gov (United States)

    Dr. Marco Marra is a highly distinguished genomics and bioinformatics researcher. He is the Director of Canada’s Michael Smith Genome Sciences Centre at the BC Cancer Agency and holds a faculty position at the University of British Columbia. The Centre is a state-of-the-art sequencing facility in Vancouver, Canada, with a major focus on the study of cancers.  Many of their research projects are undertaken in collaborations with other Canadian and international institutions.

  15. 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.

  16. 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.

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

    OpenAIRE

    Robert C. Millikan, DVM, PhD; Tejinder Rakhra-Burris, MA; Erin Shaughnessy Zuiker, MPH; Debra E. Irwin, PhD, MSPH

    2005-01-01

    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 te...

  18. Resources | Office of Cancer Genomics

    Science.gov (United States)

    OCG provides a variety of scientific and educational resources for both cancer researchers and members of the general public. These resources are divided into the following types: OCG-Supported Resources: Tools, databases, and reagents generated by initiated and completed OCG programs for researchers, educators, and students. (Note: Databases for current OCG programs are available through program-specific data matrices)

  19. TARGET Publication Guidelines | Office of Cancer Genomics

    Science.gov (United States)

    Like other NCI large-scale genomics initiatives, TARGET is a community resource project and data are made available rapidly after validation for use by other researchers. To act in accord with the Fort Lauderdale principles and support the continued prompt public release of large-scale genomic data prior to publication, researchers who plan to prepare manuscripts containing descriptions of TARGET pediatric cancer data that would be of comparable scope to an initial TARGET disease-specific comprehensive, global analysis publication, and journal editors who receive such manuscripts, are stron

  20. MRI anatomy of parametrial extension to better identify local pathways of disease spread in cervical cancer

    Science.gov (United States)

    Valentini, Anna Lia; Gui, Benedetta; Miccò, Maura; Giuliani, Michela; Rodolfino, Elena; Ninivaggi, Valeria; Iacobucci, Marta; Marino, Marzia; Gambacorta, Maria Antonietta; Testa, Antonia Carla; Zannoni, Gian Franco; Bonomo, Lorenzo

    2016-01-01

    This paper highlights an updated anatomy of parametrial extension with emphasis on magnetic resonance imaging (MRI) assessment of disease spread in the parametrium in patients with locally advanced cervical cancer. Pelvic landmarks were identified to assess the anterior and posterior extensions of the parametria, besides the lateral extension, as defined in a previous anatomical study. A series of schematic drawings and MRI images are shown to document the anatomical delineation of disease on MRI, which is crucial not only for correct image-based three-dimensional radiotherapy but also for the surgical oncologist, since neoadjuvant chemoradiotherapy followed by radical surgery is emerging in Europe as a valid alternative to standard chemoradiation. PMID:27165471

  1. 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.

  2. International Cancer Genome Consortium Data Portal--a one-stop shop for cancer genomics data.

    Science.gov (United States)

    Zhang, Junjun; Baran, Joachim; Cros, A; Guberman, Jonathan M; Haider, Syed; Hsu, Jack; Liang, Yong; Rivkin, Elena; Wang, Jianxin; Whitty, Brett; Wong-Erasmus, Marie; Yao, Long; Kasprzyk, Arek

    2011-01-01

    The International Cancer Genome Consortium (ICGC) is a collaborative effort to characterize genomic abnormalities in 50 different cancer types. To make this data available, the ICGC has created the ICGC Data Portal. Powered by the BioMart software, the Data Portal allows each ICGC member institution to manage and maintain its own databases locally, while seamlessly presenting all the data in a single access point for users. The Data Portal currently contains data from 24 cancer projects, including ICGC, The Cancer Genome Atlas (TCGA), Johns Hopkins University, and the Tumor Sequencing Project. It consists of 3478 genomes and 13 cancer types and subtypes. Available open access data types include simple somatic mutations, copy number alterations, structural rearrangements, gene expression, microRNAs, DNA methylation and exon junctions. Additionally, simple germline variations are available as controlled access data. The Data Portal uses a web-based graphical user interface (GUI) to offer researchers multiple ways to quickly and easily search and analyze the available data. The web interface can assist in constructing complicated queries across multiple data sets. Several application programming interfaces are also available for programmatic access. Here we describe the organization, functionality, and capabilities of the ICGC Data Portal. PMID:21930502

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

    Science.gov (United States)

    Gonzalez-Perez, Abel; Mustonen, Ville; Reva, Boris; Ritchie, Graham R.S.; Creixell, Pau; Karchin, Rachel; Vazquez, Miguel; Fink, J. Lynn; Kassahn, Karin S.; Pearson, John V.; Bader, Gary; Boutros, Paul C.; Muthuswamy, Lakshmi; Ouellette, B.F. Francis; Reimand, Jüri; Linding, Rune; Shibata, Tatsuhiro; Valencia, Alfonso; Butler, Adam; Dronov, Serge; Flicek, Paul; Shannon, Nick B.; Carter, Hannah; Ding, Li; Sander, Chris; Stuart, Josh M.; Stein, Lincoln D.; Lopez-Bigas, Nuria

    2014-01-01

    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 drive tumor progression. We present the result 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. PMID:23900255

  4. 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...... 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....

  5. The plant ontology as a tool for comparative plant anatomy and genomic analyses

    Science.gov (United States)

    Plant science is now a major player in the fields of genomics, gene expression analysis, phenomics and metabolomics. Recent advances in sequencing technologies have led to a windfall of data, with new species being added rapidly to the list of species whose genomes have been decoded. The Plant Ontol...

  6. 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.

  7. Perspectives of integrative cancer genomics in next generation sequencing era.

    Science.gov (United States)

    Kwon, So Mee; Cho, Hyunwoo; Choi, Ji Hye; Jee, Byul A; Jo, Yuna; Woo, Hyun Goo

    2012-06-01

    The explosive development of genomics technologies including microarrays and next generation sequencing (NGS) has provided comprehensive maps of cancer genomes, including the expression of mRNAs and microRNAs, DNA copy numbers, sequence variations, and epigenetic changes. These genome-wide profiles of the genetic aberrations could reveal the candidates for diagnostic and/or prognostic biomarkers as well as mechanistic insights into tumor development and progression. Recent efforts to establish the huge cancer genome compendium and integrative omics analyses, so-called "integromics", have extended our understanding on the cancer genome, showing its daunting complexity and heterogeneity. However, the challenges of the structured integration, sharing, and interpretation of the big omics data still remain to be resolved. Here, we review several issues raised in cancer omics data analysis, including NGS, focusing particularly on the study design and analysis strategies. This might be helpful to understand the current trends and strategies of the rapidly evolving cancer genomics research. PMID:23105932

  8. 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.

  9. Identifying driver mutations in sequenced cancer genomes

    DEFF Research Database (Denmark)

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

    2014-01-01

    protein sequence or structure. Finally, we review techniques to identify recurrent combinations of somatic mutations, including approaches that examine mutations in known pathways or protein-interaction networks, as well as de novo approaches that identify combinations of mutations according to......-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......, 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...

  10. Identification of cancer-driver genes in focal genomic alterations from whole genome sequencing data.

    Science.gov (United States)

    Jang, Ho; Hur, Youngmi; Lee, Hyunju

    2016-01-01

    DNA copy number alterations (CNAs) are the main genomic events that occur during the initiation and development of cancer. Distinguishing driver aberrant regions from passenger regions, which might contain candidate target genes for cancer therapies, is an important issue. Several methods for identifying cancer-driver genes from multiple cancer patients have been developed for single nucleotide polymorphism (SNP) arrays. However, for NGS data, methods for the SNP array cannot be directly applied because of different characteristics of NGS such as higher resolutions of data without predefined probes and incorrectly mapped reads to reference genomes. In this study, we developed a wavelet-based method for identification of focal genomic alterations for sequencing data (WIFA-Seq). We applied WIFA-Seq to whole genome sequencing data from glioblastoma multiforme, ovarian serous cystadenocarcinoma and lung adenocarcinoma, and identified focal genomic alterations, which contain candidate cancer-related genes as well as previously known cancer-driver genes. PMID:27156852

  11. Identification of cancer-driver genes in focal genomic alterations from whole genome sequencing data

    Science.gov (United States)

    Jang, Ho; Hur, Youngmi; Lee, Hyunju

    2016-01-01

    DNA copy number alterations (CNAs) are the main genomic events that occur during the initiation and development of cancer. Distinguishing driver aberrant regions from passenger regions, which might contain candidate target genes for cancer therapies, is an important issue. Several methods for identifying cancer-driver genes from multiple cancer patients have been developed for single nucleotide polymorphism (SNP) arrays. However, for NGS data, methods for the SNP array cannot be directly applied because of different characteristics of NGS such as higher resolutions of data without predefined probes and incorrectly mapped reads to reference genomes. In this study, we developed a wavelet-based method for identification of focal genomic alterations for sequencing data (WIFA-Seq). We applied WIFA-Seq to whole genome sequencing data from glioblastoma multiforme, ovarian serous cystadenocarcinoma and lung adenocarcinoma, and identified focal genomic alterations, which contain candidate cancer-related genes as well as previously known cancer-driver genes. PMID:27156852

  12. Genome anatomy of the gastrointestinal pathogen, Vibrio parahaemolyticus of crustacean origin.

    Science.gov (United States)

    Tiruvayipati, Suma; Bhassu, Subha; Kumar, Narender; Baddam, Ramani; Shaik, Sabiha; Gurindapalli, Anil Kumar; Thong, Kwai Lin; Ahmed, Niyaz

    2013-01-01

    Vibrio parahaemolyticus, an important human pathogen, is associated with gastroenteritis and transmitted through partially cooked seafood. It has become a major concern in the production and trade of marine food products. The prevalence of potentially virulent and pathogenic V. parahaemolyticus in raw seafood is of public health significance. Here we describe the genome sequence of a V. parahaemolyticus isolate of crustacean origin which was cultured from prawns in 2008 in Selangor, Malaysia (isolate PCV08-7). The next generation sequencing and analysis revealed that the genome of isolate PCV08-7 has closest similarity to that of V. parahaemolyticus RIMD2210633. However, there are certain unique features of the PCV08-7 genome such as the absence of TDH-related hemolysin (TRH), and the presence of HU-alpha insertion. The genome of isolate PCV08-7 encodes a thermostable direct hemolysin (TDH), an important virulence factor that classifies PCV08-7 isolate to be a serovariant of O3:K6 strain. Apart from these, we observed that there is certain pattern of genetic rearrangements that makes V. parahaemolyticus PCV08-7 a non-pandemic clone. We present detailed genome statistics and important genetic features of this bacterium and discuss how its survival, adaptation and virulence in marine and terrestrial hosts can be understood through the genomic blueprint and that the availability of genome sequence entailing this important Malaysian isolate would likely enhance our understanding of the epidemiology, evolution and transmission of foodborne Vibrios in Malaysia and elsewhere. PMID:24330647

  13. Genome Wide Methylome Alterations in Lung Cancer.

    Science.gov (United States)

    Mullapudi, Nandita; Ye, Bin; Suzuki, Masako; Fazzari, Melissa; Han, Weiguo; Shi, Miao K; Marquardt, Gaby; Lin, Juan; Wang, Tao; Keller, Steven; Zhu, Changcheng; Locker, Joseph D; Spivack, Simon D

    2015-01-01

    Aberrant cytosine 5-methylation underlies many deregulated elements of cancer. Among paired non-small cell lung cancers (NSCLC), we sought to profile DNA 5-methyl-cytosine features which may underlie genome-wide deregulation. In one of the more dense interrogations of the methylome, we sampled 1.2 million CpG sites from twenty-four NSCLC tumor (T)-non-tumor (NT) pairs using a methylation-sensitive restriction enzyme- based HELP-microarray assay. We found 225,350 differentially methylated (DM) sites in adenocarcinomas versus adjacent non-tumor tissue that vary in frequency across genomic compartment, particularly notable in gene bodies (GB; pLAMA3, AR]. The unique findings from this study include the discovery of numerous candidate The unique findings from this study include the discovery of numerous candidate methylation sites in both PR and GB regions not previously identified in NSCLC, and many non-canonical relationships to gene expression. These DNA methylation features could potentially be developed as risk or diagnostic biomarkers, or as candidate targets for newer methylation locus-targeted preventive or therapeutic agents. PMID:26683690

  14. 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.

  15. 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.

  16. Transcriptional consequences of genomic structural aberrations in breast cancer

    OpenAIRE

    Inaki, Koichiro; Hillmer, Axel M.; Ukil, Leena; Yao, Fei; Woo, Xing Yi; Vardy, Leah A; Zawack, Kelson Folkvard Braaten; Lee, Charlie Wah Heng; Ariyaratne, Pramila Nuwantha; Chan, Yang Sun; Desai, Kartiki Vasant; Bergh, Jonas; Hall, Per; Putti, Thomas Choudary; Ong, Wai Loon

    2011-01-01

    Using a long-span, paired-end deep sequencing strategy, we have comprehensively identified cancer genome rearrangements in eight breast cancer genomes. Herein, we show that 40%–54% of these structural genomic rearrangements result in different forms of fusion transcripts and that 44% are potentially translated. We find that single segmental tandem duplication spanning several genes is a major source of the fusion gene transcripts in both cell lines and primary tumors involving adjacent genes ...

  17. Genome Wide Methylome Alterations in Lung Cancer.

    Directory of Open Access Journals (Sweden)

    Nandita Mullapudi

    Full Text Available Aberrant cytosine 5-methylation underlies many deregulated elements of cancer. Among paired non-small cell lung cancers (NSCLC, we sought to profile DNA 5-methyl-cytosine features which may underlie genome-wide deregulation. In one of the more dense interrogations of the methylome, we sampled 1.2 million CpG sites from twenty-four NSCLC tumor (T-non-tumor (NT pairs using a methylation-sensitive restriction enzyme- based HELP-microarray assay. We found 225,350 differentially methylated (DM sites in adenocarcinomas versus adjacent non-tumor tissue that vary in frequency across genomic compartment, particularly notable in gene bodies (GB; p<2.2E-16. Further, when DM was coupled to differential transcriptome (DE in the same samples, 37,056 differential loci in adenocarcinoma emerged. Approximately 90% of the DM-DE relationships were non-canonical; for example, promoter DM associated with DE in the same direction. Of the canonical changes noted, promoter (PR DM loci with reciprocal changes in expression in adenocarcinomas included HBEGF, AGER, PTPRM, DPT, CST1, MELK; DM GB loci with concordant changes in expression included FOXM1, FERMT1, SLC7A5, and FAP genes. IPA analyses showed adenocarcinoma-specific promoter DMxDE overlay identified familiar lung cancer nodes [tP53, Akt] as well as less familiar nodes [HBEGF, NQO1, GRK5, VWF, HPGD, CDH5, CTNNAL1, PTPN13, DACH1, SMAD6, LAMA3, AR]. The unique findings from this study include the discovery of numerous candidate The unique findings from this study include the discovery of numerous candidate methylation sites in both PR and GB regions not previously identified in NSCLC, and many non-canonical relationships to gene expression. These DNA methylation features could potentially be developed as risk or diagnostic biomarkers, or as candidate targets for newer methylation locus-targeted preventive or therapeutic agents.

  18. 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.; Rowan, Andrew J.; Grönroos, Eva; Endesfelder, David; Joshi, Tejal; Mouradov, Dmitri; Gibbs, Peter; Ward, Robyn L.; Hawkins, Nicholas J.; Szallasi, Zoltan Imre; Sieber, Oliver M.; Swanton, Charles

    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 ...

  19. Comparative anatomy of the petioles of different genomic Cydonia × Malus hybrids

    Directory of Open Access Journals (Sweden)

    Elisaveta Onica

    2013-04-01

    Full Text Available In the paper morphological and anatomical structure of the petioles of 15 different genomic hybrids between quince and apple are compared with other hybrids and the initial forms. Specific and common anatomic peculiarities of the petiole for the studied hybrids in comparison to other hybrids and parental forms are given.

  20. 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.

  1. Pharynx Anatomy

    Science.gov (United States)

    ... e.g. -historical Searches are case-insensitive Pharynx Anatomy Add to My Pictures View /Download : Small: 720x576 ... View Download Large: 3000x2400 View Download Title: Pharynx Anatomy Description: Anatomy of the pharynx; drawing shows the ...

  2. Vulva Anatomy

    Science.gov (United States)

    ... e.g. -historical Searches are case-insensitive Vulva Anatomy Add to My Pictures View /Download : Small: 720x634 ... View Download Large: 3000x2640 View Download Title: Vulva Anatomy Description: Anatomy of the vulva; drawing shows the ...

  3. Larynx Anatomy

    Science.gov (United States)

    ... e.g. -historical Searches are case-insensitive Larynx Anatomy Add to My Pictures View /Download : Small: 648x576 ... View Download Large: 2700x2400 View Download Title: Larynx Anatomy Description: Anatomy of the larynx; drawing shows the ...

  4. Comprehensive copy number profiles of breast cancer cell model genomes

    OpenAIRE

    Shadeo, Ashleen; Lam, Wan L.

    2006-01-01

    Introduction Breast cancer is the most commonly diagnosed cancer in women worldwide and consequently has been extensively investigated in terms of histopathology, immunochemistry and familial history. Advances in genome-wide approaches have contributed to molecular classification with respect to genomic changes and their subsequent effects on gene expression. Cell lines have provided a renewable resource that is readily used as model systems for breast cancer cell biology. A thorough characte...

  5. Tolerance whole of genome doubling propagates chromosomal instability and accelerates cancer genome evolution

    OpenAIRE

    Dewhurst, Sally M; McGranahan, Nicholas; Burrell, Rebecca A.; Rowan, Andrew J.; Grönroos, Eva; Endesfelder, David; Joshi, Tejal; Mouradov, Dmitri; Gibbs, Peter; Ward, Robyn L.; Hawkins, Nicholas J.; Szallasi, Zoltan; Sieber, Oliver M.; Swanton, Charles

    2014-01-01

    The contribution of whole genome doubling to chromosomal instability (CIN) and tumour 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, t...

  6. Collaborative Research to Advance Precision Medicine in the Post-Genomic World | Office of Cancer Genomics

    Science.gov (United States)

    My name is Subhashini Jagu, and I am the Scientific Program Manager for the Cancer Target Discovery and Development (CTD2) Network at the Office of Cancer Genomics (OCG). In my new role, I help CTD2 work toward its mission, which is to develop new scientific approaches to accelerate the translation of genomic discoveries into new treatments. Collaborative efforts that bring together a variety of expertise and infrastructure are needed to understand and successfully treat cancer, a highly complex disease.

  7. Characterizing genomic alterations in cancer by complementary functional associations.

    Science.gov (United States)

    Kim, Jong Wook; Botvinnik, Olga B; Abudayyeh, Omar; Birger, Chet; Rosenbluh, Joseph; Shrestha, Yashaswi; Abazeed, Mohamed E; Hammerman, Peter S; DiCara, Daniel; Konieczkowski, David J; Johannessen, Cory M; Liberzon, Arthur; Alizad-Rahvar, Amir Reza; Alexe, Gabriela; Aguirre, Andrew; Ghandi, Mahmoud; Greulich, Heidi; Vazquez, Francisca; Weir, Barbara A; Van Allen, Eliezer M; Tsherniak, Aviad; Shao, Diane D; Zack, Travis I; Noble, Michael; Getz, Gad; Beroukhim, Rameen; Garraway, Levi A; Ardakani, Masoud; Romualdi, Chiara; Sales, Gabriele; Barbie, David A; Boehm, Jesse S; Hahn, William C; Mesirov, Jill P; Tamayo, Pablo

    2016-05-01

    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. We used REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of β-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations, demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes. PMID:27088724

  8. Contributions to Cancer Research: Finding a Niche in Communication | Office of Cancer Genomics

    Science.gov (United States)

    This past July, I started a journey into the fields of communications and cancer research when I joined the Office of Cancer Genomics (OCG) as a fellow in the National Cancer Institute (NCI) Health Communications Internship Program (HCIP). Cancer genomics and working in an office were new and uncharted territory for me: before I came to OCG, I was finishing a Ph.D. in cell biology at Vanderbilt University in Dr. Matthew Tyska’s laboratory.

  9. A microscopic landscape of the invasive breast cancer genome

    OpenAIRE

    Zheng Ping; Yuchao Xia; Tiansheng Shen; Vishwas Parekh; Siegal, Gene P; Isam-Eldin Eltoum; Jianbo He; Dongquan Chen; Minghua Deng; Ruibin Xi; Dejun Shen

    2016-01-01

    Histologic grade is one of the most important microscopic features used to predict the prognosis of invasive breast cancer and may serve as a marker for studying cancer driving genomic abnormalities in vivo. We analyzed whole genome sequencing data from 680 cases of TCGA invasive ductal carcinomas of the breast and correlated them to corresponding pathology information. Ten genetic abnormalities were found to be statistically associated with histologic grade, including three most prevalent ca...

  10. Perspectives of Integrative Cancer Genomics in Next Generation Sequencing Era

    OpenAIRE

    Kwon, So Mee; Cho, Hyunwoo; Choi, Ji Hye; Jee, Byul A; Jo, Yuna; Woo, Hyun Goo

    2012-01-01

    The explosive development of genomics technologies including microarrays and next generation sequencing (NGS) has provided comprehensive maps of cancer genomes, including the expression of mRNAs and microRNAs, DNA copy numbers, sequence variations, and epigenetic changes. These genome-wide profiles of the genetic aberrations could reveal the candidates for diagnostic and/or prognostic biomarkers as well as mechanistic insights into tumor development and progression. Recent efforts to establis...

  11. Human Cancer Classification: A Systems Biology- Based Model Integrating Morphology, Cancer Stem Cells, Proteomics, and Genomics

    OpenAIRE

    Halliday A Idikio

    2011-01-01

    Human cancer classification is currently based on the idea of cell of origin, light and electron microscopic attributes of the cancer. What is not yet integrated into cancer classification are the functional attributes of these cancer cells. Recent innovative techniques in biology have provided a wealth of information on the genomic, transcriptomic and proteomic changes in cancer cells. The emergence of the concept of cancer stem cells needs to be included in a classification model to capture...

  12. Genomic Copy Number Variations in the Genomes of Leukocytes Predict Prostate Cancer Clinical Outcomes.

    Directory of Open Access Journals (Sweden)

    Yan P Yu

    Full Text Available Accurate prediction of prostate cancer clinical courses remains elusive. In this study, we performed whole genome copy number analysis on leukocytes of 273 prostate cancer patients using Affymetrix SNP6.0 chip. Copy number variations (CNV were found across all chromosomes of the human genome. An average of 152 CNV fragments per genome was identified in the leukocytes from prostate cancer patients. The size distributions of CNV in the genome of leukocytes were highly correlative with prostate cancer aggressiveness. A prostate cancer outcome prediction model was developed based on large size ratio of CNV from the leukocyte genomes. This prediction model generated an average prediction rate of 75.2%, with sensitivity of 77.3% and specificity of 69.0% for prostate cancer recurrence. When combined with Nomogram and the status of fusion transcripts, the average prediction rate was improved to 82.5% with sensitivity of 84.8% and specificity of 78.2%. In addition, the leukocyte prediction model was 62.6% accurate in predicting short prostate specific antigen doubling time. When combined with Gleason's grade, Nomogram and the status of fusion transcripts, the prediction model generated a correct prediction rate of 77.5% with 73.7% sensitivity and 80.1% specificity. To our knowledge, this is the first study showing that CNVs in leukocyte genomes are predictive of clinical outcomes of a human malignancy.

  13. 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.

  14. Exploring Cancer's Fractured Genomic Landscape: Searching for Cancer Drivers and Vulnerabilities in Somatic Copy Number Alterations

    OpenAIRE

    Zack, Travis Ian

    2014-01-01

    Somatic copy number alterations (SCNAs) are a class of alterations that lead to deviations from diploidy in developing and established tumors. A feature that distinguishes SCNAs from other alterations is their genomic footprint. The large genomic footprint of SCNAs in a typical cancer's genome presents both a challenge and an opportunity to find targetable vulnerabilities in cancer. Because a single event affects many genes, it is often challenging to identify the tumorigenic targets of SCNAs...

  15. The breast cancer genome - a key for better oncology

    Directory of Open Access Journals (Sweden)

    Vollan Hans

    2011-11-01

    Full Text Available Abstract Molecular classification has added important knowledge to breast cancer biology, but has yet to be implemented as a clinical standard. Full sequencing of breast cancer genomes could potentially refine classification and give a more complete picture of the mutational profile of cancer and thus aid therapy decisions. Future treatment guidelines must be based on the knowledge derived from histopathological sub-classification of tumors, but with added information from genomic signatures when properly clinically validated. The objective of this article is to give some background on molecular classification, the potential of next generation sequencing, and to outline how this information could be implemented in the clinic.

  16. 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.

  17. 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.

  18. Methods for detection of subtle mutations in cancer genomes

    DEFF Research Database (Denmark)

    Dahl, Christina; Ralfkiaer, Ulrik; Guldberg, Per

    With the realization that cancer is a genetic disease, detection of mutations in genomic DNA has become an important discipline in many areas of cancer research. Although the publication of the human genome sequence and the immense technological advancements have facilitated the analysis of cancer...... genomes, detection of mutations in tumor specimens may still be challenging and fraught with technical problems. In this review, we describe current technologies for detection of small DNA mutations, including mutation scanning techniques to search for unknown mutations, and diagnostic techniques to...... detect known cancer mutations. We outline the principles of the different techniques and discuss their advantages and limitations. We also discuss critical issues that must be considered before choosing methodology, including sensitivity, specificity, limit of detection, throughput and cost, quantity and...

  19. Paraganglioma Anatomy

    Science.gov (United States)

    ... e.g. -historical Searches are case-insensitive Paraganglioma Anatomy Add to My Pictures View /Download : Small: 648x576 ... View Download Large: 2700x2400 View Download Title: Paraganglioma Anatomy Description: Paraganglioma of the head and neck; drawing ...

  20. Tooth anatomy

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/article/002214.htm Tooth anatomy To use the sharing features on this page, ... upper jawbone is called the maxilla. Images Tooth anatomy References Lingen MW. Head and neck. In: Kumar ...

  1. Eye Anatomy

    Science.gov (United States)

    ... News About Us Donate In This Section Eye Anatomy en Español email Send this article to a ... You at Risk For Glaucoma? Childhood Glaucoma Eye Anatomy Five Common Glaucoma Tests Glaucoma Facts and Stats ...

  2. Robottens Anatomi

    DEFF Research Database (Denmark)

    Antabi, Mimo

    Artiklen "Robottens Anatomi - mellem kunst og videnskab". Handler om brugen af robotter i kunstens og videnskabens verden.......Artiklen "Robottens Anatomi - mellem kunst og videnskab". Handler om brugen af robotter i kunstens og videnskabens verden....

  3. Hand Anatomy

    Science.gov (United States)

    ... Topics A-Z Videos Infographics Symptom Picker Hand Anatomy Hand Safety Fireworks Safety Lawnmower Safety Snowblower safety ... Topics A-Z Videos Infographics Symptom Picker Hand Anatomy Hand Safety Fireworks Safety Lawnmower Safety Snowblower safety ...

  4. Heart Anatomy

    Science.gov (United States)

    ... Incredible Machine Bonus poster (PDF) The Human Heart Anatomy Blood The Conduction System The Coronary Arteries The ... of the Leg Vasculature of the Torso Heart anatomy illustrations and animations for grades K-6. Heart ...

  5. An emerging place for lung cancer genomics in 2013.

    Science.gov (United States)

    Daniels, Marissa G; Bowman, Rayleen V; Yang, Ian A; Govindan, Ramaswamy; Fong, Kwun M

    2013-10-01

    Lung cancer is a disease with a dismal prognosis and is the biggest cause of cancer deaths in many countries. Nonetheless, rapid technological developments in genome science promise more effective prevention and treatment strategies. Since the Human Genome Project, scientific advances have revolutionized the diagnosis and treatment of human cancers, including thoracic cancers. The latest, massively parallel, next generation sequencing (NGS) technologies offer much greater sequencing capacity than traditional, capillary-based Sanger sequencing. These modern but costly technologies have been applied to whole genome-, and whole exome sequencing (WGS and WES) for the discovery of mutations and polymorphisms, transcriptome sequencing for quantification of gene expression, small ribonucleic acid (RNA) sequencing for microRNA profiling, large scale analysis of deoxyribonucleic acid (DNA) methylation and chromatin immunoprecipitation mapping of DNA-protein interaction. With the rise of personalized cancer care, based on the premise of precision medicine, sequencing technologies are constantly changing. To date, the genomic landscape of lung cancer has been captured in several WGS projects. Such work has not only contributed to our understanding of cancer biology, but has also provided impetus for technical advances that may improve our ability to accurately capture the cancer genome. Issues such as short read lengths contribute to sequenced libraries that contain challenging gaps in the aligned genome. Emerging platforms promise longer reads as well as the ability to capture a range of epigenomic signals. In addition, ongoing optimization of bioinformatics strategies for data analysis and interpretation are critical, especially for the differentiation between driver and passenger mutations. Moreover, broader deployment of these and future generations of platforms, coupled with an increasing bioinformatics workforce with access to highly sophisticated technologies, could

  6. Genomic determinants of somatic copy number alterations across human cancers.

    Science.gov (United States)

    Zhang, Yanping; Xu, Hongen; Frishman, Dmitrij

    2016-03-01

    Somatic copy number alterations (SCNAs) play an important role in carcinogenesis. However, the impact of genomic architecture on the global patterns of SCNAs in cancer genomes remains elusive. In this work, we conducted multiple linear regression (MLR) analyses of the pooled SCNA data from The Cancer Genome Atlas (TCGA) Pan-Cancer project. We performed MLR analyses for 11 individual cancer types and three different kinds of SCNAs-amplifications and deletions, telomere-bound and interstitial SCNAs and local SCNAs. Our MLR model explains >30% of the pooled SCNA breakpoint variation, with the explanatory power ranging from 13 to 32% for different cancer types and SCNA types. In addition to confirming previously identified features [e.g. long interspersed element-1 (L1) and short interspersed nuclear elements], we also identified several novel informative features, including distance to telomere, distance to centromere and low-complexity repeats. The results of the MLR analyses were additionally confirmed on an independent SCNA data set obtained from the catalogue of somatic mutations in cancer database. Using a rare-event logistic regression model and an extremely randomized tree classifier, we revealed that genomic features are informative for defining common SCNA breakpoint hotspots. Our findings shed light on the molecular mechanisms of SCNA generation in cancer. PMID:26732428

  7. 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.

  8. 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.

  9. 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.

  10. Cancer Therapy Evaluation Program | Office of Cancer Genomics

    Science.gov (United States)

    The Cancer Therapy Evaluation Program (CTEP) seeks to improve the lives of cancer patients by finding better treatments, control mechanisms, and cures for cancer. CTEP funds a national program of cancer research, sponsoring clinical trials to evaluate new anti-cancer agents.

  11. Influence of rotational setup error on tumor shift in bony anatomy matching measured with pulmonary point registration in stereotactic body radiotherapy for early lung cancer

    International Nuclear Information System (INIS)

    The objective of this study was to examine the correlation between the patient rotational error measured with pulmonary point registration and tumor shift after bony anatomy matching in stereotactic body radiotherapy for lung cancer. Twenty-six patients with lung cancer who underwent stereotactic body radiotherapy were the subjects. On 104 cone-beam computed tomography measurements performed prior to radiation delivery, rotational setup errors were measured with point registration using pulmonary structures. Translational registration using bony anatomy matching was done and the three-dimensional vector of tumor displacement was measured retrospectively. Correlation among the three-dimensional vector and rotational error and vertebra-tumor distance was investigated quantitatively. The median and maximum rotational errors of the roll, pitch and yaw were 0.8, 0.9 and 0.5, and 6.0, 4.5 and 2.5, respectively. Bony anatomy matching resulted in a 0.2-1.6 cm three-dimensional vector of tumor shift. The shift became larger as the vertebra-tumor distance increased. Multiple regression analysis for the three-dimensional vector indicated that in the case of bony anatomy matching, tumor shifts of 5 and 10 mm were expected for vertebra-tumor distances of 4.46 and 14.1 cm, respectively. Using pulmonary point registration, it was found that the rotational setup error influences the tumor shift. Bony anatomy matching is not appropriate for hypofractionated stereotactic body radiotherapy with a tight margin. (author)

  12. Endoplasmic Reticulum Stress, Genome Damage, and Cancer

    OpenAIRE

    Dicks, Naomi; Gutierrez, Karina; Michalak, Marek; Bordignon, Vilceu; Agellon, Luis B.

    2015-01-01

    Endoplasmic reticulum (ER) stress has been linked to many diseases, including cancer. A large body of work has focused on the activation of the ER stress response in cancer cells to facilitate their survival and tumor growth; however, there are some studies suggesting that the ER stress response can also mitigate cancer progression. Despite these contradictions, it is clear that the ER stress response is closely associated with cancer biology. The ER stress response classically encompasses ac...

  13. Endoplasmic reticulum stress, genome damage and cancer

    OpenAIRE

    Naomi eDicks; Karina eGutierrez; Marek eMichalak; Vilceu eBordignon; Agellon, Luis B.

    2015-01-01

    Endoplasmic reticulum (ER) stress has been linked to many diseases, including cancer. A large body of work has focused on the activation of the ER stress response in cancer cells to facilitate their survival and tumor growth, however, there are some studies suggesting that the ER stress response can also mitigate cancer progression. Despite these contradictions, it is clear that the ER stress response is closely associated with cancer biology. The ER stress response classically encompasses ...

  14. Genomic insights into a contagious cancer in Tasmanian devils.

    Science.gov (United States)

    Grueber, Catherine E; Peel, Emma; Gooley, Rebecca; Belov, Katherine

    2015-09-01

    The Tasmanian devil faces extinction due to a contagious cancer. Genetic and genomic technologies revealed that the disease arose in a Schwann cell of a female devil. Instead of dying with the original host, the tumour was passed from animal to animal, slipping under the radar of the immune system. Studying the genomes of the devil and the cancer has driven our understanding of this unique disease. From characterising immune genes and immune responses to studying tumour evolution, we have begun to uncover how a cancer can be 'caught' and are using genomic data to manage an insurance population of disease-free devils for the long-term survival of the species. PMID:26027792

  15. The evolving role of cancer cell line-based screens to define the impact of cancer genomes on drug response ?

    OpenAIRE

    Garnett, Mathew J.; McDermott, Ultan

    2014-01-01

    Over the last decade we have witnessed the convergence of two powerful experimental designs toward a common goal of defining the molecular subtypes that underpin the likelihood of a cancer patient responding to treatment in the clinic. The first of these ‘experiments’ has been the systematic sequencing of large numbers of cancer genomes through the International Cancer Genome Consortium and The Cancer Genome Atlas. This endeavour is beginning to yield a complete catalogue of the cancer genes ...

  16. A microscopic landscape of the invasive breast cancer genome

    Science.gov (United States)

    Ping, Zheng; Xia, Yuchao; Shen, Tiansheng; Parekh, Vishwas; Siegal, Gene P.; Eltoum, Isam-Eldin; He, Jianbo; Chen, Dongquan; Deng, Minghua; Xi, Ruibin; Shen, Dejun

    2016-01-01

    Histologic grade is one of the most important microscopic features used to predict the prognosis of invasive breast cancer and may serve as a marker for studying cancer driving genomic abnormalities in vivo. We analyzed whole genome sequencing data from 680 cases of TCGA invasive ductal carcinomas of the breast and correlated them to corresponding pathology information. Ten genetic abnormalities were found to be statistically associated with histologic grade, including three most prevalent cancer driver events, TP53 and PIK3CA mutations and MYC amplification. A distinct genetic interaction among these genomic abnormalities was revealed as measured by the histologic grading score. While TP53 mutation and MYC amplification were synergistic in promoting tumor progression, PIK3CA mutation was found to have alleviated the oncogenic effect of either the TP53 mutation or MYC amplification, and was associated with a significant reduction in mitotic activity in TP53 mutated and/or MYC amplified breast cancer. Furthermore, we discovered that different types of genetic abnormalities (mutation versus amplification) within the same cancer driver gene (PIK3CA or GATA3) were associated with opposite histologic changes in invasive breast cancer. In conclusion, our study suggests that histologic grade may serve as a biomarker to define cancer driving genetic events in vivo. PMID:27283966

  17. A microscopic landscape of the invasive breast cancer genome.

    Science.gov (United States)

    Ping, Zheng; Xia, Yuchao; Shen, Tiansheng; Parekh, Vishwas; Siegal, Gene P; Eltoum, Isam-Eldin; He, Jianbo; Chen, Dongquan; Deng, Minghua; Xi, Ruibin; Shen, Dejun

    2016-01-01

    Histologic grade is one of the most important microscopic features used to predict the prognosis of invasive breast cancer and may serve as a marker for studying cancer driving genomic abnormalities in vivo. We analyzed whole genome sequencing data from 680 cases of TCGA invasive ductal carcinomas of the breast and correlated them to corresponding pathology information. Ten genetic abnormalities were found to be statistically associated with histologic grade, including three most prevalent cancer driver events, TP53 and PIK3CA mutations and MYC amplification. A distinct genetic interaction among these genomic abnormalities was revealed as measured by the histologic grading score. While TP53 mutation and MYC amplification were synergistic in promoting tumor progression, PIK3CA mutation was found to have alleviated the oncogenic effect of either the TP53 mutation or MYC amplification, and was associated with a significant reduction in mitotic activity in TP53 mutated and/or MYC amplified breast cancer. Furthermore, we discovered that different types of genetic abnormalities (mutation versus amplification) within the same cancer driver gene (PIK3CA or GATA3) were associated with opposite histologic changes in invasive breast cancer. In conclusion, our study suggests that histologic grade may serve as a biomarker to define cancer driving genetic events in vivo. PMID:27283966

  18. Genomic diversity of colorectal cancer: Changing landscape and emerging targets

    Science.gov (United States)

    Ahn, Daniel H; Ciombor, Kristen K; Mikhail, Sameh; Bekaii-Saab, Tanios

    2016-01-01

    Improvements in screening and preventive measures have led to an increased detection of early stage colorectal cancers (CRC) where patients undergo treatment with a curative intent. Despite these efforts, a high proportion of patients are diagnosed with advanced stage disease that is associated with poor outcomes, as CRC remains one of the leading causes of cancer-related deaths in the world. The development of next generation sequencing and collaborative multi-institutional efforts to characterize the cancer genome has afforded us with a comprehensive assessment of the genomic makeup present in CRC. This knowledge has translated into understanding the prognostic role of various tumor somatic variants in this disease. Additionally, the awareness of the genomic alterations present in CRC has resulted in an improvement in patient outcomes, largely due to better selection of personalized therapies based on an individual’s tumor genomic makeup. The benefit of various treatments is often limited, where recent studies assessing the genomic diversity in CRC have identified the development of secondary tumor somatic variants that likely contribute to acquired treatment resistance. These studies have begun to alter the landscape of treatment for CRC that include investigating novel targeted therapies, assessing the role of immunotherapy and prospective, dynamic assessment of changes in tumor genomic alterations that occur during the treatment of CRC. PMID:27433082

  19. Onco-proteogenomics: cancer proteomics joins forces with genomics.

    Science.gov (United States)

    Alfaro, Javier A; Sinha, Ankit; Kislinger, Thomas; Boutros, Paul C

    2014-11-01

    The complexities of tumor genomes are rapidly being uncovered, but how they are regulated into functional proteomes remains poorly understood. Standard proteomics workflows use databases of known proteins, but these databases do not capture the uniqueness of the cancer transcriptome, with its point mutations, unusual splice variants and gene fusions. Onco-proteogenomics integrates mass spectrometry-generated data with genomic information to identify tumor-specific peptides. Linking tumor-derived DNA, RNA and protein measurements into a central-dogma perspective has the potential to improve our understanding of cancer biology. PMID:25357240

  20. Comprehensive genomic profiles of small cell lung cancer

    OpenAIRE

    George, J.; Lim, J; JANG, S.; Cun, Y.; Ozretic, L.; Kong, G.; Leenders, F.; Lu, X.; Fernandez-Cuesta, L.; Bosco, G.; Müller, C.(Dr. Remeis-Sternwarte and ECAP, Universität Erlangen-Nürnberg, Sternwartstr. 7, 96049 , Bamberg, Germany); Dahmen, I.; Jahchan, N.; K. Park; D. Yang

    2015-01-01

    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 ...

  1. Genomic analysis and selected molecular pathways in rare cancers

    International Nuclear Information System (INIS)

    It is widely accepted that many cancers arise as a result of an acquired genomic instability and the subsequent evolution of tumor cells with variable patterns of selected and background aberrations. The presence and behaviors of distinct neoplastic cell populations within a patient's tumor may underlie multiple clinical phenotypes in cancers. A goal of many current cancer genome studies is the identification of recurring selected driver events that can be advanced for the development of personalized therapies. Unfortunately, in the majority of rare tumors, this type of analysis can be particularly challenging. Large series of specimens for analysis are simply not available, allowing recurring patterns to remain hidden. In this paper, we highlight the use of DNA content-based flow sorting to identify and isolate DNA-diploid and DNA-aneuploid populations from tumor biopsies as a strategy to comprehensively study the genomic composition and behaviors of individual cancers in a series of rare solid tumors: intrahepatic cholangiocarcinoma, anal carcinoma, adrenal leiomyosarcoma, and pancreatic neuroendocrine tumors. We propose that the identification of highly selected genomic events in distinct tumor populations within each tumor can identify candidate driver events that can facilitate the development of novel, personalized treatment strategies for patients with cancer. (paper)

  2. Quantification of read species behavior within whole genome sequencing of cancer genomes for the stratification and visualization of genomic variation.

    Science.gov (United States)

    Hibsh, Dror; Buetow, Kenneth H; Yaari, Gur; Efroni, Sol

    2016-05-19

    The cancer genome is abnormal genome, and the ability to monitor its sequence had undergone a technological revolution. Yet prognosis and diagnosis remain an expert-based decision, with only limited abilities to provide machine-based decisions. We introduce a heterogeneity-based method for stratifying and visualizing whole-genome sequencing (WGS) reads. This method uses the heterogeneity within WGS reads to markedly reduce the dimensionality of next-generation sequencing data; it is available through the tool HiBS (Heterogeneity-Based Subclassification) that allows cancer sample classification. We validated HiBS using >200 WGS samples from nine different cancer types from The Cancer Genome Atlas (TCGA). With HiBS, we show progress with two WGS related issues: (i) differentiation between normal (NB) and tumor (TP) samples based solely on the information structure of their WGS data, and (ii) identification of specific regions of chromosomal amplification/deletion and their association with tumor stage. By comparing results to those obtained through available WGS analyses tools, we demonstrate some of the novelties obtained by the approach implemented in HiBS and also show nearly perfect normal/tumor classification, used to identify known and unknown chromosomal aberrations. Finally, the HiBS index has been associated with breast cancer tumor stage. PMID:26809676

  3. 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.

  4. Integer anatomy

    Energy Technology Data Exchange (ETDEWEB)

    Doolittle, R. [ONR, Arlington, VA (United States)

    1994-11-15

    The title integer anatomy is intended to convey the idea of a systematic method for displaying the prime decomposition of the integers. Just as the biological study of anatomy does not teach us all things about behavior of species neither would we expect to learn everything about the number theory from a study of its anatomy. But, some number-theoretic theorems are illustrated by inspection of integer anatomy, which tend to validate the underlying structure and the form as developed and displayed in this treatise. The first statement to be made in this development is: the way structure of the natural numbers is displayed depends upon the allowed operations.

  5. Cancer Genomics and Biology 2015 – Meeting Report

    Science.gov (United States)

    Chow, Louis WC.; Costa, Luis; Teh, Bin-Tean; Li, Da-Qiang; Feng, Gu; Guan, Xin-Yuan; Nair, Asha; Zhu, Li; Sugimoto, Masahiro; Dutt, Amit; Toi, Masakazu; Gupta, Sudeep; Badwe, Rajendra; Knapp, Stefan; Pillai, M. Radhakrishna; Kumar, Rakesh

    2016-01-01

    The Cancer Genomics and Biology 2015 meeting embodied a three way collaboration among colleagues from the Global Cancer Genomics Consortium (GCGC), the Unifaith Cancer Institute China and Jiujiang University of China. The meeting marks the fifth and the last meeting of GCGC, which was formed in 2010. Previous four GCGC meetings have been held at the Tata Memorial Center- Mumbai, Institute of Molecular Medicine-Lisbon, and Graduate Medical School Kyoto University-Kyoto. In contrast to the genomic themes of the previous meetings, the 2015 conference theme was at the interface of laboratory and translation research and emerging therapeutics as reflected in the shared interests of all three collaborative entities – Cancer Genomics and Biology 2015. This year's conference was co-organized by the Jiujiang University at the Run Run Shaw building, Jiujiang University, Jiujiang City, China, on November 13 and 14, 2015. The conference attracted over 174 participants with 13 platform presentations. Scientific sessions included a plenary and five platform scientific sessions with themes ranging from biomarkers, stem cells and markers of the tumor microenvironment, proteomics and epigenetics, big data, to hormone and expression profiles. The meeting concluded with closing remarks by conference co-chairs emphasizing with the need to broaden membership across the globe, establishing priorities, and redrafting a white paper to launch a new consortium.

  6. Genomic Predictors of Outcome in Prostate Cancer

    NARCIS (Netherlands)

    Bostrom, P.J.; Bjartell, A.S.; Catto, J.W.; Eggener, S.E.; Lilja, H.; Loeb, S.; Schalken, J.A.; Schlomm, T.; Cooperberg, M.R.

    2015-01-01

    CONTEXT: Given the highly variable behavior and clinical course of prostate cancer (PCa) and the multiple available treatment options, a personalized approach to oncologic risk stratification is important. Novel genetic approaches offer additional information to improve clinical decision making. OBJ

  7. 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.

  8. Significance of duon mutations in cancer genomes

    OpenAIRE

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

    2016-01-01

    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, regulat...

  9. 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:

  10. Integrative prescreening in analysis of multiple cancer genomic studies

    Directory of Open Access Journals (Sweden)

    Song Rui

    2012-07-01

    Full Text Available Abstract Background In high throughput cancer genomic studies, results from the analysis of single datasets often suffer from a lack of reproducibility because of small sample sizes. Integrative analysis can effectively pool and analyze multiple datasets and provides a cost effective way to improve reproducibility. In integrative analysis, simultaneously analyzing all genes profiled may incur high computational cost. A computationally affordable remedy is prescreening, which fits marginal models, can be conducted in a parallel manner, and has low computational cost. Results An integrative prescreening approach is developed for the analysis of multiple cancer genomic datasets. Simulation shows that the proposed integrative prescreening has better performance than alternatives, particularly including prescreening with individual datasets, an intensity approach and meta-analysis. We also analyze multiple microarray gene profiling studies on liver and pancreatic cancers using the proposed approach. Conclusions The proposed integrative prescreening provides an effective way to reduce the dimensionality in cancer genomic studies. It can be coupled with existing analysis methods to identify cancer markers.

  11. 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

  12. Targeted or whole genome sequencing of formalin fixed tissue samples: potential applications in cancer genomics.

    Science.gov (United States)

    Munchel, Sarah; Hoang, Yen; Zhao, Yue; Cottrell, Joseph; Klotzle, Brandy; Godwin, Andrew K; Koestler, Devin; Beyerlein, Peter; Fan, Jian-Bing; Bibikova, Marina; Chien, Jeremy

    2015-09-22

    Current genomic studies are limited by the poor availability of fresh-frozen tissue samples. Although formalin-fixed diagnostic samples are in abundance, they are seldom used in current genomic studies because of the concern of formalin-fixation artifacts. Better characterization of these artifacts will allow the use of archived clinical specimens in translational and clinical research studies. To provide a systematic analysis of formalin-fixation artifacts on Illumina sequencing, we generated 26 DNA sequencing data sets from 13 pairs of matched formalin-fixed paraffin-embedded (FFPE) and fresh-frozen (FF) tissue samples. The results indicate high rate of concordant calls between matched FF/FFPE pairs at reference and variant positions in three commonly used sequencing approaches (whole genome, whole exome, and targeted exon sequencing). Global mismatch rates and C · G > T · A substitutions were comparable between matched FF/FFPE samples, and discordant rates were low (<0.26%) in all samples. Finally, low-pass whole genome sequencing produces similar pattern of copy number alterations between FF/FFPE pairs. The results from our studies suggest the potential use of diagnostic FFPE samples for cancer genomic studies to characterize and catalog variations in cancer genomes. PMID:26305677

  13. 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).

  14. 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.

  15. 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

  16. 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

    2015-08-01

    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

  17. 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.

  18. Genome Sequencing and Analysis of the Tasmanian Devil and Its Transmissible Cancer

    OpenAIRE

    Murchison, Elizabeth P.; Schulz-Trieglaff, Ole B.; Ning, Zemin; Alexandrov, Ludmil B.; Bauer, Markus J.; Fu, Beiyuan; Hims, Matthew; Ding, Zhihao; Ivakhno, Sergii; Stewart, Caitlin; Ng, Bee Ling; Wong, Wendy; Aken, Bronwen; White, Simon; Alsop, Amber

    2012-01-01

    Summary The Tasmanian devil (Sarcophilus harrisii), the largest marsupial carnivore, is endangered due to a transmissible facial cancer spread by direct transfer of living cancer cells through biting. Here we describe the sequencing, assembly, and annotation of the Tasmanian devil genome and whole-genome sequences for two geographically distant subclones of the cancer. Genomic analysis suggests that the cancer first arose from a female Tasmanian devil and that the clone has subsequently genet...

  19. Robottens Anatomi

    DEFF Research Database (Denmark)

    Antabi, Mimo

    Rapport der beskriver de samlede erfaringer fra arbejdet med produktionen af teaterforestillingen Robottens Anatomi. Indehoder bl.a. interviews med medvirkende, bidrag fra instruktør, synopsis, beskrivelse af scenografi mv.......Rapport der beskriver de samlede erfaringer fra arbejdet med produktionen af teaterforestillingen Robottens Anatomi. Indehoder bl.a. interviews med medvirkende, bidrag fra instruktør, synopsis, beskrivelse af scenografi mv....

  20. Contributing to Tumor Molecular Characterization Projects with a Global Impact | Office of Cancer Genomics

    Science.gov (United States)

    My name is Nicholas Griner and I am the Scientific Program Manager for the Cancer Genome Characterization Initiative (CGCI) in the Office of Cancer Genomics (OCG). Until recently, I spent most of my scientific career working in a cancer research laboratory. In my postdoctoral training, my research focused on identifying novel pathways that contribute to both prostate and breast cancers and studying proteins within these pathways that may be targeted with cancer drugs.

  1. Underlying anatomy for CTV contouring and lymphatic drainage in rectal cancer radiation therapy.

    Science.gov (United States)

    Arcangeli, Stefano; Valentini, Vincenzo; Nori, Stefania L; Fares, Claudia; Dinapoli, Nicola; Gambacorta, Maria Antonierrta

    2003-01-01

    Despite the low local recurrence rate that can be achieved by adequate surgery (total mesorectal excision--TME), radiation therapy was shown to play a significant role in reducing this risk. The widespread use of TME in many European Centers has introduced a new terminology and the need to identify the area at major risk for local failure using this surgical procedure. In the surgical series where extended extra-mesorectal surgery was performed, the role of lymphatic spread was evidenced, especially for low rectal cancer, through the pelvic parietal fascia and lateral pelvic spaces. The aim of this study was to better define some anatomic concepts and the main risk factors which impact on CTV contouring and field conformation in rectal cancer treatment. This information helps formulating guidelines for CTV contouring in daily radiotherapy practice, in order to define the best therapy, according to the tumor stage and location. PMID:15018321

  2. Identification of genomic alterations in pancreatic cancer using array-based comparative genomic hybridization.

    Directory of Open Access Journals (Sweden)

    Jian-Wei Liang

    Full Text Available BACKGROUND: Genomic aberration is a common feature of human cancers and also is one of the basic mechanisms that lead to overexpression of oncogenes and underexpression of tumor suppressor genes. Our study aims to identify frequent genomic changes in pancreatic cancer. MATERIALS AND METHODS: We used array comparative genomic hybridization (array CGH to identify recurrent genomic alterations and validated the protein expression of selected genes by immunohistochemistry. RESULTS: Sixteen gains and thirty-two losses occurred in more than 30% and 60% of the tumors, respectively. High-level amplifications at 7q21.3-q22.1 and 19q13.2 and homozygous deletions at 1p33-p32.3, 1p22.1, 1q22, 3q27.2, 6p22.3, 6p21.31, 12q13.2, 17p13.2, 17q21.31 and 22q13.1 were identified. Especially, amplification of AKT2 was detected in two carcinomas and homozygous deletion of CDKN2C in other two cases. In 15 independent validation samples, we found that AKT2 (19q13.2 and MCM7 (7q22.1 were amplified in 6 and 9 cases, and CAMTA2 (17p13.2 and PFN1 (17p13.2 were homozygously deleted in 3 and 1 cases. AKT2 and MCM7 were overexpressed, and CAMTA2 and PFN1 were underexpressed in pancreatic cancer tissues than in morphologically normal operative margin tissues. Both GISTIC and Genomic Workbench software identified 22q13.1 containing APOBEC3A and APOBEC3B as the only homozygous deletion region. And the expression levels of APOBEC3A and APOBEC3B were significantly lower in tumor tissues than in morphologically normal operative margin tissues. Further validation showed that overexpression of PSCA was significantly associated with lymph node metastasis, and overexpression of HMGA2 was significantly associated with invasive depth of pancreatic cancer. CONCLUSION: These recurrent genomic changes may be useful for revealing the mechanism of pancreatic carcinogenesis and providing candidate biomarkers.

  3. Improving anatomical mapping of complexly deformed anatomy for external beam radiotherapy and brachytherapy dose accumulation in cervical cancer

    International Nuclear Information System (INIS)

    Purpose: In the treatment of cervical cancer, large anatomical deformations, caused by, e.g., tumor shrinkage, bladder and rectum filling changes, organ sliding, and the presence of the brachytherapy (BT) applicator, prohibit the accumulation of external beam radiotherapy (EBRT) and BT dose distributions. This work proposes a structure-wise registration with vector field integration (SW+VF) to map the largely deformed anatomies between EBRT and BT, paving the way for 3D dose accumulation between EBRT and BT. Methods: T2w-MRIs acquired before EBRT and as a part of the MRI-guided BT procedure for 12 cervical cancer patients, along with the manual delineations of the bladder, cervix-uterus, and rectum-sigmoid, were used for this study. A rigid transformation was used to align the bony anatomy in the MRIs. The proposed SW+VF method starts by automatically segmenting features in the area surrounding the delineated organs. Then, each organ and feature pair is registered independently using a feature-based nonrigid registration algorithm developed in-house. Additionally, a background transformation is calculated to account for areas far from all organs and features. In order to obtain one transformation that can be used for dose accumulation, the organ-based, feature-based, and the background transformations are combined into one vector field using a weighted sum, where the contribution of each transformation can be directly controlled by its extent of influence (scope size). The optimal scope sizes for organ-based and feature-based transformations were found by an exhaustive analysis. The anatomical correctness of the mapping was independently validated by measuring the residual distances after transformation for delineated structures inside the cervix-uterus (inner anatomical correctness), and for anatomical landmarks outside the organs in the surrounding region (outer anatomical correctness). The results of the proposed method were compared with the results of the

  4. Improving anatomical mapping of complexly deformed anatomy for external beam radiotherapy and brachytherapy dose accumulation in cervical cancer

    Energy Technology Data Exchange (ETDEWEB)

    Vásquez Osorio, Eliana M., E-mail: e.vasquezosorio@erasmusmc.nl; Kolkman-Deurloo, Inger-Karine K.; Schuring-Pereira, Monica; Zolnay, András; Heijmen, Ben J. M.; Hoogeman, Mischa S. [Department of Radiation Oncology, Erasmus MC Cancer Institute, Rotterdam 3075 (Netherlands)

    2015-01-15

    Purpose: In the treatment of cervical cancer, large anatomical deformations, caused by, e.g., tumor shrinkage, bladder and rectum filling changes, organ sliding, and the presence of the brachytherapy (BT) applicator, prohibit the accumulation of external beam radiotherapy (EBRT) and BT dose distributions. This work proposes a structure-wise registration with vector field integration (SW+VF) to map the largely deformed anatomies between EBRT and BT, paving the way for 3D dose accumulation between EBRT and BT. Methods: T2w-MRIs acquired before EBRT and as a part of the MRI-guided BT procedure for 12 cervical cancer patients, along with the manual delineations of the bladder, cervix-uterus, and rectum-sigmoid, were used for this study. A rigid transformation was used to align the bony anatomy in the MRIs. The proposed SW+VF method starts by automatically segmenting features in the area surrounding the delineated organs. Then, each organ and feature pair is registered independently using a feature-based nonrigid registration algorithm developed in-house. Additionally, a background transformation is calculated to account for areas far from all organs and features. In order to obtain one transformation that can be used for dose accumulation, the organ-based, feature-based, and the background transformations are combined into one vector field using a weighted sum, where the contribution of each transformation can be directly controlled by its extent of influence (scope size). The optimal scope sizes for organ-based and feature-based transformations were found by an exhaustive analysis. The anatomical correctness of the mapping was independently validated by measuring the residual distances after transformation for delineated structures inside the cervix-uterus (inner anatomical correctness), and for anatomical landmarks outside the organs in the surrounding region (outer anatomical correctness). The results of the proposed method were compared with the results of the

  5. Comparison of genomic abnormalities between BRCAX and sporadic breast cancers studied by comparative genomic hybridization.

    Science.gov (United States)

    Gronwald, Jacek; Jauch, Anna; Cybulski, Cezary; Schoell, Brigitte; Böhm-Steuer, Barbara; Lener, Marcin; Grabowska, Ewa; Górski, Bohdan; Jakubowska, Anna; Domagała, Wenancjusz; Chosia, Maria; Scott, Rodney J; Lubiński, Jan

    2005-03-20

    Very little is known about the chromosomal regions harbouring genes involved in initiation and progression of BRCAX-associated breast cancers. We applied comparative genomic hybridization (CGH) to identify the most frequent genomic imbalances in 18 BRCAX hereditary breast cancers and compared them to chromosomal aberrations detected in a group of 27 sporadic breast cancers. The aberrations observed most frequently in BRCAX tumours were gains of 8q (83%), 19q (67%), 19p (61%), 20q (61%), 1q (56%), 17q (56%) and losses of 8p (56%), 11q (44%) and 13q (33%). The sporadic cases most frequently showed gains of 1q (67%), 8q (48%), 17q (37%), 16p (33%), 19q (33%) and losses of 11q (26%), 8p (22%) and 16q (19%). Losses of 8p and gains 8q, 19 as well as gains of 20q (with respect to ductal tumours only) were detected significantly more often in BRCAX than in sporadic breast cancers. Analysis of 8p-losses and 8q-gains showed that these aberrations are early events in the tumorigenesis of BRCAX tumors. The findings of this report indicate similarities between BRCAX and BRCA2 tumours, possibly suggesting a common pathway of disease. These findings need confirmation by more extensive studies because only a limited number of cases were analysed and there are relatively few reports published. PMID:15540206

  6. Normal Tissue Anatomy for Oropharyngeal Cancer: Contouring Variability and Its Impact on Optimization

    International Nuclear Information System (INIS)

    Purpose: To evaluate the variability of organ at risk (OAR) delineation and the resulting impact on intensity modulated radiation therapy (IMRT) treatment plan optimization in head-and-neck cancer. Methods and Materials: An expert panel of 3 radiation oncologists jointly delineated OARs, including the parotid and submandibular glands (SM), pharyngeal constrictors (PC), larynx, and glottis (GL), in 10 patients with advanced oropharynx cancer in 3 contouring sessions, spaced at least 1 week apart. Contour variability and uncertainty, as well as their dosimetric impact on IMRT planning for each case, were assessed. Results: The mean difference in total volume for each OAR was 1 cm3 (σ 0.5 cm3). Mean fractional overlap was 0.7 (σ 0.1) and was highest (0.8) for the larynx and bilateral SMs and parotids and lowest (0.5) for PC. There were considerable spatial differences in contours, with the ipsilateral parotid and PC displaying the most variability (0.9 cm), which was most prominent in cases in which tumors obliterated fat planes. Both SMs and GL had the smallest differences (0.5 cm). The mean difference in OAR dose was 0.9 Gy (range 0.6-1.1 Gy, σ 0.1 Gy), with the smallest difference for GL and largest for both SMs and the larynx. Conclusions: Despite substantial difference in OAR contours, optimization was barely affected, with a 0.9-Gy mean difference between optimizations, suggesting relative insensitivity of dose distributions for IMRT of oropharynx cancer to the extent of OARs.

  7. 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.

  8. 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.

  9. 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.  

  10. Robust optimization in intensity-modulated proton therapy to account for anatomy changes in lung cancer patients

    International Nuclear Information System (INIS)

    Background and purpose: Robust optimization for IMPT takes setup and range uncertainties into account during plan optimization. However, anatomical changes were not prospectively included. The purpose of this study was to examine robustness and dose variation due to setup uncertainty and anatomical change in IMPT of lung cancer. Material and methods: Plans were generated with multi-field optimization based on planning target volume (MFO-PTV) and worst-case robust optimization (MFO-RO) on simulation computed tomography scans (CT0) for nine patients. Robustness was evaluated on the CT0 by computing the standard deviation of DVH (SD-DVH). Dose variations calculated on weekly CTs were compared with SD-DVH. Equivalent uniform dose (EUD) change from the original plan on weekly dose was also calculated for both plans. Results: SD-DVH and dose variation on weekly CTs were both significantly lower in the MFO-RO plans than in the MFO-PTV plans for targets, lungs, and the esophagus (p < 0.05). When comparing EUD for ITV between weekly and planned dose distributions, three patients and 28% of repeated CTs for MFO-RO plans, and six patients and 44% of repeated CTs for MFO-PTV plans, respectively, showed an EUD change of >5%. Conclusions: RO in IMPT reduces the dose variation due to setup uncertainty and anatomy changes during treatment compared with PTV-based planning. However, dose variation could still be substantial; repeated imaging and adaptive planning as needed are highly recommended for IMPT of lung tumors

  11. Genome profiling of ERBB2-amplified breast cancers

    International Nuclear Information System (INIS)

    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. 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. 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 EGFR or IGF1R and ERBB2, which could influence

  12. The Cancer Genomics Hub (CGHub): overcoming cancer through the power of torrential data.

    Science.gov (United States)

    Wilks, Christopher; Cline, Melissa S; Weiler, Erich; Diehkans, Mark; Craft, Brian; Martin, Christy; Murphy, Daniel; Pierce, Howdy; Black, John; Nelson, Donavan; Litzinger, Brian; Hatton, Thomas; Maltbie, Lori; Ainsworth, Michael; Allen, Patrick; Rosewood, Linda; Mitchell, Elizabeth; Smith, Bradley; Warner, Jim; Groboske, John; Telc, Haifang; Wilson, Daniel; Sanford, Brian; Schmidt, Hannes; Haussler, David; Maltbie, Daniel

    2014-01-01

    The Cancer Genomics Hub (CGHub) is the online repository of the sequencing programs of the National Cancer Institute (NCI), including The Cancer Genomics Atlas (TCGA), the Cancer Cell Line Encyclopedia (CCLE) and the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) projects, with data from 25 different types of cancer. The CGHub currently contains >1.4 PB of data, has grown at an average rate of 50 TB a month and serves >100 TB per week. The architecture of CGHub is designed to support bulk searching and downloading through a Web-accessible application programming interface, enforce patient genome confidentiality in data storage and transmission and optimize for efficiency in access and transfer. In this article, we describe the design of these three components, present performance results for our transfer protocol, GeneTorrent, and finally report on the growth of the system in terms of data stored and transferred, including estimated limits on the current architecture. Our experienced-based estimates suggest that centralizing storage and computational resources is more efficient than wide distribution across many satellite labs. Database URL: https://cghub.ucsc.edu. PMID:25267794

  13. Human DNA repair diseases: From genome instability to cancer

    Directory of Open Access Journals (Sweden)

    Carlos R. Machado

    1997-12-01

    Full Text Available Several human genetic syndromes have long been recognized to be defective in DNA repair mechanisms. This was first discovered by Cleaver (1968, who showed that cells from patients with xeroderma pigmentosum (XP were defective for the ability to remove ultraviolet (UV-induced lesions from their genome. Since then, new discoveries have promoted DNA repair studies to one of the most exciting areas of molecular biology. The present work intends to give a brief summary of the main known human genetic diseases related to DNA repair and how they may be linked to acquired diseases such as cancer

  14. 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.

  15. Stedets Anatomi

    DEFF Research Database (Denmark)

    Larsen, Lasse Juel

    Titlen på denne ph.d.-afhandling, Stedets Anatomi – en teoretisk undersøgelse af stedets og rumlighedens betydning for leg, computerspil og læring, skitserer ikke kun afhandlingens teoretiske dimensionering, men også dens analytiske bliks tematik i forbindelse med undersøgelsen af fænomenerne leg...

  16. Regulatory Anatomy

    DEFF Research Database (Denmark)

    Hoeyer, Klaus

    2015-01-01

    This article proposes the term “safety logics” to understand attempts within the European Union (EU) to harmonize member state legislation to ensure a safe and stable supply of human biological material for transplants and transfusions. With safety logics, I refer to assemblages of discourses, le...... arise. In short, I expose the regulatory anatomy of the policy landscape....

  17. Computed tomography of cervical and retropharyngeal lymph nodes: normal anatomy, variants of normal, and applications in staging head and neck cancer. Part 1. Normal anatomy

    International Nuclear Information System (INIS)

    The retropharyngeal and cervical lymph-node-bearing areas in 30 patients were examined with computed tomography (CT) to determine the range of normal variation in these nodal groups. The data agree with those in the pathologic, anatomic, and surgical literature, and indicate that CT can very precisely determine the size and gross morphology of normal nodes in the retropharyngeal region and the neck. This should have important applications in the management of patients with head and neck cancer

  18. Oncogenomic portals for the visualization and analysis of genome-wide cancer data.

    Science.gov (United States)

    Klonowska, Katarzyna; Czubak, Karol; Wojciechowska, Marzena; Handschuh, Luiza; Zmienko, Agnieszka; Figlerowicz, Marek; Dams-Kozlowska, Hanna; Kozlowski, Piotr

    2016-01-01

    Somatically acquired genomic alterations that drive oncogenic cellular processes are of great scientific and clinical interest. Since the initiation of large-scale cancer genomic projects (e.g., the Cancer Genome Project, The Cancer Genome Atlas, and the International Cancer Genome Consortium cancer genome projects), a number of web-based portals have been created to facilitate access to multidimensional oncogenomic data and assist with the interpretation of the data. The portals provide the visualization of small-size mutations, copy number variations, methylation, and gene/protein expression data that can be correlated with the available clinical, epidemiological, and molecular features. Additionally, the portals enable to analyze the gathered data with the use of various user-friendly statistical tools. Herein, we present a highly illustrated review of seven portals, i.e., Tumorscape, UCSC Cancer Genomics Browser, ICGC Data Portal, COSMIC, cBioPortal, IntOGen, and BioProfiling.de. All of the selected portals are user-friendly and can be exploited by scientists from different cancer-associated fields, including those without bioinformatics background. It is expected that the use of the portals will contribute to a better understanding of cancer molecular etiology and will ultimately accelerate the translation of genomic knowledge into clinical practice. PMID:26484415

  19. Connecting Genomic Alterations to Cancer Biology with Proteomics: The NCI Clinical Proteomic Tumor Analysis Consortium

    Energy Technology Data Exchange (ETDEWEB)

    Ellis, Matthew; Gillette, Michael; Carr, Steven A.; Paulovich, Amanda G.; Smith, Richard D.; Rodland, Karin D.; Townsend, Reid; Kinsinger, Christopher; Mesri, Mehdi; Rodriguez, Henry; Liebler, Daniel

    2013-10-03

    The National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium is applying the latest generation of proteomic technologies to genomically annotated tumors from The Cancer Genome Atlas (TCGA) program, a joint initiative of the NCI and the National Human Genome Research Institute. By providing a fully integrated accounting of DNA, RNA, and protein abnormalities in individual tumors, these datasets will illuminate the complex relationship between genomic abnormalities and cancer phenotypes, thus producing biologic insights as well as a wave of novel candidate biomarkers and therapeutic targets amenable to verifi cation using targeted mass spectrometry methods.

  20. The Anatomy of Learning Anatomy

    Science.gov (United States)

    Wilhelmsson, Niklas; Dahlgren, Lars Owe; Hult, Hakan; Scheja, Max; Lonka, Kirsti; Josephson, Anna

    2010-01-01

    The experience of clinical teachers as well as research results about senior medical students' understanding of basic science concepts has much been debated. To gain a better understanding about how this knowledge-transformation is managed by medical students, this work aims at investigating their ways of setting about learning anatomy.…

  1. 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. PMID:26776196

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

    OpenAIRE

    Fang Liu; Yaning Feng; Zhenye Li; Chao Pan; Yuncong Su; Rui Yang; Liying Song; Huilong Duan; Ning Deng

    2014-01-01

    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 assoc...

  3. 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).

  4. Genomic distance entrained clustering and regression modelling highlights interacting genomic regions contributing to proliferation in breast cancer

    Directory of Open Access Journals (Sweden)

    Dexter Tim J

    2010-09-01

    Full Text Available Abstract Background Genomic copy number changes and regional alterations in epigenetic states have been linked to grade in breast cancer. However, the relative contribution of specific alterations to the pathology of different breast cancer subtypes remains unclear. The heterogeneity and interplay of genomic and epigenetic variations means that large datasets and statistical data mining methods are required to uncover recurrent patterns that are likely to be important in cancer progression. Results We employed ridge regression to model the relationship between regional changes in gene expression and proliferation. Regional features were extracted from tumour gene expression data using a novel clustering method, called genomic distance entrained agglomerative (GDEC clustering. Using gene expression data in this way provides a simple means of integrating the phenotypic effects of both copy number aberrations and alterations in chromatin state. We show that regional metagenes derived from GDEC clustering are representative of recurrent regions of epigenetic regulation or copy number aberrations in breast cancer. Furthermore, detected patterns of genomic alterations are conserved across independent oestrogen receptor positive breast cancer datasets. Sequential competitive metagene selection was used to reveal the relative importance of genomic regions in predicting proliferation rate. The predictive model suggested additive interactions between the most informative regions such as 8p22-12 and 8q13-22. Conclusions Data-mining of large-scale microarray gene expression datasets can reveal regional clusters of co-ordinate gene expression, independent of cause. By correlating these clusters with tumour proliferation we have identified a number of genomic regions that act together to promote proliferation in ER+ breast cancer. Identification of such regions should enable prioritisation of genomic regions for combinatorial functional studies to pinpoint

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

    OpenAIRE

    Aaraby Yoheswaran Nielsen; Morten Frier Gjerstorff

    2016-01-01

    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 ...

  6. The Impact of Genomic Profiling for Novel Cancer Therapy--Recent Progress in Non-Small Cell Lung Cancer.

    Science.gov (United States)

    Xie, Jingwu; Zhang, Xiaoli

    2016-01-20

    There is high expectation for significant improvements in cancer patient care after completion of the human genome project in 2003. Through pains-taking analyses of genomic profiles in cancer patients, a number of targetable gene alterations have been discovered, with some leading to novel therapies, such as activating mutations of EGFR, BRAF and ALK gene fusions. As a result, clinical management of cancer through targeted therapy has finally become a reality for a subset of cancers, such as lung adenocarcinomas and melanomas. In this review, we summarize how gene mutation discovery leads to new treatment strategies using non-small cell lung cancer (NSCLC) as an example. We also discuss possible future implications of cancer genome analyses. PMID:26842989

  7. Optimal contouring of seminal vesicle for definitive radiotherapy of localized prostate cancer: comparison between EORTC prostate cancer radiotherapy guideline, RTOG0815 protocol and actual anatomy

    International Nuclear Information System (INIS)

    Intermediate- to-high-risk prostate cancer can locally invade seminal vesicle (SV). It is recommended that anatomic proximal 1-cm to 2-cm SV be included in the clinical target volume (CTV) for definitive radiotherapy based on pathology studies. However, it remains unclear whether the pathology indicated SV extent is included into the CTV defined by current guidelines. The purpose of this study is to compare the volume of proximal SV included in CTV defined by EORTC prostate cancer radiotherapy guideline and RTOG0815 protocol with the actual anatomic volume. Radiotherapy planning CT images from 114 patients with intermediate- (36.8%) or high-risk (63.2%) prostate cancer were reconstructed with 1-mm-thick sections. The starting and ending points of SV and the cross sections of SV at 1-cm and 2-cm from the starting point were determined using 3D-view. Maximum (D1H, D2H) and minimum (D1L, D2L) vertical distance from these cross sections to the starting point were measured. Then, CTV of proximal SV defined by actual anatomy, EORTC guideline and RTOG0815 protocol were contoured and compared (paired t test). Median length of D1H, D1L, D2H and D2L was 10.8 mm, 2.1 mm, 17.6 mm and 8.8 mm (95th percentile: 13.5mm, 5.0mm, 21.5mm and 13.5mm, respectively). For intermediate-risk patients, the proximal 1-cm SV CTV defined by EORTC guideline and RTOG0815 protocol inadequately included the anatomic proximal 1-cm SV in 62.3% (71/114) and 71.0% (81/114) cases, respectively. While for high-risk patients, the proximal 2-cm SV CTV defined by EORTC guideline inadequately included the anatomic proximal 2-cm SV in 17.5% (20/114) cases. SV involvement indicated by pathology studies was not completely included in the CTV defined by current guidelines. Delineation of proximal 1.4 cm and 2.2 cm SV in axial plane may be adequate to include the anatomic proximal 1-cm and 2-cm SV. However, part of SV may be over-contoured

  8. Whole-genome characterization of chemoresistant ovarian cancer.

    Science.gov (United States)

    Patch, Ann-Marie; Christie, Elizabeth L; Etemadmoghadam, Dariush; Garsed, Dale W; George, Joshy; Fereday, Sian; Nones, Katia; Cowin, Prue; Alsop, Kathryn; Bailey, Peter J; Kassahn, Karin S; Newell, Felicity; Quinn, Michael C J; Kazakoff, Stephen; Quek, Kelly; Wilhelm-Benartzi, Charlotte; Curry, Ed; Leong, Huei San; Hamilton, Anne; Mileshkin, Linda; Au-Yeung, George; Kennedy, Catherine; Hung, Jillian; Chiew, Yoke-Eng; Harnett, Paul; Friedlander, Michael; Quinn, Michael; Pyman, Jan; Cordner, Stephen; O'Brien, Patricia; Leditschke, Jodie; Young, Greg; Strachan, Kate; Waring, Paul; Azar, Walid; Mitchell, Chris; Traficante, Nadia; Hendley, Joy; Thorne, Heather; Shackleton, Mark; Miller, David K; Arnau, Gisela Mir; Tothill, Richard W; Holloway, Timothy P; Semple, Timothy; Harliwong, Ivon; Nourse, Craig; Nourbakhsh, Ehsan; Manning, Suzanne; Idrisoglu, Senel; Bruxner, Timothy J C; Christ, Angelika N; Poudel, Barsha; Holmes, Oliver; Anderson, Matthew; Leonard, Conrad; Lonie, Andrew; Hall, Nathan; Wood, Scott; Taylor, Darrin F; Xu, Qinying; Fink, J Lynn; Waddell, Nick; Drapkin, Ronny; Stronach, Euan; Gabra, Hani; Brown, Robert; Jewell, Andrea; Nagaraj, Shivashankar H; Markham, Emma; Wilson, Peter J; Ellul, Jason; McNally, Orla; Doyle, Maria A; Vedururu, Ravikiran; Stewart, Collin; Lengyel, Ernst; Pearson, John V; Waddell, Nicola; deFazio, Anna; Grimmond, Sean M; Bowtell, David D L

    2015-05-28

    Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1. PMID:26017449

  9. Mutation of mitochondria genome: trigger of somatic cell transforming to cancer cell.

    Science.gov (United States)

    Jianping, Du

    2010-01-01

    Nearly 80 years ago, scientist Otto Warburg originated a hypothesis that the cause of cancer is primarily a defect in energy metabolism. Following studies showed that mitochondria impact carcinogenesis to remodel somatic cells to cancer cells through modifying the genome, through maintenance the tumorigenic phenotype, and through apoptosis. And the Endosymbiotic Theory explains the origin of mitochondria and eukaryotes, on the other hands, the mitochondria also can fall back. Compared to chromosome genomes, the mitochondria genomes were not restricted by introns so they were mutated(fall back) easy. The result is that mitochondria lose function and internal environment of somatic cell become acid and evoked chromosome genomes to mutate, in the end somatic cells become cancer cells. It is the trigger of somatic cell transforming to cancer cell that mitochondria genome happen mutation and lose function. PMID:20181100

  10. The national cancer institute (NCI) and cancer biology in a 'post genome world'

    International Nuclear Information System (INIS)

    The National Cancer Institute (NCI) exists to reduce the burden of all cancers through research and discovery. Extensive restructuring of the NCI over the past year has been aimed at assuring that the institution functions in all ways to promote opportunities for discovery in the laboratory, in the clinic, and in the community. To do this well requires the difficult and almost paradoxical problem of planning for scientific discovery which, in turn is based on the freedom to pursue the unanticipated. The intellectual and structural landscape of science is changing and it places new challenges, new demands and new opportunities for facilitating discovery. The nature of cancer as a disease of genomic instability and of accumulated genetic change, coupled with a possibility of the development of new technologies for reading, utilizing, interpreting and manipulating the genome of single cells, provides unprecedented opportunities for a new type of high through-put biology that will change the nature of discovery, cancer detection, diagnosis, prognosis, therapeutic decision-making and therapeutic discovery. To capture these new opportunities will require attention to be paid to integrate the development of technology and new scientific discoveries with the ability to apply advances rapidly and efficiently through clinical trials

  11. 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 ...

  12. Normal Female Reproductive Anatomy

    Science.gov (United States)

    ... historical Searches are case-insensitive Reproductive System, Female, Anatomy Add to My Pictures View /Download : Small: 720x756 ... Large: 3000x3150 View Download Title: Reproductive System, Female, Anatomy Description: Anatomy of the female reproductive system; drawing ...

  13. Thymus Gland Anatomy

    Science.gov (United States)

    ... historical Searches are case-insensitive Thymus Gland, Adult, Anatomy Add to My Pictures View /Download : Small: 720x576 ... Large: 3000x2400 View Download Title: Thymus Gland, Adult, Anatomy Description: Anatomy of the thymus gland; drawing shows ...

  14. Normal Pancreas Anatomy

    Science.gov (United States)

    ... hyphen, e.g. -historical Searches are case-insensitive Pancreas Anatomy Add to My Pictures View /Download : Small: ... 1586x1534 View Download Large: 3172x3068 View Download Title: Pancreas Anatomy Description: Anatomy of the pancreas; drawing shows ...

  15. Genome sequencing and analysis of the Tasmanian devil and its transmissible cancer.

    Science.gov (United States)

    Murchison, Elizabeth P; Schulz-Trieglaff, Ole B; Ning, Zemin; Alexandrov, Ludmil B; Bauer, Markus J; Fu, Beiyuan; Hims, Matthew; Ding, Zhihao; Ivakhno, Sergii; Stewart, Caitlin; Ng, Bee Ling; Wong, Wendy; Aken, Bronwen; White, Simon; Alsop, Amber; Becq, Jennifer; Bignell, Graham R; Cheetham, R Keira; Cheng, William; Connor, Thomas R; Cox, Anthony J; Feng, Zhi-Ping; Gu, Yong; Grocock, Russell J; Harris, Simon R; Khrebtukova, Irina; Kingsbury, Zoya; Kowarsky, Mark; Kreiss, Alexandre; Luo, Shujun; Marshall, John; McBride, David J; Murray, Lisa; Pearse, Anne-Maree; Raine, Keiran; Rasolonjatovo, Isabelle; Shaw, Richard; Tedder, Philip; Tregidgo, Carolyn; Vilella, Albert J; Wedge, David C; Woods, Gregory M; Gormley, Niall; Humphray, Sean; Schroth, Gary; Smith, Geoffrey; Hall, Kevin; Searle, Stephen M J; Carter, Nigel P; Papenfuss, Anthony T; Futreal, P Andrew; Campbell, Peter J; Yang, Fengtang; Bentley, David R; Evers, Dirk J; Stratton, Michael R

    2012-02-17

    The Tasmanian devil (Sarcophilus harrisii), the largest marsupial carnivore, is endangered due to a transmissible facial cancer spread by direct transfer of living cancer cells through biting. Here we describe the sequencing, assembly, and annotation of the Tasmanian devil genome and whole-genome sequences for two geographically distant subclones of the cancer. Genomic analysis suggests that the cancer first arose from a female Tasmanian devil and that the clone has subsequently genetically diverged during its spread across Tasmania. The devil cancer genome contains more than 17,000 somatic base substitution mutations and bears the imprint of a distinct mutational process. Genotyping of somatic mutations in 104 geographically and temporally distributed Tasmanian devil tumors reveals the pattern of evolution and spread of this parasitic clonal lineage, with evidence of a selective sweep in one geographical area and persistence of parallel lineages in other populations. PMID:22341448

  16. Genome instability in blood cells of a BRCA1+ breast cancer family

    International Nuclear Information System (INIS)

    BRCA1 plays an essential role in maintaining genome stability. Inherited BRCA1 germline mutation (BRCA1+) is a determined genetic predisposition leading to high risk of breast cancer. While BRCA1+ induces breast cancer by causing genome instability, most of the knowledge is known about somatic genome instability in breast cancer cells but not germline genome instability. Using the exome-sequencing method, we analyzed the genomes of blood cells in a typical BRCA1+ breast cancer family with an exon 13-duplicated founder mutation, including six breast cancer-affected and two breast cancer unaffected members. We identified 23 deleterious mutations in the breast cancer-affected family members, which are absent in the unaffected members. Multiple mutations damaged functionally important and breast cancer-related genes, including transcriptional factor BPTF and FOXP1, ubiquitin ligase CUL4B, phosphorylase kinase PHKG2, and nuclear receptor activator SRA1. Analysis of the mutations between the mothers and daughters shows that most mutations were germline mutation inherited from the ancestor(s) while only a few were somatic mutation generated de novo. Our study indicates that BRCA1+ can cause genome instability with both germline and somatic mutations in non-breast cells

  17. Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins.

    Science.gov (United States)

    Rozenblatt-Rosen, Orit; Deo, Rahul C; Padi, Megha; Adelmant, Guillaume; Calderwood, Michael A; Rolland, Thomas; Grace, Miranda; Dricot, Amélie; Askenazi, Manor; Tavares, Maria; Pevzner, Samuel J; Abderazzaq, Fieda; Byrdsong, Danielle; Carvunis, Anne-Ruxandra; Chen, Alyce A; Cheng, Jingwei; Correll, Mick; Duarte, Melissa; Fan, Changyu; Feltkamp, Mariet C; Ficarro, Scott B; Franchi, Rachel; Garg, Brijesh K; Gulbahce, Natali; Hao, Tong; Holthaus, Amy M; James, Robert; Korkhin, Anna; Litovchick, Larisa; Mar, Jessica C; Pak, Theodore R; Rabello, Sabrina; Rubio, Renee; Shen, Yun; Singh, Saurav; Spangle, Jennifer M; Tasan, Murat; Wanamaker, Shelly; Webber, James T; Roecklein-Canfield, Jennifer; Johannsen, Eric; Barabási, Albert-László; Beroukhim, Rameen; Kieff, Elliott; Cusick, Michael E; Hill, David E; Münger, Karl; Marto, Jarrod A; Quackenbush, John; Roth, Frederick P; DeCaprio, James A; Vidal, Marc

    2012-07-26

    Genotypic differences greatly influence susceptibility and resistance to disease. Understanding genotype-phenotype relationships requires that phenotypes be viewed as manifestations of network properties, rather than simply as the result of individual genomic variations. Genome sequencing efforts have identified numerous germline mutations, and large numbers of somatic genomic alterations, associated with a predisposition to cancer. However, it remains difficult to distinguish background, or 'passenger', cancer mutations from causal, or 'driver', mutations in these data sets. Human viruses intrinsically depend on their host cell during the course of infection and can elicit pathological phenotypes similar to those arising from mutations. Here we test the hypothesis that genomic variations and tumour viruses may cause cancer through related mechanisms, by systematically examining host interactome and transcriptome network perturbations caused by DNA tumour virus proteins. The resulting integrated viral perturbation data reflects rewiring of the host cell networks, and highlights pathways, such as Notch signalling and apoptosis, that go awry in cancer. We show that systematic analyses of host targets of viral proteins can identify cancer genes with a success rate on a par with their identification through functional genomics and large-scale cataloguing of tumour mutations. Together, these complementary approaches increase the specificity of cancer gene identification. Combining systems-level studies of pathogen-encoded gene products with genomic approaches will facilitate the prioritization of cancer-causing driver genes to advance the understanding of the genetic basis of human cancer. PMID:22810586

  18. Interpreting cancer genomes using systematic host perturbations by tumour virus proteins

    Science.gov (United States)

    Rozenblatt-Rosen, Orit; Deo, Rahul C.; Padi, Megha; Adelmant, Guillaume; Calderwood, Michael A.; Rolland, Thomas; Grace, Miranda; Dricot, Amélie; Askenazi, Manor; Tavares, Maria; Pevzner, Sam; Abderazzaq, Fieda; Byrdsong, Danielle; Carvunis, Anne-Ruxandra; Chen, Alyce A.; Cheng, Jingwei; Correll, Mick; Duarte, Melissa; Fan, Changyu; Feltkamp, Mariet C.; Ficarro, Scott B.; Franchi, Rachel; Garg, Brijesh K.; Gulbahce, Natali; Hao, Tong; Holthaus, Amy M.; James, Robert; Korkhin, Anna; Litovchick, Larisa; Mar, Jessica C.; Pak, Theodore R.; Rabello, Sabrina; Rubio, Renee; Shen, Yun; Singh, Saurav; Spangle, Jennifer M.; Tasan, Murat; Wanamaker, Shelly; Webber, James T.; Roecklein-Canfield, Jennifer; Johannsen, Eric; Barabási, Albert-László; Beroukhim, Rameen; Kieff, Elliott; Cusick, Michael E.; Hill, David E.; Münger, Karl; Marto, Jarrod A.; Quackenbush, John; Roth, Frederick P.; DeCaprio, James A.; Vidal, Marc

    2012-01-01

    Genotypic differences greatly influence susceptibility and resistance to disease. Understanding genotype-phenotype relationships requires that phenotypes be viewed as manifestations of network properties, rather than simply as the result of individual genomic variations1. Genome sequencing efforts have identified numerous germline mutations associated with cancer predisposition and large numbers of somatic genomic alterations2. However, it remains challenging to distinguish between background, or “passenger” and causal, or “driver” cancer mutations in these datasets. Human viruses intrinsically depend on their host cell during the course of infection and can elicit pathological phenotypes similar to those arising from mutations3. To test the hypothesis that genomic variations and tumour viruses may cause cancer via related mechanisms, we systematically examined host interactome and transcriptome network perturbations caused by DNA tumour virus proteins. The resulting integrated viral perturbation data reflects rewiring of the host cell networks, and highlights pathways that go awry in cancer, such as Notch signalling and apoptosis. We show that systematic analyses of host targets of viral proteins can identify cancer genes with a success rate on par with their identification through functional genomics and large-scale cataloguing of tumour mutations. Together, these complementary approaches result in increased specificity for cancer gene identification. Combining systems-level studies of pathogen-encoded gene products with genomic approaches will facilitate prioritization of cancer-causing driver genes so as to advance understanding of the genetic basis of human cancer. PMID:22810586

  19. Integrating microarray gene expression object model and clinical document architecture for cancer genomics research.

    Science.gov (United States)

    Park, Yu Rang; Lee, Hye Won; Kim, Ju Han

    2005-01-01

    Systematic integration of genomic-scale expression profiles with clinical information may facilitate cancer genomics research. MAGE-OM (Microarray Gene Expression Object Model) defines standard objects for genomic but not for clinical data. HL7 CDA (Clinical Document Architecture) is a document model for clinical information, describing syntax (generic structure) but not semantics. We designed a document template in XML Schema with additional constraints for CDA to define content semantics, enabling data model-level integration of MAGE-OM and CDA for cancer genomics research. PMID:16779360

  20. 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.

  1. 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

  2. Association between invasive ovarian cancer susceptibility and 11 best candidate SNPs from breast cancer genome-wide association study

    DEFF Research Database (Denmark)

    Song, Honglin; Ramus, Susan J; Kjaer, Susanne Krüger;

    2009-01-01

    Because both ovarian and breast cancer are hormone-related and are known to have some predisposition genes in common, we evaluated 11 of the most significant hits (six with confirmed associations with breast cancer) from the breast cancer genome-wide association study for association with invasive.......01-1.13, P-trend = 0.02 for all types of ovarian cancer and OR 1.14 95% CI 1.07-1.22, P-trend = 0.00017 for serous ovarian cancer]. In conclusion, we found that rs4954956 was associated with increased ovarian cancer risk, particularly for serous ovarian cancer. However, none of the six confirmed breast...... ovarian cancer. Eleven SNPs were initially genotyped in 2927 invasive ovarian cancer cases and 4143 controls from six ovarian cancer case-control studies. Genotype frequencies in cases and controls were compared using a likelihood ratio test in a logistic regression model stratified by study. Initially...

  3. 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; Krzystanek, Marcin; Favero, Francesco; Wang, Zhigang C; Richardson, Andrea L; Silver, Daniel P; Szallasi, Zoltan Imre; Birkbak, Nicolai Juul

    2015-01-01

    accumulation of similar genomic scars also show increased sensitivity to platinum-based chemotherapy. Therefore, reliable biomarkers to identify DNA repair-deficient cancers prior to treatment may be useful for directing patients to platinum chemotherapy and possibly PARP inhibitors. Recently, three SNP array......-based signatures of chromosomal instability were published that each quantitate a distinct type of genomic scar considered likely to be caused by improper DNA repair. They measure telomeric allelic imbalance (named NtAI), large scale transition (named LST), and loss of heterozygosity (named HRD-LOH), and it is...... suggested that these signatures may act as biomarkers for the state of DNA repair deficiency in a given cancer. We explored the pan-cancer distribution of scores of the three signatures utilizing a panel of 5371 tumors representing 15 cancer types from The Cancer Genome Atlas, and found a good correlation...

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

    Science.gov (United States)

    Nielsen, Aaraby Yoheswaran; Gjerstorff, Morten Frier

    2016-01-01

    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. PMID:27275820

  5. Targeting the Human Cancer Pathway Protein Interaction Network by Structural Genomics*

    OpenAIRE

    Huang, Yuanpeng Janet; Hang, Dehua; Lu, Long Jason; Tong, Liang; Gerstein, Mark B; Montelione, Gaetano T.

    2008-01-01

    Structural genomics provides an important approach for characterizing and understanding systems biology. As a step toward better integrating protein three-dimensional (3D) structural information in cancer systems biology, we have constructed a Human Cancer Pathway Protein Interaction Network (HCPIN) by analysis of several classical cancer-associated signaling pathways and their physical protein-protein interactions. Many well known cancer-associated proteins play central roles as “hubs” or “b...

  6. Needles in a haystack: finding recurrent genomic changes in breast cancer

    OpenAIRE

    Cidado, Justin; Beaver, Julia A.; Park, Ben Ho

    2013-01-01

    Significant advances over the past decade have enabled scientists to obtain increasingly detailed molecular profiles of breast cancer. The recent analysis by The Cancer Genome Atlas published in the September 2012 issue of Nature is the most comprehensive description of breast cancer 'omics' to date. This study is impressive in its scope and scale, with the findings reconfirming the heterogeneity of breast cancer and highlighting the future challenges in translating these findings for clinica...

  7. 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.

  8. Significance of genomic instability in breast cancer in atomic bomb survivors: analysis of microarray-comparative genomic hybridization

    OpenAIRE

    Oikawa Masahiro; Yoshiura Koh-ichiro; Kondo Hisayoshi; Miura Shiro; Nagayasu Takeshi; Nakashima Masahiro

    2011-01-01

    Abstract Background It has been postulated that ionizing radiation induces breast cancers among atomic bomb (A-bomb) survivors. We have reported a higher incidence of HER2 and C-MYC oncogene amplification in breast cancers from A-bomb survivors. The purpose of this study was to clarify the effect of A-bomb radiation exposure on genomic instability (GIN), which is an important hallmark of carcinogenesis, in archival formalin-fixed paraffin-embedded (FFPE) tissues of breast cancer by using micr...

  9. 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....

  10. The search for cis-regulatory driver mutations in cancer genomes

    OpenAIRE

    Poulos, Rebecca C.; Sloane, Mathew A; Hesson, Luke B; Wong, Jason W. H.

    2015-01-01

    With the advent of high-throughput and relatively inexpensive whole-genome sequencing technology, the focus of cancer research has begun to shift toward analyses of somatic mutations in non-coding cis-regulatory elements of the cancer genome. Cis-regulatory elements play an important role in gene regulation, with mutations in these elements potentially resulting in changes to the expression of linked genes. The recent discoveries of recurrent TERT promoter mutations in melanoma, and recurrent...

  11. Pre-Diagnostic Leukocyte Genomic DNA Methylation and the Risk of Colorectal Cancer in Women

    OpenAIRE

    Hongmei Nan; Giovannucci, Edward L; Kana Wu; Jacob Selhub; Ligi Paul; Bernard Rosner; Fuchs, Charles S; Eunyoung Cho

    2013-01-01

    BACKGROUND: Abnormal one-carbon metabolism may lead to general genomic (global) hypomethylation, which may predispose an individual to the development of colorectal neoplasia. METHODS: We evaluated the association between pre-diagnostic leukocyte genomic DNA methylation level and the risk of colorectal cancer in a nested case-control study of 358 colorectal cancer cases and 661 matched controls within the all-female cohort of the Nurses' Health Study (NHS). Among control subjects, we further ...

  12. A Genome-Wide Systematic Analysis Reveals Different and Predictive Proliferation Expression Signatures of Cancerous vs. Non-Cancerous Cells

    OpenAIRE

    Waldman, Yedael Y.; Geiger, Tamar; Ruppin, Eytan

    2013-01-01

    Understanding cell proliferation mechanisms has been a long-lasting goal of the scientific community and specifically of cancer researchers. Previous genome-scale studies of cancer proliferation determinants have mainly relied on knockdown screens aimed to gauge their effects on cancer growth. This powerful approach has several limitations such as off-target effects, partial knockdown, and masking effects due to functional backups. Here we employ a complementary approach and assign each gene ...

  13. MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells | Office of Cancer Genomics

    Science.gov (United States)

    The discovery of cancer dependencies has the potential to inform therapeutic strategies and to identify putative drug targets. Integrating data from comprehensive genomic profiling of cancer cell lines and from functional characterization of cancer cell dependencies, we discovered that loss of the enzyme methylthioadenosine phosphorylase (MTAP) confers a selective dependence on protein arginine methyltransferase 5 (PRMT5) and its binding partner WDR77. MTAP is frequently lost due to its proximity to the commonly deleted tumor suppressor gene, CDKN2A.

  14. 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.

  15. Interest and Informational Preferences Regarding Genomic Testing for Modest Increases in Colorectal Cancer Risk

    Science.gov (United States)

    Anderson, Allison E.; Flores, Kristina G.; Boonyasiriwat, Watcharaporn; Gammon, Amanda; Kohlmann, Wendy; Birmingham, Wendy C.; Schwartz, Marc D.; Samadder, Jewel; Boucher, Ken; Kinney, Anita Y.

    2014-01-01

    Background/Aims To explore interest in genomic testing for modest changes in colorectal cancer risk and preferences for receiving genomic risk communications among individuals with intermediate disease risk due to a family history of colorectal cancer. Methods Surveys were conducted on 278 men and women at intermediate risk for colorectal cancer enrolled in a randomized trial comparing a remote personalized risk communication intervention (TeleCARE) aimed at promoting colonoscopy to a generic print control condition. Guided by Leventhal’s Common Sense Model of Self-regulation, we examined demographic and psychosocial factors possibly associated with interest in SNP testing. Descriptive statistics and logistic regression models were used to identify factors associated with testing interest and preferences for receiving genomic risk communications. Results Three-fourths of participants expressed interest in SNP testing for colorectal cancer risk. Testing interest did not markedly change across behavior modifier scenarios. Participants preferred to receive genomic risk communications from a variety of sources: printed materials, (69.1%), oncologists (59.5%), primary-care physicians (58.1%), and the web (57.9%). Overall, persons who were unmarried (p=0.029), younger (p=0.003), and with greater cancer-related fear (p=0.019) were more likely to express interest in predictive genomic testing for colorectal cancer risk. In a stratified analysis, cancer related fear was associated with interest in predictive genomic testing in the intervention group (p=0.017) but not the control group. Conclusions Individuals with intermediate familial risk for colorectal cancer are highly interested in genomic testing for modest increases in disease risk, specifically unmarried persons, younger age groups, and those with greater cancer fear. PMID:24435063

  16. Whole genome sequencing defines the genetic heterogeneity of familial pancreatic cancer

    Science.gov (United States)

    Roberts, Nicholas J.; Norris, Alexis L.; Petersen, Gloria M.; Bondy, Melissa L.; Brand, Randall; Gallinger, Steven; Kurtz, Robert C.; Olson, Sara H.; Rustgi, Anil K.; Schwartz, Ann G.; Stoffel, Elena; Syngal, Sapna; Zogopoulos, George; Ali, Syed Z.; Axilbund, Jennifer; Chaffee, Kari G.; Chen, Yun-Ching; Cote, Michele L.; Childs, Erica J.; Douville, Christopher; Goes, Fernando S.; Herman, Joseph M.; Iacobuzio-Donahue, Christine; Kramer, Melissa; Makohon-Moore, Alvin; McCombie, Richard W.; McMahon, K. Wyatt; Niknafs, Noushin; Parla, Jennifer; Pirooznia, Mehdi; Potash, James B.; Rhim, Andrew D.; Smith, Alyssa L.; Wang, Yuxuan; Wolfgang, Christopher L.; Wood, Laura D.; Zandi, Peter P.; Goggins, Michael; Karchin, Rachel; Eshleman, James R.; Papadopoulos, Nickolas; Kinzler, Kenneth W.; Vogelstein, Bert; Hruban, Ralph H.; Klein, Alison P.

    2015-01-01

    Pancreatic cancer is projected to become the second leading cause of cancer-related death in the United States by 2020. A familial aggregation of pancreatic cancer has been established, but the cause of this aggregation in most families is unknown. To determine the genetic basis of susceptibility in these families, we sequenced the germline genome of 638 familial pancreatic cancer patients. We also sequenced the exomes of 39 familial pancreatic adenocarcinomas. Our analyses support the role of previously identified familial pancreatic cancer susceptibility genes such as BRCA2, CDKN2A and ATM, and identify novel candidate genes harboring rare, deleterious germline variants for further characterization. We also show how somatic point mutations that occur during hematopoiesis can affect the interpretation of genome-wide studies of hereditary traits. Our observations have important implications for the etiology of pancreatic cancer and for the identification of susceptibility genes in other common cancer types. PMID:26658419

  17. Breast Cancer in Africa: Limitations and Opportunities for Application of Genomic Medicine

    Directory of Open Access Journals (Sweden)

    Allison Silverstein

    2016-01-01

    Full Text Available As genomic medicine gains clinical applicability across a spectrum of diseases, insufficient application in low-income settings stands to increase health disparity. Breast cancer screening, diagnosis, and treatment have benefited greatly from genomic medicine in high-income settings. As breast cancer is a leading cause of both cancer incidence and mortality in Africa, attention and resources must be applied to research and clinical initiatives to integrate genomic medicine into breast cancer care. In terms of research, there is a paucity of investigations into genetic determinants of breast cancer specific to African populations, despite consensus in the literature that predisposition and susceptibility genes vary between populations. Therefore, we need targeted strengthening of existing research efforts and support of new initiatives. Results will improve clinical care through screening and diagnosis with genetic testing specific to breast cancer in African populations. Clinically, genomic medicine can provide information capable of improving resource allocation to the population which most stands to benefit from increased screening or tailored treatment modalities. In situations where mammography or chemotherapy options are limited, this information will allow for the greatest impact. Implementation of genomic medicine will face numerous systemic barriers but is essential to improve breast cancer outcomes and survival.

  18. A somatic reference standard for cancer genome sequencing

    Science.gov (United States)

    Craig, David W.; Nasser, Sara; Corbett, Richard; Chan, Simon K.; Murray, Lisa; Legendre, Christophe; Tembe, Waibhav; Adkins, Jonathan; Kim, Nancy; Wong, Shukmei; Baker, Angela; Enriquez, Daniel; Pond, Stephanie; Pleasance, Erin; Mungall, Andrew J.; Moore, Richard A.; McDaniel, Timothy; Ma, Yussanne; Jones, Steven J. M.; Marra, Marco A.; Carpten, John D.; Liang, Winnie S.

    2016-01-01

    Large-scale multiplexed identification of somatic alterations in cancer has become feasible with next generation sequencing (NGS). However, calibration of NGS somatic analysis tools has been hampered by a lack of tumor/normal reference standards. We thus performed paired PCR-free whole genome sequencing of a matched metastatic melanoma cell line (COLO829) and normal across three lineages and across separate institutions, with independent library preparations, sequencing, and analysis. We generated mean mapped coverages of 99X for COLO829 and 103X for the paired normal across three institutions. Results were combined with previously generated data allowing for comparison to a fourth lineage on earlier NGS technology. Aggregate variant detection led to the identification of consensus variants, including key events that represent hallmark mutation types including amplified BRAF V600E, a CDK2NA small deletion, a 12 kb PTEN deletion, and a dinucleotide TERT promoter substitution. Overall, common events include >35,000 point mutations, 446 small insertion/deletions, and >6,000 genes affected by copy number changes. We present this reference to the community as an initial standard for enabling quantitative evaluation of somatic mutation pipelines across institutions. PMID:27094764

  19. A somatic reference standard for cancer genome sequencing.

    Science.gov (United States)

    Craig, David W; Nasser, Sara; Corbett, Richard; Chan, Simon K; Murray, Lisa; Legendre, Christophe; Tembe, Waibhav; Adkins, Jonathan; Kim, Nancy; Wong, Shukmei; Baker, Angela; Enriquez, Daniel; Pond, Stephanie; Pleasance, Erin; Mungall, Andrew J; Moore, Richard A; McDaniel, Timothy; Ma, Yussanne; Jones, Steven J M; Marra, Marco A; Carpten, John D; Liang, Winnie S

    2016-01-01

    Large-scale multiplexed identification of somatic alterations in cancer has become feasible with next generation sequencing (NGS). However, calibration of NGS somatic analysis tools has been hampered by a lack of tumor/normal reference standards. We thus performed paired PCR-free whole genome sequencing of a matched metastatic melanoma cell line (COLO829) and normal across three lineages and across separate institutions, with independent library preparations, sequencing, and analysis. We generated mean mapped coverages of 99X for COLO829 and 103X for the paired normal across three institutions. Results were combined with previously generated data allowing for comparison to a fourth lineage on earlier NGS technology. Aggregate variant detection led to the identification of consensus variants, including key events that represent hallmark mutation types including amplified BRAF V600E, a CDK2NA small deletion, a 12 kb PTEN deletion, and a dinucleotide TERT promoter substitution. Overall, common events include >35,000 point mutations, 446 small insertion/deletions, and >6,000 genes affected by copy number changes. We present this reference to the community as an initial standard for enabling quantitative evaluation of somatic mutation pipelines across institutions. PMID:27094764

  20. Using the canine genome to cure cancer and other diseases.

    Science.gov (United States)

    Olson, P N

    2007-08-01

    A high-quality draft genome sequence of the domestic dog (Canis familiaris), together with a dense map of single nucleotide polymorphisms, has been reported. Such new tools offer scientists amazing opportunities to define genetic, nutritional, environmental, and other risk factors for various canine diseases. Because many of the diseases that affect man's best friend also affect us, understanding a dog's disease may lead to new preventions and therapies for diseases that affect both dogs and people. Since a dog's life span is shorter than that for a human, monitoring potential risk factors in a well-controlled population of dogs is possible. Such a population should be one where dogs live in close relationship with their owners. Although longitudinal studies have been previously conducted on animals housed in laboratory environments, the natural environment offers a chance to study dogs in environments shared by their owners. If dogs are carefully monitored, and select exposures defined, considerable information could be collected in a dog's lifetime--the next 10-20 years. Such information could hold the clues for important discoveries, including causes and cures for cancer. PMID:17498794

  1. 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. PMID:26909576

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

    OpenAIRE

    Pesko, Kendra; Voigt, Emily A.; Swick, Adam; Morley, Valerie J.; Timm, Collin; Yin, John; Paul E. Turner

    2015-01-01

    Gene order is often highly conserved within taxonomic groups, such that organisms with rearranged genomes tend to be less fit than wild type 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 non-segmented RNA viruses (order Mononegavirales) have specific genome architecture: 3′ UTR – core protein genes – envelo...

  3. 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...

  4. Will we cure cancer by sequencing thousands of genomes?

    OpenAIRE

    Nicholson, Joshua M.

    2013-01-01

    Abstract The promise to understand cancer and develop efficacious therapies by sequencing thousands of cancers has not occurred. Mutations in specific genes termed oncogenes and tumor suppressor genes are extremely heterogeneous amongst the same type of cancer as well as between cancers. They provide little selective advantage to the cancer and in functional tests have yet to be shown to be sufficient for transformation. Here I discuss the karyotyptic theory of cancer and ask...

  5. Facilitating a Culture of Responsible and Effective Sharing of Cancer Genome Data

    Science.gov (United States)

    Siu, Lillian L.; Lawler, Mark; Haussler, David; Knoppers, Bartha Maria; Lewin, Jeremy; Vis, Daniel J.; Liao, Rachel G.; Andre, Fabrice; Banks, Ian; Barrett, J. Carl; Caldas, Carlos; Camargo, Anamaria Aranha; Fitzgerald, Rebecca C.; Mao, Mao; Mattison, John E.; Pao, William; Sellers, William R.; Sullivan, Patrick; Teh, Bin Tean; Ward, Robyn; ZenKlusen, Jean Claude; Sawyers, Charles L; Voest, Emile E.

    2016-01-01

    Rapid and affordable tumor molecular profiling has led to an explosion of clinical and genomic data poised to enhance diagnosis, prognostication and treatment of cancer. A critical point has now been reached where analysis and storage of annotated clinical and genomic information in unconnected silos will stall the advancement of precision cancer care. Information systems must be harmonized to overcome the multiple technical and logistical barriers for data sharing. Against this backdrop, the Global Alliance for Genomic Health (GA4GH) was established in 2013 to create a common framework that enables responsible, voluntary, and secure sharing of clinical and genomic data. This Perspective from the GA4GH Clinical Working Group Cancer Task Team highlights the data aggregation challenges faced by the field, suggests potential collaborative solutions, and describes how GA4GH can catalyze a harmonized data sharing culture. PMID:27149219

  6. Facilitating a culture of responsible and effective sharing of cancer genome data.

    Science.gov (United States)

    Siu, Lillian L; Lawler, Mark; Haussler, David; Knoppers, Bartha Maria; Lewin, Jeremy; Vis, Daniel J; Liao, Rachel G; Andre, Fabrice; Banks, Ian; Barrett, J Carl; Caldas, Carlos; Camargo, Anamaria Aranha; Fitzgerald, Rebecca C; Mao, Mao; Mattison, John E; Pao, William; Sellers, William R; Sullivan, Patrick; Teh, Bin Tean; Ward, Robyn L; ZenKlusen, Jean Claude; Sawyers, Charles L; Voest, Emile E

    2016-05-01

    Rapid and affordable tumor molecular profiling has led to an explosion of clinical and genomic data poised to enhance the diagnosis, prognostication and treatment of cancer. A critical point has now been reached at which the analysis and storage of annotated clinical and genomic information in unconnected silos will stall the advancement of precision cancer care. Information systems must be harmonized to overcome the multiple technical and logistical barriers to data sharing. Against this backdrop, the Global Alliance for Genomic Health (GA4GH) was established in 2013 to create a common framework that enables responsible, voluntary and secure sharing of clinical and genomic data. This Perspective from the GA4GH Clinical Working Group Cancer Task Team highlights the data-aggregation challenges faced by the field, suggests potential collaborative solutions and describes how GA4GH can catalyze a harmonized data-sharing culture. PMID:27149219

  7. High-Resolution Comparative Genomic Hybridization of Inflammatory Breast Cancer and Identification of Candidate Genes

    OpenAIRE

    Bekhouche, Ismahane; Finetti, Pascal; Adelaïde, José; Ferrari, Anthony; Tarpin, Carole; Charafe-Jauffret, Emmanuelle; Charpin, Colette; Houvenaeghel, Gilles; Jacquemier, Jocelyne; Bidaut, Ghislain; Birnbaum, Daniel; Viens, Patrice; Chaffanet, Max; Bertucci, François

    2011-01-01

    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 ...

  8. 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

  9. Cancer core modules identification through genomic and transcriptomic changes correlation detection at network level

    Directory of Open Access Journals (Sweden)

    Li Wenting

    2012-06-01

    Full Text Available Abstract Background Identification of driver mutations among numerous genomic alternations remains a critical challenge to the elucidation of the underlying mechanisms of cancer. Because driver mutations by definition are associated with a greater number of cancer phenotypes compared to other mutations, we hypothesized that driver mutations could more easily be identified once the genotype-phenotype correlations are detected across tumor samples. Results In this study, we describe a novel network analysis to identify the driver mutation through integrating both cancer genomes and transcriptomes. Our method successfully identified a significant genotype-phenotype change correlation in all six solid tumor types and revealed core modules that contain both significantly enriched somatic mutations and aberrant expression changes specific to tumor development. Moreover, we found that the majority of these core modules contained well known cancer driver mutations, and that their mutated genes tended to occur at hub genes with central regulatory roles. In these mutated genes, the majority were cancer-type specific and exhibited a closer relationship within the same cancer type rather than across cancer types. The remaining mutated genes that exist in multiple cancer types led to two cancer type clusters, one cluster consisted of three neural derived or related cancer types, and the other cluster consisted of two adenoma cancer types. Conclusions Our approach can successfully identify the candidate drivers from the core modules. Comprehensive network analysis on the core modules potentially provides critical insights into convergent cancer development in different organs.

  10. A genome-wide systematic analysis reveals different and predictive proliferation expression signatures of cancerous vs. non-cancerous cells.

    Directory of Open Access Journals (Sweden)

    Yedael Y Waldman

    Full Text Available Understanding cell proliferation mechanisms has been a long-lasting goal of the scientific community and specifically of cancer researchers. Previous genome-scale studies of cancer proliferation determinants have mainly relied on knockdown screens aimed to gauge their effects on cancer growth. This powerful approach has several limitations such as off-target effects, partial knockdown, and masking effects due to functional backups. Here we employ a complementary approach and assign each gene a cancer Proliferation Index (cPI that quantifies the association between its expression levels and growth rate measurements across 60 cancer cell lines. Reassuringly, genes found essential in cancer gene knockdown screens exhibit significant positive cPI values, while tumor suppressors exhibit significant negative cPI values. Cell cycle, DNA replication, splicing and protein production related processes are positively associated with cancer proliferation, while cellular migration is negatively associated with it - in accordance with the well known "go or grow" dichotomy. A parallel analysis of genes' non-cancerous proliferation indices (nPI across 224 lymphoblastoid cell lines reveals surprisingly marked differences between cancerous and non-cancerous proliferation. These differences highlight genes in the translation and spliceosome machineries as selective cancer proliferation-associated proteins. A cross species comparison reveals that cancer proliferation resembles that of microorganisms while non-cancerous proliferation does not. Furthermore, combining cancerous and non-cancerous proliferation signatures leads to enhanced prediction of patient outcome and gene essentiality in cancer. Overall, these results point to an inherent difference between cancerous and non-cancerous proliferation determinants, whose understanding may contribute to the future development of novel cancer-specific anti-proliferative drugs.

  11. An Integrative Genomics Approach for Associating GWAS Information with Triple-Negative Breast Cancer

    OpenAIRE

    Chindo Hicks; Ranjit Kumar; Antonio Pannuti; Kandis Backus; Alexandra Brown; Jesus Monico; Lucio Miele

    2013-01-01

    Genome-wide association studies (GWAS) have identified genetic variants associated with an increased risk of developing breast cancer. However, the association of genetic variants and their associated genes with the most aggressive subset of breast cancer, the triple-negative breast cancer (TNBC), remains a central puzzle in molecular epidemiology. The objective of this study was to determine whether genes containing single nucleotide polymorphisms (SNPs) associated with an increased risk of ...

  12. Genomic profiling identifies TITF1 as a lineage-specific oncogene amplified in lung cancer

    OpenAIRE

    Kwei, KA; Kim, YH; Girard, L; Kao, J; Pacyna-Gengelbach, M; Salari, K; Lee, J.; Choi, Y-L; Sato, M.; Wang, P.; Hernandez-Boussard, T; Gazdar, AF; Petersen, I. (Inga); Minna, JD; Pollack, JR

    2008-01-01

    Lung cancer is a leading cause of cancer death, where the amplification of oncogenes contributes to tumorigenesis. Genomic profiling of 128 lung cancer cell lines and tumors revealed frequent focal DNA amplification at cytoband 14q13.3, a locus not amplified in other tumor types. The smallest region of recurrent amplification spanned the homeobox transcription factor TITF1 (thyroid transcription factor 1; also called NKX2-1), previously linked to normal lung development and function. When amp...

  13. Colorectal cancer and the human gut microbiome: reproducibility with whole-genome shotgun sequencing

    OpenAIRE

    Emily Vogtmann; Xing Hua; Georg Zeller; Shinichi Sunagawa; Voigt, Anita Y.; Rajna Hercog; Goedert, James J.; Jianxin Shi; Peer Bork; Rashmi Sinha

    2016-01-01

    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 pub...

  14. 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,

  15. Genome-wide association study of susceptibility loci for breast cancer in Sardinian population

    International Nuclear Information System (INIS)

    Despite progress in identifying genes associated with breast cancer, many more risk loci exist. Genome-wide association analyses in genetically-homogeneous populations, such as that of Sardinia (Italy), could represent an additional approach to detect low penetrance alleles. We performed a genome-wide association study comparing 1431 Sardinian patients with non-familial, BRCA1/2-mutation-negative breast cancer to 2171 healthy Sardinian blood donors. DNA was genotyped using GeneChip Human Mapping 500 K Arrays or Genome-Wide Human SNP Arrays 6.0. To increase genomic coverage, genotypes of additional SNPs were imputed using data from HapMap Phase II. After quality control filtering of genotype data, 1367 cases (9 men) and 1658 controls (1156 men) were analyzed on a total of 2,067,645 SNPs. Overall, 33 genomic regions (67 candidate SNPs) were associated with breast cancer risk at the p < 10−6 level. Twenty of these regions contained defined genes, including one already associated with breast cancer risk: TOX3. With a lower threshold for preliminary significance to p < 10−5, we identified 11 additional SNPs in FGFR2, a well-established breast cancer-associated gene. Ten candidate SNPs were selected, excluding those already associated with breast cancer, for technical validation as well as replication in 1668 samples from the same population. Only SNP rs345299, located in intron 1 of VAV3, remained suggestively associated (p-value, 1.16x10−5), but it did not associate with breast cancer risk in pooled data from two large, mixed-population cohorts. This study indicated the role of TOX3 and FGFR2 as breast cancer susceptibility genes in BRCA1/2-wild-type breast cancer patients from Sardinian population. The online version of this article (doi:10.1186/s12885-015-1392-9) contains supplementary material, which is available to authorized users

  16. Development of cancer-initiating cells and immortalized cells with genomic instability.

    Science.gov (United States)

    Yoshioka, Ken-Ichi; Atsumi, Yuko; Nakagama, Hitoshi; Teraoka, Hirobumi

    2015-03-26

    Cancers that develop after middle age usually exhibit genomic instability and multiple mutations. This is in direct contrast to pediatric tumors that usually develop as a result of specific chromosomal translocations and epigenetic aberrations. The development of genomic instability is associated with mutations that contribute to cellular immortalization and transformation. Cancer occurs when cancer-initiating cells (CICs), also called cancer stem cells, develop as a result of these mutations. In this paper, we explore how CICs develop as a result of genomic instability, including looking at which cancer suppression mechanisms are abrogated. A recent in vitro study revealed the existence of a CIC induction pathway in differentiating stem cells. Under aberrant differentiation conditions, cells become senescent and develop genomic instabilities that lead to the development of CICs. The resulting CICs contain a mutation in the alternative reading frame of CDKN2A (ARF)/p53 module, i.e., in either ARF or p53. We summarize recently established knowledge of CIC development and cellular immortality, explore the role of the ARF/p53 module in protecting cells from transformation, and describe a risk factor for genomic destabilization that increases during the process of normal cell growth and differentiation and is associated with the downregulation of histone H2AX to levels representative of growth arrest in normal cells. PMID:25815132

  17. Robust Automatic Breast Cancer Staging Using A Combination of Functional Genomics and Image-Omics

    Science.gov (United States)

    Su, Hai; Shen, Yong; Xing, Fuyong; Qi, Xin; Hirshfield, Kim M.; Yang, Lin; Foran, David J.

    2016-01-01

    Breast cancer is one of the leading cancers worldwide. Precision medicine is a new trend that systematically examines molecular and functional genomic information within each patient's cancer to identify the patterns that may affect treatment decisions and potential outcomes. As a part of precision medicine, computer-aided diagnosis enables joint analysis of functional genomic information and image from pathological images. In this paper we propose an integrated framework for breast cancer staging using image-omics and functional genomic information. The entire biomedical imaging informatics framework consists of image-omics extraction, feature combination, and classification. First, a robust automatic nuclei detection and segmentation is presented to identify tumor regions, delineate nuclei boundaries and calculate a set of image-based morphological features; next, the low dimensional image-omics is obtained through principal component analysis and is concatenated with the functional genomic features identified by a linear model. A support vector machine for differentiating stage I breast cancer from other stages are learned. We experimentally demonstrate that compared with a single type of representation (image-omics), the combination of image-omics and functional genomic feature can improve the classification accuracy by 3%. PMID:26737959

  18. A comparative genomics approach to understanding transmissible cancer in Tasmanian devils.

    Science.gov (United States)

    Deakin, Janine E; Belov, Katherine

    2012-01-01

    A fatal contagious cancer is driving an entire species to extinction. Comparative genomics will unravel the origin and evolution of devil facial tumor disease (DFTD). The DFTD allograft arose from a Schwann cell in a female Tasmanian devil more than 15 years ago; since then, the tumor has passed through at least 100,000 hosts, evolving and mutating along the way. Tumor genome sequencing and molecular cytogenetic technologies now allow direct comparisons of candidate genes involved in tumorigenesis in human cancers. As a stable transmissible cancer, DFTD provides unique insights into cancer development, progression, and immune evasion and is likely to help increase our understanding of human cancer. In addition, these studies provide hope for discoveries of drug targets or vaccine candidates that will prevent the extinction of this iconic Australian marsupial. PMID:22657390

  19. Anatomy of the Eye

    Science.gov (United States)

    ... Conditions Frequently Asked Questions Español Condiciones Chinese Conditions Anatomy of the Eye En Español Read in Chinese External (Extraocular) Anatomy Extraocular Muscles: There are six muscles that are ...

  20. Genomic profiles of colorectal cancers differ based on patient smoking status.

    Science.gov (United States)

    Swede, Helen; Bartos, Jeremy D; Chen, Neng; Shaukat, Aasma; Dutt, Smitha S; McQuaid, Devin A; Natarajan, Nachimuthu; Rodriguez-Bigas, Miguel A; Nowak, Norma J; Wiseman, Sam M; Alrawi, Sadir; Brenner, Bruce M; Petrelli, Nicholas J; Cummings, K Michael; Stoler, Daniel L; Anderson, Garth R

    2006-07-15

    Human sporadic colorectal cancer is the result of a lengthy somatic evolutionary process facilitated by various forms of genomic instability. Such instability arises endogenously from mutations in genes whose role is to preserve genomic integrity, and exogenously from environmental agents that generate genomic damage. We have found that cigarette smoking shifts the genomic profiles and genomic instability patterns of colorectal carcinomas. The genomic profiles of 57 consecutive cancers were examined; 31 cases were current or former smokers and 26 were nonsmokers. Genome-wide allelotypes of 348 markers were examined, along with comparative genomic hybridization (CGH) on ordered BAC microarrays, microsatellite instability, and inter-(simple sequence repeat) polymerase chain reaction instability. Tumors from nonsmokers exhibited losses of heterozygosity, particularly on chromosomes 14 and 18, whereas tumors from smokers exhibited a more diffuse pattern of allelic losses. Tumors from smokers exhibited higher overall rates of loss of heterozygosity, but showed lower rates of background microsatellite instability (MSI-L). On BAC array CGH, higher levels of generalized amplifications and deletions were observed in tumors from smokers, differentially affecting male smokers. In the transforming growth factor-beta signaling pathway, MADH4 mutations were more common in tumors from smokers, whereas transforming growth factor-beta RII mutations were more common among nonsmokers. PMID:16843098

  1. Genomic instability influences the transcriptome and proteome in endometrial cancer subtypes

    Directory of Open Access Journals (Sweden)

    Habermann Jens K

    2011-10-01

    Full Text Available Abstract Background In addition to clinical characteristics, DNA aneuploidy has been identified as a prognostic factor in epithelial malignancies in general and in endometrial cancers in particular. We mapped ploidy-associated chromosomal aberrations and identified corresponding gene and protein expression changes in endometrial cancers of different prognostic subgroups. Methods DNA image cytometry classified 25 endometrioid cancers to be either diploid (n = 16 or aneuploid (n = 9, and all uterine papillary serous cancers (UPSC to be aneuploid (n = 8. All samples were subjected to comparative genomic hybridization and gene expression profiling. Identified genes were subjected to Ingenuity pathway analysis (IPA and were correlated to protein expression changes. Results Comparative genomic hybridization revealed ploidy-associated specific, recurrent genomic imbalances. Gene expression analysis identified 54 genes between diploid and aneuploid endometrioid carcinomas, 39 genes between aneuploid endometrioid cancer and UPSC, and 76 genes between diploid endometrioid and aneuploid UPSC to be differentially expressed. Protein profiling identified AKR7A2 and ANXA2 to show translational alterations consistent with the transcriptional changes. The majority of differentially expressed genes and proteins belonged to identical molecular functions, foremost Cancer, Cell Death, and Cellular Assembly and Organization. Conclusions We conclude that the grade of genomic instability rather than the histopathological subtype correlates with specific gene and protein expression changes. The identified genes and proteins might be useful as molecular targets for improved diagnostic and therapeutic intervention and merit prospective validation.

  2. 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

  3. 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...

  4. A comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing

    Science.gov (United States)

    Alioto, Tyler S.; Buchhalter, Ivo; Derdak, Sophia; Hutter, Barbara; Eldridge, Matthew D.; Hovig, Eivind; Heisler, Lawrence E.; Beck, Timothy A.; Simpson, Jared T.; Tonon, Laurie; Sertier, Anne-Sophie; Patch, Ann-Marie; Jäger, Natalie; Ginsbach, Philip; Drews, Ruben; Paramasivam, Nagarajan; Kabbe, Rolf; Chotewutmontri, Sasithorn; Diessl, Nicolle; Previti, Christopher; Schmidt, Sabine; Brors, Benedikt; Feuerbach, Lars; Heinold, Michael; Gröbner, Susanne; Korshunov, Andrey; Tarpey, Patrick S.; Butler, Adam P.; Hinton, Jonathan; Jones, David; Menzies, Andrew; Raine, Keiran; Shepherd, Rebecca; Stebbings, Lucy; Teague, Jon W.; Ribeca, Paolo; Giner, Francesc Castro; Beltran, Sergi; Raineri, Emanuele; Dabad, Marc; Heath, Simon C.; Gut, Marta; Denroche, Robert E.; Harding, Nicholas J.; Yamaguchi, Takafumi N.; Fujimoto, Akihiro; Nakagawa, Hidewaki; Quesada, Víctor; Valdés-Mas, Rafael; Nakken, Sigve; Vodák, Daniel; Bower, Lawrence; Lynch, Andrew G.; Anderson, Charlotte L.; Waddell, Nicola; Pearson, John V.; Grimmond, Sean M.; Peto, Myron; Spellman, Paul; He, Minghui; Kandoth, Cyriac; Lee, Semin; Zhang, John; Létourneau, Louis; Ma, Singer; Seth, Sahil; Torrents, David; Xi, Liu; Wheeler, David A.; López-Otín, Carlos; Campo, Elías; Campbell, Peter J.; Boutros, Paul C.; Puente, Xose S.; Gerhard, Daniela S.; Pfister, Stefan M.; McPherson, John D.; Hudson, Thomas J.; Schlesner, Matthias; Lichter, Peter; Eils, Roland; Jones, David T. W.; Gut, Ivo G.

    2015-01-01

    As whole-genome sequencing for cancer genome analysis becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Here using tumour-normal sample pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, we conduct a benchmarking exercise within the context of the International Cancer Genome Consortium. We compare sequencing methods, analysis pipelines and validation methods. We show that using PCR-free methods and increasing sequencing depth to ∼100 × shows benefits, as long as the tumour:control coverage ratio remains balanced. We observe widely varying mutation call rates and low concordance among analysis pipelines, reflecting the artefact-prone nature of the raw data and lack of standards for dealing with the artefacts. However, we show that, using the benchmark mutation set we have created, many issues are in fact easy to remedy and have an immediate positive impact on mutation detection accuracy. PMID:26647970

  5. A comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing.

    Science.gov (United States)

    Alioto, Tyler S; Buchhalter, Ivo; Derdak, Sophia; Hutter, Barbara; Eldridge, Matthew D; Hovig, Eivind; Heisler, Lawrence E; Beck, Timothy A; Simpson, Jared T; Tonon, Laurie; Sertier, Anne-Sophie; Patch, Ann-Marie; Jäger, Natalie; Ginsbach, Philip; Drews, Ruben; Paramasivam, Nagarajan; Kabbe, Rolf; Chotewutmontri, Sasithorn; Diessl, Nicolle; Previti, Christopher; Schmidt, Sabine; Brors, Benedikt; Feuerbach, Lars; Heinold, Michael; Gröbner, Susanne; Korshunov, Andrey; Tarpey, Patrick S; Butler, Adam P; Hinton, Jonathan; Jones, David; Menzies, Andrew; Raine, Keiran; Shepherd, Rebecca; Stebbings, Lucy; Teague, Jon W; Ribeca, Paolo; Giner, Francesc Castro; Beltran, Sergi; Raineri, Emanuele; Dabad, Marc; Heath, Simon C; Gut, Marta; Denroche, Robert E; Harding, Nicholas J; Yamaguchi, Takafumi N; Fujimoto, Akihiro; Nakagawa, Hidewaki; Quesada, Víctor; Valdés-Mas, Rafael; Nakken, Sigve; Vodák, Daniel; Bower, Lawrence; Lynch, Andrew G; Anderson, Charlotte L; Waddell, Nicola; Pearson, John V; Grimmond, Sean M; Peto, Myron; Spellman, Paul; He, Minghui; Kandoth, Cyriac; Lee, Semin; Zhang, John; Létourneau, Louis; Ma, Singer; Seth, Sahil; Torrents, David; Xi, Liu; Wheeler, David A; López-Otín, Carlos; Campo, Elías; Campbell, Peter J; Boutros, Paul C; Puente, Xose S; Gerhard, Daniela S; Pfister, Stefan M; McPherson, John D; Hudson, Thomas J; Schlesner, Matthias; Lichter, Peter; Eils, Roland; Jones, David T W; Gut, Ivo G

    2015-01-01

    As whole-genome sequencing for cancer genome analysis becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Here using tumour-normal sample pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, we conduct a benchmarking exercise within the context of the International Cancer Genome Consortium. We compare sequencing methods, analysis pipelines and validation methods. We show that using PCR-free methods and increasing sequencing depth to ∼ 100 × shows benefits, as long as the tumour:control coverage ratio remains balanced. We observe widely varying mutation call rates and low concordance among analysis pipelines, reflecting the artefact-prone nature of the raw data and lack of standards for dealing with the artefacts. However, we show that, using the benchmark mutation set we have created, many issues are in fact easy to remedy and have an immediate positive impact on mutation detection accuracy. PMID:26647970

  6. [Genome-wide association study(GWAS) and genetic risk of prostate cancer].

    Science.gov (United States)

    Nakagawa, Hidewaki; Akamatsu, Shusuke; Takata, Ryo

    2016-01-01

    It is evident that genetic factors play critical roles in prostate cancer development. GWAS (genome-wide association studies) in multiple ethnic groups have been identifying more than 100 loci or genes which was significantly associated with prostate cancer susceptibility. They include several loci at 8q24, prostate-specific gene, inflammation gene, and metabolism-related genes. Risk prediction for prostate cancer by combining multiple SNPs is still primitive and not sufficiently accurate for clinical use, but this model could have a potential to affect clinical decision when it is applied to patients with gray-zone PSA or very high risk of prostate cancer. PMID:26793876

  7. 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.

  8. Integrating Microarray Gene Expression Object Model and Clinical Document Architecture for Cancer Genomics Research

    OpenAIRE

    Park, Yu Rang; Lee, Hye Won; Kim, Ju Han

    2005-01-01

    Systematic integration of gene expression profiling with clinical information may facilitate cancer genomics research. MAGE-OM (MicroArray Gene Expression Object Model) defines standard objects for genomic but not for clinical data. HL7 CDA (Clinical Document Architecture) is a document model for clinical information, describing syntax but not semantics. We designed a document template and common data elements in XML Schema with additional constraints for CDA to define conte...

  9. Clinical application of high-throughput genomic technologies for treatment selection in breast cancer

    OpenAIRE

    Hansen, Aaron R.; Bedard, Philippe L.

    2013-01-01

    Large-scale collaborative initiatives using next-generation DNA sequencing and other high-throughput technologies have begun to characterize the genomic landscape of breast cancer. These landmark studies have identified infrequent driver mutations that are potential targets for therapeutic intervention with approved or investigational drug treatments, among other important discoveries. Recently, many institutions have launched molecular screening programs that apply high-throughput genomic te...

  10. AACR precision medicine series: Highlights of the integrating clinical genomics and cancer therapy meeting.

    Science.gov (United States)

    Maggi, Elaine; Montagna, Cristina

    2015-12-01

    The American Association for Cancer Research (AACR) Precision Medicine Series "Integrating Clinical Genomics and Cancer Therapy" took place June 13-16, 2015 in Salt Lake City, Utah. The conference was co-chaired by Charles L. Sawyers form Memorial Sloan Kettering Cancer Center in New York, Elaine R. Mardis form Washington University School of Medicine in St. Louis, and Arul M. Chinnaiyan from University of Michigan in Ann Arbor. About 500 clinicians, basic science investigators, bioinformaticians, and postdoctoral fellows joined together to discuss the current state of Clinical Genomics and the advances and challenges of integrating Next Generation Sequencing (NGS) technologies into clinical practice. The plenary sessions and panel discussions covered current platforms and sequencing approaches adopted for NGS assays of cancer genome at several national and international institutions, different approaches used to map and classify targetable sequence variants, and how information acquired with the sequencing of the cancer genome is used to guide treatment options. While challenges still exist from a technological perspective, it emerged that there exists considerable need for the development of tools to aid the identification of the therapy most suitable based on the mutational profile of the somatic cancer genome. The process to match patients to ongoing clinical trials is still complex. In addition, the need for centralized data repositories, preferably linked to well annotated clinical records, that aid sharing of sequencing information is central to begin understanding the contribution of variants of unknown significance to tumor etiology and response to therapy. Here we summarize the highlights of this stimulating four-day conference with a major emphasis on the open problems that the clinical genomics community is currently facing and the tools most needed for advancing this field. PMID:26554403

  11. Combined HSP90 and kinase inhibitor therapy: Insights from The Cancer Genome Atlas.

    Science.gov (United States)

    Schwartz, Harvey; Scroggins, Brad; Zuehlke, Abbey; Kijima, Toshiki; Beebe, Kristin; Mishra, Alok; Neckers, Len; Prince, Thomas

    2015-09-01

    The merging of knowledge from genomics, cellular signal transduction and molecular evolution is producing new paradigms of cancer analysis. Protein kinases have long been understood to initiate and promote malignant cell growth and targeting kinases to fight cancer has been a major strategy within the pharmaceutical industry for over two decades. Despite the initial success of kinase inhibitors (KIs), the ability of cancer to evolve resistance and reprogram oncogenic signaling networks has reduced the efficacy of kinase targeting. The molecular chaperone HSP90 physically supports global kinase function while also acting as an evolutionary capacitor. The Cancer Genome Atlas (TCGA) has compiled a trove of data indicating that a large percentage of tumors overexpress or possess mutant kinases that depend on the HSP90 molecular chaperone complex. Moreover, the overexpression or mutation of parallel activators of kinase activity (PAKA) increases the number of components that promote malignancy and indirectly associate with HSP90. Therefore, targeting HSP90 is predicted to complement kinase inhibitors by inhibiting oncogenic reprogramming and cancer evolution. Based on this hypothesis, consideration should be given by both the research and clinical communities towards combining kinase inhibitors and HSP90 inhibitors (H90Ins) in combating cancer. The purpose of this perspective is to reflect on the current understanding of HSP90 and kinase biology as well as promote the exploration of potential synergistic molecular therapy combinations through the utilization of The Cancer Genome Atlas. PMID:26070366

  12. 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.

  13. The Tip of the Iceberg: Clinical Implications of Genomic Sequencing Projects in Head and Neck Cancer

    Directory of Open Access Journals (Sweden)

    Andrew C. Birkeland

    2015-10-01

    Full Text Available Recent genomic sequencing studies have provided valuable insight into genetic aberrations in head and neck squamous cell carcinoma. Despite these great advances, certain hurdles exist in translating genomic findings to clinical care. Further correlation of genetic findings to clinical outcomes, additional analyses of subgroups of head and neck cancers and follow-up investigation into genetic heterogeneity are needed. While the development of targeted therapy trials is of key importance, numerous challenges exist in establishing and optimizing such programs. This review discusses potential upcoming steps for further genetic evaluation of head and neck cancers and implementation of genetic findings into precision medicine trials.

  14. 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; Schlangen, Karin; Weichenhan, Dieter; Minner, Sarah; Wuttig, Daniela; Warnatz, Hans-Jörg; Stehr, Henning; Rausch, Tobias; Jäger, Natalie; Gu, Lei; Bogatyrova, Olga; Stütz, Adrian M; Claus, Rainer; Eils, Jürgen; Eils, Roland; Gerhäuser, Clarissa; Huang, Po-Hsien; Hutter, Barbara; Kabbe, Rolf; Lawerenz, Christian; Radomski, Sylwester; Bartholomae, Cynthia C; Fälth, Maria; Gade, Stephan; Schmidt, Manfred; Amschler, Nina; Haß, Thomas; Galal, Rami; Gjoni, Jovisa; Kuner, Ruprecht; Baer, Constance; Masser, Sawinee; von Kalle, Christof; Zichner, Thomas; Benes, Vladimir; Raeder, Benjamin; Mader, Malte; Amstislavskiy, Vyacheslav; Avci, Meryem; Lehrach, Hans; Parkhomchuk, Dmitri; Sultan, Marc; Burkhardt, Lia; Graefen, Markus; Huland, Hartwig; Kluth, Martina; Krohn, Antje; Sirma, Hüseyin; Stumm, Laura; Steurer, Stefan; Grupp, Katharina; Sültmann, Holger; Sauter, Guido; Plass, Christoph; Brors, Benedikt; Yaspo, Marie-Laure; Korbel, Jan O; Schlomm, Thorsten

    2013-01-01

    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 pursue...

  15. Genome-wide assessment of the association of rare and common copy number variations to testicular germ cell cancer

    DEFF Research Database (Denmark)

    Edsgard, Stefan Daniel; Dalgaard, Marlene Danner; Weinhold, Nils; Wesolowska, Agata; Rajpert-De Meyts, Ewa; Ottesen, Anne Marie; Juul, Anders; Skakkebæk, Niels Erik; Jensen, Thomas Skøt; Gupta, Ramneek; Leffers, Henrik; Brunak, Søren

    2013-01-01

    Testicular germ cell cancer (TGCC) is one of the most heritable forms of cancer. Previous genome-wide association studies have focused on single nucleotide polymorphisms, largely ignoring the influence of copy number variants (CNVs). Here we present a genome-wide study of CNV on a cohort of 212...

  16. 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

  17. A Health Services Research Agenda for Cellular, Molecular and Genomic Technologies in Cancer Care

    Science.gov (United States)

    Wideroff, Louise; Phillips, Kathryn A.; Randhawa, Gurvaneet; Ambs, Anita; Armstrong, Katrina; Bennett, Charles L.; Brown, Martin L.; Donaldson, Molla S.; Follen, Michele; Goldie, Sue J.; Hiatt, Robert A.; Khoury, Muin J.; Lewis, Graham; McLeod, Howard L.; Piper, Margaret; Powell, Isaac; Schrag, Deborah; Schulman, Kevin A.; Scott, Joan

    2009-01-01

    Background In recent decades, extensive resources have been invested to develop cellular, molecular and genomic technologies with clinical applications that span the continuum of cancer care. Methods In December 2006, the National Cancer Institute sponsored the first workshop to uniquely examine the state of health services research on cancer-related cellular, molecular and genomic technologies and identify challenges and priorities for expanding the evidence base on their effectiveness in routine care. Results This article summarizes the workshop outcomes, which included development of a comprehensive research agenda that incorporates health and safety endpoints, utilization patterns, patient and provider preferences, quality of care and access, disparities, economics and decision modeling, trends in cancer outcomes, and health-related quality of life among target populations. Conclusions Ultimately, the successful adoption of useful technologies will depend on understanding and influencing the patient, provider, health care system and societal factors that contribute to their uptake and effectiveness in ‘real-world’ settings. PMID:19367091

  18. Cancer classification in the genomic era: five contemporary problems

    OpenAIRE

    Song, Qingxuan; Merajver, Sofia D.; Li, Jun Z.

    2015-01-01

    Classification is an everyday instinct as well as a full-fledged scientific discipline. Throughout the history of medicine, disease classification is central to how we develop knowledge, make diagnosis, and assign treatment. Here, we discuss the classification of cancer and the process of categorizing cancer subtypes based on their observed clinical and biological features. Traditionally, cancer nomenclature is primarily based on organ location, e.g., “lung cancer” designates a tumor originat...

  19. The Genomic and Metabolomic profiling of pancreas cancer

    OpenAIRE

    Sanyal, Sudip

    2015-01-01

    Despite the considerable expansion of knowledge in the development of pancreatic cancer, there has been little progress made in facilitating an early diagnosis of this disease and predicting an accurate response to treatment. We aim to translate this knowledge to clinical practice by using a prospective database of precursor cystic lesions in pancreas cancer, assessing the use of over-expressed genes in pancreatic juice as a surrogate marker of these pancreas cancer and finally, downstream of...

  20. GREVE: Genomic Recurrent Event ViEwer to assist the identification of patterns across individual cancer samples

    OpenAIRE

    Cazier, Jean-Baptiste; Holmes, Chris C.; Broxholme, John

    2012-01-01

    Summary: GREVE has been developed to assist with the identification of recurrent genomic aberrations across cancer samples. The exact characterization of such aberrations remains a challenge despite the availability of increasing amount of data, from SNParray to next-generation sequencing. Furthermore, genomic aberrations in cancer are especially difficult to handle because they are, by nature, unique to the patients. However, their recurrence in specific regions of the genome has been shown ...

  1. 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.

  2. Genomic and functional characterizations of phosphodiesterase subtype 4D in human cancers

    OpenAIRE

    Lin, De-Chen; Xu, Liang; Ding, Ling-Wen; Sharma, Arjun; Liu, Li-Zhen; Yang, Henry; Tan, Patrick; Vadgama, Jay; Karlan, Beth Y.; Lester, Jenny; Urban, Nicole; Schummer, Michèl; Doan, Ngan; Said, Jonathan W.; Sun, Hongmao

    2013-01-01

    Discovery of cancer genes through interrogation of genomic dosage is one of the major approaches in cancer research. In this study, we report that phosphodiesterase subtype 4D (PDE4D) gene was homozygously deleted in 198 cases of 5,569 primary solid tumors (3.56%), with most being internal microdeletions. Unexpectedly, the microdeletions did not result in loss of their gene products. Screening PDE4D expression in 11 different types of primary tumor samples (n = 165) with immunohistochemistry ...

  3. Mutation of mitochondria genome: trigger of somatic cell transforming to cancer cell

    OpenAIRE

    Jianping Du

    2010-01-01

    Abstract Nearly 80 years ago, scientist Otto Warburg originated a hypothesis that the cause of cancer is primarily a defect in energy metabolism. Following studies showed that mitochondria impact carcinogenesis to remodel somatic cells to cancer cells through modifying the genome, through maintenance the tumorigenic phenotype, and through apoptosis. And the Endosymbiotic Theory explains the origin of mitochondria and eukaryotes, on the other hands, the mitochondria also can fall back. Compare...

  4. Association between genomic recurrence risk and well-being among breast cancer patients

    International Nuclear Information System (INIS)

    Gene expression profiling (GEP) is increasingly used in the rapidly evolving field of personalized medicine. We sought to evaluate the association between GEP-assessed of breast cancer recurrence risk and patients’ well-being. Participants were Dutch women from 10 hospitals being treated for early stage breast cancer who were enrolled in the MINDACT trial (Microarray In Node-negative and 1 to 3 positive lymph node Disease may Avoid ChemoTherapy). As part of the trial, they received a disease recurrence risk estimate based on a 70-gene signature and on standard clinical criteria as scored via a modified version of Adjuvant! Online. /Women completed a questionnaire 6–8 weeks after surgery and after their decision regarding adjuvant chemotherapy. The questionnaire assessed perceived understanding, knowledge, risk perception, satisfaction, distress, cancer worry and health-related quality of life (HRQoL), 6–8 weeks after surgery and decision regarding adjuvant chemotherapy. Women (n = 347, response rate 62%) reported high satisfaction with and a good understanding of the GEP information they received. Women with low risk estimates from both the standard and genomic tests reported the lowest distress levels. Distress was higher predominately among patients who had received high genomic risk estimates, who did not receive genomic risk estimates, or who received conflicting estimates based on genomic and clinical criteria. Cancer worry was highest for patients with higher risk perceptions and lower satisfaction. Patients with concordant high-risk profiles and those for whom such profiles were not available reported lower quality of life. Patients were generally satisfied with the information they received about recurrence risk based on genomic testing. Some types of genomic test results were associated with greater distress levels, but not with cancer worry or HRQoL. ISRCTN: http://www.controlled-trials.com/ISRCTN18543567/MINDACT

  5. Isolation and genomic analysis of circulating tumor cells from castration resistant metastatic prostate cancer

    International Nuclear Information System (INIS)

    The number of circulating tumor cells (CTCs) in metastatic prostate cancer patients provides prognostic and predictive information. However, it is the molecular characterization of CTCs that offers insight into the biology of these tumor cells in the context of personalized treatment. We developed a novel approach to isolate CTCs away from hematopoietic cells with high purity, enabling genomic analysis of these cells. The isolation protocol involves immunomagnetic enrichment followed by fluorescence activated cell sorting (IE/FACS). To evaluate the feasibility of isolation of CTCs by IE/FACS and downstream genomic profiling, we conducted a pilot study in patients with metastatic castration resistant prostate cancer (CRPC). Twenty (20) sequential CRPC patients were assayed using CellSearch™. Twelve (12) patients positive for CTCs were subjected to immunomagnetic enrichment and fluorescence activated cell sorting (IE/FACS) to isolate CTCs. Genomic DNA of CTCs was subjected to whole genome amplification (WGA) followed by gene copy number analysis via array comparative genomic hybridization (aCGH). CTCs from nine (9) patients successfully profiled were observed to have multiple copy number aberrations including those previously reported in primary prostate tumors such as gains in 8q and losses in 8p. High-level copy number gains at the androgen receptor (AR) locus were observed in 7 (78%) cases. Comparison of genomic profiles between CTCs and archival primary tumors from the same patients revealed common lineage. However, high-level copy number gains in the AR locus were observed in CTCs, but not in the matched archival primary tumors. We developed a new approach to isolate prostate CTCs without significant leukocyte admixture, and to subject them to genome-wide copy number analysis. Our assay may be utilized to explore genomic events involved in cancer progression, e.g. development of castration resistance and to monitor therapeutic efficacy of targeted therapies in

  6. 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...

  7. Integrating Genomics with Proteomics - Office of Cancer Clinical Proteomics Research

    Science.gov (United States)

    Approximately 60 percent of patients diagnosed with cancer present as early stage disease (Stage I and II). Despite the favorable prognosis associated with treatment intervention of such early stage disease (typically surgical excision), there are a small, but significant, fraction of these cancers that appear to be hardwired for aggressive metastatic behavior and ultimately lethal outcome.

  8. Significance of genomic instability in breast cancer in atomic bomb survivors: analysis of microarray-comparative genomic hybridization

    Directory of Open Access Journals (Sweden)

    Oikawa Masahiro

    2011-12-01

    Full Text Available Abstract Background It has been postulated that ionizing radiation induces breast cancers among atomic bomb (A-bomb survivors. We have reported a higher incidence of HER2 and C-MYC oncogene amplification in breast cancers from A-bomb survivors. The purpose of this study was to clarify the effect of A-bomb radiation exposure on genomic instability (GIN, which is an important hallmark of carcinogenesis, in archival formalin-fixed paraffin-embedded (FFPE tissues of breast cancer by using microarray-comparative genomic hybridization (aCGH. Methods Tumor DNA was extracted from FFPE tissues of invasive ductal cancers from 15 survivors who were exposed at 1.5 km or less from the hypocenter and 13 calendar year-matched non-exposed patients followed by aCGH analysis using a high-density oligonucleotide microarray. The total length of copy number aberrations (CNA was used as an indicator of GIN, and correlation with clinicopathological factors were statistically tested. Results The mean of the derivative log ratio spread (DLRSpread, which estimates the noise by calculating the spread of log ratio differences between consecutive probes for all chromosomes, was 0.54 (range, 0.26 to 1.05. The concordance of results between aCGH and fluorescence in situ hybridization (FISH for HER2 gene amplification was 88%. The incidence of HER2 amplification and histological grade was significantly higher in the A-bomb survivors than control group (P = 0.04, respectively. The total length of CNA tended to be larger in the A-bomb survivors (P = 0.15. Correlation analysis of CNA and clinicopathological factors revealed that DLRSpread was negatively correlated with that significantly (P = 0.034, r = -0.40. Multivariate analysis with covariance revealed that the exposure to A-bomb was a significant (P = 0.005 independent factor which was associated with larger total length of CNA of breast cancers. Conclusions Thus, archival FFPE tissues from A-bomb survivors are useful for

  9. Significance of genomic instability in breast cancer in atomic bomb survivors: analysis of microarray-comparative genomic hybridization

    International Nuclear Information System (INIS)

    It has been postulated that ionizing radiation induces breast cancers among atomic bomb (A-bomb) survivors. We have reported a higher incidence of HER2 and C-MYC oncogene amplification in breast cancers from A-bomb survivors. The purpose of this study was to clarify the effect of A-bomb radiation exposure on genomic instability (GIN), which is an important hallmark of carcinogenesis, in archival formalin-fixed paraffin-embedded (FFPE) tissues of breast cancer by using microarray-comparative genomic hybridization (aCGH). Tumor DNA was extracted from FFPE tissues of invasive ductal cancers from 15 survivors who were exposed at 1.5 km or less from the hypocenter and 13 calendar year-matched non-exposed patients followed by aCGH analysis using a high-density oligonucleotide microarray. The total length of copy number aberrations (CNA) was used as an indicator of GIN, and correlation with clinicopathological factors were statistically tested. The mean of the derivative log ratio spread (DLRSpread), which estimates the noise by calculating the spread of log ratio differences between consecutive probes for all chromosomes, was 0.54 (range, 0.26 to 1.05). The concordance of results between aCGH and fluorescence in situ hybridization (FISH) for HER2 gene amplification was 88%. The incidence of HER2 amplification and histological grade was significantly higher in the A-bomb survivors than control group (P = 0.04, respectively). The total length of CNA tended to be larger in the A-bomb survivors (P = 0.15). Correlation analysis of CNA and clinicopathological factors revealed that DLRSpread was negatively correlated with that significantly (P = 0.034, r = -0.40). Multivariate analysis with covariance revealed that the exposure to A-bomb was a significant (P = 0.005) independent factor which was associated with larger total length of CNA of breast cancers. Thus, archival FFPE tissues from A-bomb survivors are useful for genome-wide aCGH analysis. Our results suggested that A

  10. Dorsal fin anatomy (Cetacean dorsal fin Anatomy)

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Cetacean dorsal fin Anatomy for ONR. Comparison within populations to ascertain phenotypic differences. Findings corroborate field observation. dorsal fin description

  11. Microenvironmental Heterogeneity Parallels Breast Cancer Progression: A Histology-Genomic Integration Analysis.

    Directory of Open Access Journals (Sweden)

    Rachael Natrajan

    2016-02-01

    Full Text Available The intra-tumor diversity of cancer cells is under intense investigation; however, little is known about the heterogeneity of the tumor microenvironment that is key to cancer progression and evolution. We aimed to assess the degree of microenvironmental heterogeneity in breast cancer and correlate this with genomic and clinical parameters.We developed a quantitative measure of microenvironmental heterogeneity along three spatial dimensions (3-D in solid tumors, termed the tumor ecosystem diversity index (EDI, using fully automated histology image analysis coupled with statistical measures commonly used in ecology. This measure was compared with disease-specific survival, key mutations, genome-wide copy number, and expression profiling data in a retrospective study of 510 breast cancer patients as a test set and 516 breast cancer patients as an independent validation set. In high-grade (grade 3 breast cancers, we uncovered a striking link between high microenvironmental heterogeneity measured by EDI and a poor prognosis that cannot be explained by tumor size, genomics, or any other data types. However, this association was not observed in low-grade (grade 1 and 2 breast cancers. The prognostic value of EDI was superior to known prognostic factors and was enhanced with the addition of TP53 mutation status (multivariate analysis test set, p = 9 × 10-4, hazard ratio = 1.47, 95% CI 1.17-1.84; validation set, p = 0.0011, hazard ratio = 1.78, 95% CI 1.26-2.52. Integration with genome-wide profiling data identified losses of specific genes on 4p14 and 5q13 that were enriched in grade 3 tumors with high microenvironmental diversity that also substratified patients into poor prognostic groups. Limitations of this study include the number of cell types included in the model, that EDI has prognostic value only in grade 3 tumors, and that our spatial heterogeneity measure was dependent on spatial scale and tumor size.To our knowledge, this is the first

  12. Microenvironmental Heterogeneity Parallels Breast Cancer Progression: A Histology–Genomic Integration Analysis

    Science.gov (United States)

    Natrajan, Rachael; Sailem, Heba; Mardakheh, Faraz K.; Arias Garcia, Mar; Tape, Christopher J.; Dowsett, Mitch; Bakal, Chris; Yuan, Yinyin

    2016-01-01

    Background The intra-tumor diversity of cancer cells is under intense investigation; however, little is known about the heterogeneity of the tumor microenvironment that is key to cancer progression and evolution. We aimed to assess the degree of microenvironmental heterogeneity in breast cancer and correlate this with genomic and clinical parameters. Methods and Findings We developed a quantitative measure of microenvironmental heterogeneity along three spatial dimensions (3-D) in solid tumors, termed the tumor ecosystem diversity index (EDI), using fully automated histology image analysis coupled with statistical measures commonly used in ecology. This measure was compared with disease-specific survival, key mutations, genome-wide copy number, and expression profiling data in a retrospective study of 510 breast cancer patients as a test set and 516 breast cancer patients as an independent validation set. In high-grade (grade 3) breast cancers, we uncovered a striking link between high microenvironmental heterogeneity measured by EDI and a poor prognosis that cannot be explained by tumor size, genomics, or any other data types. However, this association was not observed in low-grade (grade 1 and 2) breast cancers. The prognostic value of EDI was superior to known prognostic factors and was enhanced with the addition of TP53 mutation status (multivariate analysis test set, p = 9 × 10−4, hazard ratio = 1.47, 95% CI 1.17–1.84; validation set, p = 0.0011, hazard ratio = 1.78, 95% CI 1.26–2.52). Integration with genome-wide profiling data identified losses of specific genes on 4p14 and 5q13 that were enriched in grade 3 tumors with high microenvironmental diversity that also substratified patients into poor prognostic groups. Limitations of this study include the number of cell types included in the model, that EDI has prognostic value only in grade 3 tumors, and that our spatial heterogeneity measure was dependent on spatial scale and tumor size. Conclusions To

  13. Genomic heterogeneity and instability in colorectal cancer: spectral karyotyping, glutathione transferase-Ml and ras.

    Science.gov (United States)

    Bartos, Jeremy D; Stoler, Daniel L; Matsui, Sei-ichi; Swede, Helen; Willmott, Lyndsay J; Sait, Sheila N; Petrelli, Nicholas J; Anderson, Garth R

    2004-12-21

    Genomic instability in cancer is frequently described as being either chromosomal instability or microsatellite instability, although when events within chromosomes are monitored, extensive intrachromosomal instability is also found. Spectral karyotyping was used to visualize how extensively genomic instability gives rise to intratumor genomic heterogeneity in sporadic colorectal carcinomas. Two factors were then examined which might relate to intrachromosomal instability in colorectal cancers: the presence of the glutathione transferase-Ml gene to detoxify potential carcinogens, and the presence of activated ras which has been associated with chromosomal instability when first expressed. Intrachromosomal genomic instability was previously determined by inter-(simple sequence repeat) PCR (inter-SSR PCR) and by fractional allelic loss rate for 348 markers. GSTM1 status was determined for each of 49 tumors through use of specific PCR, and 28 of the tumors showed the GSTM1 null genotype. A significant association was found between GSTMl-null status and elevated inter-(simple sequence repeat) PCR instability. In contrast, no association was found with fractional allelic loss rate. The first exons of the K-ras and H-ras oncogenes were sequenced in 72 colorectal cancers; 19 of the tumors had a mutation in codon 12 of the K-ras gene (24.5%), but no H-ras mutations were found. A weak correlation (p=0.10) was observed between mutant K-ras and inter-(simple sequence repeat) PCR genomic instability, and no association existed with fractional allelic loss rate. PMID:15542115

  14. A genome-wide association study of breast and prostate cancer in the NHLBI's Framingham Heart Study

    OpenAIRE

    Kreger Bernard E; Finger Daniel; Rosenberg Carol L; Murabito Joanne M; Levy Daniel; Splansky Greta; Antman Karen; Hwang Shih-Jen

    2007-01-01

    Abstract Background Breast and prostate cancer are two commonly diagnosed cancers in the United States. Prior work suggests that cancer causing genes and cancer susceptibility genes can be identified. Methods We conducted a genome-wide association study (Affymetrix 100K SNP GeneChip) of cancer in the community-based Framingham Heart Study. We report on 2 cancer traits – prostate cancer and breast cancer – in up to 1335 participants from 330 families (54% women, mean entry age 33 years). Multi...

  15. 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

  16. 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,...

  17. AnatomiQuiz

    DEFF Research Database (Denmark)

    Brent, Mikkel Bo; Kristoffersen, Thomas

    2015-01-01

    AnatomiQuiz er en quiz-app udviklet til bevægeapparatets anatomi. Den består af mere end 2300 spørgsmål og over 1000 anatomiske billeder. Alle spørgsmål tager udgangspunkt i lærebogen Bevægeapparatets anatomi af Finn Bojsen-Møller m.fl.......AnatomiQuiz er en quiz-app udviklet til bevægeapparatets anatomi. Den består af mere end 2300 spørgsmål og over 1000 anatomiske billeder. Alle spørgsmål tager udgangspunkt i lærebogen Bevægeapparatets anatomi af Finn Bojsen-Møller m.fl....

  18. 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.

  19. 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.

  20. Methods in Mammary Gland Development and Cancer: the second ENDBC meeting - intravital imaging, genomics, modeling and metastasis

    OpenAIRE

    Stingl, John; Matthew J Smalley; Glukhova, Marina A.; Bentires-Alj, Mohamed

    2010-01-01

    The second meeting of the European Network for Breast Development and Cancer (ENBDC) on 'Methods in Mammary Gland Development and Cancer' was held in April 2010 in Weggis, Switzerland. The focus was on genomics and bioinformatics, extracellular matrix and stroma-epithelial cell interactions, intravital imaging, the search for metastasis founder cells and mouse models of breast cancer.

  1. 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

  2. Optimization of novel vector systems for functional genomics in cancer research

    DEFF Research Database (Denmark)

    Schmidt, Steffen

    Optimization of novel vector systems for functional genomics in cancer research Steffen Schmidt1*, Stephanie Blaich2, Rainer Wittig3, Stefan Lyer4, Caroline End2, Melanie Hudler2, Lukasz Kacprzyk2, Angela Riedel1,2, Helle Christiansen1, Jan Mollenhauer1,2 1 Molekylær Onkologi, Medicinsk...... for Lokal Tumor Terapi, Universitet Hospital, Waldstraße1, 91054 Erlangen, Tyskland * Præsenterende forfatter Large datasets about differentially expressed genes in cancer tissue have been recovered by expression profiling using microarray technologies. To study the effects of these genes in cancer...... cells will lead to an improved understanding of the molecular mechanisms underlying cancer and may result in the identification of novel druggable targets for cancer treatment. We established a novel rapid technique to generate stable cell lines with inducible overexpression of genes. This enables for...

  3. 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

  4. 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

  5. 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

  6. Interfractional Variations in the Setup of Pelvic Bony Anatomy and Soft Tissue, and Their Implications on the Delivery of Proton Therapy for Localized Prostate Cancer

    International Nuclear Information System (INIS)

    Purpose: To quantify daily variations in the anatomy of patients undergoing radiation therapy for prostate carcinoma, to estimate their effect on dose distribution, and to evaluate the effectiveness of current standard planning and setup approaches employed in proton therapy. Methods: We used series of computed tomography data, which included the pretreatment scan, and between 21 and 43 in-room scans acquired on different treatment days, from 10 patients treated with intensity-modulated radiation therapy at Morristown Memorial Hospital. Variations in femur rotation angles, thickness of subcutaneous adipose tissue, and physical depth to the distal surface of the prostate for lateral beam arrangement were recorded. Proton dose distributions were planned with the standard approach. Daily variations in the location of the prescription isodose were evaluated. Results: In all 10 datasets, substantial variation was observed in the lateral tissue thickness (standard deviation of 1.7-3.6 mm for individual patients, variations of >5 mm from the planning computed tomography observed in all series), and femur rotation angle (standard deviation between 1.3o and 4.8o, with the maximum excursion exceeding 10o in 6 of 10 datasets). Shifts in the position of treated volume (98% isodose) were correlated with the variations in the lateral tissue thickness. Conclusions: Analysis suggests that, combined with image-guided setup verification, the range compensator expansion technique prevents loss of dose to target from femur rotation and soft-tissue deformation, in the majority of cases. Anatomic changes coupled with the uncertainties of particle penetration in tissue restrict possibilities for margin reduction in proton therapy of prostate cancer.

  7. Understanding Cancer Prognosis

    Medline Plus

    Full Text Available ... Renal Cell) Cancer Leukemia Lung Cancer Lymphoma Pancreatic Cancer Prostate Cancer Skin Cancer Thyroid Cancer Uterine Cancer All ... Cancer Biology Cancer Genomics Causes of Cancer Diagnosis Prevention Screening & Early Detection Treatment Cancer & Public Health Cancer ...

  8. The genomics of oral cancer and wound healing

    Directory of Open Access Journals (Sweden)

    Aswini Y

    2009-03-01

    Full Text Available Oral cancer is the most common malignancy in India, where it is epidemiologically linked to the chewing of betel quid and other carcinogens. But various point mutations were detectable in the p53 and p15 genes. Hence, this review was conducted with the aim to find out genetic risks as well as markers for oral cancers and wound healing. Tobacco-related cancers are associated with polymorphisms of the CYP1A1 and GSTM1 genes in terms of genotype frequencies and cigarette smoking dose. Expression of E6/E7 were also found in tumors, most of which were derived from the oropharynx. Presence of homozygous arginine at codon 72 renders p53 about seven times more susceptible to E6-mediated proteolytic degradation. Erythropoietin, vascular permeability factor (VPF, also known as vascular endothelial growth factor or VEGF, and PDGF has been implicated as one of the principal mitogens involved in cutaneous wound healing. Activation of NF-kB is associated with enhanced cell survival. Human papilloma virus status is a significantly favorable prognostic factor in tonsilar cancer and may be used as a marker in order to optimize the treatment of patients with this type of cancer.

  9. Role of oxidative DNA damage in genome instability and cancer

    International Nuclear Information System (INIS)

    Inactivation of mismatch repair (MMR) is associated with a dramatic genomic instability that is observed experimentally as a mutator phenotype and micro satellite instability (MSI). It has been implicit that the massive genetic instability in MMR defective cells simply reflects the accumulation of spontaneous DNA polymerase errors during DNA replication. We recently identified oxidation damage, a common threat to DNA integrity to which purines are very susceptible, as an important cofactor in this genetic instability

  10. Gamma-retrovirus integration marks cell type-specific cancer genes: a novel profiling tool in cancer genomics

    OpenAIRE

    Gilroy, Kathryn L.; Terry, Anne; Naseer, Asif; De Ridder, Jeroen; Allahyar, Amin; Wang, Weiwei; Carpenter, Eric; Mason, Andrew; Wong, Gane K-S; Cameron, Ewan R; Kilbey, Anna; Neil, James C.

    2016-01-01

    Retroviruses have been foundational in cancer research since early studies identified proto-oncogenes as targets for insertional mutagenesis. Integration of murine gamma-retroviruses into the host genome favours promoters and enhancers and entails interaction of viral integrase with host BET/bromodomain factors. We report that this integration pattern is conserved in feline leukaemia virus (FeLV), a gamma-retrovirus that infects many human cell types. Analysis of FeLV insertion sites in the M...

  11. Breakpoint analysis of transcriptional and genomic profiles uncovers novel gene fusions spanning multiple human cancer types.

    Directory of Open Access Journals (Sweden)

    Craig P Giacomini

    2013-04-01

    Full Text Available Gene fusions, like BCR/ABL1 in chronic myelogenous leukemia, have long been recognized in hematologic and mesenchymal malignancies. The recent finding of gene fusions in prostate and lung cancers has motivated the search for pathogenic gene fusions in other malignancies. Here, we developed a "breakpoint analysis" pipeline to discover candidate gene fusions by tell-tale transcript level or genomic DNA copy number transitions occurring within genes. Mining data from 974 diverse cancer samples, we identified 198 candidate fusions involving annotated cancer genes. From these, we validated and further characterized novel gene fusions involving ROS1 tyrosine kinase in angiosarcoma (CEP85L/ROS1, SLC1A2 glutamate transporter in colon cancer (APIP/SLC1A2, RAF1 kinase in pancreatic cancer (ATG7/RAF1 and anaplastic astrocytoma (BCL6/RAF1, EWSR1 in melanoma (EWSR1/CREM, CDK6 kinase in T-cell acute lymphoblastic leukemia (FAM133B/CDK6, and CLTC in breast cancer (CLTC/VMP1. Notably, while these fusions involved known cancer genes, all occurred with novel fusion partners and in previously unreported cancer types. Moreover, several constituted druggable targets (including kinases, with therapeutic implications for their respective malignancies. Lastly, breakpoint analysis identified new cell line models for known rearrangements, including EGFRvIII and FIP1L1/PDGFRA. Taken together, we provide a robust approach for gene fusion discovery, and our results highlight a more widespread role of fusion genes in cancer pathogenesis.

  12. Integrating genomics in head and neck cancer treatment: Promises and pitfalls.

    Science.gov (United States)

    Thariat, Juliette; Vignot, Stéphane; Lapierre, Ariane; Falk, Alexander T; Guigay, Joel; Van Obberghen-Schilling, Ellen; Milano, Gerard

    2015-09-01

    Head and neck squamous cell carcinomas (HNSCC) represent a multifactorial disease of poor prognosis. They have lagged behind other cancers in terms of personalized therapy. With expansion and high throughput sequencing methods, recent landmark exonic studies and Cancer Genome Atlas data have identified genes relevant to carcinogenesis and cancer progression. Mutational profiles and rates vary widely depending on exposure to carcinogens, anatomic subsites and human papilloma virus (HPV) infection. Tumors may exhibit specific, tissue-specific, not exclusively HPV-related, gene alterations, such those observed in oral cavity cancers in Asia or Occident. Except for the PI3K pathway, the rate of mutations in HPV+ cancers is much lower than in tobacco/alcohol-related cancers. Somatic driver mutation analyses show that relatively few driver genes are druggable in HNSCC and that tumor suppressor gene alterations prevail. More mature for therapeutic applications is the oncogenic PI3K pathway, with preclinical human xenograft models suggesting that PI3KCA pathway mutations may be used as predictive biomarkers and clinical data showing efficacy of mTOR/Akt inhibitors. Therapeutic guidance, to date, relies on classical histoprognostic factors, anatomic subsite and HPV status, with integration of hierarchized supervised mutational profiling to provide additional therapeutic options in advanced HNSCC in a near future. Unsupervised controlled genomic analyses remain necessary to unravel potentially relevant genes. PMID:25979769

  13. The tandem duplicator phenotype as a distinct genomic configuration in cancer.

    Science.gov (United States)

    Menghi, Francesca; Inaki, Koichiro; Woo, XingYi; Kumar, Pooja A; Grzeda, Krzysztof R; Malhotra, Ankit; Yadav, Vinod; Kim, Hyunsoo; Marquez, Eladio J; Ucar, Duygu; Shreckengast, Phung T; Wagner, Joel P; MacIntyre, George; Murthy Karuturi, Krishna R; Scully, Ralph; Keck, James; Chuang, Jeffrey H; Liu, Edison T

    2016-04-26

    Next-generation sequencing studies have revealed genome-wide structural variation patterns in cancer, such as chromothripsis and chromoplexy, that do not engage a single discernable driver mutation, and whose clinical relevance is unclear. We devised a robust genomic metric able to identify cancers with a chromotype called tandem duplicator phenotype (TDP) characterized by frequent and distributed tandem duplications (TDs). Enriched only in triple-negative breast cancer (TNBC) and in ovarian, endometrial, and liver cancers, TDP tumors conjointly exhibit tumor protein p53 (TP53) mutations, disruption of breast cancer 1 (BRCA1), and increased expression of DNA replication genes pointing at rereplication in a defective checkpoint environment as a plausible causal mechanism. The resultant TDs in TDP augment global oncogene expression and disrupt tumor suppressor genes. Importantly, the TDP strongly correlates with cisplatin sensitivity in both TNBC cell lines and primary patient-derived xenografts. We conclude that the TDP is a common cancer chromotype that coordinately alters oncogene/tumor suppressor expression with potential as a marker for chemotherapeutic response. PMID:27071093

  14. The tandem duplicator phenotype as a distinct genomic configuration in cancer

    Science.gov (United States)

    Menghi, Francesca; Inaki, Koichiro; Woo, XingYi; Kumar, Pooja A.; Grzeda, Krzysztof R.; Malhotra, Ankit; Yadav, Vinod; Kim, Hyunsoo; Marquez, Eladio J.; Ucar, Duygu; Shreckengast, Phung T.; Wagner, Joel P.; MacIntyre, George; Murthy Karuturi, Krishna R.; Scully, Ralph; Keck, James; Chuang, Jeffrey H.; Liu, Edison T.

    2016-01-01

    Next-generation sequencing studies have revealed genome-wide structural variation patterns in cancer, such as chromothripsis and chromoplexy, that do not engage a single discernable driver mutation, and whose clinical relevance is unclear. We devised a robust genomic metric able to identify cancers with a chromotype called tandem duplicator phenotype (TDP) characterized by frequent and distributed tandem duplications (TDs). Enriched only in triple-negative breast cancer (TNBC) and in ovarian, endometrial, and liver cancers, TDP tumors conjointly exhibit tumor protein p53 (TP53) mutations, disruption of breast cancer 1 (BRCA1), and increased expression of DNA replication genes pointing at rereplication in a defective checkpoint environment as a plausible causal mechanism. The resultant TDs in TDP augment global oncogene expression and disrupt tumor suppressor genes. Importantly, the TDP strongly correlates with cisplatin sensitivity in both TNBC cell lines and primary patient-derived xenografts. We conclude that the TDP is a common cancer chromotype that coordinately alters oncogene/tumor suppressor expression with potential as a marker for chemotherapeutic response. PMID:27071093

  15. An anatomy-based beam segmentation tool for intensity-modulated radiation therapy and its application to head-and-neck cancer

    International Nuclear Information System (INIS)

    Purpose: In segmental intensity-modulated radiation therapy (IMRT), the beam fluences result from superposition of unmodulated beamlets (segments). In the inverse planning approach, segments are a result of 'clipping' intensity maps. At Ghent University Hospital, segments are created by an anatomy-based segmentation tool (ABST). The objective of this report is to describe ABST. Methods and Materials: For each beam direction, ABST generates segments by a multistep procedure. During the initial steps, beam's eye view (BEV) projections of the planning target volumes (PTVs) and organs at risk (OARs) are generated. These projections are used to make a segmentation grid with negative values across the expanded OAR projections and positive values elsewhere inside the expanded PTV projections. Outside these regions, grid values are set to zero. Subsequent steps transform the positive values of the segmentation grid to increase with decreasing distance to the OAR projections and to increase with longer pathlengths measured along rays from their entrance point through the skin contours to their respective grid point. The final steps involve selection of iso-value lines of the segmentation grid as segment outlines which are transformed to leaf and jaw positions of a multileaf collimator (MLC). Segment shape approximations, if imposed by MLC constraints, are done in a way that minimizes overlap between the expanded OAR projections and the segment aperture. Results: The ABST procedure takes about 3 s/segment on a Compaq Alpha XP900 workstation. In IMRT planning problems with little complexity, such as laryngeal (example shown) or thyroid cancer, plans that are in accordance with the clinical protocol can be generated by weighting the segments generated by ABST without further optimization of their shapes. For complex IMRT plans such as paranasal sinus cancer (not shown), ABST generates a start assembly of segments from which the shapes and weights are further optimized

  16. Genomic aberrations relate early and advanced stage ovarian cancer

    NARCIS (Netherlands)

    A. Zaal; W.J. Peyrot (Wouter ); P.M.J.J. Berns (Els); M.E.L. van der Burg (Maria); J.H.W. Veerbeek (Jan ); J.B. Trimbos; I. Cadron (Isabelle); P.J. van Diest (Paul); W.N. Wieringen (Wessel); O. Krijgsman (Oscar); G.A. Meijer (Gerrit); J.M.J. Piek (Jurgen ); P.J. Timmers (Petra); I. Vergote (Ignace); R.H.M. Verheijen (René); B. Ylstra (Bauke); R.P. Zweemer (Ronald )

    2012-01-01

    textabstractBackground Because of the distinct clinical presentation of early and advanced stage ovarian cancer, we aim to clarify whether these disease entities are solely separated by time of diagnosis or whether they arise from distinct molecular events. Methods Sixteen early and sixteen advanced

  17. 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...

  18. Synthetic Genetic Targeting of Genome Instability in Cancer

    International Nuclear Information System (INIS)

    Cancer is a leading cause of death throughout the World. A limitation of many current chemotherapeutic approaches is that their cytotoxic effects are not restricted to cancer cells, and adverse side effects can occur within normal tissues. Consequently, novel strategies are urgently needed to better target cancer cells. As we approach the era of personalized medicine, targeting the specific molecular defect(s) within a given patient’s tumor will become a more effective treatment strategy than traditional approaches that often target a given cancer type or sub-type. Synthetic genetic interactions are now being examined for their therapeutic potential and are designed to target the specific genetic and epigenetic phenomena associated with tumor formation, and thus are predicted to be highly selective. In general, two complementary approaches have been employed, including synthetic lethality and synthetic dosage lethality, to target aberrant expression and/or function associated with tumor suppressor genes and oncogenes, respectively. Here we discuss the concepts of synthetic lethality and synthetic dosage lethality, and explain three general experimental approaches designed to identify novel genetic interactors. We present examples and discuss the merits and caveats of each approach. Finally, we provide insight into the subsequent pre-clinical work required to validate novel candidate drug targets

  19. 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. PMID:27135401

  20. A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers.

    Science.gov (United States)

    Ferrari, Anthony; Vincent-Salomon, Anne; Pivot, Xavier; Sertier, Anne-Sophie; Thomas, Emilie; Tonon, Laurie; Boyault, Sandrine; Mulugeta, Eskeatnaf; Treilleux, Isabelle; MacGrogan, Gaëtan; Arnould, Laurent; Kielbassa, Janice; Le Texier, Vincent; Blanché, Hélène; Deleuze, Jean-François; Jacquemier, Jocelyne; Mathieu, Marie-Christine; Penault-Llorca, Frédérique; Bibeau, Frédéric; Mariani, Odette; Mannina, Cécile; Pierga, Jean-Yves; Trédan, Olivier; Bachelot, Thomas; Bonnefoi, Hervé; Romieu, Gilles; Fumoleau, Pierre; Delaloge, Suzette; Rios, Maria; Ferrero, Jean-Marc; Tarpin, Carole; Bouteille, Catherine; Calvo, Fabien; Gut, Ivo Glynne; Gut, Marta; Martin, Sancha; Nik-Zainal, Serena; Stratton, Michael R; Pauporté, Iris; Saintigny, Pierre; Birnbaum, Daniel; Viari, Alain; Thomas, Gilles

    2016-01-01

    HER2-positive breast cancer has long proven to be a clinically distinct class of breast cancers for which several targeted therapies are now available. However, resistance to the treatment associated with specific gene expressions or mutations has been observed, revealing the underlying diversity of these cancers. Therefore, understanding the full extent of the HER2-positive disease heterogeneity still remains challenging. Here we carry out an in-depth genomic characterization of 64 HER2-positive breast tumour genomes that exhibit four subgroups, based on the expression data, with distinctive genomic features in terms of somatic mutations, copy-number changes or structural variations. The results suggest that, despite being clinically defined by a specific gene amplification, HER2-positive tumours melt into the whole luminal-basal breast cancer spectrum rather than standing apart. The results also lead to a refined ERBB2 amplicon of 106 kb and show that several cases of amplifications are compatible with a breakage-fusion-bridge mechanism. PMID:27406316

  1. Genome and transcriptome sequencing in prospective metastatic triple-negative breast cancer uncovers therapeutic vulnerabilities.

    Science.gov (United States)

    Craig, David W; O'Shaughnessy, Joyce A; Kiefer, Jeffrey A; Aldrich, Jessica; Sinari, Shripad; Moses, Tracy M; Wong, Shukmei; Dinh, Jennifer; Christoforides, Alexis; Blum, Joanne L; Aitelli, Cristi L; Osborne, Cynthia R; Izatt, Tyler; Kurdoglu, Ahmet; Baker, Angela; Koeman, Julie; Barbacioru, Catalin; Sakarya, Onur; De La Vega, Francisco M; Siddiqui, Asim; Hoang, Linh; Billings, Paul R; Salhia, Bodour; Tolcher, Anthony W; Trent, Jeffrey M; Mousses, Spyro; Von Hoff, Daniel; Carpten, John D

    2013-01-01

    Triple-negative breast cancer (TNBC) is characterized by the absence of expression of estrogen receptor, progesterone receptor, and HER-2. Thirty percent of patients recur after first-line treatment, and metastatic TNBC (mTNBC) has a poor prognosis with median survival of one year. Here, we present initial analyses of whole genome and transcriptome sequencing data from 14 prospective mTNBC. We have cataloged the collection of somatic genomic alterations in these advanced tumors, particularly those that may inform targeted therapies. Genes mutated in multiple tumors included TP53, LRP1B, HERC1, CDH5, RB1, and NF1. Notable genes involved in focal structural events were CTNNA1, PTEN, FBXW7, BRCA2, WT1, FGFR1, KRAS, HRAS, ARAF, BRAF, and PGCP. Homozygous deletion of CTNNA1 was detected in 2 of 6 African Americans. RNA sequencing revealed consistent overexpression of the FOXM1 gene when tumor gene expression was compared with nonmalignant breast samples. Using an outlier analysis of gene expression comparing one cancer with all the others, we detected expression patterns unique to each patient's tumor. Integrative DNA/RNA analysis provided evidence for deregulation of mutated genes, including the monoallelic expression of TP53 mutations. Finally, molecular alterations in several cancers supported targeted therapeutic intervention on clinical trials with known inhibitors, particularly for alterations in the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways. In conclusion, whole genome and transcriptome profiling of mTNBC have provided insights into somatic events occurring in this difficult to treat cancer. These genomic data have guided patients to investigational treatment trials and provide hypotheses for future trials in this irremediable cancer. PMID:23171949

  2. Stemming Cancer: Functional Genomics of Cancer Stem Cells in Solid Tumors

    OpenAIRE

    Regenbrecht, C. R. A.; Lehrach, H; Adjaye, J.

    2008-01-01

    Cancer stem cells (CSCs) were discovered about 15 years ago in hematopoietic cancers. Subsequently, cancer stem cells were discovered in various solid tumors. Based on parallels with normal stem cells, a developmental process of cancer stem cells follows paths of organized, hierarchical structure of cells with different degrees of maturity. While some investigators have reported particular markers as identification of cancer stem cells, these markers require further research. In this review, ...

  3. Anatomy: Spotlight on Africa

    Science.gov (United States)

    Kramer, Beverley; Pather, Nalini; Ihunwo, Amadi O.

    2008-01-01

    Anatomy departments across Africa were surveyed regarding the type of curriculum and method of delivery of their medical courses. While the response rate was low, African anatomy departments appear to be in line with the rest of the world in that many have introduced problem based learning, have hours that are within the range of western medical…

  4. 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.

  5. Anatomy comic strips.

    Science.gov (United States)

    Park, Jin Seo; Kim, Dae Hyun; Chung, Min Suk

    2011-01-01

    Comics are powerful visual messages that convey immediate visceral meaning in ways that conventional texts often cannot. This article's authors created comic strips to teach anatomy more interestingly and effectively. Four-frame comic strips were conceptualized from a set of anatomy-related humorous stories gathered from the authors' collective imagination. The comics were drawn on paper and then recreated with digital graphics software. More than 500 comic strips have been drawn and labeled in Korean language, and some of them have been translated into English. All comic strips can be viewed on the Department of Anatomy homepage at the Ajou University School of Medicine, Suwon, Republic of Korea. The comic strips were written and drawn by experienced anatomists, and responses from viewers have generally been favorable. These anatomy comic strips, designed to help students learn the complexities of anatomy in a straightforward and humorous way, are expected to be improved further by the authors and other interested anatomists. PMID:21634024

  6. MuSiC: Identifying mutational significance in cancer genomes

    OpenAIRE

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

    2012-01-01

    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 sig...

  7. 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

    . Here we describe the essence of a long-term initiative undertaken by The Danish Centre for Translational Breast Cancer Research and currently underway for cancer biomarker discovery using fresh tissue biopsies and bio-fluids. The Centre is a virtual hub that brings together scientists working......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 bedside...... in various areas of basic cancer research such as cell cycle control, invasion and micro-environmental alterations, apoptosis, cell signaling, and immunology, with clinicians (oncologists, surgeons), pathologists, and epidemiologists, with the aim of understanding the molecular mechanisms underlying breast...

  8. 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.

  9. 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.

  10. High-Resolution Genomic and Expression Profiling Reveals 105 Putative Amplification Target Genes in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Eija H. Mahlamaki

    2004-09-01

    Full Text Available Comparative genomic hybridization (CGH studies have provided a wealth of information on common copy number aberrations in pancreatic cancer, but the genes affected by these aberrations are largely unknown. To identify putative amplification target genes in pancreatic cancer, we performed a parallel copy number and expression survey in 13 pancreatic cancer cell lines using a 12,232-clone cDNA microarray, providing an average resolution of 300 kb throughout the human genome. CGH on cDNA microarray allowed highly accurate mapping of copy number increases and resulted in identification of 24 independent amplicons, ranging in size from 130 kb to 11 Mb. Statistical evaluation of gene copy number and expression data across all 13 cell lines revealed a set of 105 genes whose elevated expression levels were directly attributable to increased copy number. These included genes previously reported to be amplified in cancer as well as several novel targets for copy number alterations, such as p21-activated kinase 4 (PAK4, which was previously shown to be involved in cell migration, cell adhesion, and anchorage-independent growth. In conclusion, our results implicate a set of 105 genes that is likely to be actively involved in the development and progression of pancreatic cancer.

  11. The Genomic and Proteomic Content of Cancer Cell-Derived Exosomes

    Directory of Open Access Journals (Sweden)

    Meredith C Henderson

    2012-04-01

    Full Text Available Exosomes are secreted membrane vesicles that have been proposed as an effective means to detect a variety of disease states, including cancer. The properties of exosomes, including stability in biological fluids, allow for their efficient isolation and make them an ideal vehicle for studies on early disease detection and evaluation. Much data has been collected over recent years regarding the mRNA, miRNA, and protein contents of exosomes. In addition, many studies have described the functional role that exosomes play in disease initiation and progression. Tumor cells have been shown to secrete exosomes, often in increased amounts compared to normal cells, and these exosomes can carry the genomic and proteomic signatures characteristic of the tumor cells from which they were derived. While these unique signatures make exosomes ideal for cancer detection, exosomes derived from cancer cells have also been shown to play a functional role in cancer progression. Here, we review the unique genomic and proteomic contents of exosomes originating from cancer cells as well as their functional effects to promote tumor progression.

  12. The search for cis-regulatory driver mutations in cancer genomes.

    Science.gov (United States)

    Poulos, Rebecca C; Sloane, Mathew A; Hesson, Luke B; Wong, Jason W H

    2015-10-20

    With the advent of high-throughput and relatively inexpensive whole-genome sequencing technology, the focus of cancer research has begun to shift toward analyses of somatic mutations in non-coding cis-regulatory elements of the cancer genome. Cis-regulatory elements play an important role in gene regulation, with mutations in these elements potentially resulting in changes to the expression of linked genes. The recent discoveries of recurrent TERT promoter mutations in melanoma, and recurrent mutations that create a super-enhancer regulating TAL1 expression in T-cell acute lymphoblastic leukaemia (T-ALL), have sparked significant interest in the search for other somatic cis-regulatory mutations driving cancer development. In this review, we look more closely at the TERT promoter and TAL1 enhancer alterations and use these examples to ask whether other cis-regulatory mutations may play a role in cancer susceptibility. In doing so, we make observations from the data emerging from recent research in this field, and describe the experimental and analytical approaches which could be adopted in the hope of better uncovering the true functional significance of somatic cis-regulatory mutations in cancer. PMID:26356674

  13. Genomic alterations in breast cancer patients in betel quid and non betel quid chewers.

    Science.gov (United States)

    Kaushal, Mishi; Mishra, Ashwani K; Sharma, Jagannath; Zomawia, Eric; Kataki, Amal; Kapur, Sujala; Saxena, Sunita

    2012-01-01

    Betel Quid (BQ) chewing independently contributes to oral, hepatic and esophageal carcinomas. Strong association of breast cancer risk with BQ chewing in Northeast Indian population has been reported where this habit is prodigal. We investigated genomic alterations in breast cancer patients with and without BQ chewing exposure. Twenty six BQ chewers (BQC) and 17 non BQ chewer (NBQC) breast cancer patients from Northeast India were analyzed for genomic alterations and pathway networks using SNP array and IPA. BQC tumors showed significantly (PETS2 etc in BQC and two networks "Molecular Transport, Nucleic Acid Metabolism, Small Molecule Biochemistry" and "Cellular Development, Embryonic Development, Organismal Development" including genes RPN2, EMR3, VAV1, NNAT and MUC16 etc were seen in NBQC. Common alterations (>30%) were seen in 27 regions. Three networks were significant in common regions with key roles of PTK2, RPN2, EMR3, VAV1, NNAT, MUC16, MYC and YWHAZ genes. These data show that breast cancer arising by environmental carcinogens exemplifies genetic alterations differing from those observed in the non exposed ones. A number of genetic changes are shared in both tumor groups considered as crucial in breast cancer progression. PMID:22937096

  14. A genome-wide association study of breast cancer in women of African ancestry

    OpenAIRE

    Chen, Fang; Chen, Gary K.; Stram, Daniel O.; Millikan, Robert C.; Ambrosone, Christine B.; John, Esther M; Bernstein, Leslie; Zheng, Wei; Palmer, Julie R.; Jennifer J Hu; Rebbeck, Tim R.; Ziegler, Regina G.; Nyante, Sarah; Bandera, Elisa V.; Sue A Ingles

    2012-01-01

    Genome-wide association studies (GWAS) in diverse populations are needed to reveal variants that are more common and/or limited to defined populations. We conducted a GWAS of breast cancer in women of African ancestry, with genotyping of > 1,000,000 SNPs in 3,153 African American cases and 2,831 controls, and replication testing of the top 66 associations in an additional 3,607 breast cancer cases and 11,330 controls of African ancestry. Two of the 66 SNPs replicated (p < 0.05) in stage 2, wh...

  15. Implications of using whole genome sequencing to test unselected populations for high risk breast cancer genes: a modelling study

    OpenAIRE

    Warren-Gash, Charlotte; Kroese, Mark; Burton, Hilary; Pharoah, Paul

    2016-01-01

    Background The decision to test for high risk breast cancer gene mutations is traditionally based on risk scores derived from age, family and personal cancer history. Next generation sequencing technologies such as whole genome sequencing (WGS) make wider population testing more feasible. In the UK’s 100,000 Genomes Project, mutations in 16 genes including BRCA1 and BRCA2 are to be actively sought regardless of clinical presentation. The implications of deploying this approach at scale for pa...

  16. The Path(way) Less Traveled: A Pathway-Oriented Approach to Providing Information about Precision Cancer Medicine on My Cancer Genome12

    Science.gov (United States)

    Taylor, Alexandria D.; Micheel, Christine M.; Anderson, Ingrid A.; Levy, Mia A.; Lovly, Christine M.

    2016-01-01

    This perspective describes the motivation, development, and implementation of pathway-based content for My Cancer Genome, an online precision medicine knowledge resource describing clinical implications of genetic alterations in cancer. As researchers uncover more about cancer pathogenesis, we are learning more not only about the specific genes and proteins involved but also about how those genes and proteins interact with others along cell signaling pathways. This knowledge has led researchers and clinicians to begin to think about cancer therapy using a pathway-based approach. To facilitate this approach, My Cancer Genome used a list of more than 800 cancer-related genes to identify 20 cancer-relevant pathways and then created content focused on demonstrating the therapeutic relevance of these pathways. PMID:27084433

  17. The Path(way Less Traveled: A Pathway-Oriented Approach to Providing Information about Precision Cancer Medicine on My Cancer Genome

    Directory of Open Access Journals (Sweden)

    Alexandria D. Taylor

    2016-04-01

    Full Text Available This perspective describes the motivation, development, and implementation of pathway-based content for My Cancer Genome, an online precision medicine knowledge resource describing clinical implications of genetic alterations in cancer. As researchers uncover more about cancer pathogenesis, we are learning more not only about the specific genes and proteins involved but also about how those genes and proteins interact with others along cell signaling pathways. This knowledge has led researchers and clinicians to begin to think about cancer therapy using a pathway-based approach. To facilitate this approach, My Cancer Genome used a list of more than 800 cancer-related genes to identify 20 cancer-relevant pathways and then created content focused on demonstrating the therapeutic relevance of these pathways.

  18. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution.

    Science.gov (United States)

    de Bruin, Elza C; McGranahan, Nicholas; Mitter, Richard; Salm, Max; Wedge, David C; Yates, Lucy; Jamal-Hanjani, Mariam; Shafi, Seema; Murugaesu, Nirupa; Rowan, Andrew J; Grönroos, Eva; Muhammad, Madiha A; Horswell, Stuart; Gerlinger, Marco; Varela, Ignacio; Jones, David; Marshall, John; Voet, Thierry; Van Loo, Peter; Rassl, Doris M; Rintoul, Robert C; Janes, Sam M; Lee, Siow-Ming; Forster, Martin; Ahmad, Tanya; Lawrence, David; Falzon, Mary; Capitanio, Arrigo; Harkins, Timothy T; Lee, Clarence C; Tom, Warren; Teefe, Enock; Chen, Shann-Ching; Begum, Sharmin; Rabinowitz, Adam; Phillimore, Benjamin; Spencer-Dene, Bradley; Stamp, Gordon; Szallasi, Zoltan; Matthews, Nik; Stewart, Aengus; Campbell, Peter; Swanton, Charles

    2014-10-10

    Spatial and temporal dissection of the genomic changes occurring during the evolution of human non-small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis. We sequenced 25 spatially distinct regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity. Despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC-associated mutations. In tumors from former smokers, genome-doubling occurred within a smoking-signature context before subclonal diversification, which suggested that a long period of tumor latency had preceded clinical detection. The regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes, are likely to confound treatment success in NSCLC. PMID:25301630

  19. 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.

  20. Short Inverted Repeats Are Hotspots for Genetic Instability: Relevance to Cancer Genomes

    Directory of Open Access Journals (Sweden)

    Steve Lu

    2015-03-01

    Full Text Available Analyses of chromosomal aberrations in human genetic disorders have revealed that inverted repeat sequences (IRs often co-localize with endogenous chromosomal instability and breakage hotspots. Approximately 80% of all IRs in the human genome are short (<100 bp, yet the mutagenic potential of such short cruciform-forming sequences has not been characterized. Here, we find that short IRs are enriched at translocation breakpoints in human cancer and stimulate the formation of DNA double-strand breaks (DSBs and deletions in mammalian and yeast cells. We provide evidence for replication-related mechanisms of IR-induced genetic instability and a novel XPF cleavage-based mechanism independent of DNA replication. These discoveries implicate short IRs as endogenous sources of DNA breakage involved in disease etiology and suggest that these repeats represent a feature of genome plasticity that may contribute to the evolution of the human genome by providing a means for diversity within the population.

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

    OpenAIRE

    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

    2014-01-01

    Genetic alterations are frequently observed in bladder cancer. In this study, we demonstrate that bladder tumors can be classified into two different types based on the spectrum of genetic diversity they confer. In one class of tumors, we observed tumor protein p53 mutations and a large number of single-nucleotide and structural variants. Another characteristic of this group was chromosome shattering, known as chromothripsis, and mutational heterogeneity. The other two bladder tumors did not ...

  2. Genomic alterations indicate tumor origin and varied metastatic potential of disseminated cells from prostate-cancer patients

    OpenAIRE

    Holcomb, Ilona N.; Grove, Douglas I.; Kinnunen, Martin; Friedman, Cynthia L.; Gallaher, Ian S.; Todd M. Morgan; Sather, Cassandra L.; Delrow, Jeffrey J; Peter S Nelson; Lange, Paul H.; Ellis, William J; True, Lawrence D.; Janet M Young; Hsu, Li; Trask, Barbara J.

    2008-01-01

    Disseminated epithelial cells can be isolated from the bone marrow of a far greater fraction of prostate-cancer patients than the fraction of patients who progress to metastatic disease. To provide a better understanding of these cells, we have characterized their genomic alterations. We first present an array comparative genomic hybridization method capable of detecting genomic changes in the small number of disseminated cells (10-20) that can typically be obtained from bone-marrow aspirates...

  3. 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

    2011-01-01

    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. PMID:21467267

  4. Large BRCA1 and BRCA2 genomic rearrangements in Danish high risk breast-ovarian cancer families

    DEFF Research Database (Denmark)

    Hansen, Thomas v O; Jønson, Lars; Albrechtsen, Anders;

    2009-01-01

    BRCA1 and BRCA2 germ-line mutations predispose to breast and ovarian cancer. Large genomic rearrangements of BRCA1 account for 0-36% of all disease causing mutations in various populations, while large genomic rearrangements in BRCA2 are more rare. We examined 642 East Danish breast and/or ovarian...

  5. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution

    OpenAIRE

    de Bruin, Elza C.; McGranahan, Nicholas; Mitter, Richard; Salm, Max; Wedge, David C; Yates, Lucy; Jamal-Hanjani, Mariam; Shafi, Seema; Murugaesu, Nirupa; Rowan, Andrew J.; Grönroos, Eva; Muhammad, Madiha A.; Horswell, Stuart; Gerlinger, Marco; Varela, Ignacio

    2014-01-01

    Spatial and temporal dissection of the genomic changes occurring during the evolution of human non–small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis. We sequenced 25 spatially distinct regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC...

  6. Genomics and premalignant breast lesions: clues to the development and progression of lobular breast cancer

    OpenAIRE

    Mastracci, Teresa L; Boulos, Fouad I; Andrulis, Irene L.; Lam, Wan L.

    2007-01-01

    Advances in genomic technology have improved our understanding of the genetic events that parallel breast cancer development. Because almost all mammary carcinomas develop in the terminal duct lobular units of the breast, understanding the events involved in mammary gland development make it possible to recognize those events that, when altered, contribute to breast neoplasia. In this review we focus on lobular carcinomas, discussing the pathology, development, and progression of premalignant...

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

    OpenAIRE

    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...

  8. Expression genomics in breast cancer research: microarrays at the crossroads of biology and medicine

    OpenAIRE

    Miller, Lance D; Liu, Edison T

    2007-01-01

    Genome-wide expression microarray studies have revealed that the biological and clinical heterogeneity of breast cancer can be partly explained by information embedded within a complex but ordered transcriptional architecture. Comprising this architecture are gene expression networks, or signatures, reflecting biochemical and behavioral properties of tumors that might be harnessed to improve disease subtyping, patient prognosis and prediction of therapeutic response. Emerging 'hypothesis-driv...

  9. Functional genomic analysis of drug sensitivity pathways to guide adjuvant strategies in breast cancer

    DEFF Research Database (Denmark)

    Swanton, Charles; Szallasi, Zoltan Imre; Brenton, James D.;

    2008-01-01

    ) as well as endocrine therapies such as tamoxifen. Given the limited power of microarray signatures to predict therapeutic response in associative studies of small clinical trial cohorts, the use of functional genomic data combined with expression or sequence analysis of genes and microRNAs implicated...... in drug response in human tumours may provide a more robust method to guide adjuvant treatment strategies in breast cancer that are transferable across different expression platforms and patient cohorts....

  10. Genomic analysis to define molecular basis of aggressiveness in a mouse model of oral cancer

    OpenAIRE

    Varun Chalivendra; Krishna Latha Kanchi; Onken, Michael D.; Ashley E. Winkler; Elaine Mardis; Ravindra Uppaluri

    2014-01-01

    To investigate the molecular basis underlying aggressive behavior in oral squamous cell carcinoma (OSCC), our laboratory developed a carcinogen-induced mouse oral cancer (MOC) cell line model that encompasses the growth and metastasis spectrum of its human counterpart. We performed next-generation sequencing (NGS) and gene expression microarray profiles to explore the genomic and transcriptional backgrounds of the differential MOC line phenotypes, as well as, the cross-species relevance of th...

  11. Functional genomics identifies therapeutic targets for MYC-driven cancer

    OpenAIRE

    Toyoshima, Masafumi; Howie, Heather L; Imakura, Maki; Walsh, Ryan M.; Annis, James E.; Chang, Aaron N; Frazier, Jason; Chau, B. Nelson; Loboda, Andrey; Linsley, Peter S; Cleary, Michele A.; Park, Julie R.; Grandori, Carla

    2012-01-01

    MYC oncogene family members are broadly implicated in human cancers, yet are considered “undruggable” as they encode transcription factors. MYC also carries out essential functions in proliferative tissues, suggesting that its inhibition could cause severe side effects. We elected to identify synthetic lethal interactions with c-MYC overexpression (MYC-SL) in a collection of ∼3,300 druggable genes, using high-throughput siRNA screening. Of 49 genes selected for follow-up, 48 were confirmed by...

  12. Identifying common prognostic factors in genomic cancer studies: A novel index for censored outcomes

    Directory of Open Access Journals (Sweden)

    Moreau Thierry

    2010-03-01

    Full Text Available Abstract Background With the growing number of public repositories for high-throughput genomic data, it is of great interest to combine the results produced by independent research groups. Such a combination allows the identification of common genomic factors across multiple cancer types and provides new insights into the disease process. In the framework of the proportional hazards model, classical procedures, which consist of ranking genes according to the estimated hazard ratio or the p-value obtained from a test statistic of no association between survival and gene expression level, are not suitable for gene selection across multiple genomic datasets with different sample sizes. We propose a novel index for identifying genes with a common effect across heterogeneous genomic studies designed to remain stable whatever the sample size and which has a straightforward interpretation in terms of the percentage of separability between patients according to their survival times and gene expression measurements. Results The simulations results show that the proposed index is not substantially affected by the sample size of the study and the censoring. They also show that its separability performance is higher than indices of predictive accuracy relying on the likelihood function. A simulated example illustrates the good operating characteristics of our index. In addition, we demonstrate that it is linked to the score statistic and possesses a biologically relevant interpretation. The practical use of the index is illustrated for identifying genes with common effects across eight independent genomic cancer studies of different sample sizes. The meta-selection allows the identification of four genes (ESPL1, KIF4A, HJURP, LRIG1 that are biologically relevant to the carcinogenesis process and have a prognostic impact on survival outcome across various solid tumors. Conclusion The proposed index is a promising tool for identifying factors having a

  13. 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.

  14. 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.

  15. A genome-wide scan for breast cancer risk haplotypes among African American women.

    Directory of Open Access Journals (Sweden)

    Chi Song

    Full Text Available Genome-wide association studies (GWAS simultaneously investigating hundreds of thousands of single nucleotide polymorphisms (SNP have become a powerful tool in the investigation of new disease susceptibility loci. Haplotypes are sometimes thought to be superior to SNPs and are promising in genetic association analyses. The application of genome-wide haplotype analysis, however, is hindered by the complexity of haplotypes themselves and sophistication in computation. We systematically analyzed the haplotype effects for breast cancer risk among 5,761 African American women (3,016 cases and 2,745 controls using a sliding window approach on the genome-wide scale. Three regions on chromosomes 1, 4 and 18 exhibited moderate haplotype effects. Furthermore, among 21 breast cancer susceptibility loci previously established in European populations, 10p15 and 14q24 are likely to harbor novel haplotype effects. We also proposed a heuristic of determining the significance level and the effective number of independent tests by the permutation analysis on chromosome 22 data. It suggests that the effective number was approximately half of the total (7,794 out of 15,645, thus the half number could serve as a quick reference to evaluating genome-wide significance if a similar sliding window approach of haplotype analysis is adopted in similar populations using similar genotype density.

  16. 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.

  17. Applied peritoneal anatomy

    International Nuclear Information System (INIS)

    The peritoneal cavity is a complex anatomical structure with multiple attachments and connections. These are better understood with reference to the embryological development of this region. Armed with this knowledge, the diagnosis and assessment of a wide range of common intra-abdominal diseases becomes straightforward. This article will review and simplify the terminology, complex embryological development, and anatomy of the peritoneum, peritoneal attachments, and the reflections forming the peritoneal boundaries. Normal anatomy will be described using schematic diagrams with corresponding computed tomography (CT) and magnetic resonance imaging (MRI) images, including CT peritoneograms. The relevance of intra- and extra-peritoneal anatomy to common pathological processes will be demonstrated

  18. Anatomy of Sarcocaulon

    Directory of Open Access Journals (Sweden)

    R. L. Verhoeven

    1983-12-01

    Full Text Available The anatomy of the leaf blade, petiole, stem and root of the genus Sarcocaulon (DC. Sweet is discussed. On the basis of the leaf anatomy, the four sections recognized by Moffett (1979 can be identified: section Denticulati (dorsiventral leaves, section Multifidi (isobilateral leaves and adaxial and abaxial palisade continuous at midvein, section Crenati (isobilateral leaves, short curved trichomes and glandular hairs, section Sarcocaulon (isobilateral leaves and glandular hairs only. The anatomy of the stem is typically that of a herbaceous dicotyledon with a thick periderm. The root structure shows that the function of the root is not food storage.

  19. Integrative genomic analyses of a novel cytokine, interleukin-34 and its potential role in cancer prediction.

    Science.gov (United States)

    Wang, Bo; Xu, Wenming; Tan, Miaolian; Xiao, Yan; Yang, Haiwei; Xia, Tian-Song

    2015-01-01

    Interleukin-34 (IL-34) is a novel cytokine, which is composed of 222 amino acids and forms homodimers. It binds to the macrophage colony-stimulating factor (M-CSF) receptor and plays an important role in innate immunity and inflammatory processes. In the present study, we identified the completed IL-34 gene in 25 various mammalian genomes and found that IL-34 existed in all types of vertebrates, including fish, amphibians, birds and mammals. These species have a similar 7 exon/6 intron gene organization. The phylogenetic tree indicated that the IL-34 gene from the primate lineage, rodent lineage and teleost lineage form a species-specific cluster. It was found mammalian that IL-34 was under positive selection pressure with the identified positively selected site, 196Val. Fifty-five functionally relevant single nucleotide polymorphisms (SNPs), including 32 SNPs causing missense mutations, 3 exonic splicing enhancer SNPs and 20 SNPs causing nonsense mutations were identified from 2,141 available SNPs in the human IL-34 gene. IL-34 was expressed in various types of cancer, including blood, brain, breast, colorectal, eye, head and neck, lung, ovarian and skin cancer. A total of 5 out of 40 tests (1 blood cancer, 1 brain cancer, 1 colorectal cancer and 2 lung cancer) revealed an association between IL-34 gene expression and cancer prognosis. It was found that the association between the expression of IL-34 and cancer prognosis varied in different types of cancer, even in the same types of cancer from different databases. This suggests that the function of IL-34 in these tumors may be multidimensional. The upstream transcription factor 1 (USF1), regulatory factor X-1 (RFX1), the Sp1 transcription factor 1 , POU class 3 homeobox 2 (POU3F2) and forkhead box L1 (FOXL1) regulatory transcription factor binding sites were identified in the IL-34 gene upstream (promoter) region, which may be involved in the effects of IL-34 in tumors. PMID:25395235

  20. Cancer Therapy Directed by Comprehensive Genomic Profiling: A Single Center Study.

    Science.gov (United States)

    Wheler, Jennifer J; Janku, Filip; Naing, Aung; Li, Yali; Stephen, Bettzy; Zinner, Ralph; Subbiah, Vivek; Fu, Siqing; Karp, Daniel; Falchook, Gerald S; Tsimberidou, Apostolia M; Piha-Paul, Sarina; Anderson, Roosevelt; Ke, Danxia; Miller, Vincent; Yelensky, Roman; Lee, J Jack; Hong, David S; Kurzrock, Razelle

    2016-07-01

    Innovative molecular diagnostics deployed in the clinic enable new ways to stratify patients into appropriate treatment regimens. These approaches may resolve a major challenge for early-phase clinical trials, which is to recruit patients who, while having failed previous treatments, may nevertheless respond to molecularly targeted drugs. We report the findings of a prospective, single-center study conducted in patients with diverse refractory cancers who underwent comprehensive genomic profiling (CGP; next-generation sequencing, 236 genes). Of the 500 patients enrolled, 188 (37.6%) received either matched (N = 122/188, 65%) or unmatched therapy (N = 66/188, 35%). The most common reasons that patients were not evaluable for treatment included insufficient tissue, death, or hospice transfer. The median number of molecular alterations per patient was five (range, 1-14); median number of prior therapies, four. The most common diagnoses were ovarian cancer (18%), breast cancer (16%), sarcoma (13%), and renal cancer (7%). Of the 339 successfully profiled patients, 317 (93.5%) had at least one potentially actionable alteration. By calculating matching scores, based on the number of drug matches and genomic aberrations per patient, we found that high scores were independently associated with a greater frequency of stable disease ≥6 months/partial/complete remission [22% (high scores) vs. 9% (low scores), P = 0.024], longer time-to-treatment failure [hazard ratio (HR) = 0.52; 95% confidence interval (CI) = 0.36-0.74; P = 0.0003], and survival (HR = 0.65; 95% CI = 0.43-1.0; P = 0.05). Collectively, this study offers a clinical proof of concept for the utility of CGP in assigning therapy to patients with refractory malignancies, especially in those patients with multiple genomic aberrations for whom combination therapies could be implemented. Cancer Res; 76(13); 3690-701. ©2016 AACR. PMID:27197177

  1. 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.

  2. 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 K J; 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

    2016-06-01

    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. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized 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 operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer. PMID:27135926

  3. 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.

  4. 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.

  5. 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.

  6. 乳腺癌腋窝清扫术后淋巴结解剖方法临床研究%Clinical research of the method of lymph node anatomy after axillary dissection in breast cancer

    Institute of Scientific and Technical Information of China (English)

    张琴琴; 王宁霞

    2014-01-01

    目的:探讨脂肪溶解液预处理乳腺癌腋淋巴组织标本对解剖的影响。方法选取暨南大学第一附属医院2011年3月至2013年10月收治的临床分期为Ⅱ期并行乳腺癌改良根治术的病人共82例,术后腋窝淋巴组织标本予脂肪溶解液浸泡15~20 min后再进行解剖(实验组),将解剖淋巴结的数目、最小径及解剖时间等各指标与传统解剖方法(对照组)对比。结果实验组解剖淋巴结的数目(23.10枚)多于对照组(18.38枚)(P=0.000),最小径(0.16 cm)小于对照组(0.25 cm)(P=0.000),解剖时间(19.95 min)少于对照组(24.02 min)(P=0.000)。肥胖病人中两组间淋巴结数目上的差值(7.00枚)要较非肥胖病人显著(3.52枚)。两组病人病理切片比较无明显差别。结论对乳腺癌腋淋巴结标本的解剖,用脂解液预处理的方法可增加淋巴结检出的数目,降低解剖难度以及缩短解剖时间,该法尤其适用于肥胖病人。%Objective To explore the effect of pretreating the axillary lymphatic tissue by liposuction before the anatomy in breast cancer patients. Methods A total of 82 cases of stage Ⅱ breast cancer were performed modified radical mastectomy between March 2011 and October 2013 in the First Affiliated Hospital of Jinan University. The axillary lymphatic tissue was soaked in liposuction by 15-20 minutes after the modified radical mastectomy (experimental group). The number of lymph node, the minimum diameter and the time of anatomy in experimental group were compared with those in control group (traditional anatomy method). Results The mean number of lymph node in experimental group was higher than that in control group (23.10 vs. 18.38, P=0.000). The mean minimum diameter in experimental group was less than that in control group (0.16cm vs. 0.25 cm, P=0.000). The median time of the duration of anatomy in experimental group was shorter than that in control

  7. Comparison of a Gross Anatomy Laboratory to Online Anatomy Software for Teaching Anatomy

    Science.gov (United States)

    Mathiowetz, Virgil; Yu, Chih-Huang; Quake-Rapp, Cindee

    2016-01-01

    This study was designed to assess the grades, self-perceived learning, and satisfaction between occupational therapy students who used a gross anatomy laboratory versus online anatomy software (AnatomyTV) as tools to learn anatomy at a large public university and a satellite campus in the mid-western United States. The goal was to determine if…

  8. Anatomy of the Eye

    Science.gov (United States)

    ... Errors Scientists in the Laboratory Visual Acuity Testing Anatomy of the Eye View complete NEI image albums ... the NEI Website Manager . Department of Health and Human Services | The National Institutes of Health | USA.gov ...

  9. Genome-wide DNA methylation profiling in triple-negative breast cancer reveals epigenetic signatures with important clinical value

    Science.gov (United States)

    Stirzaker, Clare; Zotenko, Elena; Clark, Susan J

    2016-01-01

    abstract Analysis of cancer methylomes has dramatically changed our concept of the potential of diagnostic and prognostic methylation biomarkers in disease stratification. Through whole-genome methylation capture sequencing of triple-negative breast cancers (TNBCs) we recently identified differentially methylated regions with diagnostic and prognostic value that promise to stratify TNBCs for more personalized management. PMID:27308556

  10. Genome-wide association study identifies a common variant in RAD51B associated with male breast cancer risk

    DEFF Research Database (Denmark)

    Orr, Nick; Lemnrau, Alina; Cooke, Rosie;

    2012-01-01

    We conducted a genome-wide association study of male breast cancer comprising 823 cases and 2,795 controls of European ancestry, with validation in independent sample sets totaling 438 cases and 474 controls. A SNP in RAD51B at 14q24.1 was significantly associated with male breast cancer risk (P ...

  11. 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

  12. Identification of seven new prostate cancer susceptibility loci through a genome-wide association study

    Science.gov (United States)

    Eeles, Rosalind A.; Kote-Jarai, Zsofia; Olama, Ali Amin Al; Giles, Graham G.; Guy, Michelle; Severi, Gianluca; Muir, Kenneth; Hopper, John L.; Henderson, Brian E.; Haiman, Christopher A.; Schleutker, Johanna; Hamdy, Freddie C.; Neal, David E.; Donovan, Jenny L.; Stanford, Janet L.; Ostrander, Elaine A.; Ingles, Sue A.; John, Esther M.; Thibodeau, Stephen N.; Schaid, Daniel; Park, Jong Y.; Spurdle, Amanda; Clements, Judith; Dickinson, Joanne L.; Maier, Christiane; Vogel, Walther; Dörk, Thilo; Rebbeck, Timothy R.; Cooney, Kathleen A.; Cannon-Albright, Lisa; Chappuis, Pierre O.; Hutter, Pierre; Zeegers, Maurice; Kaneva, Radka; Zhang, Hong-Wei; Lu, Yong-Jie; Foulkes, William D.; English, Dallas R.; Leongamornlert, Daniel A.; Tymrakiewicz, Malgorzata; Morrison, Jonathan; Ardern-Jones, Audrey T.; Hall, Amanda L.; O’Brien, Lynne T.; Wilkinson, Rosemary A.; Saunders, Edward J.; Page, Elizabeth C.; Sawyer, Emma J.; Edwards, Stephen M.; Dearnaley, David P.; Horwich, Alan; Huddart, Robert A.; Khoo, Vincent S.; Parker, Christopher C.; Van As, Nicholas; Woodhouse, Christopher J.; Thompson, Alan; Christmas, Tim; Ogden, Chris; Cooper, Colin S.; Southey, Melissa C.; Lophatananon, Artitaya; Liu, Jo-Fen; Kolonel, Laurence N.; Le Marchand, Loic; Wahlfors, Tiina; Tammela, Teuvo L.; Auvinen, Anssi; Lewis, Sarah J.; Cox, Angela; FitzGerald, Liesel M.; Koopmeiners, Joseph S.; Karyadi, Danielle M.; Kwon, Erika M.; Stern, Mariana C.; Corral, Roman; Joshi, Amit D.; Shahabi, Ahva; McDonnell, Shannon K.; Sellers, Thomas A; Pow-Sang, Julio; Chambers, Suzanne; Aitken, Joanne; Gardiner, R.A. (Frank); Batra, Jyotsna; Kedda, Mary Anne; Lose, Felicity; Polanowski, Andrea; Patterson, Briony; Serth, Jürgen; Meyer, Andreas; Luedeke, Manuel; Stefflova, Klara; Ray, Anna M.; Lange, Ethan M.; Farnham, Jim; Khan, Humera; Slavov, Chavdar; Mitkova, Atanaska; Cao, Guangwen; Easton, Douglas F.

    2010-01-01

    Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. To identify common PrCa susceptibility alleles, we have previously conducted a genome-wide association study in which 541, 129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and 1,894 controls. We have now evaluated promising associations in a second stage, in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls, and a third stage, involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to previously identified loci, we identified a further seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11, and 22 (P=1.6×10−8 to P=2.7×10−33). PMID:19767753

  13. My Cancer Genome: Evaluating an Educational Model to Introduce Patients and Caregivers to Precision Medicine Information.

    Science.gov (United States)

    Kusnoor, Sheila V; Koonce, Taneya Y; Levy, Mia A; Lovly, Christine M; Naylor, Helen M; Anderson, Ingrid A; Micheel, Christine M; Chen, Sheau-Chiann; Ye, Fei; Giuse, Nunzia B

    2016-01-01

    This study tested an innovative model for creating consumer-level content about precision medicine based on health literacy and learning style principles. "Knowledge pearl" videos, incorporating multiple learning modalities, were created to explain genetic and cancer medicine concepts. Cancer patients and caregivers (n=117) were randomized to view professional-level content directly from the My Cancer Genome (MCG) website (Group A; control), content from MCG with knowledge pearls embedded (Group B), or a consumer translation, targeted at the sixth grade level, with knowledge pearls embedded (Group C). A multivariate analysis showed that Group C, but not Group B, showed greater knowledge gains immediately after viewing the educational material than Group A. Statistically significant group differences in test performance were no longer observed three weeks later. These findings suggest that adherence to health literacy and learning style principles facilitates comprehension of precision medicine concepts and that ongoing review of the educational information is necessary. PMID:27570660

  14. Genome sequence analysis of Helicobacter pylori strains associated with gastric ulceration and gastric cancer

    Directory of Open Access Journals (Sweden)

    Peek Richard M

    2009-01-01

    Full Text Available Abstract Background Persistent colonization of the human stomach by Helicobacter pylori is associated with asymptomatic gastric inflammation (gastritis and an increased risk of duodenal ulceration, gastric ulceration, and non-cardia gastric cancer. In previous studies, the genome sequences of H. pylori strains from patients with gastritis or duodenal ulcer disease have been analyzed. In this study, we analyzed the genome sequences of an H. pylori strain (98-10 isolated from a patient with gastric cancer and an H. pylori strain (B128 isolated from a patient with gastric ulcer disease. Results Based on multilocus sequence typing, strain 98-10 was most closely related to H. pylori strains of East Asian origin and strain B128 was most closely related to strains of European origin. Strain 98-10 contained multiple features characteristic of East Asian strains, including a type s1c vacA allele and a cagA allele encoding an EPIYA-D tyrosine phosphorylation motif. A core genome of 1237 genes was present in all five strains for which genome sequences were available. Among the 1237 core genes, a subset of alleles was highly divergent in the East Asian strain 98-10, encoding proteins that exhibited H. pylori strains associated with gastric cancer or premalignant gastric lesions. Conclusion These data provide insight into the diversity that exists among H. pylori strains from diverse clinical and geographic origins. Highly divergent alleles and strain-specific genes identified in this study may represent useful biomarkers for analyzing geographic partitioning of H. pylori and for identifying strains capable of inducing malignant or premalignant gastric lesions.

  15. Substantial contribution of extrinsic risk factors to cancer development | Office of Cancer Genomics

    Science.gov (United States)

    Recent research has highlighted a strong correlation between tissue-specific cancer risk and the lifetime number of tissue-specific stem-cell divisions. Whether such correlation implies a high unavoidable intrinsic cancer risk has become a key public health debate with the dissemination of the 'bad luck' hypothesis. Here we provide evidence that intrinsic risk factors contribute only modestly (less than ~10-30% of lifetime risk) to cancer development.

  16. 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.

  17. 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.

  18. An Integrative Approach for the Large-scale Identification of Human Genome Kinases Regulating Cancer Metastasis

    Science.gov (United States)

    Zhang, Hanshuo; Wu, Pu-Yen; Ma, Ming; Ye, Yanzheng; Hao, Yang; Yang, Junyu; Yin, Shenyi; Sun, Changhong; Phan, John H.; Wang, May D.; Xi, Jianzhong Jeff

    2016-01-01

    Kinases regulate the majority of biological processes and become one of important groups of drug targets. To identify more kinases being potential for cancer therapy, we developed an integrative approach for the large-scale screen of functional genes capable of regulating the main traits of cancer metastasis, including cell migration as well as invasion. We first employed self-assembled cell microarray (SAMcell) to screen functional genes that regulate cancer cell migration using a siRNA library targeting 710 human genome kinase genes. We identified 81 genes capable of significantly regulating cancer cell migration. Following with invasion assays and bio-informatics analysis, we discovered that 16 genes with differentially expression in cancer samples can regulate both cell migration and invasion, among which 10 genes have been well known to play critical roles in the cancer development. The remaining 6 genes were experimentally validated to have the capacities of regulating the metastasis-related traits, including cell proliferation, apoptosis and anoikis activities besides cell motility. Together, these findings provide a new insight into the therapeutic use of human kinases. PMID:23751374

  19. 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.

  20. Genome-wide linkage scan for colorectal cancer susceptibility genes supports linkage to chromosome 3q

    Directory of Open Access Journals (Sweden)

    Velculescu Victor E

    2008-04-01

    Full Text Available Abstract Background Colorectal cancer is one of the most common causes of cancer-related mortality. The disease is clinically and genetically heterogeneous though a strong hereditary component has been identified. However, only a small proportion of the inherited susceptibility can be ascribed to dominant syndromes, such as Hereditary Non-Polyposis Colorectal Cancer (HNPCC or Familial Adenomatous Polyposis (FAP. In an attempt to identify novel colorectal cancer predisposing genes, we have performed a genome-wide linkage analysis in 30 Swedish non-FAP/non-HNPCC families with a strong family history of colorectal cancer. Methods Statistical analysis was performed using multipoint parametric and nonparametric linkage. Results Parametric analysis under the assumption of locus homogeneity excluded any common susceptibility regions harbouring a predisposing gene for colorectal cancer. However, several loci on chromosomes 2q, 3q, 6q, and 7q with suggestive linkage were detected in the parametric analysis under the assumption of locus heterogeneity as well as in the nonparametric analysis. Among these loci, the locus on chromosome 3q21.1-q26.2 was the most consistent finding providing positive results in both parametric and nonparametric analyses Heterogeneity LOD score (HLOD = 1.90, alpha = 0.45, Non-Parametric LOD score (NPL = 2.1. Conclusion The strongest evidence of linkage was seen for the region on chromosome 3. Interestingly, the same region has recently been reported as the most significant finding in a genome-wide analysis performed with SNP arrays; thus our results independently support the finding on chromosome 3q.

  1. 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; Knoop, Ann S; Jensen, Jeanette D; Bak, Martin; Mollenhauer, Jan; Kruse, Torben A; Thomassen, Mads

    2015-01-01

    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......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...

  2. 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; Knoop, Ann; Jensen, Jeanette Dupont; Bak, Martin; Mollenhauer, Jan; Kruse, Torben A; Thomassen, Mads

    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......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...

  3. Anatomy of The Anatomy of Racial Inequality

    OpenAIRE

    Steven Raphael

    2002-01-01

    In this review, I summarize and offer thoughts about two arguments key to Glenn Loury's analysis of the anatomy of racial inequality. The first concerns the idea that many negative stereotypes held about blacks in the United States are self-fulfilling, despite little evidence of inherent differences between the races in human potential. The second argument concerns the proposition that the racial stigmatization of blacks is deeply embedded in the public consciousness and that such stigma raci...

  4. 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.

  5. Integrated clinical, whole-genome, and transcriptome analysis of multisampled lethal metastatic prostate cancer.

    Science.gov (United States)

    Bova, G Steven; Kallio, Heini M L; Annala, Matti; Kivinummi, Kati; Högnäs, Gunilla; Häyrynen, Sergei; Rantapero, Tommi; Kivinen, Virpi; Isaacs, William B; Tolonen, Teemu; Nykter, Matti; Visakorpi, Tapio

    2016-05-01

    We report the first combined analysis of whole-genome sequence, detailed clinical history, and transcriptome sequence of multiple prostate cancer metastases in a single patient (A21). Whole-genome and transcriptome sequence was obtained from nine anatomically separate metastases, and targeted DNA sequencing was performed in cancerous and noncancerous foci within the primary tumor specimen removed 5 yr before death. Transcriptome analysis revealed increased expression of androgen receptor (AR)-regulated genes in liver metastases that harbored an AR p.L702H mutation, suggesting a dominant effect by the mutation despite being present in only one of an estimated 16 copies per cell. The metastases harbored several alterations to the PI3K/AKT pathway, including a clonal truncal mutation in PIK3CG and present in all metastatic sites studied. The list of truncal genomic alterations shared by all metastases included homozygous deletion of TP53, hemizygous deletion of RB1 and CHD1, and amplification of FGFR1. If the patient were treated today, given this knowledge, the use of second-generation androgen-directed therapies, cessation of glucocorticoid administration, and therapeutic inhibition of the PI3K/AKT pathway or FGFR1 receptor could provide personalized benefit. Three previously unreported truncal clonal missense mutations (ABCC4 p.R891L, ALDH9A1 p.W89R, and ASNA1 p.P75R) were expressed at the RNA level and assessed as druggable. The truncal status of mutations may be critical for effective actionability and merit further study. Our findings suggest that a large set of deeply analyzed cases could serve as a powerful guide to more effective prostate cancer basic science and personalized cancer medicine clinical trials. PMID:27148588

  6. Integrated clinical, whole-genome, and transcriptome analysis of multisampled lethal metastatic prostate cancer

    Science.gov (United States)

    Bova, G. Steven; Kallio, Heini M.L.; Annala, Matti; Kivinummi, Kati; Högnäs, Gunilla; Häyrynen, Sergei; Rantapero, Tommi; Kivinen, Virpi; Isaacs, William B.; Tolonen, Teemu; Nykter, Matti; Visakorpi, Tapio

    2016-01-01

    We report the first combined analysis of whole-genome sequence, detailed clinical history, and transcriptome sequence of multiple prostate cancer metastases in a single patient (A21). Whole-genome and transcriptome sequence was obtained from nine anatomically separate metastases, and targeted DNA sequencing was performed in cancerous and noncancerous foci within the primary tumor specimen removed 5 yr before death. Transcriptome analysis revealed increased expression of androgen receptor (AR)-regulated genes in liver metastases that harbored an AR p.L702H mutation, suggesting a dominant effect by the mutation despite being present in only one of an estimated 16 copies per cell. The metastases harbored several alterations to the PI3K/AKT pathway, including a clonal truncal mutation in PIK3CG and present in all metastatic sites studied. The list of truncal genomic alterations shared by all metastases included homozygous deletion of TP53, hemizygous deletion of RB1 and CHD1, and amplification of FGFR1. If the patient were treated today, given this knowledge, the use of second-generation androgen-directed therapies, cessation of glucocorticoid administration, and therapeutic inhibition of the PI3K/AKT pathway or FGFR1 receptor could provide personalized benefit. Three previously unreported truncal clonal missense mutations (ABCC4 p.R891L, ALDH9A1 p.W89R, and ASNA1 p.P75R) were expressed at the RNA level and assessed as druggable. The truncal status of mutations may be critical for effective actionability and merit further study. Our findings suggest that a large set of deeply analyzed cases could serve as a powerful guide to more effective prostate cancer basic science and personalized cancer medicine clinical trials.

  7. Whole-genome sequencing of bladder cancers reveals somatic CDKN1A mutations and clinicopathological associations with mutation burden

    OpenAIRE

    Cazier, J.-B.; Rao, S. R.; Mclean, C. M.; A. L. Walker; Wright, B J; Jaeger, E. E. M.; Kartsonaki, C.; Marsden, L.; Yau, C; Camps, C.; Kaisaki, P.; ,; Allan, Christopher; Attar, Moustafa; Bell, John

    2014-01-01

    Bladder cancers are a leading cause of death from malignancy. Molecular markers might predict disease progression and behaviour more accurately than the available prognostic factors. Here we use whole-genome sequencing to identify somatic mutations and chromosomal changes in 14 bladder cancers of different grades and stages. As well as detecting the known bladder cancer driver mutations, we report the identification of recurrent protein-inactivating mutations in CDKN1A and FAT1. The former ar...

  8. Impact of a bronchial genomic classifier on clinical decision making in patients undergoing diagnostic evaluation for lung cancer

    OpenAIRE

    Ferguson, J. Scott; Van Wert, Ryan; Choi, Yoonha; Rosenbluth, Michael J.; Smith, Kate Porta; Huang, Jing; Spira, Avrum

    2016-01-01

    Background Bronchoscopy is frequently used for the evaluation of suspicious pulmonary lesions found on computed tomography, but its sensitivity for detecting lung cancer is limited. Recently, a bronchial genomic classifier was validated to improve the sensitivity of bronchoscopy for lung cancer detection, demonstrating a high sensitivity and negative predictive value among patients at intermediate risk (10–60 %) for lung cancer with an inconclusive bronchoscopy. Our objective for this study w...

  9. [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. PMID:26507715

  10. Combining Chromosomal Arm Status and Significantly Aberrant Genomic Locations Reveals New Cancer Subtypes

    Directory of Open Access Journals (Sweden)

    Tal Shay

    2009-01-01

    Full Text Available Many types of tumors exhibit characteristic chromosomal losses or gains, as well as local amplifications and deletions. Within any given tumor type, sample specific amplifications and deletions are also observed. Typically, a region that is aberrant in more tumors, or whose copy number change is stronger, would be considered as a more promising candidate to be biologically relevant to cancer. We sought for an intuitive method to define such aberrations and prioritize them. We define V, the “volume” associated with an aberration, as the product of three factors: (a fraction of patients with the aberration, (b the aberration’s length and (c its amplitude. Our algorithm compares the values of V derived from the real data to a null distribution obtained by permutations, and yields the statistical significance (p-value of the measured value of V. We detected genetic locations that were significantly aberrant, and combine them with chromosomal arm status (gain/loss to create a succinct fingerprint of the tumor genome. This genomic fingerprint is used to visualize the tumors, highlighting events that are co-occurring or mutually exclusive. We apply the method on three different public array CGH datasets of Medulloblastoma and Neuroblastoma, and demonstrate its ability to detect chromosomal regions that were known to be altered in the tested cancer types, as well as to suggest new genomic locations to be tested. We identified a potential new subtype of Medulloblastoma, which is analogous to Neuroblastoma type 1.

  11. Gamma-Retrovirus Integration Marks Cell Type-Specific Cancer Genes: A Novel Profiling Tool in Cancer Genomics

    Science.gov (United States)

    Gilroy, Kathryn L.; Terry, Anne; Naseer, Asif; de Ridder, Jeroen; Wang, Weiwei; Carpenter, Eric; Mason, Andrew; Wong, Gane K-S.; Kilbey, Anna; Neil, James C.

    2016-01-01

    Retroviruses have been foundational in cancer research since early studies identified proto-oncogenes as targets for insertional mutagenesis. Integration of murine gamma-retroviruses into the host genome favours promoters and enhancers and entails interaction of viral integrase with host BET/bromodomain factors. We report that this integration pattern is conserved in feline leukaemia virus (FeLV), a gamma-retrovirus that infects many human cell types. Analysis of FeLV insertion sites in the MCF-7 mammary carcinoma cell line revealed strong bias towards active chromatin marks with no evidence of significant post-integration growth selection. The most prominent FeLV integration targets had little overlap with the most abundantly expressed transcripts, but were strongly enriched for annotated cancer genes. A meta-analysis based on several gamma-retrovirus integration profiling (GRIP) studies in human cells (CD34+, K562, HepG2) revealed a similar cancer gene bias but also remarkable cell-type specificity, with prominent exceptions including a universal integration hotspot at the long non-coding RNA MALAT1. Comparison of GRIP targets with databases of super-enhancers from the same cell lines showed that these have only limited overlap and that GRIP provides unique insights into the upstream drivers of cell growth. These observations elucidate the oncogenic potency of the gamma-retroviruses and support the wider application of GRIP to identify the genes and growth regulatory circuits that drive distinct cancer types. PMID:27097319

  12. Gamma-Retrovirus Integration Marks Cell Type-Specific Cancer Genes: A Novel Profiling Tool in Cancer Genomics.

    Science.gov (United States)

    Gilroy, Kathryn L; Terry, Anne; Naseer, Asif; de Ridder, Jeroen; Allahyar, Amin; Wang, Weiwei; Carpenter, Eric; Mason, Andrew; Wong, Gane K-S; Cameron, Ewan R; Kilbey, Anna; Neil, James C

    2016-01-01

    Retroviruses have been foundational in cancer research since early studies identified proto-oncogenes as targets for insertional mutagenesis. Integration of murine gamma-retroviruses into the host genome favours promoters and enhancers and entails interaction of viral integrase with host BET/bromodomain factors. We report that this integration pattern is conserved in feline leukaemia virus (FeLV), a gamma-retrovirus that infects many human cell types. Analysis of FeLV insertion sites in the MCF-7 mammary carcinoma cell line revealed strong bias towards active chromatin marks with no evidence of significant post-integration growth selection. The most prominent FeLV integration targets had little overlap with the most abundantly expressed transcripts, but were strongly enriched for annotated cancer genes. A meta-analysis based on several gamma-retrovirus integration profiling (GRIP) studies in human cells (CD34+, K562, HepG2) revealed a similar cancer gene bias but also remarkable cell-type specificity, with prominent exceptions including a universal integration hotspot at the long non-coding RNA MALAT1. Comparison of GRIP targets with databases of super-enhancers from the same cell lines showed that these have only limited overlap and that GRIP provides unique insights into the upstream drivers of cell growth. These observations elucidate the oncogenic potency of the gamma-retroviruses and support the wider application of GRIP to identify the genes and growth regulatory circuits that drive distinct cancer types. PMID:27097319

  13. Ovarian Cancer Stage I

    Science.gov (United States)

    ... An inset shows cancer cells in the pelvic peritoneum. Also shown are the fallopian tubes, uterus, cervix, ... c) cancer cells are found in the pelvic peritoneum. Topics/Categories: Anatomy -- Gynecologic Cancer Types -- Ovarian Cancer ...

  14. Cervical Cancer Stage IVB

    Science.gov (United States)

    ... of the body, such as the lymph nodes, lung, liver, intestine, or bone. Stage IVB cervical cancer. Topics/Categories: Anatomy -- Gynecologic Cancer Types -- Cervical Cancer Staging Type: Color, Medical Illustration Source: National Cancer Institute ...

  15. Understanding Cancer Prognosis

    Medline Plus

    Full Text Available ... Types Recurrent Cancer Common Cancer Types Bladder Cancer Breast Cancer Colorectal Cancer Kidney (Renal Cell) Cancer Leukemia Lung ... Biology Cancer Genomics Causes of Cancer Diagnosis Prevention Screening & Early Detection Treatment Cancer & Public Health Cancer Health ...

  16. Cancer-predisposition gene KLLN maintains pericentric H3K9 trimethylation protecting genomic stability.

    Science.gov (United States)

    Nizialek, Emily A; Sankunny, Madhav; Niazi, Farshad; Eng, Charis

    2016-05-01

    Maintenance of proper chromatin states and genomic stability is vital for normal development and health across a range of organisms. Here, we report on the role of KLLN in maintenance of pericentric H3K9 trimethylation (H3K9me3) and genomic stability. Germline hypermethylation of KLLN, a gene uncovered well after the human genome project, has been linked to Cowden cancer-predisposition syndrome (CS) in PTEN wild-type cases. KLLN first identified as a p53-dependent tumor suppressor gene, was believed to bind randomly to DNA and cause S-phase arrest. Using chromatin immunoprecipitation-based sequencing (ChIP-seq), we demonstrated that KLLN binds to DNA regions enriched with H3K9me3. KLLN overexpression correlated with increased H3K9 methyltransferase activity and increased global H3K9me3, while knockdown of KLLN had an opposite effect. We also found KLLN to localize to pericentric regions, with loss of KLLN resulting in dysregulation of pericentric heterochromatin, with consequent chromosomal instability manifested by increased micronuclei formation and numerical chromosomal aberrations. Interestingly, we show that KLLN interacts with DBC1, with consequent abrogation of DBC1 inhibition of SUV39H1, a H3K9 methyltransferase, suggesting the mode of KLLN regulating H3K9me3. These results suggest a critical role for KLLN as a potential regulator of pericentric heterochromatin formation, genomic stability and gene expression. PMID:26673699

  17. Cancer-predisposition gene KLLN maintains pericentric H3K9 trimethylation protecting genomic stability

    Science.gov (United States)

    Nizialek, Emily A.; Sankunny, Madhav; Niazi, Farshad; Eng, Charis

    2016-01-01

    Maintenance of proper chromatin states and genomic stability is vital for normal development and health across a range of organisms. Here, we report on the role of KLLN in maintenance of pericentric H3K9 trimethylation (H3K9me3) and genomic stability. Germline hypermethylation of KLLN, a gene uncovered well after the human genome project, has been linked to Cowden cancer-predisposition syndrome (CS) in PTEN wild-type cases. KLLN first identified as a p53-dependent tumor suppressor gene, was believed to bind randomly to DNA and cause S-phase arrest. Using chromatin immunoprecipitation-based sequencing (ChIP-seq), we demonstrated that KLLN binds to DNA regions enriched with H3K9me3. KLLN overexpression correlated with increased H3K9 methyltransferase activity and increased global H3K9me3, while knockdown of KLLN had an opposite effect. We also found KLLN to localize to pericentric regions, with loss of KLLN resulting in dysregulation of pericentric heterochromatin, with consequent chromosomal instability manifested by increased micronuclei formation and numerical chromosomal aberrations. Interestingly, we show that KLLN interacts with DBC1, with consequent abrogation of DBC1 inhibition of SUV39H1, a H3K9 methyltransferase, suggesting the mode of KLLN regulating H3K9me3. These results suggest a critical role for KLLN as a potential regulator of pericentric heterochromatin formation, genomic stability and gene expression. PMID:26673699

  18. 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

  19. Cancer Biomarkers from Genome-Scale DNA Methylation: Comparison of Evolutionary and Semantic Analysis Methods

    Directory of Open Access Journals (Sweden)

    Ioannis Valavanis

    2015-11-01

    Full Text Available DNA methylation profiling exploits microarray technologies, thus yielding a wealth of high-volume data. Here, an intelligent framework is applied, encompassing epidemiological genome-scale DNA methylation data produced from the Illumina’s Infinium Human Methylation 450K Bead Chip platform, in an effort to correlate interesting methylation patterns with cancer predisposition and, in particular, breast cancer and B-cell lymphoma. Feature selection and classification are employed in order to select, from an initial set of ~480,000 methylation measurements at CpG sites, predictive cancer epigenetic biomarkers and assess their classification power for discriminating healthy versus cancer related classes. Feature selection exploits evolutionary algorithms or a graph-theoretic methodology which makes use of the semantics information included in the Gene Ontology (GO tree. The selected features, corresponding to methylation of CpG sites, attained moderate-to-high classification accuracies when imported to a series of classifiers evaluated by resampling or blindfold validation. The semantics-driven selection revealed sets of CpG sites performing similarly with evolutionary selection in the classification tasks. However, gene enrichment and pathway analysis showed that it additionally provides more descriptive sets of GO terms and KEGG pathways regarding the cancer phenotypes studied here. Results support the expediency of this methodology regarding its application in epidemiological studies.

  20. 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.

  1. Translocation and deletion breakpoints in cancer genomes are associated with potential non-B DNA-forming sequences

    Science.gov (United States)

    Bacolla, Albino; Tainer, John A.; Vasquez, Karen M.; Cooper, David N.

    2016-01-01

    Gross chromosomal rearrangements (including translocations, deletions, insertions and duplications) are a hallmark of cancer genomes and often create oncogenic fusion genes. An obligate step in the generation of such gross rearrangements is the formation of DNA double-strand breaks (DSBs). Since the genomic distribution of rearrangement breakpoints is non-random, intrinsic cellular factors may predispose certain genomic regions to breakage. Notably, certain DNA sequences with the potential to fold into secondary structures [potential non-B DNA structures (PONDS); e.g. triplexes, quadruplexes, hairpin/cruciforms, Z-DNA and single-stranded looped-out structures with implications in DNA replication and transcription] can stimulate the formation of DNA DSBs. Here, we tested the postulate that these DNA sequences might be found at, or in close proximity to, rearrangement breakpoints. By analyzing the distribution of PONDS-forming sequences within ±500 bases of 19 947 translocation and 46 365 sequence-characterized deletion breakpoints in cancer genomes, we find significant association between PONDS-forming repeats and cancer breakpoints. Specifically, (AT)n, (GAA)n and (GAAA)n constitute the most frequent repeats at translocation breakpoints, whereas A-tracts occur preferentially at deletion breakpoints. Translocation breakpoints near PONDS-forming repeats also recur in different individuals and patient tumor samples. Hence, PONDS-forming sequences represent an intrinsic risk factor for genomic rearrangements in cancer genomes. PMID:27084947

  2. Ovarian Cancers Harboring Inactivating Mutations in CDK12 Display a Distinct Genomic Instability Pattern Characterized by Large Tandem Duplications.

    Science.gov (United States)

    Popova, Tatiana; Manié, Elodie; Boeva, Valentina; Battistella, Aude; Goundiam, Oumou; Smith, Nicholas K; Mueller, Christopher R; Raynal, Virginie; Mariani, Odette; Sastre-Garau, Xavier; Stern, Marc-Henri

    2016-04-01

    CDK12 is a recurrently mutated gene in serous ovarian carcinoma, whose downregulation is associated with impaired expression of DNA damage repair genes and subsequent hypersensitivity to DNA-damaging agents and PARP1/2 inhibitors. In this study, we investigated the genomic landscape associated with CDK12 inactivation in patients with serous ovarian carcinoma. We show that CDK12 loss was consistently associated with a particular genomic instability pattern characterized by hundreds of tandem duplications of up to 10 megabases (Mb) in size. Tandem duplications were characterized by a bimodal (∼0.3 and ∼3 Mb) size distribution and overlapping microhomology at the breakpoints. This genomic instability, denoted as the CDK12 TD-plus phenotype, is remarkably distinct from other alteration patterns described in breast and ovarian cancers. The CDK12 TD-plus phenotype was associated with a greater than 10% gain in genomic content and occurred at a 3% to 4% rate in The Cancer Genome Atlas-derived and in-house cohorts of patients with serous ovarian carcinoma. Moreover, CDK12-inactivating mutations together with the TD-plus phenotype were also observed in prostate cancers. Our finding provides new insight toward deciphering the function of CDK12 in genome maintenance and oncogenesis. Cancer Res; 76(7); 1882-91. ©2016 AACR. PMID:26787835

  3. 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...... 85 antimetabolites that can inhibit growth of, or even kill, any of the cell lines, while at the same time not being toxic for 83 different healthy human cell types. 60 of these antimetabolites were found to inhibit growth in all cell lines. Finally, we experimentally validated one of the 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...

  4. Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer.

    Science.gov (United States)

    Singhal, Hari; Greene, Marianne E; Tarulli, Gerard; Zarnke, Allison L; Bourgo, Ryan J; Laine, Muriel; Chang, Ya-Fang; Ma, Shihong; Dembo, Anna G; Raj, Ganesh V; Hickey, Theresa E; Tilley, Wayne D; Greene, Geoffrey L

    2016-06-01

    The functional role of progesterone receptor (PR) and its impact on estrogen signaling in breast cancer remain controversial. In primary ER(+) (estrogen receptor-positive)/PR(+) human tumors, we report that PR reprograms estrogen signaling as a genomic agonist and a phenotypic antagonist. In isolation, estrogen and progestin act as genomic agonists by regulating the expression of common target genes in similar directions, but at different levels. Similarly, in isolation, progestin is also a weak phenotypic agonist of estrogen action. However, in the presence of both hormones, progestin behaves as a phenotypic estrogen antagonist. PR remodels nucleosomes to noncompetitively redirect ER genomic binding to distal enhancers enriched for BRCA1 binding motifs and sites that link PR and ER/PR complexes. When both hormones are present, progestin modulates estrogen action, such that responsive transcriptomes, cellular processes, and ER/PR recruitment to genomic sites correlate with those observed with PR alone, but not ER alone. Despite this overall correlation, the transcriptome patterns modulated by dual treatment are sufficiently different from individual treatments, such that antagonism of oncogenic processes is both predicted and observed. Combination therapies using the selective PR modulator/antagonist (SPRM) CDB4124 in combination with tamoxifen elicited 70% cytotoxic tumor regression of T47D tumor xenografts, whereas individual therapies inhibited tumor growth without net regression. Our findings demonstrate that PR redirects ER chromatin binding to antagonize estrogen signaling and that SPRMs can potentiate responses to antiestrogens, suggesting that cotargeting of ER and PR in ER(+)/PR(+) breast cancers should be explored. PMID:27386569

  5. Colorectal Cancer and the Human Gut Microbiome: Reproducibility with Whole-Genome Shotgun Sequencing

    Science.gov (United States)

    Hua, Xing; Zeller, Georg; Sunagawa, Shinichi; Voigt, Anita Y.; Hercog, Rajna; Goedert, James J.; Shi, Jianxin; Bork, Peer; Sinha, Rashmi

    2016-01-01

    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 power to detect

  6. Colorectal Cancer and the Human Gut Microbiome: Reproducibility with Whole-Genome Shotgun Sequencing.

    Science.gov (United States)

    Vogtmann, Emily; Hua, Xing; Zeller, Georg; Sunagawa, Shinichi; Voigt, Anita Y; Hercog, Rajna; Goedert, James J; Shi, Jianxin; Bork, Peer; Sinha, Rashmi

    2016-01-01

    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 power to detect

  7. Colorectal Cancer and the Human Gut Microbiome: Reproducibility with Whole-Genome Shotgun Sequencing.

    Directory of Open Access Journals (Sweden)

    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

  8. Genome-wide association studies identify four ER negative–specific breast cancer risk loci

    OpenAIRE

    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.

    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 can...

  9. [Viennese school of anatomy].

    Science.gov (United States)

    Angetter, D C

    1999-10-01

    Anatomical science played a minor role in Vienna for centuries until Gerard van Swieten, in the 18th century, recognized the importance of anatomy for medical education. In the 19th century the anatomical school at the University of Vienna development to its height. A new building and a collection of preparations attracted a large number of students. Finally, a second department of anatomy was established. Political ideologies started to affect this institution in the beginning of the 20th century. Anti-Semitism emerged and caused uproars and fights among the students of the two departments. In 1938 both were united under Eduard Pernkopf, a dedicated Nazi and chairman of the department of anatomy, Decan of the medical faculty (1938-1943) and later on President of the University of Vienna (1943-1945). He was suspected of using cadavers of executed persons for the purpose of research and education. PMID:10546321

  10. GENOMIC LANDSCAPE OF NON-SMALL CELL LUNG CANCER IN SMOKERS AND NEVER SMOKERS

    Science.gov (United States)

    Govindan, Ramaswamy; Ding, Li; Griffith, Malachi; Subramanian, Janakiraman; Dees, Nathan D.; Kanchi, Krishna L.; Maher, Christopher A.; Fulton, Robert; Fulton, Lucinda; Wallis, John; Chen, Ken; Walker, Jason; McDonald, Sandra; Bose, Ron; Ornitz, David; Xiong, Donghai; You, Ming; Dooling, David J.; Watson, Mark; Mardis, Elaine R.

    2013-01-01

    Summary We report the results of whole genome and transcriptome sequencing of tumor and adjacent normal tissue samples from 17 patients with non-small cell lung carcinoma (NSCLC). We identified 3,726 point mutations and over 90 indels in the coding sequence, with an average mutation frequency more than 10-fold higher in smokers than in never-smokers. Novel alterations in genes involved in chromatic modification and DNA repair pathways were identified along with DACH1, CFTR, RELN, ABCB5, and HGF. Deep digital sequencing revealed diverse clonality patterns in both never smokers and smokers. All validated EFGR and KRAS mutations were present in the founder clones, suggesting possible roles in cancer initiation. Analysis revealed 14 fusions including ROS1 and ALK as well as novel metabolic enzymes. Cell cycle and JAK-STAT pathways are significantly altered in lung cancer along with perturbations in 54 genes that are potentially targetable with currently available drugs. PMID:22980976

  11. Variation in root wood anatomy

    NARCIS (Netherlands)

    Cutler, D.F.

    1976-01-01

    Variability in the anatomy of root wood of selected specimens particularly Fraxinus excelsior L. and Acer pseudoplatanus L. in the Kew reference microscope slide collection is discussed in relation to generalised statements in the literature on root wood anatomy.

  12. Biosemiotic Entropy of the Genome: Mutations and Epigenetic Imbalances Resulting in Cancer

    Directory of Open Access Journals (Sweden)

    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

  13. Genomic instability and radiation risk in molecular pathways to colon cancer.

    Science.gov (United States)

    Kaiser, Jan Christian; Meckbach, Reinhard; Jacob, Peter

    2014-01-01

    Colon cancer is caused by multiple genomic alterations which lead to genomic instability (GI). GI appears in molecular pathways of microsatellite instability (MSI) and chromosomal instability (CIN) with clinically observed case shares of about 15-20% and 80-85%. Radiation enhances the colon cancer risk by inducing GI, but little is known about different outcomes for MSI and CIN. Computer-based modelling can facilitate the understanding of the phenomena named above. Comprehensive biological models, which combine the two main molecular pathways to colon cancer, are fitted to incidence data of Japanese a-bomb survivors. The preferred model is selected according to statistical criteria and biological plausibility. Imprints of cell-based processes in the succession from adenoma to carcinoma are identified by the model from age dependences and secular trends of the incidence data. Model parameters show remarkable compliance with mutation rates and growth rates for adenoma, which has been reported over the last fifteen years. Model results suggest that CIN begins during fission of intestinal crypts. Chromosomal aberrations are generated at a markedly elevated rate which favors the accelerated growth of premalignant adenoma. Possibly driven by a trend of Westernization in the Japanese diet, incidence rates for the CIN pathway increased notably in subsequent birth cohorts, whereas rates pertaining to MSI remained constant. An imbalance between number of CIN and MSI cases began to emerge in the 1980s, whereas in previous decades the number of cases was almost equal. The CIN pathway exhibits a strong radio-sensitivity, probably more intensive in men. Among young birth cohorts of both sexes the excess absolute radiation risk related to CIN is larger by an order of magnitude compared to the MSI-related risk. Observance of pathway-specific risks improves the determination of the probability of causation for radiation-induced colon cancer in individual patients, if their exposure

  14. Genomic instability and radiation risk in molecular pathways to colon cancer.

    Directory of Open Access Journals (Sweden)

    Jan Christian Kaiser

    Full Text Available Colon cancer is caused by multiple genomic alterations which lead to genomic instability (GI. GI appears in molecular pathways of microsatellite instability (MSI and chromosomal instability (CIN with clinically observed case shares of about 15-20% and 80-85%. Radiation enhances the colon cancer risk by inducing GI, but little is known about different outcomes for MSI and CIN. Computer-based modelling can facilitate the understanding of the phenomena named above. Comprehensive biological models, which combine the two main molecular pathways to colon cancer, are fitted to incidence data of Japanese a-bomb survivors. The preferred model is selected according to statistical criteria and biological plausibility. Imprints of cell-based processes in the succession from adenoma to carcinoma are identified by the model from age dependences and secular trends of the incidence data. Model parameters show remarkable compliance with mutation rates and growth rates for adenoma, which has been reported over the last fifteen years. Model results suggest that CIN begins during fission of intestinal crypts. Chromosomal aberrations are generated at a markedly elevated rate which favors the accelerated growth of premalignant adenoma. Possibly driven by a trend of Westernization in the Japanese diet, incidence rates for the CIN pathway increased notably in subsequent birth cohorts, whereas rates pertaining to MSI remained constant. An imbalance between number of CIN and MSI cases began to emerge in the 1980s, whereas in previous decades the number of cases was almost equal. The CIN pathway exhibits a strong radio-sensitivity, probably more intensive in men. Among young birth cohorts of both sexes the excess absolute radiation risk related to CIN is larger by an order of magnitude compared to the MSI-related risk. Observance of pathway-specific risks improves the determination of the probability of causation for radiation-induced colon cancer in individual patients

  15. 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

  16. Translating genomics: cancer genetics, public health and the making of the (de)molecularised body in Cuba and Brazil.

    Science.gov (United States)

    Gibbon, Sahra

    2016-03-01

    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. PMID:27008076

  17. An interactive anatomy dissection DVD

    OpenAIRE

    Al-Sabah, Fadel YS

    2013-01-01

    Anatomy remains the cornerstone of medical education. Human anatomy has not changed, yet our understanding of the topic and the methods by which we teach anatomy continue to evolve. At present lectures, tutorials and human cadaveric dissection in the anatomy room remain central to anatomical education in the Republic of Ireland and throughout many parts of the world. With the emergence of new technologies, new teaching methods can be explored. In-house and on-line teaching of Radiology and...

  18. 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. PMID:24588670

  19. Open pipelines for integrated tumor genome profiles reveal differences between pancreatic cancer tumors and cell lines

    International Nuclear Information System (INIS)

    We describe open, reproducible pipelines that create an integrated genomic profile of a cancer and use the profile to find mutations associated with disease and potentially useful drugs. These pipelines analyze high-throughput cancer exome and transcriptome sequence data together with public databases to find relevant mutations and drugs. The three pipelines that we have developed are: (1) an exome analysis pipeline, which uses whole or targeted tumor exome sequence data to produce a list of putative variants (no matched normal data are needed); (2) a transcriptome analysis pipeline that processes whole tumor transcriptome sequence (RNA-seq) data to compute gene expression and find potential gene fusions; and (3) an integrated variant analysis pipeline that uses the tumor variants from the exome pipeline and tumor gene expression from the transcriptome pipeline to identify deleterious and druggable mutations in all genes and in highly expressed genes. These pipelines are integrated into the popular Web platform Galaxy at #http://usegalaxy.org/cancer# to make them accessible and reproducible, thereby providing an approach for doing standardized, distributed analyses in clinical studies. We have used our pipeline to identify similarities and differences between pancreatic adenocarcinoma cancer cell lines and primary tumors

  20. Personalized medicine approaches for colon cancer driven by genomics and systems biology: OncoTrack.

    Science.gov (United States)

    Henderson, David; Ogilvie, Lesley A; Hoyle, Nicholas; Keilholz, Ulrich; Lange, Bodo; Lehrach, Hans

    2014-09-01

    The post-genomic era promises to pave the way to a personalized understanding of disease processes, with technological and analytical advances helping to solve some of the world's health challenges. Despite extraordinary progress in our understanding of cancer pathogenesis, the disease remains one of the world's major medical problems. New therapies and diagnostic procedures to guide their clinical application are urgently required. OncoTrack, a consortium between industry and academia, supported by the Innovative Medicines Initiative, signifies a new era in personalized medicine, which synthesizes current technological advances in omics techniques, systems biology approaches, and mathematical modeling. A truly personalized molecular imprint of the tumor micro-environment and subsequent diagnostic and therapeutic insight is gained, with the ultimate goal of matching the "right" patient to the "right" drug and identifying predictive biomarkers for clinical application. This comprehensive mapping of the colon cancer molecular landscape in tandem with crucial, clinical functional annotation for systems biology analysis provides unprecedented insight and predictive power for colon cancer management. Overall, we show that major biotechnological developments in tandem with changes in clinical thinking have laid the foundations for the OncoTrack approach and the future clinical application of a truly personalized approach to colon cancer theranostics. PMID:25074435

  1. Radiotherapy for glioblastoma: reorganization of genome maintenance mechanisms involved in the process of inhibiting cancer

    International Nuclear Information System (INIS)

    Glioblastoma is a very aggressive brain tumor, which occurs in Glial cells. The treatment consists in chemotherapy, surgery and radiotherapy. The radiotherapy is a treatment method that uses ionizing radiation to kill cancer cells. The cells have genome maintenance mechanisms (MMG) distributed in apoptosis, DNA damage response, and cell cycle pathways. These pathways are formed by sets of proteins and perform specific functions within the cell (example: induce cell death). The mutation of these proteins associated with the failure of the MMG can cause the activation of mutations and consequently induce the development of cancer. This work, objective has to identify pathways and proteins expressed in cancer treatment using free software of the statistical analysis, developed in Fortran and R platforms to show the effects caused by radiation in the proteins of cancerous tissues. The results, were fond to pathways of glioblastoma treated with radiotherapy, activation of apoptosis and response to DNA damage pathways, indicating that there is death of carcinogenic tissue caused by radiation and that some cells are triggering a process of DNA repair. (author)

  2. Recent patents and advances in genomic biomarker discovery for colorectal cancers.

    Science.gov (United States)

    Quyun, Chen; Ye, Zhiyun; Lin, Sheng-Cai; Lin, Biaoyang

    2010-06-01

    Colorectal cancer (CRC) is the third most common cancer in the world. Early diagnosis of colorectal cancer is the key to reducing the death rate of CRC patients. Predicting the response to current therapeutic modalities of CRC will also have a great impact on patient care. This review summarizes recent advances and patents in biomarker discovery in CRC under five major categories; including genomic changes, expression changes, mutations, epigenetic changes and microRNAs. The interesting patents include: 1) a patent for a method to differentiate normal exfoliated cells from cancer cells based on whether they were subjected to apoptosis and DNA degradation; 2) A model (PM-33 multiple molecular marker model) based on expression changes of up-regulation of the MDM2, DUSP6, and NFl genes down-regulation of the RNF4, MMD and EIF2S3 genes, which achieved an 88% sensitivity, and an 82% specificity for CRC diagnosis; 3) gene mutations in PTEN, KRAS, PIK3CA for predicting the response to anti-EGFR therapies, a common drug used for CRC treatment; 4) patents on epigenetic changes of ITGA4, SEPT9, ALX4, TFAP2E FOXL2, SARM1, ID4 etc. and many key miRNAs. Finally, future directions in the fields were commented on or suggested, including the combination of multiple categories of biomarkers and pathway central or network-based biomarker panels. PMID:20426761

  3. Learning Anatomy Enhances Spatial Ability

    Science.gov (United States)

    Vorstenbosch, Marc A. T. M.; Klaassen, Tim P. F. M.; Donders, A. R. T.; Kooloos, Jan G. M.; Bolhuis, Sanneke M.; Laan, Roland F. J. M.

    2013-01-01

    Spatial ability is an important factor in learning anatomy. Students with high scores on a mental rotation test (MRT) systematically score higher on anatomy examinations. This study aims to investigate if learning anatomy also oppositely improves the MRT-score. Five hundred first year students of medicine ("n" = 242, intervention) and…

  4. 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.

  5. Genomic Profiling of Thyroid Cancer Reveals a Role for Thyroglobulin in Metastasis.

    Science.gov (United States)

    Siraj, Abdul K; Masoodi, Tariq; Bu, Rong; Beg, Shaham; Al-Sobhi, Saif S; Al-Dayel, Fouad; Al-Dawish, Mohammed; Alkuraya, Fowzan S; Al-Kuraya, Khawla S

    2016-06-01

    Papillary thyroid carcinoma (PTC) has a wide geographic variation in incidence; it is most common in Saudi Arabia, where it is only second to breast cancer as the most common cancer among females. Genomic profiling of PTC from Saudi Arabia has not been attempted previously. We performed whole-exome sequencing of 101 PTC samples and the corresponding genomic DNA to identify genes with recurrent somatic mutations, then sequenced these genes by using a next-generation gene-panel approach in an additional 785 samples. In addition to BRAF, N-RAS, and H-RAS, which have previously been shown to be recurrently mutated in PTC, our analysis highlights additional genes, including thyroglobulin (TG), which harbored somatic mutations in 3% of the entire cohort. Surprisingly, although TG mutations were not exclusive to mutations in the RAS-MAP kinase pathway, their presence was associated with a significantly worse clinical outcome, which suggests a pathogenic role beyond driving initial oncogenesis. Analysis of metastatic PTC tissue revealed significant enrichment for TG mutations (p evolution. PMID:27236916

  6. Development of cancer-initiating cells and immortalizedcells with genomic instability

    Institute of Scientific and Technical Information of China (English)

    Ken-ichi Yoshioka; Yuko Atsumi; Hitoshi Nakagama; Hirobumi Teraoka

    2015-01-01

    Cancers that develop after middle age usually exhibitgenomic instability and multiple mutations. This is indirect contrast to pediatric tumors that usually developas a result of specific chromosomal translocations andepigenetic aberrations. The development of genomicinstability is associated with mutations that contributeto cellular immortalization and transformation. Canceroccurs when cancer-initiating cells (CICs), also calledcancer stem cells, develop as a result of these mutations.In this paper, we explore how CICs develop as a resultof genomic instability, including looking at which cancersuppression mechanisms are abrogated. A recent in vitrostudy revealed the existence of a CIC induction pathwayin differentiating stem cells. Under aberrant differentiationconditions, cells become senescent and develop genomicinstabilities that lead to the development of CICs. Theresulting CICs contain a mutation in the alternativereading frame of CDKN2A (ARF)/p53 module, i.e. , ineither ARF or p53. We summarize recently establishedknowledge of CIC development and cellular immortality,explore the role of the ARF/p53 module in protectingcells from transformation, and describe a risk factorfor genomic destabilization that increases during theprocess of normal cell growth and differentiation and isassociated with the downregulation of histone H2AX tolevels representative of growth arrest in normal cells.

  7. Optimization of primer design for the detection of variable genomic lesions in cancer.

    Science.gov (United States)

    Bashir, Ali; Liu, Yu-Tsueng; Raphael, Benjamin J; Carson, Dennis; Bafna, Vineet

    2007-11-01

    Primer approximation multiplex PCR (PAMP) is a new experimental protocol for efficiently assaying structural variation in genomes. PAMP is particularly suited to cancer genomes where the precise breakpoints of alterations such as deletions or translocations vary between patients. The design of PCR primer sets for PAMP is challenging because a large number of primer pairs are required to detect alterations in the hundreds of kilobases range that can occur in cancer. These sets of primers must achieve high coverage of the region of interest, while avoiding primer dimers and satisfying the physico-chemical constraints of good PCR primers. We describe a natural formulation of these constraints as a combinatorial optimization problem. We show that the PAMP primer design problem is NP-hard, and design algorithms based on simulated annealing and integer programming, that provide good solutions to this problem in practice. The algorithms are applied to a test region around the known CDKN2A deletion, which show excellent results even in a 1:49 mixture of mutated:wild-type cells. We use these test results to help set design parameters for larger problems. We can achieve near-optimal designs for regions close to 1 Mb. PMID:17766270

  8. Colon Cancer-associated DNA Polymerase β Variant Induces Genomic Instability and Cellular Transformation*

    Science.gov (United States)

    Nemec, Antonia A.; Donigan, Katherine A.; Murphy, Drew L.; Jaeger, Joachim; Sweasy, Joann B.

    2012-01-01

    Rapidly advancing technology has resulted in the generation of the genomic sequences of several human tumors. We have identified several mutations of the DNA polymerase β (pol β) gene in human colorectal cancer. We have demonstrated that the expression of the pol β G231D variant increased chromosomal aberrations and induced cellular transformation. The transformed phenotype persisted in the cells even once the expression of G231D was extinguished, suggesting that it resulted as a consequence of genomic instability. Biochemical analysis revealed that its catalytic rate was 140-fold slower than WT pol β, and this was a result of the decreased binding affinity of nucleotides by G231D. Residue 231 of pol β lies in close proximity to the template strand of the DNA. Molecular modeling demonstrated that the change from a small and nonpolar glycine to a negatively charged aspartate resulted in a repulsion between the template and residue 231 leading to the distortion of the dNTP binding pocket. In addition, expression of G231D was insufficient to rescue pol β-deficient cells treated with chemotherapeutic agents suggesting that these agents may be effectively used to treat tumors harboring this mutation. More importantly, this suggests that the G231D variant has impaired base excision repair. Together, these data indicate that the G231D variant plays a role in driving cancer. PMID:22573322

  9. Allelic losses at genomic instability-associated loci in villous adenomas and adjacent colorectal cancers.

    Science.gov (United States)

    Brenner, Bruce M; Stoler, Daniel L; Rodriguez, Luz; Karpenko, Matthew J; Swede, Helen; Petrelli, Nicholas J; Anderson, Garth R

    2007-04-01

    Allelic imbalances in premalignant villous adenomas were compared with those in adjacent microdissected colorectal carcinoma that had arisen directly from the adenomas. Carcinoma-adenoma pairs were examined from 17 patients who underwent resections for colorectal cancer. In all, 28 microsatellite markers were examined, from regions of the genome where individual allelic losses have been associated with overall genomic instability in colorectal carcinomas. Microsatellite instability (MSI) was also evaluated for each marker in each tissue type. Loss of heterozygosity for multiple markers was found in 35% of adenomas and 65% of carcinomas; the average fractional allelic loss rate was 2.5 times higher in carcinomas than in adenomas. Of the 17 patients, 4 had MSI for >30% of markers in both adenoma and carcinoma, with no significant differences between the two tissues. Markers with particularly high imbalance rates in adenomas were seen on chromosomes 11, 14, and 15. These findings provide further evidence that genomic instability is an ongoing process during carcinogenesis, with a markedly increased frequency of allelic losses seen in carcinomas, compared with adjacent adenomas. Markers on chromosomes 11, 14, and 15 may become valuable tools in the identification of patients destined to progress to colorectal carcinomas. PMID:17350461

  10. Quantitative and Sensitive Detection of Cancer Genome Amplifications from Formalin Fixed Paraffin Embedded Tumors with Droplet Digital PCR.

    Science.gov (United States)

    Nadauld, Lincoln; Regan, John F; Miotke, Laura; Pai, Reet K; Longacre, Teri A; Kwok, Shirley S; Saxonov, Serge; Ford, James M; Ji, Hanlee P

    2012-01-01

    For the analysis of cancer, there is great interest in rapid and accurate detection of cancer genome amplifications containing oncogenes that are potential therapeutic targets. The vast majority of cancer tissue samples are formalin fixed and paraffin embedded (FFPE) which enables histopathological examination and long term archiving. However, FFPE cancer genomic DNA is oftentimes degraded and generally a poor substrate for many molecular biology assays. To overcome the issues of poor DNA quality from FFPE samples and detect oncogenic copy number amplifications with high accuracy and sensitivity, we developed a novel approach. Our assay requires nanogram amounts of genomic DNA, thus facilitating study of small amounts of clinical samples. Using droplet digital PCR (ddPCR), we can determine the relative copy number of specific genomic loci even in the presence of intermingled normal tissue. We used a control dilution series to determine the limits of detection for the ddPCR assay and report its improved sensitivity on minimal amounts of DNA compared to standard real-time PCR. To develop this approach, we designed an assay for the fibroblast growth factor receptor 2 gene (FGFR2) that is amplified in a gastric and breast cancers as well as others. We successfully utilized ddPCR to ascertain FGFR2 amplifications from FFPE-preserved gastrointestinal adenocarcinomas. PMID:23682346

  11. 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. PMID:27328919

  12. Extensive Transcriptomic and Genomic Analysis Provides New Insights about Luminal Breast Cancers

    Science.gov (United States)

    Tishchenko, Inna; Milioli, Heloisa Helena; Riveros, Carlos; Moscato, Pablo

    2016-01-01

    Despite constituting approximately two thirds of all breast cancers, the luminal A and B tumours are poorly classified at both clinical and molecular levels. There are contradictory reports on the nature of these subtypes: some define them as intrinsic entities, others as a continuum. With the aim of addressing these uncertainties and identifying molecular signatures of patients at risk, we conducted a comprehensive transcriptomic and genomic analysis of 2,425 luminal breast cancer samples. Our results indicate that the separation between the molecular luminal A and B subtypes—per definition—is not associated with intrinsic characteristics evident in the differentiation between other subtypes. Moreover, t-SNE and MST-kNN clustering approaches based on 10,000 probes, associated with luminal tumour initiation and/or development, revealed the close connections between luminal A and B tumours, with no evidence of a clear boundary between them. Thus, we considered all luminal tumours as a single heterogeneous group for analysis purposes. We first stratified luminal tumours into two distinct groups by their HER2 gene cluster co-expression: HER2-amplified luminal and ordinary-luminal. The former group is associated with distinct transcriptomic and genomic profiles, and poor prognosis; it comprises approximately 8% of all luminal cases. For the remaining ordinary-luminal tumours we further identified the molecular signature correlated with disease outcomes, exhibiting an approximately continuous gene expression range from low to high risk. Thus, we employed four virtual quantiles to segregate the groups of patients. The clinico-pathological characteristics and ratios of genomic aberrations are concordant with the variations in gene expression profiles, hinting at a progressive staging. The comparison with the current separation into luminal A and B subtypes revealed a substantially improved survival stratification. Concluding, we suggest a review of the definition of

  13. Flexible positions, managed hopes: the promissory bioeconomy of a whole genome sequencing cancer study.

    Science.gov (United States)

    Haase, Rachel; Michie, Marsha; Skinner, Debra

    2015-04-01

    Genomic research has rapidly expanded its scope and ambition over the past decade, promoted by both public and private sectors as having the potential to revolutionize clinical medicine. This promissory bioeconomy of genomic research and technology is generated by, and in turn generates, the hopes and expectations shared by investors, researchers and clinicians, patients, and the general public alike. Examinations of such bioeconomies have often focused on the public discourse, media representations, and capital investments that fuel these "regimes of hope," but also crucial are the more intimate contexts of small-scale medical research, and the private hopes, dreams, and disappointments of those involved. Here we examine one local site of production in a university-based clinical research project that sought to identify novel cancer predisposition genes through whole genome sequencing in individuals at high risk for cancer. In-depth interviews with 24 adults who donated samples to the study revealed an ability to shift flexibly between positioning themselves as research participants on the one hand, and as patients or as family members of patients, on the other. Similarly, interviews with members of the research team highlighted the dual nature of their positions as researchers and as clinicians. For both parties, this dual positioning shaped their investment in the project and valuing of its possible outcomes. In their narratives, all parties shifted between these different relational positions as they managed hopes and expectations for the research project. We suggest that this flexibility facilitated study implementation and participation in the face of potential and probable disappointment on one or more fronts, and acted as a key element in the resilience of this local promissory bioeconomy. We conclude that these multiple dimensions of relationality and positionality are inherent and essential in the creation of any complex economy, "bio" or otherwise. PMID

  14. A gross anatomy ontology for hymenoptera.

    Science.gov (United States)

    Yoder, Matthew J; Mikó, István; Seltmann, Katja C; Bertone, Matthew A; Deans, Andrew R

    2010-01-01

    Hymenoptera is an extraordinarily diverse lineage, both in terms of species numbers and morphotypes, that includes sawflies, bees, wasps, and ants. These organisms serve critical roles as herbivores, predators, parasitoids, and pollinators, with several species functioning as models for agricultural, behavioral, and genomic research. The collective anatomical knowledge of these insects, however, has been described or referred to by labels derived from numerous, partially overlapping lexicons. The resulting corpus of information--millions of statements about hymenopteran phenotypes--remains inaccessible due to language discrepancies. The Hymenoptera Anatomy Ontology (HAO) was developed to surmount this challenge and to aid future communication related to hymenopteran anatomy. The HAO was built using newly developed interfaces within mx, a Web-based, open source software package, that enables collaborators to simultaneously contribute to an ontology. Over twenty people contributed to the development of this ontology by adding terms, genus differentia, references, images, relationships, and annotations. The database interface returns an Open Biomedical Ontology (OBO) formatted version of the ontology and includes mechanisms for extracting candidate data and for publishing a searchable ontology to the Web. The application tools are subject-agnostic and may be used by others initiating and developing ontologies. The present core HAO data constitute 2,111 concepts, 6,977 terms (labels for concepts), 3,152 relations, 4,361 sensus (links between terms, concepts, and references) and over 6,000 text and graphical annotations. The HAO is rooted with the Common Anatomy Reference Ontology (CARO), in order to facilitate interoperability with and future alignment to other anatomy ontologies, and is available through the OBO Foundry ontology repository and BioPortal. The HAO provides a foundation through which connections between genomic, evolutionary developmental biology

  15. Anatomy of the Brain

    Science.gov (United States)

    ... Dictionary Webinars Anytime Learning About Us Our Founders Board of Directors Staff Leadership Strategic Plan Financials News Careers Brain Tumor Information Brain Anatomy Brain Tumor Symptoms Diagnosis Types of Tumors Tumor Grade Risk Factors Brain Tumor Statistics ABTA Publications Brain Tumor ...

  16. The Anatomy Puzzle Book.

    Science.gov (United States)

    Jacob, Willis H.; Carter, Robert, III

    This document features review questions, crossword puzzles, and word search puzzles on human anatomy. Topics include: (1) Anatomical Terminology; (2) The Skeletal System and Joints; (3) The Muscular System; (4) The Nervous System; (5) The Eye and Ear; (6) The Circulatory System and Blood; (7) The Respiratory System; (8) The Urinary System; (9) The…

  17. Accumulation of mutations over the complete mitochondrial genome in tobacco-related oral cancer from northeast India.

    Science.gov (United States)

    Mondal, Rosy; Ghosh, Sankar Kumar

    2013-08-01

    Northeast India has one of the world's highest incidences of oral cancer and 90% of them are related to tobacco. We examined the complete mitochondrial genome to determine hot spot mutations in oral cancer. The complete mitochondrial genome was sequenced using PGM™ from 10 patients matched blood and tumour tissue. Overall, 26 somatic mutations were found of which nine mutations in d-loop and 17 mutations in the coding region. The mutations at nucleotide positions 16294, 16325 and 16463 in d-loop and 4136, 13542 and 13869 in coding region are probably an indication to be a hot spot mutation in oral cancer. The knowledge about role, patterns and timing of mitochondrial mutations may serve to be facilitating clinical applications and hot spot mutations may be helpful in assessing cancer risk in tumour. PMID:23350716

  18. 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 & ...

  19. The Role of Genomic Profiling in Advanced Breast Cancer: The Two Faces of Janus

    Science.gov (United States)

    Eralp, Yesim

    2016-01-01

    Recent advances in genomic technology have led to considerable improvement in our understanding of the molecular basis that underpins breast cancer biology. Through the use of comprehensive whole genome genomic profiling by next-generation sequencing, an unprecedented bulk of data on driver mutations, key genomic rearrangements, and mechanisms on tumor evolution has been generated. These developments have marked the beginning of a new era in oncology called “personalized or precision medicine.” Elucidation of biologic mechanisms that underpin carcinogenetic potential and metastatic behavior has led to an inevitable explosion in the development of effective targeted agents, many of which have gained approval over the past decade. Despite energetic efforts and the enormous support gained within the oncology community, there are many obstacles in the clinical implementation of precision medicine. Other than the well-known biologic markers, such as ER and Her-2/neu, no proven predictive marker exists to determine the responsiveness to a certain biologic agent. One of the major issues in this regard is teasing driver mutations among the background noise within the bulk of coexisting passenger mutations. Improving bioinformatics tools through electronic models, enhanced by improved insight into pathway dependency may be the step forward to overcome this problem. Next, is the puzzle on spatial and temporal tumoral heterogeneity, which remains to be solved by ultra-deep sequencing and optimizing liquid biopsy techniques. Finally, there are multiple logistical and financial issues that have to be meticulously tackled in order to optimize the use of “precision medicine” in the real-life setting. PMID:27547031

  20. 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.

  1. 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. PMID:24318985

  2. Prognostic Impact of Array-based Genomic Profiles in Esophageal Squamous Cell Cancer

    International Nuclear Information System (INIS)

    Esophageal squamous cell carcinoma (ESCC) is a genetically complex tumor type and a major cause of cancer related mortality. Although distinct genetic alterations have been linked to ESCC development and prognosis, the genetic alterations have not gained clinical applicability. We applied array-based comparative genomic hybridization (aCGH) to obtain a whole genome copy number profile relevant for identifying deranged pathways and clinically applicable markers. A 32 k aCGH platform was used for high resolution mapping of copy number changes in 30 stage I-IV ESCC. Potential interdependent alterations and deranged pathways were identified and copy number changes were correlated to stage, differentiation and survival. Copy number alterations affected median 19% of the genome and included recurrent gains of chromosome regions 5p, 7p, 7q, 8q, 10q, 11q, 12p, 14q, 16p, 17p, 19p, 19q, and 20q and losses of 3p, 5q, 8p, 9p and 11q. High-level amplifications were observed in 30 regions and recurrently involved 7p11 (EGFR), 11q13 (MYEOV, CCND1, FGF4, FGF3, PPFIA, FAD, TMEM16A, CTTS and SHANK2) and 11q22 (PDFG). Gain of 7p22.3 predicted nodal metastases and gains of 1p36.32 and 19p13.3 independently predicted poor survival in multivariate analysis. aCGH profiling verified genetic complexity in ESCC and herein identified imbalances of multiple central tumorigenic pathways. Distinct gains correlate with clinicopathological variables and independently predict survival, suggesting clinical applicability of genomic profiling in ESCC

  3. Whole genome RNA expression profiling for the identification of novel biomarkers in the diagnosis and prognosis of biliary tract cancer

    OpenAIRE

    Chapman, M H

    2011-01-01

    Biliary tract cancer (BTC) is difficult to diagnose, in part related to the lack of reliable tumour markers. The aim of this project was to use whole genome RNA expression profiling in order to identify novel biomarkers for diagnosis and prognosis in biliary tract cancer. Chapter 1 summarises clinical aspects of BTC as well as current diagnostic and prognostic tests. Chapter 2 addresses the identification of circulating tumour cells for the diagnosis of BTC. It includes d...

  4. Computational methods for detecting copy number variations in cancer genome using next generation sequencing: principles and challenges

    OpenAIRE

    Liu, Biao; Morrison, Carl D.; Johnson, Candace S.; Trump, Donald L.; Qin, Maochun; Conroy, Jeffrey C.; Wang, Jianmin; Liu, Song

    2013-01-01

    Accurate detection of somatic copy number variations (CNVs) is an essential part of cancer genome analysis, and plays an important role in oncotarget identifications. Next generation sequencing (NGS) holds the promise to revolutionize somatic CNV detection. In this review, we provide an overview of current analytic tools used for CNV detection in NGS-based cancer studies. We summarize the NGS data types used for CNV detection, decipher the principles for data preprocessing, segmentation, and ...

  5. 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.

    2015-01-01

    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. PMID:27148575

  6. 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.

  7. "Cancer 2015": A Prospective, Population-Based Cancer Cohort-Phase 1: Feasibility of Genomics-Guided Precision Medicine in the Clinic.

    Science.gov (United States)

    Parisot, John P; Thorne, Heather; Fellowes, Andrew; Doig, Ken; Lucas, Mark; McNeil, John J; Doble, Brett; Dobrovic, Alexander; John, Thomas; James, Paul A; Lipton, Lara; Ashley, David; Hayes, Theresa; McMurrick, Paul; Richardson, Gary; Lorgelly, Paula; Fox, Stephen B; Thomas, David M

    2015-01-01

    "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. PMID:26529019

  8. Cancer 2015”: A Prospective, Population-Based Cancer Cohort—Phase 1: Feasibility of Genomics-Guided Precision Medicine in the Clinic

    Science.gov (United States)

    Parisot, John P.; Thorne, Heather; Fellowes, Andrew; Doig, Ken; Lucas, Mark; McNeil, John J.; Doble, Brett; Dobrovic, Alexander; John, Thomas; James, Paul A.; Lipton, Lara; Ashley, David; Hayes, Theresa; McMurrick, Paul; Richardson, Gary; Lorgelly, Paula; Fox, Stephen B.; Thomas, David M.

    2015-01-01

    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. PMID:26529019

  9. 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.

  10. Integrated Bioinformatics, Environmental Epidemiologic and Genomic Approaches to Identify Environmental and Molecular Links between Endometriosis and Breast Cancer

    OpenAIRE

    Deodutta Roy; Marisa Morgan; Changwon Yoo; Alok Deoraj; Sandhya Roy; Vijay Kumar Yadav; Mohannad Garoub; Hamza Assaggaf; Mayur Doke

    2015-01-01

    We present a combined environmental epidemiologic, genomic, and bioinformatics approach to identify: exposure of environmental chemicals with estrogenic activity; epidemiologic association between endocrine disrupting chemical (EDC) and health effects, such as, breast cancer or endometriosis; and gene-EDC interactions and disease associations. Human exposure measurement and modeling confirmed estrogenic activity of three selected class of environmental chemicals, polychlorinated biphenyls (PC...

  11. Genetic profiles of gastroesophageal cancer: combined analysis using expression array and tiling array--comparative genomic hybridization

    DEFF Research Database (Denmark)

    Jönsson, Mats; Isinger-Ekstrand, Anna; Johansson, Jan; Ohlsson, Mattias; Francis, Princy; Staaf, Johan; Jönsson, Mats; Borg, Ake; Nilbert, Mef

    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-resol...

  12. Data Mining on Survival Prediction after Chemotherapy for Diffuse Large-B-Cell Lymphoma and Genomics of Metastasis Cancer

    Directory of Open Access Journals (Sweden)

    Shen Lu

    2014-12-01

    Full Text Available This research pertains to the applications of data mining of microarray databases for large-B-cell Lymphoma and metastasis cancer, the latter of which little has been known about the genomic events that regulate the transformation of a tumor into a metastatic phenotype.

  13. 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...

  14. Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer.

    Science.gov (United States)

    Weischenfeldt, Joachim; Simon, Ronald; Feuerbach, Lars; Schlangen, Karin; Weichenhan, Dieter; Minner, Sarah; Wuttig, Daniela; Warnatz, Hans-Jörg; Stehr, Henning; Rausch, Tobias; Jäger, Natalie; Gu, Lei; Bogatyrova, Olga; Stütz, Adrian M; Claus, Rainer; Eils, Jürgen; Eils, Roland; Gerhäuser, Clarissa; Huang, Po-Hsien; Hutter, Barbara; Kabbe, Rolf; Lawerenz, Christian; Radomski, Sylwester; Bartholomae, Cynthia C; Fälth, Maria; Gade, Stephan; Schmidt, Manfred; Amschler, Nina; Haß, Thomas; Galal, Rami; Gjoni, Jovisa; Kuner, Ruprecht; Baer, Constance; Masser, Sawinee; von Kalle, Christof; Zichner, Thomas; Benes, Vladimir; Raeder, Benjamin; Mader, Malte; Amstislavskiy, Vyacheslav; Avci, Meryem; Lehrach, Hans; Parkhomchuk, Dmitri; Sultan, Marc; Burkhardt, Lia; Graefen, Markus; Huland, Hartwig; Kluth, Martina; Krohn, Antje; Sirma, Hüseyin; Stumm, Laura; Steurer, Stefan; Grupp, Katharina; Sültmann, Holger; Sauter, Guido; Plass, Christoph; Brors, Benedikt; Yaspo, Marie-Laure; Korbel, Jan O; Schlomm, Thorsten

    2013-02-11

    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 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 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 of a characteristic "androgen-type" pathomechanism in EO-PCA. PMID:23410972

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

    OpenAIRE

    Lan, Qing; Hsiung, Chao A.; Matsuo, Keitaro; Hong, Yun-Chul; Seow, Adeline; Wang, Zhaoming; Hosgood, H Dean; Chen, Kexin; Wang, Jiu-Cun; Chatterjee, Nilanjan; Hu, Wei; Wong, Maria Pik; Zheng, Wei; Caporaso, Neil; PARK, JAE YONG

    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 China, South Korea, Japan, Singapore, Taiwan, and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10-6) in an additional 1,099 cases and 2,913 controls. We identified three...

  16. 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. PMID:23509716

  17. The anatomy workbook

    International Nuclear Information System (INIS)

    This is an atlas of human anatomy presented in the form of line drawings, many of which correspond to imaging planes used in ultrasound (US), computed tomography (CT), and magnetic resonance (MR). The book is organized into 17 sections, each covering a specific structure or organ system. Large, uncluttered drawings are labeled for identification of structures of interest. Many illustrations include captions consisting of comments explaining major divisions within organs, specific anatomic relationships and landmarks, and pertinent vascular anatomy. Most organs are first depicted in isolation or in relation to important adjacent organs or blood vessels and are rendered as if viewed from anterior, posterior, inferior, or superior perspectives. The organs are demonstrated again in serial transverse, saggital, and coronal sections, each accompanied by a drawing of a body in anatomic position denoting the plane of the section

  18. Penile Embryology and Anatomy

    OpenAIRE

    Yiee, Jenny H.; Baskin, Laurence S

    2010-01-01

    Knowledge of penile embryology and anatomy is essential to any pediatric urologist in order to fully understand and treat congenital anomalies. Sex differentiation of the external genitalia occurs between the 7thand 17th weeks of gestation. The Y chromosome initiates male differentiation through the SRY gene, which triggers testicular development. Under the influence of androgens produced by the testes, external genitalia then develop into the penis and scrotum. Dorsal nerves supply penile sk...

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

    DEFF Research Database (Denmark)

    Lu, Yi; Chen, Xiaoqing; Beesley, Jonathan; Johnatty, Sharon E; Defazio, Anna; Lambrechts, Sandrina; Lambrechts, Diether; Despierre, Evelyn; Vergotes, Ignace; Chang-Claude, Jenny; Hein, Rebecca; Nickels, Stefan; Wang-Gohrke, Shan; Dörk, Thilo; Dürst, Matthias; Antonenkova, Natalia; Bogdanova, Natalia; Goodman, Marc T; Lurie, Galina; Wilkens, Lynne R; Carney, Michael E; Butzow, Ralf; Nevanlinna, Heli; Heikkinen, Tuomas; Leminen, Arto; Kiemeney, Lambertus A; Massuger, Leon F A G; van Altena, Anne M; Aben, Katja K; Kjaer, Susanne Krüger; Høgdall, Estrid; Jensen, Allan; Brooks-Wilson, Angela; Le, Nhu; Cook, Linda; Earp, Madalene; Kelemen, Linda; Easton, Douglas; Pharoah, Paul; Song, Honglin; Tyrer, Jonathan; Ramus, Susan; Menon, Usha; Gentry-Maharaj, Alexandra; Gayther, Simon A; Bandera, Elisa V; Olson, Sara H; Orlow, Irene; Rodriguez-Rodriguez, Lorna; Macgregor, Stuart; Chenevix-Trench, Georgia

    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...... the previous studies, which would account for some of the remaining risk. We therefore conducted a time- and cost-effective stage 1 GWAS on 342 invasive serous cases and 643 controls genotyped on pooled DNA using the high-density Illumina 1M-Duo array. We followed up 20 of the most significantly...... associated SNPs, which are not well tagged by the lower density arrays used by the published GWAS, and genotyping them on individual DNA. Most of the top 20 SNPs were clearly validated by individually genotyping the samples used in the pools. However, none of the 20 SNPs replicated when tested for...

  20. An Integrated Genome-Wide Systems Genetics Screen for Breast Cancer Metastasis Susceptibility Genes.

    Science.gov (United States)

    Bai, Ling; Yang, Howard H; Hu, Ying; Shukla, Anjali; Ha, Ngoc-Han; Doran, Anthony; Faraji, Farhoud; Goldberger, Natalie; Lee, Maxwell P; Keane, Thomas; Hunter, Kent W

    2016-04-01

    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. PMID:27074153

  1. Genomic analysis to define molecular basis of aggressiveness in a mouse model of oral cancer

    Directory of Open Access Journals (Sweden)

    Varun Chalivendra

    2015-03-01

    Full Text Available To investigate the molecular basis underlying aggressive behavior in oral squamous cell carcinoma (OSCC, our laboratory developed a carcinogen-induced mouse oral cancer (MOC cell line model that encompasses the growth and metastasis spectrum of its human counterpart. We performed next-generation sequencing (NGS and gene expression microarray profiles to explore the genomic and transcriptional backgrounds of the differential MOC line phenotypes, as well as, the cross-species relevance of the model. Here we describe the comparative analysis of NGS (www.ncbi.nlm.nih.gov/biosample?LinkName=bioproject_biosample_all&from_uid=247825 and expression microarray (www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE50041 data from the MOC lines and corresponding human data, as described in our recent publication [1].

  2. Executions and scientific anatomy.

    Science.gov (United States)

    Dolezal, Antonín; Jelen, Karel; Stajnrtova, Olga

    2015-12-01

    The very word "anatomy" tells us about this branch's connection with dissection. Studies of anatomy have taken place for approximately 2.300 years already. Anatomy's birthplace lies in Greece and Egypt. Knowledge in this specific field of science was necessary during surgical procedures in ophthalmology and obstetrics. Embalming took place without public disapproval just like autopsies and manipulation with relics. Thus, anatomical dissection became part of later forensic sciences. Anatomical studies on humans themselves, which needed to be compared with the knowledge gained through studying procedures performed on animals, elicited public disapprobation and prohibition. When faced with a shortage of cadavers, anatomists resorted to obtaining bodies of the executed and suicide victims - since torture, public display of the mutilated body, (including anatomical autopsy), were perceived as an intensification of the death penalty. Decapitation and hanging were the main execution methods meted out for death sentences. Anatomists preferred intact bodies for dissection; hence, convicts could thus avoid torture. This paper lists examples of how this process was resolved. It concerns the manners of killing, vivisection on people in the antiquity and middle-ages, experiments before the execution and after, vivifying from seeming death, experiments with galvanizing electricity on fresh cadavers, evaluating of sensibility after guillotine execution, and making perfect anatomical preparations and publications during Nazism from fresh bodies of the executed. PMID:26859596

  3. Bystander effects, genomic instability, adaptive response, and cancer risk assessment for radiation and chemical exposures

    International Nuclear Information System (INIS)

    There is an increased interest in utilizing mechanistic data in support of the cancer risk assessment process for ionizing radiation and environmental chemical exposures. In this regard, the use of biologically based dose-response models is particularly advocated. The aim is to provide an enhanced basis for describing the nature of the dose-response curve for induced tumors at low levels of exposure. Cellular responses that might influence the nature of the dose-response curve at low exposures are understandably receiving attention. These responses (bystander effects, genomic instability, and adaptive responses) have been studied most extensively for radiation exposures. The former two could result in an enhancement of the tumor response at low doses and the latter could lead to a reduced response compared to that predicted by a linear extrapolation from high dose responses. Bystander responses, whereby cells other than those directly traversed by radiation tracks are damaged, can alter the concept of target cell population per unit dose. Similarly, induced genomic instability can alter the concept of total response to an exposure. There appears to be a role for oxidative damage and cellular signaling in the etiology of these cellular responses. The adaptive response appears to be inducible at very low doses of radiation or of some chemicals and reduces the cellular response to a larger challenge dose. It is currently unclear how these cellular toxic responses might be involved in tumor formation, if indeed they are. In addition, it is not known how widespread they are as regards inducing agents. Thus, their impact on low dose cancer risk remains to be established

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

    Science.gov (United States)

    Peifer, Martin; Fernández-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; Müller, Christian; Di Cerbo, Vincenzo; Schildhaus, Hans-Ulrich; Altmüller, Janine; Baessmann, Ingelore; Becker, Christian; de Wilde, Bram; Vandesompele, Jo; Böhm, Diana; Ansén, 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; Grütter, 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, Daniëlle AM; Snijders, Peter JF; Cappuzzo, Federico; Ligorio, Claudia; Damiani, Stefania; Field, John; Solberg, Steinar; Brustugun, Odd Terje; Lund-Iversen, Marius; Sänger, Jörg; 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; Büttner, Reinhard; Wolf, Jürgen; Nürnberg, Peter; Perner, Sven; Heukamp, Lukas C; Brindle, Paul K; Haas, Stefan; Thomas, Roman K

    2016-01-01

    Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor survival1–3. We sequenced 29 SCLC exomes, two genomes and 15 transcriptomes and found an extremely high mutation rate of 7.4±1 protein-changing mutations per million basepairs. Therefore, we conducted integrated analyses of the various data sets to identify pathogenetically relevant mutated genes. In all cases we found evidence for inactivation of TP53 and RB1 and identified recurrent mutations in histone-modifying genes, CREBBP, EP300, and MLL. Furthermore, we observed mutations in PTEN, in SLIT2, and EPHA7, as well as focal amplifications of the FGFR1 tyrosine kinase gene. Finally, we detected many of the alterations found in humans in SCLC tumors from p53/Rb1-deficient mice4. Our study implicates histone modification as a major feature of SCLC, reveals potentially therapeutically tractable genome alterations, and provides a generalizable framework for identification of biologically relevant genes in the context of high mutational background. PMID:22941188

  5. [Genome-cohort studies for the development of personalized cancer prevention programs in Japan].

    Science.gov (United States)

    Tanaka, Hideo

    2015-05-01

    One of the most important roles of molecular epidemiology is to investigate gene-environment interactions in order to provide data for personalized risk modification. A case-control study conducted in Aichi showed that an aldehyde dehydrogenase- 2(ALDH2)polymorphism together with cigarette smoking significantly affects the risk of lung cancer. The main purpose of this large-scale genome-cohort study of healthy individuals is to confirm that these factors are associated with the development of diseases and to set optimal thresholds for the environmental factors. The Japan Multi-Institutional Collaborative Cohort(J-MICC)Study was launched in 2005. It has recruited 100,600 healthy participants up to the end of 2014, and plans to follow them until 2025. Although Japanese genome-cohort studies, including the J-MICC Study, the Japan Public Health Center-based Prospective(JPHC)Study, and the Tohoku Medical Megabank Organization Study, consist of different research teams with different financial resources, collaboration to standardize the data collection format for successful pooled analysis is being discussed. PMID:25981648

  6. 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

    /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......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...

  7. 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

  8. Non-gaussian distributions affect identification of expression patterns, functional annotation, and prospective classification in human cancer genomes.

    Directory of Open Access Journals (Sweden)

    Nicholas F Marko

    Full Text Available INTRODUCTION: Gene expression data is often assumed to be normally-distributed, but this assumption has not been tested rigorously. We investigate the distribution of expression data in human cancer genomes and study the implications of deviations from the normal distribution for translational molecular oncology research. METHODS: We conducted a central moments analysis of five cancer genomes and performed empiric distribution fitting to examine the true distribution of expression data both on the complete-experiment and on the individual-gene levels. We used a variety of parametric and nonparametric methods to test the effects of deviations from normality on gene calling, functional annotation, and prospective molecular classification using a sixth cancer genome. RESULTS: Central moments analyses reveal statistically-significant deviations from normality in all of the analyzed cancer genomes. We observe as much as 37% variability in gene calling, 39% variability in functional annotation, and 30% variability in prospective, molecular tumor subclassification associated with this effect. CONCLUSIONS: Cancer gene expression profiles are not normally-distributed, either on the complete-experiment or on the individual-gene level. Instead, they exhibit complex, heavy-tailed distributions characterized by statistically-significant skewness and kurtosis. The non-Gaussian distribution of this data affects identification of differentially-expressed genes, functional annotation, and prospective molecular classification. These effects may be reduced in some circumstances, although not completely eliminated, by using nonparametric analytics. This analysis highlights two unreliable assumptions of translational cancer gene expression analysis: that "small" departures from normality in the expression data distributions are analytically-insignificant and that "robust" gene-calling algorithms can fully compensate for these effects.

  9. New genomic structure for prostate cancer specific gene PCA3 within BMCC1: implications for prostate cancer detection and progression.

    Directory of Open Access Journals (Sweden)

    Raymond A Clarke

    Full Text Available BACKGROUND: The prostate cancer antigen 3 (PCA3/DD3 gene is a highly specific biomarker upregulated in prostate cancer (PCa. In order to understand the importance of PCA3 in PCa we investigated the organization and evolution of the PCA3 gene locus. METHODS/PRINCIPAL FINDINGS: We have employed cDNA synthesis, RTPCR and DNA sequencing to identify 4 new transcription start sites, 4 polyadenylation sites and 2 new differentially spliced exons in an extended form of PCA3. Primers designed from these novel PCA3 exons greatly improve RT-PCR based discrimination between PCa, PCa metastases and BPH specimens. Comparative genomic analyses demonstrated that PCA3 has only recently evolved in an anti-sense orientation within a second gene, BMCC1/PRUNE2. BMCC1 has been shown previously to interact with RhoA and RhoC, determinants of cellular transformation and metastasis, respectively. Using RT-PCR we demonstrated that the longer BMCC1-1 isoform - like PCA3 - is upregulated in PCa tissues and metastases and in PCa cell lines. Furthermore PCA3 and BMCC1-1 levels are responsive to dihydrotestosterone treatment. CONCLUSIONS/SIGNIFICANCE: Upregulation of two new PCA3 isoforms in PCa tissues improves discrimination between PCa and BPH. The functional relevance of this specificity is now of particular interest given PCA3's overlapping association with a second gene BMCC1, a regulator of Rho signalling. Upregulation of PCA3 and BMCC1 in PCa has potential for improved diagnosis.

  10. Predicting survival within the lung cancer histopathological hierarchy using a multi-scale genomic model of development.

    Directory of Open Access Journals (Sweden)

    Hongye Liu

    2006-07-01

    Full Text Available BACKGROUND: The histopathologic heterogeneity of lung cancer remains a significant confounding factor in its diagnosis and prognosis-spurring numerous recent efforts to find a molecular classification of the disease that has clinical relevance. METHODS AND FINDINGS: Molecular profiles of tumors from 186 patients representing four different lung cancer subtypes (and 17 normal lung tissue samples were compared with a mouse lung development model using principal component analysis in both temporal and genomic domains. An algorithm for the classification of lung cancers using a multi-scale developmental framework was developed. Kaplan-Meier survival analysis was conducted for lung adenocarcinoma patient subgroups identified via their developmental association. We found multi-scale genomic similarities between four human lung cancer subtypes and the developing mouse lung that are prognostically meaningful. Significant association was observed between the localization of human lung cancer cases along the principal mouse lung development trajectory and the corresponding patient survival rate at three distinct levels of classical histopathologic resolution: among different lung cancer subtypes, among patients within the adenocarcinoma subtype, and within the stage I adenocarcinoma subclass. The earlier the genomic association between a human tumor profile and the mouse lung development sequence, the poorer the patient's prognosis. Furthermore, decomposing this principal lung development trajectory identified a gene set that was significantly enriched for pyrimidine metabolism and cell-adhesion functions specific to lung development and oncogenesis. CONCLUSIONS: From a multi-scale disease modeling perspective, the molecular dynamics of murine lung development provide an effective framework that is not only data driven but also informed by the biology of development for elucidating the mechanisms of human lung cancer biology and its clinical outcome.

  11. Three-dimensional disorganization of the cancer genome occurs coincident with long-range genetic and epigenetic alterations.

    Science.gov (United States)

    Taberlay, Phillippa C; Achinger-Kawecka, Joanna; Lun, Aaron T L; Buske, Fabian A; Sabir, Kenneth; Gould, Cathryn M; Zotenko, Elena; Bert, Saul A; Giles, Katherine A; Bauer, Denis C; Smyth, Gordon K; Stirzaker, Clare; O'Donoghue, Sean I; Clark, Susan J

    2016-06-01

    A three-dimensional chromatin state underpins the structural and functional basis of the genome by bringing regulatory elements and genes into close spatial proximity to ensure proper, cell-type-specific gene expression profiles. Here, we performed Hi-C chromosome conformation capture sequencing to investigate how three-dimensional chromatin organization is disrupted in the context of copy-number variation, long-range epigenetic remodeling, and atypical gene expression programs in prostate cancer. We find that cancer cells retain the ability to segment their genomes into megabase-sized topologically associated domains (TADs); however, these domains are generally smaller due to establishment of additional domain boundaries. Interestingly, a large proportion of the new cancer-specific domain boundaries occur at regions that display copy-number variation. Notably, a common deletion on 17p13.1 in prostate cancer spanning the TP53 tumor suppressor locus results in bifurcation of a single TAD into two distinct smaller TADs. Change in domain structure is also accompanied by novel cancer-specific chromatin interactions within the TADs that are enriched at regulatory elements such as enhancers, promoters, and insulators, and associated with alterations in gene expression. We also show that differential chromatin interactions across regulatory regions occur within long-range epigenetically activated or silenced regions of concordant gene activation or repression in prostate cancer. Finally, we present a novel visualization tool that enables integrated exploration of Hi-C interaction data, the transcriptome, and epigenome. This study provides new insights into the relationship between long-range epigenetic and genomic dysregulation and changes in higher-order chromatin interactions in cancer. PMID:27053337

  12. Who Is Repeating Anatomy? Trends in an Undergraduate Anatomy Course

    Science.gov (United States)

    Schutte, Audra F.

    2016-01-01

    Anatomy courses frequently serve as prerequisites or requirements for health sciences programs. Due to the challenging nature of anatomy, each semester there are students remediating the course (enrolled in the course for a second time), attempting to earn a grade competitive for admissions into a program of study. In this retrospective study,…

  13. Who is repeating anatomy? Trends in an undergraduate anatomy course.

    Science.gov (United States)

    Schutte, Audra F

    2016-03-01

    Anatomy courses frequently serve as prerequisites or requirements for health sciences programs. Due to the challenging nature of anatomy, each semester there are students remediating the course (enrolled in the course for a second time), attempting to earn a grade competitive for admissions into a program of study. In this retrospective study, remediation rates and trends in an undergraduate anatomy course with over 400 students enrolled each semester at a large Midwestern university were identified. Demographic data was collected from spring 2004 to spring 2010, including students' age, ethnicity, major of study, class standing, college admission tests (ACT and SAT®) scores, anatomy laboratory and lecture examination scores, and final anatomy grades for each semester. Eleven percent of the students repeated the course at least once. Gender, ethnicity, major of study and SAT scores were all shown to be associated with whether or not a student would need to repeat the course. On average, students who repeated anatomy demonstrated significant improvements in lecture and laboratory scores when comparing first and second enrollments in anatomy, and therefore also saw improved final course grades in their second enrollment. These findings will aid future instructors to identify and assist at-risk students to succeed in anatomy. Instructors from other institutions may also find the results to be useful for identifying students at risk for struggling. Anat Sci Educ 9: 171-178. © 2015 American Association of Anatomists. PMID:26179910

  14. Frequent genomic loss at chr16p13.2 is associated with poor prognosis in colorectal cancer

    DEFF Research Database (Denmark)

    Andersen, Claus Lindbjerg; Lamy, Philippe; Thorsen, Kasper; Kjeldsen, Eigil; Wikman, Friedrik; Villesen, Palle; Øster, Bodil; Laurberg, Søren; Ørntoft, Torben Falck

    2010-01-01

    Genomic alterations play important roles in colorectal cancer (CRC) carcinogenesis. Here we aimed to identify and characterize recurrent copy number alterations associated with clinical outcome of CRC by the use of single nucleotide polymorphism arrays, genomic qPCR, and fluorescence in situ...... stability and could be validated by q-PCR in an independent sample cohort (n=71). In stage II/III MSS CRC it was associated with poor recurrence free survival (HR 2.4; p = 0.02; Multivariate Cox regression analysis). No transcriptional consequences of the losses were observed, and the only gene, A2BP1...

  15. Genome-wide analysis identifies novel loci associated with ovarian cancer outcomes: findings from the Ovarian Cancer Association Consortium

    Science.gov (United States)

    Johnatty, Sharon E.; Tyrer, Jonathan P.; Kar, Siddhartha; Beesley, Jonathan; Lu, Yi; Gao, Bo; Fasching, Peter A.; Hein, Alexander; Ekici, Arif B.; Beckmann, Matthias W.; Lambrechts, Diether; Nieuwenhuysen, Els Van; Vergote, Ignace; Lambrechts, Sandrina; Rossing, Mary Anne; Doherty, Jennifer A.; Chang-Claude, Jenny; Modugno, Francesmary; Ness, Roberta B.; Moysich, Kirsten B.; Levine, Douglas A.; Kiemeney, Lambertus A.; Massuger, Leon F.A.G.; Gronwald, Jacek; Lubiński, Jan; Jakubowska, Anna; Cybulski, Cezary; Brinton, Louise; Lissowska, Jolanta; Wentzensen, Nicolas; Song, Honglin; Rhenius, Valerie; Campbell, Ian; Eccles, Diana; Sieh, Weiva; Whittemore, Alice S.; McGuire, Valerie; Rothstein, Joseph H.; Sutphen, Rebecca; Anton-Culver, Hoda; Ziogas, Argyrios; Gayther, Simon A.; Gentry-Maharaj, Aleksandra; Menon, Usha; Ramus, Susan J.; Pearce, Celeste L; Pike, Malcolm C; Stram, Daniel O.; Wu, Anna H.; Kupryjanczyk, Jolanta; Dansonka-Mieszkowska, Agnieszka; Rzepecka, Iwona K.; Spiewankiewicz, Beata; Goodman, Marc T.; Wilkens, Lynne R.; Carney, Michael E.; Thompson, Pamela J; Heitz, Florian; du Bois, Andreas; Schwaab, Ira; Harter, Philipp; Pisterer, Jacobus; Hillemanns, Peter; Karlan, Beth Y.; Walsh, Christine; Lester, Jenny; Orsulic, Sandra; Winham, Stacey J; Earp, Madalene; Larson, Melissa C.; Fogarty, Zachary C.; Høgdall, Estrid; Jensen, Allan; Kjaer, Susanne Kruger; Fridley, Brooke L.; Cunningham, Julie M.; Vierkant, Robert A.; Schildkraut, Joellen M.; Iversen, Edwin S.; Terry, Kathryn L.; Cramer, Daniel W.; Bandera, Elisa V.; Orlow, Irene; Pejovic, Tanja; Bean, Yukie; Høgdall, Claus; Lundvall, Lene; McNeish, Ian; Paul, James; Carty, Karen; Siddiqui, Nadeem; Glasspool, Rosalind; Sellers, Thomas; Kennedy, Catherine; Chiew, Yoke-Eng; Berchuck, Andrew; MacGregor, Stuart; deFazio, Anna; Pharoah, Paul D.P.; Goode, Ellen L.; deFazio, Anna; Webb, Penelope M.; Chenevix-Trench, Georgia

    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 ~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 firstline 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. Additionally 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 associated (p≤1.0x10−5) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23) and rs6674079 (1q22) were located in long non-coding RNAs (lncRNAs) RP11–179A10.1, RP11–314O13.1 and RP11–284F21.8 respectively (p≤7.1x10−6). ENCODE ChIP-seq data at 1q22 for normal ovary shows evidence of histone modification around RP11–284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression, and HDL-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA≤6x10−3). Conclusion We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies. PMID:26152742

  16. Understanding Cancer Prognosis

    Medline Plus

    Full Text Available ... Laboratory for Cancer Research Partners & Collaborators Spotlight on Scientists Research Areas Cancer Biology Cancer Genomics Causes of ... Centers Frederick National Lab Partners & Collaborators Spotlight on Scientists NCI Research Areas Cancer Biology Cancer Genomics Causes ...

  17. [Pandora's box of anatomy].

    Science.gov (United States)

    Weinberg, Uri; Reis, Shmuel

    2008-05-01

    Physicians in Nazi Germany were among the first to join the Nazi party and the SS, and were considered passionate and active supporters of the regime. Their actions included development and implementation of the racial theory thus legitimizing the development of the Nazi genocide plan, leadership and execution of the sterilization and euthanasia programs as well as atrocious human experimentation. Nazi law allowed the use of humans and their remains in research institutions. One of the physicians whose involvement in the Nazi regime was particularly significant was Eduard Pernkopf. He was the head of the Anatomy Institute at the University of Vienna, and later became the president of the university. Pernkopf was a member of the Nazi party, promoted the idea of "racial hygiene", and in 1938, "purified" the university from all Jews. In Pernkopfs atlas of anatomy, the illustrators expressed their sympathy to Nazism by adding Nazi symbols to their illustrations. In light of the demand stated by the "Yad Vashem" Institute, the sources of the atlas were investigated. The report, which was published in 1998, determined that Pernkopfs Anatomy Institute received almost 1400 corpses from the Gestapo's execution chambers. Copies of Pernkopfs atlas, accidentally exposed at the Rappaport School of Medicine in the Technion, led to dilemmas concerning similar works with a common background. The books initiated a wide debate in Israel and abroad, regarding ethical aspects of using information originated in Nazi crimes. Moreover, these findings are evidence of the evil to which science and medicine can give rise, when they are captured as an unshakable authority. PMID:18770971

  18. Normal cranial CT anatomy

    International Nuclear Information System (INIS)

    The human brain consists of well-known anatomical components. Some parts of these components have been shown to be concerned with certain functions. A complete cranial CT examination consists of a series of several slices obtained in a sequence usually from the base to the vertex of the cranial vault, in the axial mode. The ultimate goal of this chapter is to pinpoint those slices that depict a given anatomical structure or several structures that deal with a given function. To achieve this goal, the discussion of CT cranial anatomy is presented in three sections

  19. Genomics and Health Impact Update

    Science.gov (United States)

    ... CDC Blog Post Prostate Cancer: Family History & Genetics Microbiome: Public Health Implications Colorectal Cancer: Screening & Genomics About ... 23) Birth Defects and Child Health Cancer Cardiovascular Disease Chronic Diseases Ethics/ Policy/ Law Genomics in Practice ...

  20. Structural analysis of the genome of breast cancer cell line ZR-75-30 identifies twelve expressed fusion genes

    Directory of Open Access Journals (Sweden)

    Schulte Ina

    2012-12-01

    Full Text Available Abstract Background It has recently emerged that common epithelial cancers such as breast cancers have fusion genes like those in leukaemias. In a representative breast cancer cell line, ZR-75-30, we searched for fusion genes, by analysing genome rearrangements. Results We first analysed rearrangements of the ZR-75-30 genome, to around 10kb resolution, by molecular cytogenetic approaches, combining array painting and array CGH. We then compared this map with genomic junctions determined by paired-end sequencing. Most of the breakpoints found by array painting and array CGH were identified in the paired end sequencing—55% of the unamplified breakpoints and 97% of the amplified breakpoints (as these are represented by more sequence reads. From this analysis we identified 9 expressed fusion genes: APPBP2-PHF20L1, BCAS3-HOXB9, COL14A1-SKAP1, TAOK1-PCGF2, TIAM1-NRIP1, TIMM23-ARHGAP32, TRPS1-LASP1, USP32-CCDC49 and ZMYM4-OPRD1. We also determined the genomic junctions of a further three expressed fusion genes that had been described by others, BCAS3-ERBB2, DDX5-DEPDC6/DEPTOR and PLEC1-ENPP2. Of this total of 12 expressed fusion genes, 9 were in the coamplification. Due to the sensitivity of the technologies used, we estimate these 12 fusion genes to be around two-thirds of the true total. Many of the fusions seem likely to be driver mutations. For example, PHF20L1, BCAS3, TAOK1, PCGF2, and TRPS1 are fused in other breast cancers. HOXB9 and PHF20L1 are members of gene families that are fused in other neoplasms. Several of the other genes are relevant to cancer—in addition to ERBB2, SKAP1 is an adaptor for Src, DEPTOR regulates the mTOR pathway and NRIP1 is an estrogen-receptor coregulator. Conclusions This is the first structural analysis of a breast cancer genome that combines classical molecular cytogenetic approaches with sequencing. Paired-end sequencing was able to detect almost all breakpoints, where there was adequate read depth. It supports

  1. TEACHING ANATOMY TO UNDERGRADUATE STUDENTS

    Directory of Open Access Journals (Sweden)

    Sharadkumar Pralhad Sawant,

    2015-09-01

    Full Text Available Introduction: Anatomy is the base of medical science in India and is taught practically to all disciplines of undergraduate health sciences in the first year. It is an acknowledged fact that a basic knowledge of Anatomy is a prerequisite to learn any other branch of medicine. All medical professionals must have a basic knowledge of Anatomy so as to ensure safe medical practice. Traditionally Anatomy teaching consists of didactic lectures as well as dissections or prosections as per the requirement of the course. Lecture is defined as an oral discourse on a given subject before an audience for purpose of instruction and leaning. In the traditional method lectures were taken via chalk & board, but nowadays power point presentations are increasingly being used. To make Anatomy learning both pleasant and motivating, new methods of teaching gross anatomy are being assessed as medical colleges endeavour to find time in their curricula for new content without fore-going fundamental anatomical knowledge. This paper examines the other teaching methodologies for teaching gross anatomy. Conclusion: Proper utilization of newer technologies along with the traditional teaching methods will certainly lead to enhanced understanding of gross anatomy and will ultimately improve students’ performance.

  2. Non-random integration of the HPV genome in cervical cancer.

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    Martina Schmitz

    Full Text Available HPV DNA integration into the host genome is a characteristic but not an exclusive step during cervical carcinogenesis. It is still a matter of debate whether viral integration contributes to the transformation process beyond ensuring the constitutive expression of the viral oncogenes. There is mounting evidence for a non-random distribution of integration loci and the direct involvement of cellular cancer-related genes. In this study we addressed this topic by extending the existing data set by an additional 47 HPV16 and HPV18 positive cervical carcinoma. We provide supportive evidence for previously defined integration hotspots and have revealed another cluster of integration sites within the cytogenetic band 3q28. Moreover, in the vicinity of these hotspots numerous microRNAs (miRNAs are located and may be influenced by the integrated HPV DNA. By compiling our data and published reports 9 genes could be identified which were affected by HPV integration at least twice in independent tumors. In some tumors the viral-cellular fusion transcripts were even identical with respect to the viral donor and cellular acceptor sites used. However, the exact integration sites are likely to differ since none of the integration sites analysed thus far have shown more than a few nucleotides of homology between viral and host sequences. Therefore, DNA recombination involving large stretches of homology at the integration site can be ruled out. It is however intriguing that by sequence alignment several regions of the HPV16 genome were found to have highly homologous stretches of up to 50 nucleotides to the aforementioned genes and the integration hotspots. One common region of homologies with cellular sequences is between the viral gene E5 and L2 (nucleotides positions 4100 to 4240. We speculate that this and other regions of homology are involved in the integration process. Our observations suggest that targeted disruption, possibly also of critical cellular

  3. Genome-wide association study of coronary and aortic calcification in lung cancer screening CT

    Science.gov (United States)

    de Vos, Bob D.; van Setten, Jessica; de Jong, Pim A.; Mali, Willem P.; Oudkerk, Matthijs; Viergever, Max A.; Išgum, Ivana

    2016-03-01

    Arterial calcification has been related to cardiovascular disease (CVD) and osteoporosis. However, little is known about the role of genetics and exact pathways leading to arterial calcification and its relation to bone density changes indicating osteoporosis. In this study, we conducted a genome-wide association study of arterial calcification burden, followed by a look-up of known single nucleotide polymorphisms (SNPs) for coronary artery disease (CAD) and myocardial infarction (MI), and bone mineral density (BMD) to test for a shared genetic basis between the traits. The study included a subcohort of the Dutch-Belgian lung cancer screening trial comprised of 2,561 participants. Participants underwent baseline CT screening in one of two hospitals participating in the trial. Low-dose chest CT images were acquired without contrast enhancement and without ECG-synchronization. In these images coronary and aortic calcifications were identified automatically. Subsequently, the detected calcifications were quantified using coronary artery calcium Agatston and volume scores. Genotype data was available for these participants. A genome-wide association study was conducted on 10,220,814 SNPs using a linear regression model. To reduce multiple testing burden, known CAD/MI and BMD SNPs were specifically tested (45 SNPs from the CARDIoGRAMplusC4D consortium and 60 SNPS from the GEFOS consortium). No novel significant SNPs were found. Significant enrichment for CAD/MI SNPs was observed in testing Agatston and coronary artery calcium volume scores. Moreover, a significant enrichment of BMD SNPs was shown in aortic calcium volume scores. This may indicate genetic relation of BMD SNPs and arterial calcification burden.

  4. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer

    OpenAIRE

    Amundadottir, Laufey; Kraft, Peter; Stolzenberg-Solomon, Rachael Z; Fuchs, Charles S; Petersen, Gloria M.; Arslan, Alan A.; Bueno-de-Mesquita, H Bas; Gross, Myron; Helzlsouer, Kathy; Jacobs, Eric J.; LaCroix, Andrea; Zheng, Wei; Albanes, Demetrius; Bamlet, William; Berg, Christine D

    2009-01-01

    We conducted a two-stage genome-wide association study (GWAS) of pancreatic cancer, a cancer with one of the poorest survival rates worldwide. Initially, we genotyped 558,542 single nucleotide polymorphisms in 1,896 incident cases and 1,939 controls drawn from twelve prospective cohorts plus one hospital-based case-control study. In a combined analysis adjusted for study, sex, ancestry and five principal components that included an additional 2,457 cases and 2,654 controls from eight case-con...

  5. Genome-wide retroviral insertional tagging of genes involved in cancer in Cdkn2a-deficient mice

    DEFF Research Database (Denmark)

    Lund, Anders H; Turner, Geoffrey; Trubetskoy, Alla; Verhoeven, Els; Wientjens, Ellen; Hulsman, Danielle; Russell, Robert; DePinho, Ronald A; Lenz, Jack; van Lohuizen, Maarten

    2002-01-01

    retroviral integration sites and mapped them against the mouse genome sequence databases from Celera and Ensembl. In addition to 17 insertions targeting gene loci known to be cancer-related, we identified a total of 37 new common insertion sites (CISs), of which 8 encode components of signaling pathways that...... that large-scale retroviral insertional mutagenesis in genetically predisposed mice is useful both as a system for identifying genes underlying cancer and as a genetic framework for the assignment of such genes to specific oncogenic pathways....

  6. Genome-Wide Pattern of TCF7L2/TCF4 Chromatin Occupancy in Colorectal Cancer Cells▿ †

    OpenAIRE

    Hatzis, Pantelis; van der Flier, Laurens G.; van Driel, Marc A.; Guryev, Victor; Nielsen, Fiona; Denissov, Sergei; Nijman, Isaäc J; Koster, Jan; Santo, Evan E.; Welboren, Willem; Versteeg, Rogier; Cuppen, Edwin; van de Wetering, Marc; Clevers, Hans; Stunnenberg, Hendrik G.

    2008-01-01

    Wnt signaling activates gene expression through the induced formation of complexes between DNA-binding T-cell factors (TCFs) and the transcriptional coactivator β-catenin. In colorectal cancer, activating Wnt pathway mutations transform epithelial cells through the inappropriate activation of a TCF7L2/TCF4 target gene program. Through a DNA array-based genome-wide analysis of TCF4 chromatin occupancy, we have identified 6,868 high-confidence TCF4-binding sites in the LS174T colorectal cancer ...

  7. 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...... pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC......], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated...

  8. Therapeutic potential of PRL-3 targeting and clinical significance of PRL-3 genomic amplification in gastric cancer

    International Nuclear Information System (INIS)

    Phosphatase of regenerating liver-3 (PRL-3) has deserved attention as a crucial molecule in the multiple steps of metastasis. In the present study, we examined the mechanisms regulating PRL-3 expression, and assessed the clinical potential of PRL-3-targeted therapy in gastric cancer. PRL-3 genomic amplification was analyzed using quantitative-polymerase chain reaction and/or fluorescence in situ hybridization in 77 primary gastric tumors. The anticancer activity of PRL-3 inhibitor (1-4-bromo-2-benzylidene rhodanine) treatment was evaluated against cancer cells with different genetic and expression status. PRL-3 genomic amplification was closely concordant with high level of its protein expression in cell lines, and was found in 20% (8/40) among human primary tumors with its expression, which were all stage III/IV disease (40%, 8/20), but in none (0/37) among those without expression. Additionally, PRL-3 genomic amplification was associated with metastatic lymph node status, leading to advanced stage and thereby poor outcomes in patients with lymph node metastasis (P = 0.021). PRL-3 small interfering RNA robustly repressed metastatic properties, including cell proliferation, invasion, and anchorage-independent colony formation. Although neither PRL-3 genomic amplification nor expression level was responsible for the sensitivity to PRL-3 inhibitor treatment, the inhibitor showed dose-dependent anticancer efficacy, and remarkably induced apoptosis on all the tested cell lines with PRL-3 expression. We have for the first time, demonstrated that PRL-3 genomic amplification is one of the predominant mechanisms inducing its expression, especially in more advanced stage, and that PRL-3-targeted therapy may have a great potential against gastric cancer with its expression

  9. Therapeutic potential of PRL-3 targeting and clinical significance of PRL-3 genomic amplification in gastric cancer

    Directory of Open Access Journals (Sweden)

    Nishimiya Hiroshi

    2011-04-01

    Full Text Available Abstract Background Phosphatase of regenerating liver-3 (PRL-3 has deserved attention as a crucial molecule in the multiple steps of metastasis. In the present study, we examined the mechanisms regulating PRL-3 expression, and assessed the clinical potential of PRL-3-targeted therapy in gastric cancer. Methods PRL-3 genomic amplification was analyzed using quantitative-polymerase chain reaction and/or fluorescence in situ hybridization in 77 primary gastric tumors. The anticancer activity of PRL-3 inhibitor (1-4-bromo-2-benzylidene rhodanine treatment was evaluated against cancer cells with different genetic and expression status. Results PRL-3 genomic amplification was closely concordant with high level of its protein expression in cell lines, and was found in 20% (8/40 among human primary tumors with its expression, which were all stage III/IV disease (40%, 8/20, but in none (0/37 among those without expression. Additionally, PRL-3 genomic amplification was associated with metastatic lymph node status, leading to advanced stage and thereby poor outcomes in patients with lymph node metastasis (P = 0.021. PRL-3 small interfering RNA robustly repressed metastatic properties, including cell proliferation, invasion, and anchorage-independent colony formation. Although neither PRL-3 genomic amplification nor expression level was responsible for the sensitivity to PRL-3 inhibitor treatment, the inhibitor showed dose-dependent anticancer efficacy, and remarkably induced apoptosis on all the tested cell lines with PRL-3 expression. Conclusions We have for the first time, demonstrated that PRL-3 genomic amplification is one of the predominant mechanisms inducing its expression, especially in more advanced stage, and that PRL-3-targeted therapy may have a great potential against gastric cancer with its expression.

  10. Association analysis of a chemo-response signature identified within The Cancer Genome Atlas aimed at predicting genetic risk for chemo-response in ovarian cancer

    Science.gov (United States)

    Salinas, Erin A; Newtson, Andreea M; Leslie, Kimberly K; Gonzalez-Bosquet, Jesus

    2016-01-01

    Background: A gene signature associated with chemo-response in ovarian cancer was created through integration of biological data in The Cancer Genome Atlas (TCGA) and validated in five independent microarray experiments. Our study aimed to determine if single nucleotide polymorphisms (SNPs) within the 422-gene signature were associated with a genetic predisposition to platinum-based chemotherapy response in serous ovarian cancer. Methods: An association analysis between SNPs within the 422-gene signature and chemo-response in serous ovarian cancer was performed under the log-additive genetic model using the ‘SNPassoc’ package within the R environment (p<0.0001). Subsequent validation of statistically significant SNPs was done in the Ovarian Cancer Association Consortium (OCAC) database. Results: 19 SNPs were found to be associated with chemo-response with statistical significance. None of the SNPs found significant in TCGA were validated within OCAC for the outcome of interest, chemo-response. Conclusions: SNPs associated with chemo-response in ovarian cancer within TGCA database were not validated in a larger database of patients and controls from OCAC. New strategies integrating somatic and germline information may help to characterize genetic predictors for treatment response in ovarian cancer. PMID:27186327

  11. Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer

    OpenAIRE

    Li, Donghui; Duell, Eric J.; Yu, Kai; Risch, Harvey A.; Olson, Sara H.; Kooperberg, Charles; Wolpin, Brian M.; Jiao, Li; Dong, Xiaoqun; Wheeler, Bill; Arslan, Alan A.; Bueno-De-Mesquita, H Bas; Fuchs, Charles S; Gallinger, Steven; Gross, Myron

    2012-01-01

    Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease-associated single-nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3851 pancreatic...

  12. Integrative genomic analysis of interleukin-36RN and its prognostic value in cancer.

    Science.gov (United States)

    Lv, Zhilei; Fan, Jinshuo; Zhang, Xiuxiu; Huang, Qi; Han, Jieli; Wu, Feng; Hu, Guorong; Guo, Mengfei; Jin, Yang

    2016-02-01

    Interleukin (IL)-36RN, previously known as IL1-F5 and IL-1δ, shares a 360-kb region of chromosome 2q13 with members of IL-1 systems. IL-36RN encodes an anti-inflammatory cytokine, IL-36 receptor antagonist (IL-36Ra). In spite of IL-36Ra showing the highest homology to IL-1 receptor (IL-1R) antagonist, it differs from the latter in aspects including its binding to IL-lRrp2 but not to IL-1R1. IL-36RN is mainly expressed in epithelial cells and has important roles in inflammatory diseases. In the present study, IL-36RN was identified in the genomes of 27 species, including human, chimpanzee, mouse, horse and dolphin. Human IL-36RN was mainly expressed in the eye, head and neck, fetal heart, lung, testis, cervix and placenta; furthermore, it was highly expressed in bladder and parathyroid tumors. Furthermore, a total of 30 single nucleotide polymorphisms causing missense mutations were determined, which are considered to be the causes of various diseases, such as generalized pustular psoriasis. In addition, the link between IL-36RN and the prognosis of certain cancer types was revealed through meta-analysis. Tumor-associated transcriptional factors c-Fos, activator protein-1, c-Jun and nuclear factor κB were found to bind to the upstream region in the IL-36RN gene. This may indicate that IL-36RN is involved in tumorigenesis and tumor progression through the regulation of tumor-associated transcriptional factors. The present study identified IL-36RN in various species and investigated the associations between IL-36RN and cancer prognosis, which would determine whether IL-36RN drove the evolution of the various species with regard to tumorigenesis. PMID:26676204

  13. A genome-wide "pleiotropy scan" does not identify new susceptibility loci for estrogen receptor negative breast cancer.

    Directory of Open Access Journals (Sweden)

    Daniele Campa

    Full Text Available Approximately 15-30% of all breast cancer tumors are estrogen receptor negative (ER-. Compared with ER-positive (ER+ disease they have an earlier age at onset and worse prognosis. Despite the vast number of risk variants identified for numerous cancer types, only seven loci have been unambiguously identified for ER-negative breast cancer. With the aim of identifying new susceptibility SNPs for this disease we performed a pleiotropic genome-wide association study (GWAS. We selected 3079 SNPs associated with a human complex trait or disease at genome-wide significance level (P<5 × 10(-8 to perform a secondary analysis of an ER-negative GWAS from the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3, including 1998 cases and 2305 controls from prospective studies. We then tested the top ten associations (i.e. with the lowest P-values using three additional populations with a total sample size of 3509 ER+ cases, 2543 ER- cases and 7031 healthy controls. None of the 3079 selected variants in the BPC3 ER-GWAS were significant at the adjusted threshold. 186 variants were associated with ER- breast cancer risk at a conventional threshold of P<0.05, with P-values ranging from 0.049 to 2.3 × 10(-4. None of the variants reached statistical significance in the replication phase. In conclusion, this study did not identify any novel susceptibility loci for ER-breast cancer using a "pleiotropic approach".

  14. A whole-genome massively parallel sequencing analysis of BRCA1 mutant oestrogen receptor negative and positive breast cancers

    Science.gov (United States)

    Weigelt, Britta; Wilkerson, Paul M; Manie, Elodie; Grigoriadis, Anita; A’Hern, Roger; van der Groep, Petra; Kozarewa, Iwanka; Popova, Tatiana; Mariani, Odette; Turaljic, Samra; Furney, Simon J; Marais, Richard; Rodruigues, Daniel-Nava; Flora, Adriana C; Wai, Patty; Pawar, Vidya; McDade, Simon; Carroll, Jason; Stoppa-Lyonnet, Dominique; Green, Andrew R; Ellis, Ian O; Swanton, Charles; van Diest, Paul; Delattre, Olivier; Lord, Christopher J; Foulkes, William D; Vincent-Salomon, Anne; Ashworth, Alan; Stern, Marc Henri; Reis-Filho, Jorge S

    2016-01-01

    BRCA1 encodes a tumour suppressor protein that plays pivotal roles in homologous recombination (HR) DNA repair, cell-cycle checkpoints, and transcriptional regulation. BRCA1 germline mutations confer a high risk of early-onset breast and ovarian cancer. In >80% of cases, tumours arising in BRCA1 germline mutation carriers are oestrogen receptor (ER)-negative, however up to 15% are ER-positive. It has been suggested that BRCA1 ER-positive breast cancers constitute sporadic cancers arising in the context of a BRCA1 germline mutation rather than being causally related to BRCA1 loss-of-function. Whole-genome massively parallel sequencing of ER-positive and ER-negative BRCA1 breast cancers, and their respective germline DNAs, was used to characterise the genetic landscape of BRCA1 cancers at base-pair resolution. Only BRCA1 germline mutations and somatic loss of the wild-type allele, and TP53 somatic mutations were recurrently found in the index cases. BRCA1 breast cancers displayed a mutational signature consistent with that caused by lack of HR DNA repair in both ER-positive and ER-negative cases. Sequencing analysis of independent cohorts of hereditary BRCA1 and sporadic non-BRCA1 breast cancers for the presence of recurrent pathogenic mutations and/or homozygous deletions found in the index cases revealed that DAPK3, TMEM135, KIAA1797, PDE4D and GATA4 are potential additional drivers of breast cancers. This study demonstrates that BRCA1 pathogenic germline mutations coupled with somatic loss of the wild-type allele are not sufficient for hereditary breast cancers to display an ER-negative phenotype, and has led to the identification of three potential novel breast cancer genes (i.e. DAPK3, TMEM135 and GATA4). PMID:22362584

  15. Identification of genes containing expanded purine repeats in the human genome and their apparent protective role against cancer.

    Science.gov (United States)

    Singh, Himanshu Narayan; Rajeswari, Moganty R

    2016-01-01

    Purine repeat sequences present in a gene are unique as they have high propensity to form unusual DNA-triple helix structures. Friedreich's ataxia is the only human disease that is well known to be associated with DNA-triplexes formed by purine repeats. The purpose of this study was to recognize the expanded purine repeats (EPRs) in human genome and find their correlation with cancer pathogenesis. We developed "PuRepeatFinder.pl" algorithm to identify non-overlapping EPRs without pyrimidine interruptions in the human genome and customized for searching repeat lengths, n ≥ 200. A total of 1158 EPRs were identified in the genome which followed Wakeby distribution. Two hundred and ninety-six EPRs were found in geneic regions of 282 genes (EPR-genes). Gene clustering of EPR-genes was done based on their cellular function and a large number of EPR-genes were found to be enzymes/enzyme modulators. Meta-analysis of 282 EPR-genes identified only 63 EPR-genes in association with cancer, mostly in breast, lung, and blood cancers. Protein-protein interaction network analysis of all 282 EPR-genes identified proteins including those in cadherins and VEGF. The two observations, that EPRs can induce mutations under malignant conditions and that identification of some EPR-gene products in vital cell signaling-mediated pathways, together suggest the crucial role of EPRs in carcinogenesis. The new link between EPR-genes and their functionally interacting proteins throws a new dimension in the present understanding of cancer pathogenesis and can help in planning therapeutic strategies. Validation of present results using techniques like NGS is required to establish the role of the EPR genes in cancer pathology. PMID:25990537

  16. Targeted Sequencing of the Mitochondrial Genome of Women at High Risk of Breast Cancer without Detectable Mutations in BRCA1/2.

    Directory of Open Access Journals (Sweden)

    Sophie Blein

    Full Text Available Breast Cancer is a complex multifactorial disease for which high-penetrance mutations have been identified. Approaches used to date have identified genomic features explaining about 50% of breast cancer heritability. A number of low- to medium penetrance alleles (per-allele odds ratio < 1.5 and 4.0, respectively have been identified, suggesting that the remaining heritability is likely to be explained by the cumulative effect of such alleles and/or by rare high-penetrance alleles. Relatively few studies have specifically explored the mitochondrial genome for variants potentially implicated in breast cancer risk. For these reasons, we propose an exploration of the variability of the mitochondrial genome in individuals diagnosed with breast cancer, having a positive breast cancer family history but testing negative for BRCA1/2 pathogenic mutations. We sequenced the mitochondrial genome of 436 index breast cancer cases from the GENESIS study. As expected, no pathogenic genomic pattern common to the 436 women included in our study was observed. The mitochondrial genes MT-ATP6 and MT-CYB were observed to carry the highest number of variants in the study. The proteins encoded by these genes are involved in the structure of the mitochondrial respiration chain, and variants in these genes may impact reactive oxygen species production contributing to carcinogenesis. More functional and epidemiological studies are needed to further investigate to what extent variants identified may influence familial breast cancer risk.

  17. Targeted Sequencing of the Mitochondrial Genome of Women at High Risk of Breast Cancer without Detectable Mutations in BRCA1/2

    Science.gov (United States)

    Blein, Sophie; Barjhoux, Laure; Damiola, Francesca; Dondon, Marie-Gabrielle; Eon-Marchais, Séverine; Marcou, Morgane; Caron, Olivier; Lortholary, Alain; Buecher, Bruno; Berthet, Pascaline; Noguès, Catherine; Lasset, Christine; Gauthier-Villars, Marion; Mazoyer, Sylvie; Stoppa-Lyonnet, Dominique; Andrieu, Nadine; Cox, David G.

    2015-01-01

    Breast Cancer is a complex multifactorial disease for which high-penetrance mutations have been identified. Approaches used to date have identified genomic features explaining about 50% of breast cancer heritability. A number of low- to medium penetrance alleles (per-allele odds ratio < 1.5 and 4.0, respectively) have been identified, suggesting that the remaining heritability is likely to be explained by the cumulative effect of such alleles and/or by rare high-penetrance alleles. Relatively few studies have specifically explored the mitochondrial genome for variants potentially implicated in breast cancer risk. For these reasons, we propose an exploration of the variability of the mitochondrial genome in individuals diagnosed with breast cancer, having a positive breast cancer family history but testing negative for BRCA1/2 pathogenic mutations. We sequenced the mitochondrial genome of 436 index breast cancer cases from the GENESIS study. As expected, no pathogenic genomic pattern common to the 436 women included in our study was observed. The mitochondrial genes MT-ATP6 and MT-CYB were observed to carry the highest number of variants in the study. The proteins encoded by these genes are involved in the structure of the mitochondrial respiration chain, and variants in these genes may impact reactive oxygen species production contributing to carcinogenesis. More functional and epidemiological studies are needed to further investigate to what extent variants identified may influence familial breast cancer risk. PMID:26406445

  18. Discovery and validation of prognostic markers in gastric cancer by genome-wide expression profiling

    Directory of Open Access Journals (Sweden)

    Yue-Zheng Zhang, Lian-Hai Zhang, Yang Gao, Chao-Hua Li, Shu-Qin Jia, Ni Liu, Feng Cheng, De-Yun Niu, William CS Cho, Jia-Fu Ji, Chang-Qing Zeng

    2011-04-01

    Full Text Available AIM: To develop a prognostic gene set that can predict patient overall survival status based on the whole genome expression analysis.METHODS: Using Illumina HumanWG-6 BeadChip followed by semi-supervised analysis, we analyzed the expression of 47 296 transcripts in two batches of gastric cancer patients who underwent surgical resection. Thirty-nine samples in the first batch were used as the training set to discover candidate markers correlated to overall survival, and thirty-three samples in the second batch were used for validation.RESULTS: A panel of ten genes were identified as prognostic marker in the first batch samples and classified patients into a low- and a high-risk group with significantly different survival times (P = 0.000047. This prognostic marker was then verified in an independent validation sample batch (P = 0.0009. By comparing with the traditional Tumor-node-metastasis (TNM staging system, this ten-gene prognostic marker showed consistent prognosis results. It was the only independent prognostic value by multivariate Cox regression analysis (P = 0.007. Interestingly, six of these ten genes are ribosomal proteins, suggesting a possible association between the deregulation of ribosome related gene expression and the poor prognosis.CONCLUSION: A ten-gene marker correlated with overall prognosis, including 6 ribosomal proteins, was identified and verified, which may complement the predictive value of TNM staging system.

  19. Mathematical modelling of the radiation-induced bystander effect and transmissible genomic instability applied to cancer

    Energy Technology Data Exchange (ETDEWEB)

    Little, M.P. (Dept. of Epidemiology and Public Health, Imperial College Faculty of Medicine, London (United Kingdom)); Prise, K.; Folkard, M. (Gray Cancer Institute, Mount Vernon Hospital, Northwood (United Kingdom)); Belyakov, O. (Radiation and Nuclear Safety Authority, Research and Environmental Surveillance, Radiation Biology Laboratory, Helsinki (Finland))

    2008-12-15

    A variety of quasi-mechanistic models of carcinogenesis are reviewed, and in particular, the multi-stage model of Armitage and Doll and the two-mutation model of Moolgavkar, Venzon, and Knudson. Both the latter models, and various generalizations of them also, are capable of describing at least qualitatively many of the observed patterns of excess cancer risk following ionizing radiation exposure. However, there are certain inconsistencies with the biological and epidemiological data both for the multi-stage model and the two-mutation model. In particular, there are indications that the two-mutation model is not totally suitable for describing the pattern of excess risk for solid cancers that is often seen after exposure to radiation, although leukaemia may be better fitted by this type of model. Generalizations of the model of Moolgavkar, Venzon, and Knudson which require three or more mutations, and models allowing for genomic instability, are easier to reconcile with the epidemiological and biological data relating to solid cancers. Bystander effects, whereby cells that are not directly exposed to ionizing radiation exhibit adverse biological effects, have been observed in a number of experimental systems. In contrast to the large amount of work on developing carcinogenesis models over the last 50 years, there has been comparatively little work on developing quasi-mechanistic models of the bystander effect, reflecting the comparatively recently available experimental data elucidating this phenomenon. The few quasi-mechanistic models of the bystander effect that have been developed are surveyed. In particular, a novel stochastic model of the radiation-induced bystander effect is considered that takes account of spatial location, cell killing and repopulation, features not explicitly taken into account in many previous models. The ionizing radiation dose- and time-responses of this model are explored, and it is shown to exhibit pronounced downward curvature in the

  20. [Surgery without anatomy?].

    Science.gov (United States)

    Stelzner, F

    2016-08-01

    Anatomy is the basis of all operative medicine. While this branch of scientific medicine is frequently not explicitly mentioned in surgical publications, it is nonetheless quintessential to medical education. In the era of video sequences and digitized images, surgical methods are frequently communicated in the form of cinematic documentation of surgical procedures; however, this occurs without the help of explanatory drawings or subtexts that would illustrate the underlying anatomical nomenclature, comment on fine functionally important details or even without making any mention of the surgeon. In scientific manuscripts color illustrations frequently appear in such overwhelming quantities that they resemble long arrays of trophies but fail to give detailed explanations that would aid the therapeutic translation of the novel datasets. In a similar fashion, many anatomy textbooks prefer to place emphasis on illustrations and photographs while supplying only a paucity of explanations that would foster the understanding of functional contexts and thus confuse students and practitioners alike. There is great temptation to repeat existing data and facts over and over again, while it is proportionally rare to make reference to truly original scientific discoveries. A number of examples are given in this article to illustrate how discoveries that were made even a long time ago can still contribute to scientific progress in current times. This includes the NO signaling molecules, which were first described in 1775 but were only discovered to have a pivotal role as neurotransmitters in the function of human paradoxical sphincter muscles in 2012 and 2015. Readers of scientific manuscripts often long for explanations by the numerous silent coauthors of a publication who could contribute to the main topic by adding in-depth illustrations (e. g. malignograms, evolution and involution of lymph node structures). PMID:27251482

  1. Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk

    Science.gov (United States)

    Lindström, Sara; Thompson, Deborah J.; Paterson, Andrew D.; Li, Jingmei; Gierach, Gretchen L.; Scott, Christopher; Stone, Jennifer; Douglas, Julie A.; dos-Santos-Silva, Isabel; Fernandez-Navarro, Pablo; Verghase, Jajini; Smith, Paula; Brown, Judith; Luben, Robert; Wareham, Nicholas J.; Loos, Ruth J.F.; Heit, John A.; Pankratz, V. Shane; Norman, Aaron; Goode, Ellen L.; Cunningham, Julie M.; deAndrade, Mariza; Vierkant, Robert A.; Czene, Kamila; Fasching, Peter A.; Baglietto, Laura; Southey, Melissa C.; Giles, Graham G.; Shah, Kaanan P.; Chan, Heang-Ping; Helvie, Mark A.; Beck, Andrew H.; Knoblauch, Nicholas W.; Hazra, Aditi; Hunter, David J.; Kraft, Peter; Pollan, Marina; Figueroa, Jonine D.; Couch, Fergus J.; Hopper, John L.; Hall, Per; Easton, Douglas F.; Boyd, Norman F.; Vachon, Celine M.; Tamimi, Rulla M.

    2015-01-01

    Mammographic density reflects the amount of stromal and epithelial tissues in relation to adipose tissue in the breast and is a strong risk factor for breast cancer. Here we report the results from meta-analysis of genome-wide association studies (GWAS) of three mammographic density phenotypes: dense area, non-dense area and percent density in up to 7,916 women in stage 1 and an additional 10,379 women in stage 2. We identify genome-wide significant (P<5×10−8) loci for dense area (AREG, ESR1, ZNF365, LSP1/TNNT3, IGF1, TMEM184B, SGSM3/MKL1), non-dense area (8p11.23) and percent density (PRDM6, 8p11.23, TMEM184B). Four of these regions are known breast cancer susceptibility loci, and four additional regions were found to be associated with breast cancer (P<0.05) in a large meta-analysis. These results provide further evidence of a shared genetic basis between mammographic density and breast cancer and illustrate the power of studying intermediate quantitative phenotypes to identify putative disease susceptibility loci. PMID:25342443

  2. Carpal Ligament Anatomy and Biomechanics.

    Science.gov (United States)

    Pulos, Nicholas; Bozentka, David J

    2015-08-01

    A fundamental understanding of the ligamentous anatomy of the wrist is critical for any physician attempting to treat carpal instability. The anatomy of the wrist is complex, not only because of the number of named structures and their geometry but also because of the inconsistencies in describing these ligaments. The complex anatomy of the wrist is described through a review of the carpal ligaments and their effect on normal carpal motion. Mastery of this topic facilitates the physician's understanding of the patterns of instability that are seen clinically. PMID:26205699

  3. Epidemiology & Genomics Research Program

    Science.gov (United States)

    The Epidemiology and Genomics Research Program, in the National Cancer Institute's Division of Cancer Control and Population Sciences, funds research in human populations to understand the determinants of cancer occurrence and outcomes.

  4. Integrative Pathway Analysis of Metabolic Signature in Bladder Cancer: A Linkage to The Cancer Genome Atlas Project and Prediction of Survival

    Science.gov (United States)

    von Rundstedt, Friedrich-Carl; Rajapakshe, Kimal; Ma, Jing; Arnold, James M.; Gohlke, Jie; Putluri, Vasanta; Krishnapuram, Rashmi; Piyarathna, D. Badrajee; Lotan, Yair; Gödde, Daniel; Roth, Stephan; Störkel, Stephan; Levitt, Jonathan M.; Michailidis, George; Sreekumar, Arun; Lerner, Seth P.; Coarfa, Cristian; Putluri, Nagireddy

    2016-01-01

    Purpose We used targeted mass spectrometry to study the metabolic fingerprint of urothelial cancer and determine whether the biochemical pathway analysis gene signature would have a predictive value in independent cohorts of patients with bladder cancer. Materials and Methods Pathologically evaluated, bladder derived tissues, including benign adjacent tissue from 14 patients and bladder cancer from 46, were analyzed by liquid chromatography based targeted mass spectrometry. Differential metabolites associated with tumor samples in comparison to benign tissue were identified by adjusting the p values for multiple testing at a false discovery rate threshold of 15%. Enrichment of pathways and processes associated with the metabolic signature were determined using the GO (Gene Ontology) Database and MSigDB (Molecular Signature Database). Integration of metabolite alterations with transcriptome data from TCGA (The Cancer Genome Atlas) was done to identify the molecular signature of 30 metabolic genes. Available outcome data from TCGA portal were used to determine the association with survival. Results We identified 145 metabolites, of which analysis revealed 31 differential metabolites when comparing benign and tumor tissue samples. Using the KEGG (Kyoto Encyclopedia of Genes and Genomes) Database we identified a total of 174 genes that correlated with the altered metabolic pathways involved. By integrating these genes with the transcriptomic data from the corresponding TCGA data set we identified a metabolic signature consisting of 30 genes. The signature was significant in its prediction of survival in 95 patients with a low signature score vs 282 with a high signature score (p = 0.0458). Conclusions Targeted mass spectrometry of bladder cancer is highly sensitive for detecting metabolic alterations. Applying transcriptome data allows for integration into larger data sets and identification of relevant metabolic pathways in bladder cancer progression. PMID:26802582

  5. Combined array-comparative genomic hybridization and single-nucleotide polymorphism-loss of heterozygosity analysis reveals complex changes and multiple forms of chromosomal instability in colorectal cancers

    DEFF Research Database (Denmark)

    Gaasenbeek, Michelle; Howarth, Kimberley; Rowan, Andrew J;

    2006-01-01

    Cancers with chromosomal instability (CIN) are held to be aneuploid/polyploid with multiple large-scale gains/deletions, but the processes underlying CIN are unclear and different types of CIN might exist. We investigated colorectal cancer cell lines using array-comparative genomic hybridization ...

  6. Draft Genome Sequence of Erythromycin-Resistant Streptococcus gallolyticus subsp. gallolyticus NTS 31106099 Isolated from a Patient with Infective Endocarditis and Colorectal Cancer

    OpenAIRE

    Kambarev, Stanimir; Caté, Clément; Corvec, Stéphane; Pecorari, Frédéric

    2015-01-01

    Streptococcus gallolyticus subsp. gallolyticus is known for its close association with infective endocarditis and colorectal cancer in humans. Here, we report the draft genome sequence of highly erythromycin-resistant strain NTS 31106099 isolated from a patient with infective endocarditis and colorectal cancer.

  7. Computational methods for detecting copy number variations in cancer genome using next generation sequencing: principles and challenges

    Science.gov (United States)

    Liu, Biao; Morrison, Carl D.; Johnson, Candace S.; Trump, Donald L.; Qin, Maochun; Conroy, Jeffrey C.; Wang, Jianmin; Liu, Song

    2013-01-01

    Accurate detection of somatic copy number variations (CNVs) is an essential part of cancer genome analysis, and plays an important role in oncotarget identifications. Next generation sequencing (NGS) holds the promise to revolutionize somatic CNV detection. In this review, we provide an overview of current analytic tools used for CNV detection in NGS-based cancer studies. We summarize the NGS data types used for CNV detection, decipher the principles for data preprocessing, segmentation, and interpretation, and discuss the challenges in somatic CNV detection. This review aims to provide a guide to the analytic tools used in NGS-based cancer CNV studies, and to discuss the important factors that researchers need to consider when analyzing NGS data for somatic CNV detections. PMID:24240121

  8. Cancer Treatment Scams

    Science.gov (United States)

    ... Related Items Anatomy of a Cancer Treatment Scam Miracle Health Claims Discount Plan or Health Insurance? Cancer ... Talk to Your Doctor First. Tagged with: health , miracle claims , scam September 2008 You Might Also Like ...

  9. Genomic Prostate Cancer Classifier Predicts Biochemical Failure and Metastases in Patients After Postoperative Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Den, Robert B., E-mail: Robert.Den@jeffersonhospital.org [Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Feng, Felix Y. [University of Michigan, Michigan Union, Michigan (United States); Showalter, Timothy N. [University of Virginia School of Medicine, Charlottesville, Virginia (United States); Mishra, Mark V. [University of Maryland Medical Center, Baltimore, Maryland (United States); Trabulsi, Edouard J.; Lallas, Costas D.; Gomella, Leonard G.; Kelly, W. Kevin; Birbe, Ruth C.; McCue, Peter A. [Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Ghadessi, Mercedeh; Yousefi, Kasra; Davicioni, Elai [GenomeDx Biosciences Inc., Vancouver, British Columbia (Canada); Knudsen, Karen E.; Dicker, Adam P. [Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States)

    2014-08-01

    Purpose: To test the hypothesis that a genomic classifier (GC) would predict biochemical failure (BF) and distant metastasis (DM) in men receiving radiation therapy (RT) after radical prostatectomy (RP). Methods and Materials: Among patients who underwent post-RP RT, 139 were identified for pT3 or positive margin, who did not receive neoadjuvant hormones and had paraffin-embedded specimens. Ribonucleic acid was extracted from the highest Gleason grade focus and applied to a high-density-oligonucleotide microarray. Receiver operating characteristic, calibration, cumulative incidence, and Cox regression analyses were performed to assess GC performance for predicting BF and DM after post-RP RT in comparison with clinical nomograms. Results: The area under the receiver operating characteristic curve of the Stephenson model was 0.70 for both BF and DM, with addition of GC significantly improving area under the receiver operating characteristic curve to 0.78 and 0.80, respectively. Stratified by GC risk groups, 8-year cumulative incidence was 21%, 48%, and 81% for BF (P<.0001) and for DM was 0, 12%, and 17% (P=.032) for low, intermediate, and high GC, respectively. In multivariable analysis, patients with high GC had a hazard ratio of 8.1 and 14.3 for BF and DM. In patients with intermediate or high GC, those irradiated with undetectable prostate-specific antigen (PSA ≤0.2 ng/mL) had median BF survival of >8 years, compared with <4 years for patients with detectable PSA (>0.2 ng/mL) before initiation of RT. At 8 years, the DM cumulative incidence for patients with high GC and RT with undetectable PSA was 3%, compared with 23% with detectable PSA (P=.03). No outcome differences were observed for low GC between the treatment groups. Conclusion: The GC predicted BF and metastasis after post-RP irradiation. Patients with lower GC risk may benefit from delayed RT, as opposed to those with higher GC; however, this needs prospective validation. Genomic-based models

  10. Genomic Prostate Cancer Classifier Predicts Biochemical Failure and Metastases in Patients After Postoperative Radiation Therapy

    International Nuclear Information System (INIS)

    Purpose: To test the hypothesis that a genomic classifier (GC) would predict biochemical failure (BF) and distant metastasis (DM) in men receiving radiation therapy (RT) after radical prostatectomy (RP). Methods and Materials: Among patients who underwent post-RP RT, 139 were identified for pT3 or positive margin, who did not receive neoadjuvant hormones and had paraffin-embedded specimens. Ribonucleic acid was extracted from the highest Gleason grade focus and applied to a high-density-oligonucleotide microarray. Receiver operating characteristic, calibration, cumulative incidence, and Cox regression analyses were performed to assess GC performance for predicting BF and DM after post-RP RT in comparison with clinical nomograms. Results: The area under the receiver operating characteristic curve of the Stephenson model was 0.70 for both BF and DM, with addition of GC significantly improving area under the receiver operating characteristic curve to 0.78 and 0.80, respectively. Stratified by GC risk groups, 8-year cumulative incidence was 21%, 48%, and 81% for BF (P<.0001) and for DM was 0, 12%, and 17% (P=.032) for low, intermediate, and high GC, respectively. In multivariable analysis, patients with high GC had a hazard ratio of 8.1 and 14.3 for BF and DM. In patients with intermediate or high GC, those irradiated with undetectable prostate-specific antigen (PSA ≤0.2 ng/mL) had median BF survival of >8 years, compared with <4 years for patients with detectable PSA (>0.2 ng/mL) before initiation of RT. At 8 years, the DM cumulative incidence for patients with high GC and RT with undetectable PSA was 3%, compared with 23% with detectable PSA (P=.03). No outcome differences were observed for low GC between the treatment groups. Conclusion: The GC predicted BF and metastasis after post-RP irradiation. Patients with lower GC risk may benefit from delayed RT, as opposed to those with higher GC; however, this needs prospective validation. Genomic-based models

  11. UTSW Researchers Identify Potential Therapeutic Targets for High-grade Neuroendocrine Lung Cancers | Office of Cancer Genomics

    Science.gov (United States)

    Neuroendocrine specific lung cancers comprise about 10% of non-small cell lung cancer (NSCLC) cases and all small cell lung cancer (SCLC) cases. Studies have previously shown that the transcription factor achaete-scute homolog 1 (ASCL1) is a cancer “lineage” factor required for the development and survival of SCLC, and is highly expressed in neuroendocrine-specific NSCLC (NE-NSCLC).

  12. Olfaction: anatomy, physiology and behavior

    OpenAIRE

    Benignus, Vernon A.; Prah, James D.

    1982-01-01

    The anatomy, physiology and function of the olfactory system are reviewed, as are the normal effects of olfactory stimulation. It is speculated that olfaction may have important but unobtrusive effects on human behavior.

  13. OLFACTION: ANATOMY, PHYSIOLOGY AND BEHAVIOR

    Science.gov (United States)

    The anatomy, physiology and function of the olfactory system are reviewed, as are the normal effects of olfactory stimulation. It is speculated that olfaction may have important but unobtrusive effects on human behavior.

  14. Genomic instability at 13q31 locus and somatic mtDNA mutation in D-loop site correlate with tumor aggressiveness in sporadic Brazilian breast cancer cases

    OpenAIRE

    Gilson Costa dos Santos, Jr; de Souza Góes, AC; de Vitto, H; Moreira, CC; Avvad, E; Rumjanek, FD; de Moura GalloI, CV

    2012-01-01

    OBJECTIVE: Genomic instability is a hallmark of malignant tissues. In this work, we aimed to characterize nuclear and mitochondrial instabilities by determining short tandem repeats and somatic mitochondrial mutations, respectively, in a cohort of Brazilian sporadic breast cancer cases. Furthermore, we performed an association analysis of the molecular findings and the clinical pathological data. METHODS: We analyzed 64 matched pairs of breast cancer and adjacent non-cancerous breast samples ...

  15. Surgical Anatomy of the Eyelids.

    Science.gov (United States)

    Sand, Jordan P; Zhu, Bovey Z; Desai, Shaun C

    2016-05-01

    Slight alterations in the intricate anatomy of the upper and lower eyelid or their underlying structures can have pronounced consequences for ocular esthetics and function. The understanding of periorbital structures and their interrelationships continues to evolve and requires consideration when performing complex eyelid interventions. Maintaining a detailed appreciation of this region is critical to successful cosmetic or reconstructive surgery. This article presents a current review of the anatomy of the upper and lower eyelid with a focus on surgical implications. PMID:27105794

  16. Anatomie et identification des bois

    OpenAIRE

    Jourez, Benoît

    2010-01-01

    Anatomie des bois Structure anatomique des résineux et des feuillus Structure de la membrane cellulaire structure submicroscopique Anatomie du bois des essences feuillues tropicales Caractères anatomiques servant à l'identification des essences Reconnaissance microscopique du bois des essences résineuses et feuillues Duramen et duraminisation Formations anormales ( bois de compression et bois de tension) Chimie du bois Composition générale Cellulose, hé...

  17. Aging Impacts Transcriptome but not Genome of Hormone-dependentBreast Cancers

    Energy Technology Data Exchange (ETDEWEB)

    Yau, Christina; Fedele, Vita; Roydasgupta, Ritu; Fridlyand, Jane; Hubbard, Alan; Gray, Joe W.; Chew, Karen; Dairkee, Shanaz H.; Moore, DanH.; Schittulli, Francesco; Tommasi, Stefania; Paradiso, Angelo; Albertson, Donna G.; Benz, Christopher C.

    2007-10-09

    Age is one of the most important risk factors for human malignancies, including breast cancer; in addition, age-at-diagnosis has been shown to be an independent indicator of breast cancer prognosis. However, except for inherited forms of breast cancer, there is little genetic or epigenetic understanding of the biological basis linking aging with sporadic breast cancer incidence and its clinical behavior.

  18. Integrated genomic and functional analyses of histone demethylases identify oncogenic KDM2A isoform in breast cancer.

    Science.gov (United States)

    Liu, Hui; Liu, Lanxin; Holowatyj, Andreana; Jiang, Yuanyuan; Yang, Zeng-Quan

    2016-05-01

    Histone lysine demethylases (KDMs) comprise a large class of enzymes that catalyze site-specific demethylation of lysine residues on histones and other proteins. They play critical roles in controlling transcription, chromatin architecture, and cellular differentiation. However, the genomic landscape and clinical significance of KDMs in breast cancer remain poorly characterized. Here, we conducted a meta-analysis of 24 KDMs in breast cancer and identified associations among recurrent copy number alterations, gene expression, breast cancer subtypes, and clinical outcome. Two KDMs, KDM2A and KDM5B, had the highest frequency of genetic amplification and overexpression. Furthermore, among the 24 KDM genes, KDM2A had the highest correlation between copy number and mRNA expression, and high mRNA levels of KDM2A were significantly associated with shorter survival of breast cancer patients. KDM2A has two isoforms: the long isoform is comprised of a JmjC domain, CXXC-zinc finger, PHD zinc finger, F-box, and the AMN1 protein domain; whereas the short isoform of KDM2A lacks the N-terminal JmjC domain but contains all other motifs. Detailed characterization of KDM2A in breast cancer revealed that the short isoform of KDM2A is more abundant than the long isoform at DNA, mRNA, and protein levels in a subset of breast cancers. Furthermore, our data indicate that the short isoform of KDM2A has oncogenic potential and functions as an oncogenic isoform in a subset of breast cancers. Taken together, our findings suggest that amplification and overexpression of the KDM2A short isoform is critical in breast cancer progression. © 2015 Wiley Periodicals, Inc. PMID:26207617

  19. OncoScape: Exploring the cancer aberration landscape by genomic data fusion

    OpenAIRE

    Andreas Schlicker; Magali Michaut; Rubayte Rahman; Wessels, Lodewyk F. A.

    2016-01-01

    Although large-scale efforts for molecular profiling of cancer samples provide multiple data types for many samples, most approaches for finding candidate cancer genes rely on somatic mutations and DNA copy number only. We present a new method, OncoScape, which exploits five complementary data types across 11 cancer types to identify new candidate cancer genes. We find many rarely mutated genes that are strongly affected by other aberrations. We retrieve the majority of known cancer genes but...

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

    OpenAIRE

    CORRÊA, NATÁSSIA C.R.; Kuasne, Hellen; Faria, Jerusa A. Q. A.; SEIXAS, CIÇA C.S.; SANTOS, IRIA G.D.; ABREU, FRANCINE B.; Nonogaki, Suely; Rocha, Rafael M.; Silva, Gerluza Aparecida Borges; Gobbi, Helenice; Silvia R Rogatto; Alfredo M. Goes; Gomes, Dawidson 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 ...

  1. Penile Embryology and Anatomy

    Directory of Open Access Journals (Sweden)

    Jenny H. Yiee

    2010-01-01

    Full Text Available Knowledge of penile embryology and anatomy is essential to any pediatric urologist in order to fully understand and treat congenital anomalies. Sex differentiation of the external genitalia occurs between the 7thand 17th weeks of gestation. The Y chromosome initiates male differentiation through the SRY gene, which triggers testicular development. Under the influence of androgens produced by the testes, external genitalia then develop into the penis and scrotum. Dorsal nerves supply penile skin sensation and lie within Buck's fascia. These nerves are notably absent at the 12 o'clock position. Perineal nerves supply skin sensation to the ventral shaft skin and frenulum. Cavernosal nerves lie within the corpora cavernosa and are responsible for sexual function. Paired cavernosal, dorsal, and bulbourethral arteries have extensive anastomotic connections. During erection, the cavernosal artery causes engorgement of the cavernosa, while the deep dorsal artery leads to glans enlargement. The majority of venous drainage occurs through a single, deep dorsal vein into which multiple emissary veins from the corpora and circumflex veins from the spongiosum drain. The corpora cavernosa and spongiosum are all made of spongy erectile tissue. Buck's fascia circumferentially envelops all three structures, splitting into two leaves ventrally at the spongiosum. The male urethra is composed of six parts: bladder neck, prostatic, membranous, bulbous, penile, and fossa navicularis. The urethra receives its blood supply from both proximal and distal directions.

  2. Penile embryology and anatomy.

    Science.gov (United States)

    Yiee, Jenny H; Baskin, Laurence S

    2010-01-01

    Knowledge of penile embryology and anatomy is essential to any pediatric urologist in order to fully understand and treat congenital anomalies. Sex differentiation of the external genitalia occurs between the 7th and 17th weeks of gestation. The Y chromosome initiates male differentiation through the SRY gene, which triggers testicular development. Under the influence of androgens produced by the testes, external genitalia then develop into the penis and scrotum. Dorsal nerves supply penile skin sensation and lie within Buck's fascia. These nerves are notably absent at the 12 o'clock position. Perineal nerves supply skin sensation to the ventral shaft skin and frenulum. Cavernosal nerves lie within the corpora cavernosa and are responsible for sexual function. Paired cavernosal, dorsal, and bulbourethral arteries have extensive anastomotic connections. During erection, the cavernosal artery causes engorgement of the cavernosa, while the deep dorsal artery leads to glans enlargement. The majority of venous drainage occurs through a single, deep dorsal vein into which multiple emissary veins from the corpora and circumflex veins from the spongiosum drain. The corpora cavernosa and spongiosum are all made of spongy erectile tissue. Buck's fascia circumferentially envelops all three structures, splitting into two leaves ventrally at the spongiosum. The male urethra is composed of six parts: bladder neck, prostatic, membranous, bulbous, penile, and fossa navicularis. The urethra receives its blood supply from both proximal and distal directions. PMID:20602076

  3. Pathway-based analysis using genome-wide association data from a Korean non-small cell lung cancer study.

    Directory of Open Access Journals (Sweden)

    Donghoon Lee

    Full Text Available Pathway-based analysis, used in conjunction with genome-wide association study (GWAS techniques, is a powerful tool to detect subtle but systematic patterns in genome that can help elucidate complex diseases, like cancers. Here, we stepped back from genetic polymorphisms at a single locus and examined how multiple association signals can be orchestrated to find pathways related to lung cancer susceptibility. We used single-nucleotide polymorphism (SNP array data from 869 non-small cell lung cancer (NSCLC cases from a previous GWAS at the National Cancer Center and 1,533 controls from the Korean Association Resource project for the pathway-based analysis. After mapping single-nucleotide polymorphisms to genes, considering their coding region and regulatory elements (±20 kbp, multivariate logistic regression of additive and dominant genetic models were fitted against disease status, with adjustments for age, gender, and smoking status. Pathway statistics were evaluated using Gene Set Enrichment Analysis (GSEA and Adaptive Rank Truncated Product (ARTP methods. Among 880 pathways, 11 showed relatively significant statistics compared to our positive controls (PGSEA≤0.025, false discovery rate≤0.25. Candidate pathways were validated using the ARTP method and similarities between pathways were computed against each other. The top-ranked pathways were ABC Transporters (PGSEA<0.001, PARTP = 0.001, VEGF Signaling Pathway (PGSEA<0.001, PARTP = 0.008, G1/S Check Point (PGSEA = 0.004, PARTP = 0.013, and NRAGE Signals Death through JNK (PGSEA = 0.006, PARTP = 0.001. Our results demonstrate that pathway analysis can shed light on post-GWAS research and help identify potential targets for cancer susceptibility.

  4. Matrix-comparative genomic hybridization from multicenter formalin-fixed paraffin-embedded colorectal cancer tissue blocks

    International Nuclear Information System (INIS)

    The identification of genomic signatures of colorectal cancer for risk stratification requires the study of large series of cancer patients with an extensive clinical follow-up. Multicentric clinical studies represent an ideal source of well documented archived material for this type of analyses. To verify if this material is technically suitable to perform matrix-CGH, we performed a pilot study using macrodissected 29 formalin-fixed, paraffin-embedded tissue samples collected within the framework of the EORTC-GI/PETACC-2 trial for colorectal cancer. The scientific aim was to identify prognostic genomic signatures differentiating locally restricted (UICC stages II-III) from systemically advanced (UICC stage IV) colorectal tumours. The majority of archived tissue samples collected in the different centers was suitable to perform matrix-CGH. 5/7 advanced tumours displayed 13q-gain and 18q-loss. In locally restricted tumours, only 6/12 tumours showed a gain on 13q and 7/12 tumours showed a loss on 18q. Interphase-FISH and high-resolution array-mapping of the gain on 13q confirmed the validity of the array-data and narrowed the chromosomal interval containing potential oncogenes. Archival, paraffin-embedded tissue samples collected in multicentric clinical trials are suitable for matrix-CGH analyses and allow the identification of prognostic signatures and aberrations harbouring potential new oncogenes

  5. Screening Metastasis-associated Genes from Anoikis Resistant A549 Lung Cancer Cells by Human Genome Array

    Directory of Open Access Journals (Sweden)

    Xiaoping WANG

    2010-01-01

    Full Text Available Background and objective As a barrier to metastases, cells normally undergo apoptosis after they lose contact with their extra cellular matrix (ECM. This process has been termed “anoikis”. Tumour cells that acquire malignant potential have developed mechanisms to resist anoikis and thereby survive after detachment from their primary site while traveling through the lymphatic and circulatory systems. This “anoikis resistance” is considered the first step to tumor metastases. The aim of this study was to screen metastasis-associated genes from anoikis resistant and adherent growth A549 lung cancer cell by Human Genome Array. Methods Establish anoikis resistant A549 lung cancer cell lines by using poly-hydroxyethyl methacrylate resin processed petri dishes, which causes cell free from adherent. The different expressed gene between anoikis resistant A549 cell and adherent growth A549 cell was tested using human V2.0 whole-genome oligonucleotide microarray, a product of Capitalbio Corporation, Beijing. Screen metastasis-associated genes. Results 745 different expressed genes were screened, including 63 highly metastasis-associated genes. Conclusion The successfully established anoikis resistant A549 cell lines and screened different expressed genes provide us basis for further research on metastasis of lung cancer.

  6. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

    Science.gov (United States)

    Michailidou, Kyriaki; Beesley, Jonathan; Lindstrom, Sara; Canisius, Sander; Dennis, Joe; Lush, Michael; 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, Børge 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; Aittomäki, 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; 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; Guénel, Pascal; Truong, Thérèse; 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; González-Neira, Anna; Benitez, Javier; Zamora, M Pilar; Perez, Jose Ignacio Arias; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Cox, Angela; Cross, Simon S; Reed, Malcolm WR; 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 WM; Collée, 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, Dmitrios; 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; Labrèche, France; Dumont, Martine; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Brauch, Hiltrud; Hamann, Ute; Brüning, Thomas; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Bernard, Loris; Bogdanova, Natalia V; Dörk, Thilo; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Devilee, Peter; Tollenaar, Robert AEM; 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; Alonso, M Rosario; Álvarez, Nuria; Herrero, Daniel; Simard, Jacques; Pharoah, Paul PDP; 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 ~14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS comprising of 15,748 breast cancer cases and 18,084 controls, and 46,785 cases and 42,892 controls from 41 studies genotyped on a 200K custom array (iCOGS). Analyses were restricted to women of European ancestry. Genotypes for more than 11M SNPs were generated by imputation using the 1000 Genomes Project reference panel. We identified 15 novel loci associated with breast cancer at P<5×10−8. Combining association analysis with ChIP-Seq data in mammary cell lines and ChIA-PET chromatin interaction data in ENCODE, we identified likely target genes in two regions: SETBP1 on 18q12.3 and RNF115 and PDZK1 on 1q21.1. One association appears to be driven by an amino-acid substitution in EXO1. PMID:25751625

  7. Matrix-comparative genomic hybridization from multicenter formalin-fixed paraffin-embedded colorectal cancer tissue blocks

    Directory of Open Access Journals (Sweden)

    Köhne Claus-Henning

    2007-04-01

    Full Text Available Abstract Background The identification of genomic signatures of colorectal cancer for risk stratification requires the study of large series of cancer patients with an extensive clinical follow-up. Multicentric clinical studies represent an ideal source of well documented archived material for this type of analyses. Methods To verify if this material is technically suitable to perform matrix-CGH, we performed a pilot study using macrodissected 29 formalin-fixed, paraffin-embedded tissue samples collected within the framework of the EORTC-GI/PETACC-2 trial for colorectal cancer. The scientific aim was to identify prognostic genomic signatures differentiating locally restricted (UICC stages II-III from systemically advanced (UICC stage IV colorectal tumours. Results The majority of archived tissue samples collected in the different centers was suitable to perform matrix-CGH. 5/7 advanced tumours displayed 13q-gain and 18q-loss. In locally restricted tumours, only 6/12 tumours showed a gain on 13q and 7/12 tumours showed a loss on 18q. Interphase-FISH and high-resolution array-mapping of the gain on 13q confirmed the validity of the array-data and narrowed the chromosomal interval containing potential oncogenes. Conclusion Archival, paraffin-embedded tissue samples collected in multicentric clinical trials are suitable for matrix-CGH analyses and allow the identification of prognostic signatures and aberrations harbouring potential new oncogenes.

  8. Intrachromosomal genomic instability in human sporadic colorectal cancer measured by genome-wide allelotyping and inter-(simple sequence repeat) PCR.

    Science.gov (United States)

    Anderson, G R; Brenner, B M; Swede, H; Chen, N; Henry, W M; Conroy, J M; Karpenko, M J; Issa, J P; Bartos, J D; Brunelle, J K; Jahreis, G P; Kahlenberg, M S; Basik, M; Sait, S; Rodriguez-Bigas, M A; Nowak, N J; Petrelli, N J; Shows, T B; Stoler, D L

    2001-11-15

    We have used genome-wide allelotyping with 348 polymorphic autosomal markers spaced, on average, 10 cM apart to quantitate the extent of intrachromosomal instability in 59 human sporadic colorectal carcinomas. We have compared instability measured by this method with that measured by inter-(simple sequence repeat) PCR and microsatellite instability assays. Instability quantitated by fractional allelic loss rates was found to be independent of that detected by microsatellite instability analyses but was weakly associated with that measured by inter-(simple sequence repeat) PCR. A set of seven loci were identified that were most strongly associated with elevated rates of fractional allelic loss and/or inter-(simple sequence repeat) PCR instability; these seven loci were on chromosomes 3, 8, 11, 13, 14, 18, and 20. A lesser association was seen with two loci flanking p53 on chromosome 17. Coordinate loss patterns for these loci suggest that at least two separate sets of cooperating loci exist for intrachromosomal genomic instability in human colorectal cancer. PMID:11719460

  9. An improved CTC isolation scheme for pairing with downstream genomics: Demonstrating clinical utility in metastatic prostate, lung and pancreatic cancer.

    Science.gov (United States)

    Premasekharan, Gayatri; Gilbert, Elizabeth; Okimoto, Ross A; Hamirani, Ashiya; Lindquist, Karla J; Ngo, Vy T; Roy, Ritu; Hough, Jeffrey; Edwards, Matthew; Paz, Rosa; Foye, Adam; Sood, Riddhi; Copren, Kirsten A; Gubens, Matthew; Small, Eric J; Bivona, Trever G; Collisson, Eric A; Friedlander, Terence W; Paris, Pamela L

    2016-09-28

    Improvements in technologies to yield purer circulating tumor cells (CTCs) will enable a broader range of clinical applications. We have previously demonstrated the use of a commercially available cell-adhesion matrix (CAM) assay to capture invasive CTCs (iCTCs). To improve the purity of the isolated iCTCs, here we used fluorescence-activated cell sorting (FACS) in combination with the CAM assay (CAM + FACS). Our results showed an increase of median purity from the CAM assay to CAM + FACS for the spiked-in cell lines and patient samples analyzed from three different metastatic cancer types: castration resistant prostate cancer (mCRPC), non-small cell lung cancer (mNSCLC) and pancreatic ductal adenocarcinoma cancer (mPDAC). Copy number profiles for spiked-in mCRPC cell line and mCRPC patient iCTCs were similar to expected mCRPC profiles and a matched biopsy. A somatic epidermal growth factor receptor (EGFR) mutation specific to mNSCLC was observed in the iCTCs recovered from EGFR(+) mNSCLC cell lines and patient samples. Next-generation sequencing (NGS) of spiked-in pancreatic cancer cell line and mPDAC patient iCTCs showed mPDAC common mutations. CAM + FACS iCTC enrichment enables multiple downstream genomic characterizations across different tumor types. PMID:27343980

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

    Science.gov (United States)

    Lan, Qing; Hsiung, Chao A; Matsuo, Keitaro; Hong, Yun-Chul; Seow, Adeline; Wang, Zhaoming; Hosgood, H Dean; Chen, Kexin; Wang, Jiu-Cun; Chatterjee, Nilanjan; Hu, Wei; Wong, Maria Pik; Zheng, Wei; Caporaso, Neil; Park, Jae Yong; Chen, Chien-Jen; Kim, Yeul Hong; Kim, Young Tae; Landi, Maria Teresa; Shen, Hongbing; Lawrence, Charles; Burdett, Laurie; Yeager, Meredith; Yuenger, Jeffrey; Jacobs, Kevin B; Chang, I-Shou; Mitsudomi, Tetsuya; Kim, Hee Nam; Chang, Gee-Chen; Bassig, Bryan A; Tucker, Margaret; Wei, Fusheng; Yin, Zhihua; Wu, Chen; An, She-Juan; Qian, Biyun; Lee, Victor Ho Fun; Lu, Daru; Liu, Jianjun; Jeon, Hyo-Sung; Hsiao, Chin-Fu; Sung, Jae Sook; Kim, Jin Hee; Gao, Yu-Tang; Tsai, Ying-Huang; Jung, Yoo Jin; Guo, Huan; Hu, Zhibin; Hutchinson, Amy; Wang, Wen-Chang; Klein, Robert; Chung, Charles C; Oh, In-Jae; Chen, Kuan-Yu; Berndt, Sonja I; He, Xingzhou; Wu, Wei; Chang, Jiang; Zhang, Xu-Chao; Huang, Ming-Shyan; Zheng, Hong; Wang, Junwen; Zhao, Xueying; Li, Yuqing; Choi, Jin Eun; Su, Wu-Chou; Park, Kyong Hwa; Sung, Sook Whan; Shu, Xiao-Ou; Chen, Yuh-Min; Liu, Li; Kang, Chang Hyun; Hu, Lingmin; Chen, Chung-Hsing; Pao, William; Kim, Young-Chul; Yang, Tsung-Ying; Xu, Jun; Guan, Peng; Tan, Wen; Su, Jian; Wang, Chih-Liang; Li, Haixin; Sihoe, Alan Dart Loon; Zhao, Zhenhong; Chen, Ying; Choi, Yi Young; Hung, Jen-Yu; Kim, Jun Suk; Yoon, Ho-Il; Cai, Qiuyin; Lin, Chien-Chung; Park, In Kyu; Xu, Ping; Dong, Jing; Kim, Christopher; He, Qincheng; Perng, Reury-Perng; Kohno, Takashi; Kweon, Sun-Seog; Chen, Chih-Yi; Vermeulen, Roel; Wu, Junjie; Lim, Wei-Yen; Chen, Kun-Chieh; Chow, Wong-Ho; Ji, Bu-Tian; Chan, John K C; Chu, Minjie; Li, Yao-Jen; Yokota, Jun; Li, Jihua; Chen, Hongyan; Xiang, Yong-Bing; Yu, Chong-Jen; Kunitoh, Hideo; Wu, Guoping; Jin, Li; Lo, Yen-Li; Shiraishi, Kouya; Chen, Ying-Hsiang; Lin, Hsien-Chih; Wu, Tangchun; Wu, Yi-Long; Yang, Pan-Chyr; Zhou, Baosen; Shin, Min-Ho; Fraumeni, Joseph F; Lin, Dongxin; Chanock, Stephen J; Rothman, Nathaniel

    2012-12-01

    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 China, South Korea, Japan, Singapore, Taiwan and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10(-6)) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10(-18)), 6q22.2 (rs9387478, P = 4.14 × 10(-10)) and 6p21.32 (rs2395185, P = 9.51 × 10(-9)). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking. PMID:23143601

  11. Integrated Bioinformatics, Environmental Epidemiologic and Genomic Approaches to Identify Environmental and Molecular Links between Endometriosis and Breast Cancer

    Directory of Open Access Journals (Sweden)

    Deodutta Roy

    2015-10-01

    Full Text Available We present a combined environmental epidemiologic, genomic, and bioinformatics approach to identify: exposure of environmental chemicals with estrogenic activity; epidemiologic association between endocrine disrupting chemical (EDC and health effects, such as, breast cancer or endometriosis; and gene-EDC interactions and disease associations. Human exposure measurement and modeling confirmed estrogenic activity of three selected class of environmental chemicals, polychlorinated biphenyls (PCBs, bisphenols (BPs, and phthalates. Meta-analysis showed that PCBs exposure, not Bisphenol A (BPA and phthalates, increased the summary odds ratio for breast cancer and endometriosis. Bioinformatics analysis of gene-EDC interactions and disease associations identified several hundred genes that were altered by exposure to PCBs, phthalate or BPA. EDCs-modified genes in breast neoplasms and endometriosis are part of steroid hormone signaling and inflammation pathways. All three EDCs–PCB 153, phthalates, and BPA influenced five common genes—CYP19A1, EGFR, ESR2, FOS, and IGF1—in breast cancer as well as in endometriosis. These genes are environmentally and estrogen responsive, altered in human breast and uterine tumors and endometriosis lesions, and part of Mitogen Activated Protein Kinase (MAPK signaling pathways in cancer. Our findings suggest that breast cancer and endometriosis share some common environmental and molecular risk factors.

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

    Science.gov (United States)

    Lan, Qing; Hsiung, Chao A; Matsuo, Keitaro; Hong, Yun-Chul; Seow, Adeline; Wang, Zhaoming; Hosgood, H Dean; Chen, Kexin; Wang, Jiu-Cun; Chatterjee, Nilanjan; Hu, Wei; Wong, Maria Pik; Zheng, Wei; Caporaso, Neil; Park, Jae Yong; Chen, Chien-Jen; Kim, Yeul Hong; Kim, Young Tae; Landi, Maria Teresa; Shen, Hongbing; Lawrence, Charles; Burdett, Laurie; Yeager, Meredith; Yuenger, Jeffrey; Jacobs, Kevin B; Chang, I-Shou; Mitsudomi, Tetsuya; Kim, Hee Nam; Chang, Gee-Chen; Bassig, Bryan A; Tucker, Margaret; Wei, Fusheng; Yin, Zhihua; Wu, Chen; An, She-Juan; Qian, Biyun; Lee, Victor Ho Fun; Lu, Daru; Liu, Jianjun; Jeon, Hyo-Sung; Hsiao, Chin-Fu; Sung, Jae Sook; Kim, Jin Hee; Gao, Yu-Tang; Tsai, Ying-Huang; Jung, Yoo Jin; Guo, Huan; Hu, Zhibin; Hutchinson, Amy; Wang, Wen-Chang; Klein, Robert; Chung, Charles C; Oh, In-Jae; Chen, Kuan-Yu; Berndt, Sonja I; He, Xingzhou; Wu, Wei; Chang, Jiang; Zhang, Xu-Chao; Huang, Ming-Shyan; Zheng, Hong; Wang, Junwen; Zhao, Xueying; Li, Yuqing; Choi, Jin Eun; Su, Wu-Chou; Park, Kyong Hwa; Sung, Sook Whan; Shu, Xiao-Ou; Chen, Yuh-Min; Liu, Li; Kang, Chang Hyun; Hu, Lingmin; Chen, Chung-Hsing; Pao, William; Kim, Young-Chul; Yang, Tsung-Ying; Xu, Jun; Guan, Peng; Tan, Wen; Su, Jian; Wang, Chih-Liang; Li, Haixin; Sihoe, Alan Dart Loon; Zhao, Zhenhong; Chen, Ying; Choi, Yi Young; Hung, Jen-Yu; Kim, Jun Suk; Yoon, Ho-Il; Cai, Qiuyin; Lin, Chien-Chung; Park, In Kyu; Xu, Ping; Dong, Jing; Kim, Christopher; He, Qincheng; Perng, Reury-Perng; Kohno, Takashi; Kweon, Sun-Seog; Chen, Chih-Yi; Vermeulen, Roel; Wu, Junjie; Lim, Wei-Yen; Chen, Kun-Chieh; Chow, Wong-Ho; Ji, Bu-Tian; Chan, John K C; Chu, Minjie; Li1, Yao-Jen; Yokota, Jun; Li, Jihua; Chen, Hongyan; Xiang, Yong-Bing; Yu, Chong-Jen; Kunitoh, Hideo; Wu, Guoping; Jin, Li; Lo, Yen-Li; Shiraishi, Kouya; Chen, Ying-Hsiang; Lin, Hsien-Chih; Wu, Tangchun; Wu, Yi-Long; Yang, Pan-Chyr; Zhou, Baosen; Shin, Min-Ho; Fraumeni, Joseph F; Lin, Dongxin; Chanock, Stephen J; Rothman, Nathaniel

    2014-01-01

    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 China, South Korea, Japan, Singapore, Taiwan, and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10-6) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10-18), 6q22.2 (rs9387478, P = 4.14 × 10-10) and 6p21.32 (rs2395185, P = 9.51 × 10-9). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking. PMID:23143601

  13. A novel method, digital genome scanning detects KRAS gene amplification in gastric cancers: involvement of overexpressed wild-type KRAS in downstream signaling and cancer cell growth

    Directory of Open Access Journals (Sweden)

    Yanagihara Kazuyoshi

    2009-06-01

    Full Text Available Abstract Background Gastric cancer is the third most common malignancy affecting the general population worldwide. Aberrant activation of KRAS is a key factor in the development of many types of tumor, however, oncogenic mutations of KRAS are infrequent in gastric cancer. We have developed a novel quantitative method of analysis of DNA copy number, termed digital genome scanning (DGS, which is based on the enumeration of short restriction fragments, and does not involve PCR or hybridization. In the current study, we used DGS to survey copy-number alterations in gastric cancer cells. Methods DGS of gastric cancer cell lines was performed using the sequences of 5000 to 15000 restriction fragments. We screened 20 gastric cancer cell lines and 86 primary gastric tumors for KRAS amplification by quantitative PCR, and investigated KRAS amplification at the DNA, mRNA and protein levels by mutational analysis, real-time PCR, immunoblot analysis, GTP-RAS pull-down assay and immunohistochemical analysis. The effect of KRAS knock-down on the activation of p44/42 MAP kinase and AKT and on cell growth were examined by immunoblot and colorimetric assay, respectively. Results DGS analysis of the HSC45 gastric cancer cell line revealed the amplification of a 500-kb region on chromosome 12p12.1, which contains the KRAS gene locus. Amplification of the KRAS locus was detected in 15% (3/20 of gastric cancer cell lines (8–18-fold amplification and 4.7% (4/86 of primary gastric tumors (8–50-fold amplification. KRAS mutations were identified in two of the three cell lines in which KRAS was amplified, but were not detected in any of the primary tumors. Overexpression of KRAS protein correlated directly with increased KRAS copy number. The level of GTP-bound KRAS was elevated following serum stimulation in cells with amplified wild-type KRAS, but not in cells with amplified mutant KRAS. Knock-down of KRAS in gastric cancer cells that carried amplified wild

  14. A novel method, digital genome scanning detects KRAS gene amplification in gastric cancers: involvement of overexpressed wild-type KRAS in downstream signaling and cancer cell growth

    International Nuclear Information System (INIS)

    Gastric cancer is the third most common malignancy affecting the general population worldwide. Aberrant activation of KRAS is a key factor in the development of many types of tumor, however, oncogenic mutations of KRAS are infrequent in gastric cancer. We have developed a novel quantitative method of analysis of DNA copy number, termed digital genome scanning (DGS), which is based on the enumeration of short restriction fragments, and does not involve PCR or hybridization. In the current study, we used DGS to survey copy-number alterations in gastric cancer cells. DGS of gastric cancer cell lines was performed using the sequences of 5000 to 15000 restriction fragments. We screened 20 gastric cancer cell lines and 86 primary gastric tumors for KRAS amplification by quantitative PCR, and investigated KRAS amplification at the DNA, mRNA and protein levels by mutational analysis, real-time PCR, immunoblot analysis, GTP-RAS pull-down assay and immunohistochemical analysis. The effect of KRAS knock-down on the activation of p44/42 MAP kinase and AKT and on cell growth were examined by immunoblot and colorimetric assay, respectively. DGS analysis of the HSC45 gastric cancer cell line revealed the amplification of a 500-kb region on chromosome 12p12.1, which contains the KRAS gene locus. Amplification of the KRAS locus was detected in 15% (3/20) of gastric cancer cell lines (8–18-fold amplification) and 4.7% (4/86) of primary gastric tumors (8–50-fold amplification). KRAS mutations were identified in two of the three cell lines in which KRAS was amplified, but were not detected in any of the primary tumors. Overexpression of KRAS protein correlated directly with increased KRAS copy number. The level of GTP-bound KRAS was elevated following serum stimulation in cells with amplified wild-type KRAS, but not in cells with amplified mutant KRAS. Knock-down of KRAS in gastric cancer cells that carried amplified wild-type KRAS resulted in the inhibition of cell growth and

  15. Genomic Characterization of High-Grade Serous Ovarian Cancer: Dissecting Its Molecular Heterogeneity as a Road Towards Effective Therapeutic Strategies.

    Science.gov (United States)

    Mittempergher, Lorenza

    2016-07-01

    High-grade serous ovarian carcinoma (HGSOC) accounts for the majority of the ovarian cancer deaths, but over the last years little improvement in overall survival has been achieved. HGSOC is a molecularly and clinically heterogeneous disease. At genomic level, it represents a C-class malignancy having frequent gene losses (NF1, RB1, PTEN) and gains (CCNE1, MYC). HGSOC shows a simple mutational profile with TP53 nearly always mutated and with other genes mutated at low frequency. Importantly, 50 % of all HGSOCs have genetic features indicating a homologous recombination (HR) deficiency. HR deficient tumors are highly sensitive to PARP inhibitor anticancer agents, which exhibit synthetic lethality with a defective HR pathway. Transcriptionally, HGSOCs can be grouped into different molecular subtypes with distinct biology and prognosis. Molecular stratification of HGSOC based on these genomic features may result in improved therapeutic strategies. PMID:27241520

  16. A genomic and transcriptomic approach for a differential diagnosis between primary and secondary ovarian carcinomas in patients with a previous history of breast cancer

    International Nuclear Information System (INIS)

    The distinction between primary and secondary ovarian tumors may be challenging for pathologists. The purpose of the present work was to develop genomic and transcriptomic tools to further refine the pathological diagnosis of ovarian tumors after a previous history of breast cancer. Sixteen paired breast-ovary tumors from patients with a former diagnosis of breast cancer were collected. The genomic profiles of paired tumors were analyzed using the Affymetrix GeneChip® Mapping 50 K Xba Array or Genome-Wide Human SNP Array 6.0 (for one pair), and the data were normalized with ITALICS (ITerative and Alternative normaLIzation and Copy number calling for affymetrix Snp arrays) algorithm or Partek Genomic Suite, respectively. The transcriptome of paired samples was analyzed using Affymetrix GeneChip® Human Genome U133 Plus 2.0 Arrays, and the data were normalized with gc-Robust Multi-array Average (gcRMA) algorithm. A hierarchical clustering of these samples was performed, combined with a dataset of well-identified primary and secondary ovarian tumors. In 12 of the 16 paired tumors analyzed, the comparison of genomic profiles confirmed the pathological diagnosis of primary ovarian tumor (n = 5) or metastasis of breast cancer (n = 7). Among four cases with uncertain pathological diagnosis, genomic profiles were clearly distinct between the ovarian and breast tumors in two pairs, thus indicating primary ovarian carcinomas, and showed common patterns in the two others, indicating metastases from breast cancer. In all pairs, the result of the transcriptomic analysis was concordant with that of the genomic analysis. In patients with ovarian carcinoma and a previous history of breast cancer, SNP array analysis can be used to distinguish primary and secondary ovarian tumors. Transcriptomic analysis may be used when primary breast tissue specimen is not available

  17. Genomic alterations in BCL2L1 and DLC1 contribute to drug sensitivity in gastric cancer.

    Science.gov (United States)

    Park, Hansoo; Cho, Sung-Yup; Kim, Hyerim; Na, Deukchae; Han, Jee Yun; Chae, Jeesoo; Park, Changho; Park, Ok-Kyoung; Min, Seoyeon; Kang, Jinjoo; Choi, Boram; Min, Jimin; Kwon, Jee Young; Suh, Yun-Suhk; Kong, Seong-Ho; Lee, Hyuk-Joon; Liu, Edison T; Kim, Jong-Il; Kim, Sunghoon; Yang, Han-Kwang; Lee, Charles

    2015-10-01

    Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. Recent high-throughput analyses of genomic alterations revealed several driver genes and altered pathways in GC. However, therapeutic applications from genomic data are limited, largely as a result of the lack of druggable molecular targets and preclinical models for drug selection. To identify new therapeutic targets for GC, we performed array comparative genomic hybridization (aCGH) of DNA from 103 patients with GC for copy number alteration (CNA) analysis, and whole-exome sequencing from 55 GCs from the same patients for mutation profiling. Pathway analysis showed recurrent alterations in the Wnt signaling [APC, CTNNB1, and DLC1 (deleted in liver cancer 1)], ErbB signaling (ERBB2, PIK3CA, and KRAS), and p53 signaling/apoptosis [TP53 and BCL2L1 (BCL2-like 1)] pathways. In 18.4% of GC cases (19/103), amplification of the antiapoptotic gene BCL2L1 was observed, and subsequently a BCL2L1 inhibitor was shown to markedly decrease cell viability in BCL2L1-amplified cell lines and in similarly altered patient-derived GC xenografts, especially when combined with other chemotherapeutic agents. In 10.9% of cases (6/55), mutations in DLC1 were found and were also shown to confer a growth advantage for these cells via activation of Rho-ROCK signaling, rendering these cells more susceptible to a ROCK inhibitor. Taken together, our study implicates BCL2L1 and DLC1 as potential druggable targets for specific subsets of GC cases. PMID:26401016

  18. Elevated levels of adaption in Helicobacter pylori genomes from Japan; a link to higher incidences of gastric cancer?

    Science.gov (United States)

    Soto-Girón, Maria Juliana; Ospina, Oscar E; Massey, Steven Edward

    2015-01-01

    Helicobacter pylori is a bacterium that lives in the human stomach and is a major risk factor for gastric cancer and ulcers. H.pylori is host dependent and has been carried with human populations around the world after their departure from Africa. We wished to investigate how H.pylori has coevolved with its host during that time, focusing on strains from Japanese and European populations, given that gastric cancer incidence is high in Japanese populations, while low in European. A positive selection analysis of eight H.pylori genomes was conducted, using maximum likelihood based pairwise comparisons in order to maximize the number of strain-specific genes included in the study. Using the genic Ka/Ks ratio, comparisons of four Japanese H.pylori genomes suggests 25-34 genes under positive selection, while four European H.pylori genomes suggests 16-21 genes; few of the genes identified were in common between lineages. Of the identified genes which were annotated, 38% possessed homologs associated with pathogenicity and / or host adaptation, consistent with their involvement in a coevolutionary 'arms race' with the host. Given the efficacy of identifying host interaction factors de novo, in the absence of functionally annotated homologs our evolutionary approach may have value in identifying novel genes which H.pylori employs to interact with the human gut environment. In addition, the larger number of genes inferred as being under positive selection in Japanese strains compared to European implies a stronger overall adaptive pressure, potentially resulting from an elevated immune response which may be linked to increased inflammation, an initial stage in the development of gastric cancer. PMID:25788149

  19. Genome-wide identification of genes with amplification and/or fusion in small cell lung cancer

    OpenAIRE

    Iwakawa, Reika; Takenaka, Masataka; Kohno, Takashi; Shimada, Yoko; Totoki, Yasushi; Shibata, Tatsuhiro; Tsuta, Koji; Nishikawa, Ryo; Noguchi, Masayuki; Sato-Otsubo, Aiko; Ogawa, Seishi; Yokota, Jun

    2013-01-01

    To obtain a landscape of gross genetic alterations in small cell lung cancer (SCLC), genome-wide copy number analysis and whole-transcriptome sequencing were performed in 58 and 42 SCLCs, respectively. Focal amplification of known oncogene loci, MYCL1 (1p34.2), MYCN (2p24.3), and MYC (8q24.21), was frequently and mutually exclusively detected. MYCL1 and MYC were co-amplified with other regions on either the same or the different chromosome in several cases. In addition, the 9p24.1 region was ...

  20. An anatomy precourse enhances student learning in veterinary anatomy.

    Science.gov (United States)

    McNulty, Margaret A; Stevens-Sparks, Cathryn; Taboada, Joseph; Daniel, Annie; Lazarus, Michelle D

    2016-07-01

    Veterinary anatomy is often a source of trepidation for many students. Currently professional veterinary programs, similar to medical curricula, within the United States have no admission requirements for anatomy as a prerequisite course. The purpose of the current study was to evaluate the impact of a week-long precourse in veterinary anatomy on both objective student performance and subjective student perceptions of the precourse educational methods. Incoming first year veterinary students in the Louisiana State University School of Veterinary Medicine professional curriculum were asked to participate in a free precourse before the start of the semester, covering the musculoskeletal structures of the canine thoracic limb. Students learned the material either via dissection only, instructor-led demonstrations only, or a combination of both techniques. Outcome measures included student performance on examinations throughout the first anatomy course of the professional curriculum as compared with those who did not participate in the precourse. This study found that those who participated in the precourse did significantly better on examinations within the professional anatomy course compared with those who did not participate. Notably, this significant improvement was also identified on the examination where both groups were exposed to the material for the first time together, indicating that exposure to a small portion of veterinary anatomy can impact learning of anatomical structures beyond the immediate scope of the material previously learned. Subjective data evaluation indicated that the precourse was well received and students preferred guided learning via demonstrations in addition to dissection as opposed to either method alone. Anat Sci Educ 9: 344-356. © 2015 American Association of Anatomists. PMID:26669269