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Sample records for lynch creek calwater

  1. Calwater

    Data.gov (United States)

    California Natural Resource Agency — California Spatial Information System (CaSIL) is a project designed to improve access to geo-spatial and geo-spatial related data information throughout the state of...

  2. Lynching Luther

    DEFF Research Database (Denmark)

    Backe, Hans-Joachim

    2016-01-01

    , cerebral detective – two character-types traditionally rather juxtaposed as irreconcilable opposites. In this fashion, the overall story arc meshes together elements from Thomas Harris-style serial killer fiction and intuitive detection in the tradition of George Simenon’s Maigret. Similarly......, the individual episodes oscillate between carefully plotted psychology and lurid plot-holes. In other words: taken at face value, Luther is as interesting as it is messy. This paper proposes a reading of Luther that reconciles its many inconsistencies by treating it as if it was a David Lynch movie. If one...

  3. Mike Lynch

    DEFF Research Database (Denmark)

    Horst, Maja; Irwin, Alan

    associated with this position and especially its relationship to STS traditions of policy relevance and engagement. What does it mean for STS to do its job? Or rather, what does it mean for us to do our jobs? Taking inspiration both from Lynch’s published work and the different ways he has performed his STS...... jobs, this presentation will discuss the relationship between vacation, work, professional ethos and personal contribution in the context of STS.......In ’Science as a vacation’, Michael Lynch argues that ’STS might aim for something other than the serious job of doing business’. In so doing, he makes a strong case for an STS that does not aim to be useful but instead does ‘its own job’. In our presentation, we will explore some of the challenges...

  4. Extracolonic Manifestations of Lynch Syndrome

    OpenAIRE

    Bansidhar, Brian J.

    2012-01-01

    Lynch syndrome has classically been defined by several predominant malignancies. Initial clinical criteria for diagnosis of Lynch syndrome would miss 40% of affected individuals. As time has passed, our understanding of Lynch syndrome has evolved and will continue to do so. The number of cancer types that are included in the Lynch phenotype is growing. This has allowed clinicians to redefine Lynch syndrome, at risk populations, screening needs, and diagnostic criteria. Inclusion of extracolon...

  5. Lynch syndrome: the patients' perspective

    NARCIS (Netherlands)

    Seppen, Jurgen; Bruzzone, Linda

    2013-01-01

    People with Lynch syndrome have a high lifetime risk for the development of colorectal, endometrial and several other types of cancer. Lynch syndrome is caused by germline mutations in genes encoding DNA mismatch repair proteins. In this review, issues that concern Lynch patients are highlighted

  6. Diagnosing Lynch Syndrome

    LENUS (Irish Health Repository)

    Gleeson, J

    2016-11-01

    Lynch Syndrome, also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC), is a hereditary condition that increases an individual’s risk of developing a constellation of cancers. These most commonly arise in the colon, but also involve other solid organs such as the endometrium and ovaries in women, the stomach, brain and the skin. Ireland’s small population offers an opportunity to identify all those with Lynch Syndrome (LS) in the country, which would represent a powerful preventive opportunity to meaningfully impact on the incidence of cancer in Ireland.

  7. CalWater 2 - Precipitation, Aerosols, and Pacific Atmospheric Rivers Experiment

    Science.gov (United States)

    Spackman, J. R.; Ralph, F. M.; Prather, K. A.; Cayan, D. R.; DeMott, P. J.; Dettinger, M. D.; Fairall, C. W.; Leung, L. R.; Rosenfeld, D.; Rutledge, S. A.; Waliser, D. E.; White, A. B.

    2014-12-01

    Emerging research has identified two phenomena that play key roles in the variability of the water supply and the incidence of extreme precipitation events along the West Coast of the United States. These phenomena include the role of (1) atmospheric rivers (ARs) in delivering much of the precipitation associated with major storms along the U.S. West Coast, and (2) aerosols—from local sources as well as those transported from remote continents—and their modulating effects on western U.S. precipitation. A better understanding of these processes is needed to reduce uncertainties in weather predictions and climate projections of extreme precipitation and its effects, including the provision of beneficial water supply. This presentation summarizes the science objectives and strategies to address gaps associated with (1) the evolution and structure of ARs including cloud and precipitation processes and air-sea interaction, and (2) aerosol interaction with ARs and the impact on precipitation, including locally-generated aerosol effects on orographic precipitation along the U.S. West Coast. Observations are proposed for multiple winter seasons as part of a 5-year broad interagency vision referred to as CalWater 2 to address these science gaps (http://esrl.noaa.gov/psd/calwater). In January-February 2015, a field campaign has been planned consisting of a targeted set of aircraft and ship-based measurements and associated evaluation of data in near-shore regions of California and in the eastern Pacific. In close coordination with NOAA, DOE's Atmospheric Radiation Measurement (ARM) program is also contributing air and shipborne facilities for ACAPEX (ARM Cloud Aerosol and Precipitation Experiment), a DOE-sponsored study complementing CalWater 2. Ground-based measurements from NOAA's HydroMeteorological Testbed (HMT) network in California and aerosol chemical instrumentation at Bodega Bay, California have been designed to add important near surface-level context for the

  8. CalWater 2 - Precipitation, Aerosols, and Pacific Atmospheric Rivers Experiment

    Science.gov (United States)

    Spackman, Ryan; Ralph, Marty; Prather, Kim; Cayan, Dan; DeMott, Paul; Dettinger, Mike; Fairall, Chris; Leung, Ruby; Rosenfeld, Daniel; Rutledge, Steven; Waliser, Duane; White, Allen

    2014-05-01

    Emerging research has identified two phenomena that play key roles in the variability of the water supply and the incidence of extreme precipitation events along the West Coast of the United States. These phenomena include the role of (1) atmospheric rivers (ARs) in delivering much of the precipitation associated with major storms along the U.S. West Coast, and (2) aerosols—from local sources as well as those transported from remote continents—and their modulating effects on western U.S. precipitation. A better understanding of these processes is needed to reduce uncertainties in weather predictions and climate projections of extreme precipitation and its effects, including the provision of beneficial water supply. This presentation summarizes science gaps associated with (1) the evolution and structure of ARs including cloud and precipitation processes and air-sea interaction, and (2) aerosol interaction with ARs and the impact on precipitation, including locally-generated aerosol effects on orographic precipitation along the U.S. West Coast. Observations are proposed for multiple winter seasons as part of a 5-year broad interagency vision referred to as CalWater 2 to address these science gaps (http://esrl.noaa.gov/psd/calwater). In the near term, a science investigation is being planned including a targeted set of aircraft and ship-based measurements and associated evaluation of data in near-shore regions of California and in the eastern Pacific for an intensive observing period between January 2015 and March 2015. DOE's Atmospheric Radiation Measurement (ARM) program and NOAA are coordinating on deployment of airborne and ship-borne facilities for this period in a DOE-sponsored study called ACAPEX (ARM Cloud Aerosol and Precipitation Experiment) to complement CalWater 2. The motivation for this major study is based on findings that have emerged in the last few years from airborne and ground-based studies including CalWater and NOAA's HydroMeterology Testbed

  9. Lynch Syndrome: An Updated Review

    Directory of Open Access Journals (Sweden)

    Rishabh Sehgal

    2014-06-01

    Full Text Available Lynch syndrome is one of the most common cancer susceptibility syndromes. Individuals with Lynch syndrome have a 50%–70% lifetime risk of colorectal cancer, 40%–60% risk of endometrial cancer, and increased risks of several other malignancies. It is caused by germline mutations in the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2. In a subset of patients, Lynch syndrome is caused by 3' end deletions of the EPCAM gene, which can lead to epigenetic silencing of the closely linked MSH2. Relying solely on age and family history based criteria inaccurately identifies eligibility for Lynch syndrome screening or testing in 25%–70% of cases. There has been a steady increase in Lynch syndrome tumor screening programs since 2000 and institutions are rapidly adopting a universal screening approach to identify the patients that would benefit from genetic counseling and germline testing. These include microsatellite instability testing and/or immunohistochemical testing to identify tumor mismatch repair deficiencies. However, universal screening is not standard across institutions. Furthermore, variation exists regarding the optimum method for tracking and disclosing results. In this review, we summarize traditional screening criteria for Lynch syndrome, and discuss universal screening methods. International guidelines are necessary to standardize Lynch syndrome high-risk clinics.

  10. Lynch syndrome-associated neoplasms

    DEFF Research Database (Denmark)

    Shia, Jinru; Holck, Susanne; Depetris, Giovanni

    2013-01-01

    It was a century ago that Warthin, a pathologist, first described the clinical condition now known as Lynch syndrome. One hundred years later, our understanding of this syndrome has advanced significantly. Much of the progress took place over the last 25 years and was marked by a series...... of interacting developments from the disciplines of clinical oncology, pathology, and molecular genetics, with each development serving to guide or enhance the next. The advancement of our understanding about the pathology of Lynch syndrome associated tumors exemplifies such intimate interplay among disciplines....... Today, accumulative knowledge has enabled surgical pathologists to detect tumors that are likely to be associated with Lynch syndrome, and the pathologist is playing an increasingly more important role in the care of these patients. The pathologist's ability is afforded primarily by information gained...

  11. Genetics Home Reference: Lynch syndrome

    Science.gov (United States)

    ... Genetic Changes Variations in the MLH1 , MSH2 , MSH6 , PMS2 , or EPCAM gene increase the risk of developing Lynch syndrome . The MLH1 , MSH2 , MSH6 , and PMS2 genes are involved in the repair of errors ...

  12. CCN and IN Effects on Cloud Properties and Precipitation - Case Studies from CalWater 2011

    Science.gov (United States)

    Fan, J.; Leung, L.; Comstock, J. M.; Tomlinson, J. M.

    2011-12-01

    Aerosols in the atmosphere can serve as cloud condensation nuclei (CCN) and ice nuclei (IN) to modify cloud microphysical processes, which could potentially change the location, intensity, and type of precipitation. Dust aerosols are often observed over California in the Sierra Nevada Mountains in winter/spring, associated with long-range transport from Asia. Although anthropogenic pollution has been postulated to contribute to reduction of precipitation in the Sierra Nevada Mountains, the effects of dust aerosols on the winter clouds and precipitation has not been examined in detail particularly with model simulations. We incorporate recent progress in ice nucleation parameterizations to link dust with ice crystal formation in a spectral-bin cloud microphysical model coupled with WRF, to exclusively look into how dust can possibly affect cloud properties and precipitation type and intensity. Simulations are carried out for two cases under different environmental conditions with atmospheric river (AR) and Sierra barrier jet (SBJ) from the CalWater 2011 field campaign. It is shown that increasing IN concentrations or adding a dust layer at 4-6 km as IN enhances surface rain and snow due to enhanced production of ice and snow in clouds. However, increasing CCN suppresses surface rain and snow, and significantly redistributes surface precipitation upwind and downwind of the mountains, with important implication to improving our understanding of the impacts of aerosols on orographic precipitation and water supply in the region.

  13. Milestones of Lynch syndrome: 1895-2015.

    Science.gov (United States)

    Lynch, Henry T; Snyder, Carrie L; Shaw, Trudy G; Heinen, Christopher D; Hitchins, Megan P

    2015-03-01

    Lynch syndrome, which is now recognized as the most common hereditary colorectal cancer condition, is characterized by the predisposition to a spectrum of cancers, primarily colorectal cancer and endometrial cancer. We chronicle over a century of discoveries that revolutionized the diagnosis and clinical management of Lynch syndrome, beginning in 1895 with Warthin's observations of familial cancer clusters, through the clinical era led by Lynch and the genetic era heralded by the discovery of causative mutations in mismatch repair (MMR) genes, to ongoing challenges.

  14. Lynch syndrome-related small intestinal adenocarcinomas.

    Science.gov (United States)

    Jun, Sun-Young; Lee, Eui-Jin; Kim, Mi-Ju; Chun, Sung Min; Bae, Young Kyung; Hong, Soon Uk; Choi, Jene; Kim, Joon Mee; Jang, Kee-Taek; Kim, Jung Yeon; Kim, Gwang Il; Jung, Soo Jin; Yoon, Ghilsuk; Hong, Seung-Mo

    2017-03-28

    Lynch syndrome is an autosomal-dominant disorder caused by defective DNA mismatch repair (MMR) genes and is associated with increased risk of malignancies in multiple organs. Small-intestinal adenocarcinomas are common initial manifestations of Lynch syndrome. To define the incidence and characteristics of Lynch syndrome-related small-intestinal adenocarcinomas, meticulous familial and clinical histories were obtained from 195 patients with small-intestinal adenocarcinoma, and MMR protein immunohistochemistry, microsatellite instability, MLH1 methylation, and germline mutational analyses were performed. Lynch syndrome was confirmed in eight patients (4%), all of whom had synchronous/metachronous malignancies without noticeable familial histories. Small-intestinal adenocarcinomas were the first clinical manifestation in 37% (3/8) of Lynch syndrome patients, and second malignancies developed within 5 years in 63% (5/8). The patients with accompanying Lynch syndrome were younger (≤50 years; P=0.04) and more likely to have mucinous adenocarcinomas (P=0.003), and tended to survive longer (P=0.11) than those with sporadic cases. A meticulous patient history taking, MMR protein immunolabeling, and germline MMR gene mutational analysis are important for the diagnosis of Lynch syndrome-related small-intestinal adenocarcinomas. Identifying Lynch syndrome in patients with small-intestinal adenocarcinoma can be beneficial for the early detection and treatment of additional Lynch syndrome-related cancers, especially in patients who are young or have mucinous adenocarcinomas.

  15. CalWater Field Studies Designed to Quantify the Roles of Atmospheric Rivers and Aerosols in Modulating U.S. West Coast Precipitation in a Changing Climate

    Energy Technology Data Exchange (ETDEWEB)

    Ralph, F. M.; Prather, K. A.; Cayan, D.; Spackman, J. R.; DeMott, P.; Dettinger, M.; Fairall, C.; Leung, R.; Rosenfeld, D.; Rutledge, S.; Waliser, D.; White, A. B.; Cordeira, J.; Martin, A.; Helly, J.; Intrieri, J.

    2016-07-01

    The variability of precipitation and water supply along the U.S. West Coast creates major challenges to the region’s economy and environment, as evidenced by the recent California drought. This variability is strongly influenced by atmospheric rivers (AR), which deliver much of the precipitation along the U.S. West Coast and can cause flooding, and by aerosols (from local sources and transported from remote continents and oceans) that modulate clouds and precipitation. A better understanding of these processes is needed to reduce uncertainties in weather predictions and climate projections of droughts and floods, both now and under changing climate conditions.To address these gaps a group of meteorologists, hydrologists, climate scientists, atmospheric chemists, and oceanographers have created an interdisciplinary research effort, with support from multiple agencies. From 2009-2011 a series of field campaigns (CalWater 1) collected atmospheric chemistry, cloud microphysics and meteorological measurements in California and associated modeling and diagnostic studies were carried out. Based on remaining gaps, a vision was developed to extend these studies offshore over the Eastern North Pacific and to enhance land based measurements from 2014-2018 (CalWater 2). The data set and selected results from CalWater 1 are summarized here. The goals of CalWater-2, and measurements to date, are then described. CalWater is producing new findings and exploring new technologies to evaluate and improve global climate models and their regional performance and to develop tools supporting water and hydropower management. These advances also have potential to enhance hazard mitigation by improving near-term weather prediction and subseasonal and seasonal outlooks.

  16. Modernization and Lynching in the New South

    Directory of Open Access Journals (Sweden)

    Mattias Smångs

    2016-09-01

    Full Text Available This article evaluates an emerging body of historical scholarship that challenges prevailing views of the primacy of rural conditions in southern lynching by positing that it was symbiotically associated with the processes of modernization underway in the region in the decades around 1900. Statistical analyses of lynching data that differentiate among events according to communal participation, support, and ceremony in Georgia and Louisiana from 1882 to 1930 and local-level indices of modernization (urbanization, rural depopulation, industrialization, agricultural commercialization, and dissolution of traditional family roles yield results that both support and contradict such a modernization thesis of lynching. The findings imply that the consequences of the social transformation in the South coinciding with the lynching era were not uniform throughout the region with regard to racial conflict and violence and that broad arguments proposing an intrinsic connection between modernization and lynchings therefore are overstated.

  17. Diagnosis of Lynch Syndrome: Genetic Testing Identifies a Potentially Deadly Hereditary Disease

    Science.gov (United States)

    ... of Lynch Syndrome Follow us A Diagnosis of Lynch Syndrome Genetic testing identifies a potentially deadly hereditary disease ... helped Jack learn what was wrong. Jack had Lynch Syndrome—an inherited disorder. Lynch Syndrome increases the risk ...

  18. Clinicopathological comparison of colorectal and endometrial carcinomas in patients with Lynch-like syndrome versus patients with Lynch syndrome.

    Science.gov (United States)

    Mas-Moya, Jenny; Dudley, Beth; Brand, Randall E; Thull, Darcy; Bahary, Nathan; Nikiforova, Marina N; Pai, Reetesh K

    2015-11-01

    Screening for DNA mismatch repair (MMR) deficiency in colorectal and endometrial carcinomas identifies patients at risk for Lynch syndrome. Some patients with MMR-deficient tumors have no evidence of a germline mutation and have been described as having Lynch-like syndrome. We compared the clinicopathological features of colorectal and endometrial carcinomas in patients with Lynch-like syndrome and Lynch syndrome. Universal screening identified 356 (10.6%) of 3352 patients with colorectal carcinoma and 72 (33%) of 215 patients with endometrial carcinoma with deficient DNA MMR. Sixty-six patients underwent germline mutation analysis with 45 patients (68%) having evidence of a germline MMR gene mutation confirming Lynch syndrome and 21 patients (32%) having Lynch-like syndrome with no evidence of a germline mutation. Most patients with Lynch-like syndrome had carcinoma involving the right colon compared to patients with Lynch syndrome (93% versus 45%; P Lynch syndrome confirmed by germline mutation analysis. Synchronous or metachronous Lynch syndrome-associated carcinoma was more frequently identified in patients with Lynch syndrome compared to Lynch-like syndrome (38% versus 7%; P = .04). There were no significant differences in clinicopathological variables between patients with Lynch-like syndrome and Lynch syndrome with endometrial carcinoma. In summary, 32% of patients with MMR deficiency concerning Lynch syndrome will have Lynch-like syndrome. Our results demonstrate that patients with Lynch-like syndrome are more likely to have right-sided colorectal carcinoma, less likely to have synchronous or metachronous Lynch syndrome-associated carcinoma, and less likely to demonstrate isolated loss of MSH6 expression within their tumor. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Lynch Syndrome: Genomics Update and Imaging Review.

    Science.gov (United States)

    Cox, Veronica L; Saeed Bamashmos, Anas A; Foo, Wai Chin; Gupta, Shiva; Yedururi, Sireesha; Garg, Naveen; Kang, Hyunseon Christine

    2018-01-01

    Lynch syndrome is the most common hereditary cancer syndrome, the most common cause of heritable colorectal cancer, and the only known heritable cause of endometrial cancer. Other cancers associated with Lynch syndrome include cancers of the ovary, stomach, urothelial tract, and small bowel, and less frequently, cancers of the brain, biliary tract, pancreas, and prostate. The oncogenic tendency of Lynch syndrome stems from a set of genomic alterations of mismatch repair proteins. Defunct mismatch repair proteins cause unusually high instability of regions of the genome called microsatellites. Over time, the accumulation of mutations in microsatellites and elsewhere in the genome can affect the production of important cellular proteins, spurring tumorigenesis. Universal testing of colorectal tumors for microsatellite instability (MSI) is now recommended to (a) prevent cases of Lynch syndrome being missed owing to the use of clinical criteria alone, (b) reduce morbidity and mortality among the relatives of affected individuals, and (c) guide management decisions. Organ-specific cancer risks and associated screening paradigms vary according to the sex of the affected individual and the type of germline DNA alteration causing the MSI. Furthermore, Lynch syndrome-associated cancers have different pathologic, radiologic, and clinical features compared with their sporadic counterparts. Most notably, Lynch syndrome-associated tumors tend to be more indolent than non-Lynch syndrome-associated neoplasms and thus may respond differently to traditional chemotherapy regimens. The high MSI in cases of colorectal cancer reflects a difference in the biologic features of the tumor, possibly with a unique susceptibility to immunotherapy. © RSNA, 2018.

  20. Role for Genetic Anticipation in Lynch Syndrome

    DEFF Research Database (Denmark)

    Nilbert, Mef; Timshel, Susanne; Bernstein, Inge

    2009-01-01

    PURPOSE: Anticipation (ie, an earlier age at onset in successive generations) is linked to repeat expansion in neurodegenerative syndromes, whereas its role in hereditary cancer is unclear. We assessed anticipation in Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]), in which DNA...... mismatch repair (MMR) defects cause early and accelerated tumor development with a broad tumor spectrum. PATIENTS AND METHODS: In the population-based Danish HNPCC registry, 407 MMR gene mutation carriers who had developed cancer associated with Lynch syndrome, were identified. These individuals formed 290....... The effect remained when cancers diagnosed at surveillance were excluded, applied to maternal as well as paternal inheritance, and was independent of the MMR gene mutated. CONCLUSION: The effect from anticipation demonstrated in this large, population-based Lynch syndrome cohort underscores the need...

  1. Lynch syndrome: still not a familiar picture

    Directory of Open Access Journals (Sweden)

    Hes Frederik J

    2008-02-01

    Full Text Available Abstract Background Germ line mutations in mismatch repair genes underlie Lynch syndrome and predispose carriers for colorectal carcinoma and malignancies in many other organ systems. Case presentation A large Lynch syndrome family with 15 affected family members and involvement in 7 organs is reported. It illustrates a lack of awareness and knowledge about this hereditary tumor syndrome among doctors as well as patients. None of the described family members underwent presymptomatic screening on the basis of the family history. Conclusion Hereditary features, like young age at diagnosis, multiple tumors in multiple organs and a positive family history, should lead to timely referral of suspected cases for genetic counseling and diagnostics. For Lynch syndrome, these features can be found in the Amsterdam and Bethesda criteria. Subsequently, early identification of mutation carriers might have diminished, at least in part, the high and early morbidity and mortality observed in this family.

  2. The Lynch syndrome: a management dilemma.

    Science.gov (United States)

    Palumbo, Piergaspare; Amatucci, Chiara; Perotti, Bruno; Dezzi, Claudia; Girolami, Marco; Illuminati, Giulio; Angelici, Alberto M

    2013-05-01

    The case of a familial Lynch syndrome is reported. The criteria for early diagnosis, management and surveillance are briefly reviewed. A germline mutation of genes responsible for mismatch repair is at the basis of the Lynch syndrome. Carriers are predisposed to colorectal cancer and other tumors. Two members of the presently reported family developed colorectal cancer, whereas two others developed other neoplasms. The syndrome was confirmed in members of the same family with appropriate genetic workup. Clinical examination and endoscopy were consequently scheduled once-a-year. Given the high risk of neoplastic disease, such yearly controls can be proposed as the standard follow-up of this condition.

  3. Twenty hanging Dolls and a Lynching:

    DEFF Research Database (Denmark)

    Risør, Helene

    2010-01-01

    The article sets lynching of presumed criminals in the city of El Alto, Bolivia, in relation to both everyday experiences of insecurity about crime and violence and the enactment of neighborliness as a grounded notion of citizenship. Focusing on the experience and management of insecurity and its...

  4. Value-based healthcare in Lynch syndrome

    NARCIS (Netherlands)

    Hennink, Simone D; Hofland, N.; Gopie, J.P.; van der Kaa, C.; de Koning, K.; Nielsen, M.; Tops, C.; Morreau, H.; de Vos Tot Nederveen Cappel, W.H.; Langers, A.M.; Hardwick, J.C.; Gaarenstroom, K.N.; Tollenaar, R.A.; Veenendaal, R.A.; Tibben, A.; Wijnen, J.; van Heck, M.; van Asperen, C.; Roukema, J.A.; Hommes, D.W.; Hes, F.J.; Vasen, H.F.A.

    2013-01-01

    Lynch syndrome (LS), one of the most frequent forms of hereditary colorectal cancer (CRC), is caused by a defect in one of the mismatch repair (MMR) genes. Carriers of MMR defects have a strongly increased risk of developing CRC and endometrial cancer. Over the last few years, value-based healthcare

  5. 100 years lynch syndrome

    DEFF Research Database (Denmark)

    Bleiker, Eveline M A; Esplen, Mary Jane; Meiser, Bettina

    2013-01-01

    In the care of patients with Lynch Syndrome (LS), a range of psychosocial issues are encountered, which significantly affect patient outcomes. A brief historical background of 'psycho-onco-genetics' (the domain where psychology, oncology and genetics meet) in relation to LS is presented, followed...

  6. Genetic counseling and cascade genetic testing in Lynch syndrome.

    Science.gov (United States)

    Hampel, Heather

    2016-07-01

    Lynch syndrome is the most common cause of inherited colorectal and endometrial cancers. Individuals with Lynch syndrome have a 10-80 % lifetime risk for colorectal cancer and a 15-60 % lifetime risk for endometrial cancer. Both cancers are preventable through chemoprevention, intensive cancer surveillance, and risk-reducing surgery options. Efforts to identify as many individuals with Lynch syndrome as possible will prevent cancers and save lives. This includes the traditional cancer genetic counseling model whereby individuals with and without cancer are evaluated for a possible Lynch syndrome diagnosis based on their personal and family history of colon polyps and cancers. It also includes universal tumor screening for Lynch syndrome whereby all individuals with colorectal or endometrial cancer are screened for tumor features of Lynch syndrome at the time of diagnosis. Those with tumors suspicious for Lynch syndrome are referred for cancer genetic counseling regardless of their family history of cancer. This two approaches must be maximized to attain high patient reach. Finally, and perhaps most importantly, cascade testing among the at-risk relatives of those diagnosed with Lynch syndrome is critically important to maximize the diagnosis of individuals with Lynch syndrome. In fact, the cost-effectiveness of universal tumor screening for Lynch syndrome relies entirely on counseling and testing as many at-risk individuals as possible since young unaffected individuals stand to benefit the most from an early diagnosis of Lynch syndrome. This approach must be optimized to achieve high family reach. It will take a concerted effort from patients, clinicians and public health officials to improve current approaches to the diagnosis of Lynch syndrome and the prevention and treatment of Lynch syndrome-associated cancer but these lessons can be applied to other conditions as the ultimate example of personalized medicine.

  7. Hail creek

    Energy Technology Data Exchange (ETDEWEB)

    Chadwick, J.

    2005-09-01

    The paper examines the development of one of the largest coking coal deposits in the world. Hail Creek is 100 km west of Mackay and 35 km northeast of Nebo, Queensland and has proven opencut reserves of 195.6 as at December 2003. Coal processing stated in July 2003. The award winning project included construction of a coal handling and preparation plant, a railway, a village and offsite infrastructure and mine buildings and site services. Coal is mined by conventional dragline and truck/shovel techniques. 1 photo.

  8. Childhood cancers in families with and without Lynch syndrome.

    Science.gov (United States)

    Heath, John A; Reece, Jeanette C; Buchanan, Daniel D; Casey, Graham; Durno, Carol A; Gallinger, Steven; Haile, Robert W; Newcomb, Polly A; Potter, John D; Thibodeau, Stephen N; Le Marchand, Loïc; Lindor, Noralane M; Hopper, John L; Jenkins, Mark A; Win, Aung Ko

    2015-12-01

    Inheritance of a germline mutation in one of the DNA mismatch repair (MMR) genes or the EPCAM gene is associated with an increased risk of colorectal cancer, endometrial cancer, and other adult malignancies (Lynch syndrome). The risk of childhood cancers in Lynch syndrome families, however, is not well studied. Using data from the Colon Cancer Family Registry, we compared the proportion of childhood cancers (diagnosed before 18 years of age) in the first-, second-, and third-degree relatives of 781 probands with a pathogenic mutation in one of the MMR genes; MLH1 (n = 275), MSH2 (n = 342), MSH6 (n = 99), or PMS2 (n = 55) or in EPCAM (n = 10) (Lynch syndrome families), with that of 5073 probands with MMR-deficient colorectal cancer (non-Lynch syndrome families). There was no evidence of a difference in the proportion of relatives with a childhood cancer between Lynch syndrome families (41/17,230; 0.24%) and non-Lynch syndrome families (179/94,302; 0.19%; p = 0.19). Incidence rate of all childhood cancers was estimated to be 147 (95% CI 107-206) per million population per year in Lynch syndrome families and 115 (95% CI 99.1-134) per million population per year in non-Lynch syndrome families. There was no evidence for a significant increase in the risk of all childhood cancers, hematologic cancers, brain and central nervous system cancers, Lynch syndrome-associated cancers, or other cancers in Lynch syndrome families compared with non-Lynch syndrome families. Larger studies, however, are required to more accurately define the risk of specific individual childhood cancers in Lynch syndrome families.

  9. Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer

    Science.gov (United States)

    Carethers, John M; Stoffel, Elena M

    2015-01-01

    Hereditary non-polyposis colorectal cancer (HNPCC) was previously synonymous with Lynch syndrome; however, identification of the role of germline mutations in the DNA mismatch repair (MMR) genes has made it possible to differentiate Lynch syndrome from other conditions associated with familial colorectal cancer (CRC). Broadly, HNPCC may be dichotomized into conditions that demonstrate defective DNA MMR and microsatellite instability (MSI) vs those conditions that demonstrate intact DNA MMR. Conditions characterized by MMR deficient CRCs include Lynch syndrome (germline MMR mutation), Lynch-like syndrome (biallelic somatic MMR mutations), constitutional MMR deficiency syndrome (biallelic germline MMR mutations), and sporadic MSI CRC (somatic biallelic methylation of MLH1). HNPCC conditions with intact DNA MMR associated with familial CRC include polymerase proofreading associated polyposis and familial colorectal cancer type X. Although next generation sequencing technologies have elucidated the genetic cause for some HNPCC conditions, others remain genetically undefined. Differentiating between Lynch syndrome and the other HNPCC disorders has profound implications for cancer risk assessment and surveillance of affected patients and their at-risk relatives. Clinical suspicion coupled with molecular tumor analysis and testing for germline mutations can help differentiate the clinical mimicry within HNPCC and facilitate diagnosis and management. PMID:26309352

  10. Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer.

    Science.gov (United States)

    Carethers, John M; Stoffel, Elena M

    2015-08-21

    Hereditary non-polyposis colorectal cancer (HNPCC) was previously synonymous with Lynch syndrome; however, identification of the role of germline mutations in the DNA mismatch repair (MMR) genes has made it possible to differentiate Lynch syndrome from other conditions associated with familial colorectal cancer (CRC). Broadly, HNPCC may be dichotomized into conditions that demonstrate defective DNA MMR and microsatellite instability (MSI) vs those conditions that demonstrate intact DNA MMR. Conditions characterized by MMR deficient CRCs include Lynch syndrome (germline MMR mutation), Lynch-like syndrome (biallelic somatic MMR mutations), constitutional MMR deficiency syndrome (biallelic germline MMR mutations), and sporadic MSI CRC (somatic biallelic methylation of MLH1). HNPCC conditions with intact DNA MMR associated with familial CRC include polymerase proofreading associated polyposis and familial colorectal cancer type X. Although next generation sequencing technologies have elucidated the genetic cause for some HNPCC conditions, others remain genetically undefined. Differentiating between Lynch syndrome and the other HNPCC disorders has profound implications for cancer risk assessment and surveillance of affected patients and their at-risk relatives. Clinical suspicion coupled with molecular tumor analysis and testing for germline mutations can help differentiate the clinical mimicry within HNPCC and facilitate diagnosis and management.

  11. Lynch Syndrome: Female Genital Tract Cancer Diagnosis and Screening.

    Science.gov (United States)

    Mills, Anne M; Longacre, Teri A

    2016-06-01

    Lynch syndrome is responsible for approximately 5% of endometrial cancers and 1% of ovarian cancers. The molecular basis for Lynch syndrome is a heritable functional deficiency in the DNA mismatch repair system, typically due to a germline mutation. This review discusses the rationales and relative merits of current Lynch syndrome screening tests for endometrial and ovarian cancers and provides pathologists with an informed algorithmic approach to Lynch syndrome testing in gynecologic cancers. Pitfalls in test interpretation and strategies to resolve discordant test results are presented. The potential role for next-generation sequencing panels in future screening efforts is discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Merrill Lynch kavandab äridelegatsiooni visiiti Eestisse

    Index Scriptorium Estoniae

    2000-01-01

    Investeerimispanga Merrill Lynch eestvedamisel kavandatakse mais ärimeeste visiiti Eestisse, ütles Jüri Mõis, kes viibis New Yorgis toimunud Maailmapanga seminaril "Omavalitsused rahvusvahelistel kapitaliturgudel"

  13. Immunohistochemical Pitfalls: Common Mistakes in the Evaluation of Lynch Syndrome.

    Science.gov (United States)

    Markow, Michael; Chen, Wei; Frankel, Wendy L

    2017-12-01

    At least 15% of colorectal cancers diagnosed in the United States are deficient in mismatch repair mechanisms. Most of these are sporadic, but approximately 3% of colorectal cancers result from germline alterations in mismatch repair genes and represent Lynch syndrome. It is critical to identify patients with Lynch syndrome to institute appropriate screening and surveillance for patients and their families. Exclusion of Lynch syndrome in sporadic cases is equally important because it reduces anxiety for patients and prevents excessive spending on unnecessary surveillance. Immunohistochemistry is one of the most widely used screening tools for identifying patients with Lynch syndrome. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Genetic anticipation in Swedish Lynch syndrome families

    OpenAIRE

    von Salomé, Jenny; Boonstra, Philip S.; Karimi, Masoud; Silander, Gustav; Stenmark-Askmalm, Marie; Gebre-Medhin, Samuel; Aravidis, Christos; Nilbert, Mef; Lindblom, Annika; Lagerstedt-Robinson, Kristina

    2017-01-01

    Among hereditary colorectal cancer predisposing syndromes, Lynch syndrome (LS) caused by mutations in DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2 is the most common. Patients with LS have an increased risk of early onset colon and endometrial cancer, but also other tumors that generally have an earlier onset compared to the general population. However, age at first primary cancer varies within families and genetic anticipation, i.e. decreasing age at onset in successive generations, ha...

  15. Lynch Syndrome: A Primer for Urologists and Panel Recommendations.

    Science.gov (United States)

    Mork, Maureen; Hubosky, Scott G; Rouprêt, Morgan; Margulis, Vitaly; Raman, Jay; Lotan, Yair; O'Brien, Timothy; You, Nancy; Shariat, Shahrokh F; Matin, Surena F

    2015-07-01

    Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is a common genetic disease. The predisposition of patients with Lynch syndrome to urological cancer, particularly upper tract urothelial carcinoma, is underappreciated. Urologists may be involved in several aspects of care involving Lynch syndrome, including identifying undiagnosed patients, surveillance of those with established Lynch syndrome or screening family members, in addition to treating patients with Lynch syndrome in whom upper tract urothelial carcinoma develops. We sought to increase awareness in the urological community about Lynch syndrome and provide some guidance where little currently exists. Using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement we reviewed the available published literature and guidelines from 1998 to 2014 on Lynch syndrome and its association with upper tract urothelial carcinoma. Recommendations based on the literature and the consensus of expert opinion are provided. No randomized or prospective study has been done to evaluate Lynch syndrome in the setting of urological cancer. All data were based on retrospective studies. Lynch syndrome is an autosomal dominant genetic disease caused by germline mutations in 4 mismatch repair genes, leading to the accumulation of DNA errors in microsatellite regions. Upper tract urothelial carcinoma develops in up to 28% of patients with known Lynch syndrome. The diagnosis of Lynch syndrome is established by clinical criteria, tumor tissue testing and genetic evaluation. Urologists should suspect Lynch syndrome when a patient with upper tract urothelial carcinoma presents before age 60 years or meets the 3-2-1 rule. Screening patients with Lynch syndrome for upper tract urothelial carcinoma presents a particular challenge. While no ideal screening test exists, at a minimum routine urinalysis is recommended using the American Urological Association guideline of 3 or more red

  16. Three molecular pathways model colorectal carcinogenesis in Lynch syndrome.

    Science.gov (United States)

    Ahadova, Aysel; Gallon, Richard; Gebert, Johannes; Ballhausen, Alexej; Endris, Volker; Kirchner, Martina; Stenzinger, Albrecht; Burn, John; von Knebel Doeberitz, Magnus; Bläker, Hendrik; Kloor, Matthias

    2018-07-01

    Lynch syndrome is caused by germline mutations of DNA mismatch repair (MMR) genes. MMR deficiency has long been regarded as a secondary event in the pathogenesis of Lynch syndrome colorectal cancers. Recently, this concept has been challenged by the discovery of MMR-deficient crypt foci in the normal mucosa. We aimed to reconstruct colorectal carcinogenesis in Lynch syndrome by collecting molecular and histology evidence from Lynch syndrome adenomas and carcinomas. We determined the frequency of MMR deficiency in adenomas from Lynch syndrome mutation carriers by immunohistochemistry and by systematic literature analysis. To trace back the pathways of pathogenesis, histological growth patterns and mutational signatures were analyzed in Lynch syndrome colorectal cancers. Literature and immunohistochemistry analysis demonstrated MMR deficiency in 491 (76.7%) out of 640 adenomas (95% CI: 73.3% to 79.8%) from Lynch syndrome mutation carriers. Histologically normal MMR-deficient crypts were found directly adjacent to dysplastic adenoma tissue, proving their role as tumor precursors in Lynch syndrome. Accordingly, mutation signature analysis in Lynch colorectal cancers revealed that KRAS and APC mutations commonly occur after the onset of MMR deficiency. Tumors lacking evidence of polypous growth frequently presented with CTNNB1 and TP53 mutations. Our findings demonstrate that Lynch syndrome colorectal cancers can develop through three pathways, with MMR deficiency commonly representing an early and possibly initiating event. This underlines that targeting MMR-deficient cells by chemoprevention or vaccines against MMR deficiency-induced frameshift peptide neoantigens holds promise for tumor prevention in Lynch syndrome. © 2018 UICC.

  17. Locating inputs of freshwater to Lynch Cove, Hood Canal, Washington, using aerial infrared photography

    Science.gov (United States)

    Sheibley, Rich W.; Josberger, Edward G.; Chickadel, Chris

    2010-01-01

    The input of freshwater and associated nutrients into Lynch Cove and lower Hood Canal (fig. 1) from sources such as groundwater seeps, small streams, and ephemeral creeks may play a major role in the nutrient loading and hydrodynamics of this low dissolved-oxygen (hypoxic) system. These disbursed sources exhibit a high degree of spatial variability. However, few in-situ measurements of groundwater seepage rates and nutrient concentrations are available and thus may not represent adequately the large spatial variability of groundwater discharge in the area. As a result, our understanding of these processes and their effect on hypoxic conditions in Hood Canal is limited. To determine the spatial variability and relative intensity of these sources, the U.S. Geological Survey Washington Water Science Center collaborated with the University of Washington Applied Physics Laboratory to obtain thermal infrared (TIR) images of the nearshore and intertidal regions of Lynch Cove at or near low tide. In the summer, cool freshwater discharges from seeps and streams, flows across the exposed, sun-warmed beach, and out on the warm surface of the marine water. These temperature differences are readily apparent in aerial thermal infrared imagery that we acquired during the summers of 2008 and 2009. When combined with co-incident video camera images, these temperature differences allow identification of the location, the type, and the relative intensity of the sources.

  18. PMS2 Involvement in Patients Suspected of Lynch Syndrome

    NARCIS (Netherlands)

    Niessen, Renee C.; Kleibeuker, Jan H.; Westers, Helga; Jager, Paul O. J.; Rozeveld, Dennie; Bos, Krista K.; Boersma-van Ek, Wytske; Hollema, Harry; Sijmons, Rolf H.; Hofstra, Robert M. W.

    It is well-established that germline mutations in the mismatch repair genes MLH1, MSH2, and MSH6 cause Lynch syndrome. However, mutations in these three genes do not account for all Lynch syndrome (suspected) families. Recently, it was shown that germline mutations in another mismatch repair gene,

  19. Recurrence and Variability of Germline EPCAM Deletions in Lynch Syndrome

    NARCIS (Netherlands)

    Kuiper, Roland P.; Vissers, Lisenka E. L. M.; Venkatachalam, Ramprasath; Bodmer, Danielle; Hoenselaar, Eveline; Goossens, Monique; Haufe, Aline; Kamping, Eveline; Niessen, Renee C.; Hogervorst, Frans B. L.; Gille, Johan J. P.; Redeker, Bert; Tops, Carli M. J.; van Gijn, Marielle E.; van den Ouweland, Ans M. W.; Rahner, Nils; Steinke, Verena; Kahl, Philip; Holinski-Feder, Elke; Morak, Monika; Kloor, Matthias; Stemmler, Susanne; Betz, Beate; Hutter, Pierre; Bunyan, David J.; Syngal, Sapna; Culver, Julie O.; Graham, Tracy; Chan, Tsun L.; Nagtegaal, Iris D.; van Krieken, J. Han J. M.; Schackert, Hans K.; Hoogerbrugge, Nicoline; van Kessel, Ad Geurts; Ligtenberg, Marjolijn J. L.

    Recently, we identified 3' end deletions in the EPCAM gene as a novel cause of Lynch syndrome. These truncating EPCAM deletions cause allele-specific epigenetic silencing of the neighboring DNA mismatch repair gene MSH2 in tissues expressing EPCAM. Here we screened a cohort of unexplained Lynch-like

  20. Management of extracolonic tumours in patients with Lynch syndrome

    NARCIS (Netherlands)

    Koornstra, Jan J; Mourits, Marian Je; Sijmons, Rolf H; Leliveld-Kors, Anna; Hollema, Harry; Kleibeuker, Jan H

    Hereditary nonpolyposis colorectal cancer, or Lynch syndrome, is responsible for 2-3% of all colorectal cancers. Lynch syndrome is also associated with a high risk of extracolonic cancers, including endometrial, stomach, small bowel, pancreas, biliary tract, ovary, urinary tract, brain, and skin

  1. Advances in the study of Lynch syndrome in China.

    Science.gov (United States)

    Lu, Jun-Yu; Sheng, Jian-Qiu

    2015-06-14

    Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is an autosomal dominant genetic condition that has a high risk of colon cancer as well as other cancers due to inherited mutations in mismatch repair (MMR) genes. During the last decades, there have been great advances in research on Chinese Lynch syndrome. This review mainly focuses on the genetic basis, clinicopathologic features, diagnosis, intervention, chemoprevention, and surveillance of Lynch syndrome in China. In addition to frequently altered MMR genes, such as MLH1, MSH2, MSH6, and MLH3, other MMR-associated genes, such as those encoding human exonuclease 1, transforming growth factor β receptor 2, and alanine aminopeptidase, metastasis-associated protein 2, adenomatosis polyposis coli down-regulated 1, and hepatic and glial cell adhesion molecule have also been implicated in Chinese Lynch syndrome. Most Chinese researchers focused on the clinicopathologic features of Lynch syndrome, and it is noticeable that the most frequent extracolonic tumor in northeast China is lung cancer, which is different from other areas in China. The Chinese diagnostic criteria for Lynch syndrome have been established to identify gene mutation or methylation. With regard to chemoprevention, celecoxib may be effective to prevent polyps relapse in Lynch syndrome carriers. Additionally, a colonoscopy-based surveillance strategy for the prevention and early detection of neoplasms in Lynch-syndrome carriers has been proposed.

  2. Features of ovarian cancer in Lynch syndrome (Review).

    Science.gov (United States)

    Nakamura, Kanako; Banno, Kouji; Yanokura, Megumi; Iida, Miho; Adachi, Masataka; Masuda, Kenta; Ueki, Arisa; Kobayashi, Yusuke; Nomura, Hiroyuki; Hirasawa, Akira; Tominaga, Eiichiro; Aoki, Daisuke

    2014-11-01

    Lynch syndrome is a hereditary ovarian cancer with a prevalence of 0.9-2.7%. Lynch syndrome accounts for 10-15% of hereditary ovarian cancers, while hereditary breast and ovarian cancer syndrome accounts for 65-75% of these cancers. The lifetime risk for ovarian cancer in families with Lynch syndrome is ~8%, which is lower than colorectal and endometrial cancers, and ovarian cancer is not listed in the Amsterdam Criteria II. More than half of sporadic ovarian cancers are diagnosed in stage III or IV, but ≥80% of ovarian cancers in Lynch syndrome are diagnosed in stage I or II. Ovarian cancers in Lynch syndrome mostly have non-serous histology and different properties from those of sporadic ovarian cancers. A screening method for ovarian cancers in Lynch syndrome has yet to be established and clinical studies of prophylactic administration of oral contraceptives are not available. However, molecular profiles at the genetic level indicate that ovarian cancer in Lynch syndrome has a more favorable prognosis than sporadic ovarian cancer. Inhibitors of the phosphatidylinositol 3-kinase/mammalian target of the rapamycin pathway and anti-epidermal growth factor antibodies may have efficacy for the disease. To the best of our knowledge, this is the first review focusing on ovarian cancer in Lynch syndrome.

  3. Mutation spectrum in South American Lynch syndrome families

    DEFF Research Database (Denmark)

    Dominguez-Valentin, Mev; Nilbert, Mef; Wernhoff, Patrik

    2013-01-01

    Genetic counselling and testing for Lynch syndrome have recently been introduced in several South American countries, though yet not available in the public health care system.......Genetic counselling and testing for Lynch syndrome have recently been introduced in several South American countries, though yet not available in the public health care system....

  4. Molecular subtype classification of urothelial carcinoma in Lynch syndrome

    DEFF Research Database (Denmark)

    Therkildsen, Christina; Eriksson, Pontus; Höglund, Mattias

    2018-01-01

    Lynch syndrome confers an increased risk for urothelial carcinoma (UC). Molecular subtypes may be relevant to prognosis and therapeutic possibilities, but have to date not been defined in Lynch syndrome-associated urothelial cancer. We aimed to provide a molecular description of Lynch syndrome......-associated UC. Thus, Lynch syndrome-associated UC of the upper urinary tract and the urinary bladder were identified in the Danish hereditary non-polyposis colorectal cancer (HNPCC) register and were transcriptionally and immunohistochemically profiled and further related to data from 307 sporadic urothelial...... carcinomas. Whole genome mRNA expression profiles of 41 tumors and immunohistochemical stainings against FGFR3, KRT5, CCNB1, RB1, and CDKN2A (p16) of 37 tumors from Lynch syndrome patients were generated. Pathological data, microsatellite instability, anatomic location, and overall survival data was analyzed...

  5. Recent discoveries in the molecular genetics of Lynch syndrome.

    Science.gov (United States)

    Boland, C Richard

    2016-07-01

    Lynch syndrome is the inherited predisposition to cancer caused by a germline mutation in a DNA mismatch repair gene. The consequent tumors have a characteristic microsatellite instability (MSI) phenotype. Genomic sequencing of Lynch syndrome-associated colorectal cancers (CRCs) has demonstrated that these tumors have a substantially greater number of mutations than non-MSI CRCs, and that the target mutations driving tumor behavior are also different from what occurs in sporadic tumors. There are multiple non-Lynch syndrome entities that can create clinical confusion with that disease, including the acquired methylation of MLH1, Lynch-like syndrome, and Familial CRC-Type X. Patients with Lynch syndrome-associated CRCs have a substantially better prognosis, and there is growing evidence that this is due to the generation of immunogenic frameshift peptides as a consequence of defective DNA mismatch repair, and an effective immune response to the tumor.

  6. Molecular subtype classification of urothelial carcinoma in Lynch syndrome.

    Science.gov (United States)

    Therkildsen, Christina; Eriksson, Pontus; Höglund, Mattias; Jönsson, Mats; Sjödahl, Gottfrid; Nilbert, Mef; Liedberg, Fredrik

    2018-05-23

    Lynch syndrome confers an increased risk for urothelial carcinoma (UC). Molecular subtypes may be relevant to prognosis and therapeutic possibilities, but have to date not been defined in Lynch syndrome-associated urothelial cancer. We aimed to provide a molecular description of Lynch syndrome-associated UC. Thus, Lynch syndrome-associated UC of the upper urinary tract and the urinary bladder were identified in the Danish hereditary non-polyposis colorectal cancer (HNPCC) register and were transcriptionally and immunohistochemically profiled and further related to data from 307 sporadic urothelial carcinomas. Whole genome mRNA expression profiles of 41 tumors and immunohistochemical stainings against FGFR3, KRT5, CCNB1, RB1, and CDKN2A (p16) of 37 tumors from Lynch syndrome patients were generated. Pathological data, microsatellite instability, anatomic location, and overall survival data was analyzed and compared with sporadic bladder cancer. The 41 Lynch syndrome-associated UC developed at a mean age of 61 years with 59% women. mRNA expression profiling and immunostaining classified the majority of the Lynch syndrome-associated UC as Urothelial-like tumors with only 20% being Genomically Unstable, Basal/SCC-like or other subtypes. The subtypes were associated with stage, grade, and microsatellite instability. Comparison to larger data sets revealed that Lynch syndrome-associated UC share molecular similarities with sporadic UC. In conclusion, transcriptomic and immunohistochemical profiling identifies a predominance of the Urothelial-like molecular subtype in Lynch syndrome and reveals that the molecular subtypes of sporadic bladder cancer are relevant also within this hereditary, mismatch-repair defective subset. This article is protected by copyright. All rights reserved. Molecular Oncology (2018) © 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

  7. Indsigter og udfordringer i danske Lynch-syndrom-familier

    DEFF Research Database (Denmark)

    Therkildsen, Christina; Timshel, Susanne; Nilbert, Mef

    2008-01-01

    identified 88 unique mutations in 164 Danish families delineated as Lynch syndrome families. Predictive genetic diagnostics enables the identification of high risk individuals, who are offered participation in surveillance programmes that effectively reduce morbidity and mortality in colorectal cancer....

  8. Quality colonoscopy and risk of interval cancer in Lynch syndrome

    NARCIS (Netherlands)

    Haanstra, J. F.; Vasen, H. F. A.; Sanduleanu, S.; van der Wouden, E. J.; Koornstra, J. J.; Kleibeuker, J. H.; Cappel, W. H. de Vos Tot Nederveen

    2013-01-01

    Despite colonoscopic surveillance, Lynch syndrome patients develop colorectal cancer (CRC). Identification of modifiable factors has the potential to improve outcome of surveillance. The aims of this study were to determine (1) characteristics of patients with CRC, (2) endoscopic and histological

  9. [A Case of Ascending Colon Cancer with Lynch Syndrome Who Underwent XELOX Adjuvant Chemotherapy].

    Science.gov (United States)

    Takase, Koki; Murata, Kohei; Kagawa, Yoshinori; Nose, Yohei; Kawai, Kenji; Sakamoto, Takuya; Naito, Atsushi; Murakami, Kohei; Katsura, Yoshiteru; Omura, Yoshiaki; Takeno, Atsushi; Nakatsuka, Shinichi; Takeda, Yutaka; Kato, Takeshi; Tamura, Shigeyuki

    2018-01-01

    Lynch syndrome is an inherited syndrome with the development of the colorectal and various other cancers. Lynch syndrome is caused by mutations in the mismatch repair genes. A 33 year-old male underwent XELOX adjuvant chemotherapy for ascending colon cancer with Lynch syndrome. Although efficacy of 5-FU is not demonstrated in Lynch syndrome, MOSAIC trial had suggested a benefit from FOLFOX compared with 5-FU in patients who have colorectal cancer with Lynch syndrome. Oxaliplatin-based adjuvant chemotherapy can be a therapeutic option for colorectal cancer in lynch syndrome patients.

  10. Upper urinary tract carcinoma in Lynch syndrome cases.

    Science.gov (United States)

    Crockett, David G; Wagner, David G; Holmäng, Sten; Johansson, Sonny L; Lynch, Henry T

    2011-05-01

    Patients with Lynch syndrome are much more likely to have generally rare upper urinary tract urothelial carcinoma but not bladder urothelial carcinoma. While the risk has been quantified, to our knowledge there is no description of how this population of patients with Lynch syndrome and upper urinary tract cancer differs from the general population with upper urinary tract cancer. We obtained retrospective data on a cohort of patients with Lynch syndrome from the Hereditary Cancer Center in Omaha, Nebraska and compared the data to those on a control general population from western Sweden. These data were supplemented by a new survey about exposure to known risk factors. Of the patients with Lynch syndrome 91% had mutations in MSH2 rather than in MSH1 and 79% showed upper tract urothelial carcinoma a mean of 15.85 years after prior Lynch syndrome-type cancer. Median age at diagnosis was 62 years vs 70 in the general population (p Lynch syndrome 51% had urothelial carcinoma in the ureter while it occurred in the renal pelvis in 65% of the general population (p = 0.0013). Similar numbers of high grade tumors were found in the Lynch syndrome and general populations (88% and 74%, respectively, p = 0.1108). Upper urinary tract tumors develop at a younger age and are more likely to be in the ureter with an almost equal gender ratio in patients with Lynch syndrome. It has high grade potential similar to that in the general population. Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  11. PMS2 involvement in patients suspected of Lynch syndrome.

    Science.gov (United States)

    Niessen, Renée C; Kleibeuker, Jan H; Westers, Helga; Jager, Paul O J; Rozeveld, Dennie; Bos, Krista K; Boersma-van Ek, Wytske; Hollema, Harry; Sijmons, Rolf H; Hofstra, Robert M W

    2009-04-01

    It is well-established that germline mutations in the mismatch repair genes MLH1, MSH2, and MSH6 cause Lynch syndrome. However, mutations in these three genes do not account for all Lynch syndrome (suspected) families. Recently, it was shown that germline mutations in another mismatch repair gene, PMS2, play a far more important role in Lynch syndrome than initially thought. To explore this further, we determined the prevalence of pathogenic germline PMS2 mutations in a series of Lynch syndrome-suspected patients. Ninety-seven patients who had early-onset microsatellite instable colorectal or endometrial cancer, or multiple Lynch syndrome-associated tumors and/or were from an Amsterdam Criteria II-positive family were selected for this study. These patients carried no pathogenic germline mutation in MLH1, MSH2, or MSH6. When available, tumors were investigated for immunohistochemical staining (IHC) for PMS2. PMS2 was screened in all patients by exon-by-exon sequencing. We identified four patients with a pathogenic PMS2 mutation (4%) among the 97 patients we selected. IHC of PMS2 was informative in one of the mutation carriers, and in this case, the tumor showed loss of PMS2 expression. In conclusion, our study confirms the finding of previous studies that PMS2 is more frequently involved in Lynch syndrome than originally expected.

  12. Genetic anticipation in Swedish Lynch syndrome families

    DEFF Research Database (Denmark)

    von Salomé, Jenny; Boonstra, Philip S; Karimi, Masoud

    2017-01-01

    Among hereditary colorectal cancer predisposing syndromes, Lynch syndrome (LS) caused by mutations in DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2 is the most common. Patients with LS have an increased risk of early onset colon and endometrial cancer, but also other tumors that generally have......-2013. We analyzed a homogenous group of mutation carriers, utilizing information from both affected and non-affected family members. In total, 239 families with a mismatch repair gene mutation (96 MLH1 families, 90 MSH2 families including one family with an EPCAM-MSH2 deletion, 39 MSH6 families, 12 PMS2...... families, and 2 MLH1+PMS2 families) comprising 1028 at-risk carriers were identified among the Swedish LS families, of which 1003 mutation carriers had available follow-up information and could be included in the study. Using a normal random effects model (NREM) we estimate a 2.1 year decrease in age...

  13. Role for Genetic Anticipation in Lynch Syndrome

    DEFF Research Database (Denmark)

    Nilbert, Mef; Timshel, Susanne; Bernstein, Inge

    2009-01-01

    PURPOSE: Anticipation (ie, an earlier age at onset in successive generations) is linked to repeat expansion in neurodegenerative syndromes, whereas its role in hereditary cancer is unclear. We assessed anticipation in Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]), in which DNA...... parent-child pairs in which age at the first cancer diagnosis was assessed. A paired t-test and a specifically developed bivariate model were used to assess a possible role of anticipation. RESULTS: Both methods revealed anticipation with children developing cancer mean 9.8 years (P ... parents using the paired t-test and 5.5 years (P anticipation with 7.2 years earlier age at onset was identified also in the oldest cohort, in which the children were observed until they were older than 80 years...

  14. Haematuria in association with Lynch syndrome

    Directory of Open Access Journals (Sweden)

    Marwan Ma'ayeh

    2012-04-01

    Full Text Available A 40-year-old Caucasian male presented to the Emergency Department complaining of intermittent painless frank haematuria. Past medical history was significant for Hereditary Non-Polyposis Colon Cancer (HNPCC and a prophylactic total colectomy. Computed tomography urogram showed thickening in the posterior wall of the bladder. Cystoscopy showed a small bladder mass. Histology showed a papillary urothelial neoplasm of low malignant potential. HNPCC, also known as Lynch Syndrome, is an autosomal dominant disorder responsible for 3-5% of colorectal cancers. There are certain cancers known to be associated with HNPCC; colorectal cancer, endometrial, ovarian, stomach, pancreas, biliary tract, small bowel, brain, renal pelvic and ureteric tumours, sebaceous gland adenomas and keratocanthomas. An association with bladder tumours is not well established.

  15. Mismatch repair genes in Lynch syndrome: a review

    Directory of Open Access Journals (Sweden)

    Felipe Cavalcanti Carneiro da Silva

    Full Text Available Lynch syndrome represents 1-7% of all cases of colorectal cancer and is an autosomal-dominant inherited cancer predisposition syndrome caused by germline mutations in deoxyribonucleic acid (DNA mismatch repair genes. Since the discovery of the major human genes with DNA mismatch repair function, mutations in five of them have been correlated with susceptibility to Lynch syndrome: mutS homolog 2 (MSH2; mutL homolog 1 (MLH1; mutS homolog 6 (MSH6; postmeiotic segregation increased 2 (PMS2; and postmeiotic segregation increased 1 (PMS1. It has been proposed that one additional mismatch repair gene, mutL homolog 3 (MLH3, also plays a role in Lynch syndrome predisposition, but the clinical significance of mutations in this gene is less clear. According to the InSiGHT database (International Society for Gastrointestinal Hereditary Tumors, approximately 500 different LS-associated mismatch repair gene mutations are known, primarily involving MLH1 (50% and MSH2 (40%, while others account for 10%. Much progress has been made in understanding the molecular basis of Lynch Syndrome. Molecular characterization will be the most accurate way of defining Lynch syndrome and will provide predictive information of greater accuracy regarding the risks of colon and extracolonic cancer and enable optimal cancer surveillance regimens.

  16. Women with double primary cancers of the colorectum and endometrium: do they have Lynch syndrome?

    Science.gov (United States)

    Song, Taejong; Kim, Min Kyu; Lee, Yoo-Young; Choi, Chel Hun; Kim, Tae-Joong; Lee, Jeong-Won; Bae, Duk-Soo; Kim, Byoung-Gie

    2016-04-01

    The aim of this study was to determine the clinical characteristics of women with double primary cancers of the colorectum and endometrium and assess the probability of Lynch syndrome. We identified 15 women with paraffin-embedded blocks available who were diagnosed, treated and followed for double primary colorectal and endometrial cancers at in a single institution between 1994 and 2014. If there was a family history that met the revised Amsterdam criteria for Lynch syndrome, the woman was considered to have 'clinically defined Lynch syndrome'. If immunohistochemical (IHC) loss of expression of mismatch repair genes (MLH1, MSH2, MSH6, or PMS2) or high microsatellite instability (MSI) was demonstrated in molecular testing, the case was considered 'suspected Lynch syndrome'. The incidence of clinically defined Lynch syndrome according to the revised Amsterdam criteria was 66% (8 of 15). All 8 of the women clinically diagnosed with Lynch syndrome had either abnormal IHC loss or MSI-high, indicating a suspected Lynch syndrome. Furthermore, 27% (4 of 15) experienced second primary colorectal cancer or other Lynch syndrome-related cancers. Overall, 66% (10 of 15) met the criteria for clinically defined Lynch syndrome or suspected Lynch syndrome. Based on our findings, a large percentage (66%) of women with double primary cancers of the colorectum and endometrium are likely to be diagnosed with Lynch syndrome. Copyright © 2015. Published by Elsevier Ireland Ltd.

  17. Diagnosing lynch syndrome in absence of colorectal cancer.

    Science.gov (United States)

    Lynch, Henry T; Knezetic, Joseph; Lanspa, Stephen

    2012-11-01

    There are many ways in which a diagnosis of Lynch syndrome can be made, most prominent of which is family history, presence of cancer, high microsatellite instability, immunohistochemistry, and a mismatch repair germline mutation. There are at least four molecular pathways for colorectal cancer carcinogenesis: 1) adenoma-carcinoma sequence; 2) hereditary microsatellite instability; 3) serrated pathway; 4) epidermal growth factor receptor. The answer to diagnosing Lynch syndrome in the absence of colorectal cancer may be partially based upon the phenotypic characteristics of the colonic polyps should they be identified at colonoscopy, specifically their phenotypic characteristics of location, size, histology, number, and age of polyp onset.

  18. Big Creek Pit Tags

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The BCPITTAGS database is used to store data from an Oncorhynchus mykiss (steelhead/rainbow trout) population dynamics study in Big Creek, a coastal stream along the...

  19. Revised guidelines for the clinical management of Lynch syndrome (HNPCC)

    DEFF Research Database (Denmark)

    Vasen, Hans F A; Blanco, Ignacio; Aktan-Collan, Katja

    2013-01-01

    Lynch syndrome (LS) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. In 2007, a group of European experts (the Mallorca group) published guidelines...

  20. Colorectal choriocarcinoma in a patient with probable Lynch syndrome

    Directory of Open Access Journals (Sweden)

    Viktor Hendrik Koelzer

    2016-11-01

    Full Text Available Background: Personalized therapy of colorectal cancer (CRC is influenced by morphological, molecular and host-related factors. Here we report the comprehensive clinicopathological and molecular analysis of a pure extra-gestational colorectal choriocarcinoma in a patient with probable Lynch syndrome.Case presentation: A 61 year old female with history of gastric cancer at age 36 presented with a transmurally invasive tumor of the right hemicolon and liver metastasis. A right hemicolectomy was performed. Histopathological analysis showed a mixed trophoblastic and syncytiotrophoblastic differentiation, consistent with choriocarcinoma. Disease progression was rapid under oxaliplatin, capecitabine, irinotecan (XELOXIRI and bevacizumab. Molecular phenotyping identified loss of the mismatch-repair (MMR protein PMS2, microsatellite instability, a lack of MLH1 promoter methylation and lack of of BRAF mutation suggestive of Lynch-Syndrome. Targeted next generation sequencing revealed an Ataxia Telangiectasia Mutated (ATM p.P604S missense mutation. A bleomycin, etoposide and cisplatin (BEP treatment protocol targeting germ-cell neoplasia lead to disease remission and prolonged survival of 34 months.Conclusions: Comprehensive immunohistochemical and genetic testing is essential to identify uncommon cancers possibly related to Lynch syndrome. For rare tumors, personalized therapeutic approaches should take both molecular and morphological information into account.Key words: Colorectal cancer, choriocarcinoma, histopathology, prognostic factors, Lynch syndrome, microsatellite instability, ataxia telangiectasia mutated, molecular pathology, next generation sequencing, personalized medicine

  1. Pain evaluation during gynaecological surveillance in women with Lynch syndrome

    NARCIS (Netherlands)

    Helder-Woolderink, Jorien; de Bock, Geertruida; Hollema, Harry; van Oven, Magda; Mourits, Marian

    To evaluate perceived pain during repetitive annual endometrial sampling at gynaecologic surveillance in asymptomatic women with Lynch syndrome (LS) over time and in addition to symptomatic women without LS, undergoing single endometrial sampling. In this prospective study, 52 women with LS or first

  2. Pathological assessment of mismatch repair gene variants in Lynch syndrome

    DEFF Research Database (Denmark)

    Rasmussen, Lene Juel; Heinen, Christopher D; Royer-Pokora, Brigitte

    2012-01-01

    Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair (MMR) genes and is the most prevalent hereditary colorectal cancer syndrome. A significant proportion of variants identified in MMR and other common cancer susceptibility genes are missense or noncoding changes whose...

  3. Sense of coherence and self-concept in Lynch syndrome

    DEFF Research Database (Denmark)

    Petersen, Helle Vendel; Ladelund, Steen; Carlsson, Christina

    2013-01-01

    Most individuals who learn about hereditary cancer manage well, but identification of subgroups who find this knowledge burdening would allow psychosocial intervention. The objective of the study was to assess sense of coherence (SOC) in individuals with Lynch syndrome with comparison to a general...

  4. Small bowel endoscopy in familial adenomatous polyposis and Lynch syndrome

    NARCIS (Netherlands)

    Koornstra, Jan Jacob

    Patients with familial adenomatous polyposis (FAP) and patients with Lynch syndrome have an increased risk of developing small intestinal neoplasia. In both conditions, the lifetime risk to develop small bowel cancer is estimated to be around 5%. In FAP, this risk is associated with the degree of

  5. Surveillance for urinary tract cancer in Lynch syndrome

    DEFF Research Database (Denmark)

    Bernstein, Inge Thomsen; Myrhøj, Torben

    2013-01-01

    Hereditary non-polyposis colorectal cancer (HNPCC) is an inherited multiorgan cancer syndrome, which when caused by a germline mutation in the mismatch repair (MMR) genes is known as Lynch syndrome (LS). Mutation carriers are at risk for developing cancers primarily in the colon, rectum...

  6. Fas Ligand Expression in Lynch Syndrome-Associated Colorectal Tumours

    NARCIS (Netherlands)

    Koornstra, Jan J.; de Jong, Steven; Boersma-van Eck, Wietske; Zwart, Nynke; Hollema, Harry; de Vries, Elisabeth G. E.; Kleibeuker, Jan H.

    Fas Ligand (FasL) expression by cancer cells may contribute to tumour immune escape via the Fas counterattack against tumour-infiltrating lymphocytes (TILs). Whether this plays a role in colorectal carcinogenesis in Lynch syndrome was examined studying FasL expression, tumour cell apoptosis and

  7. Role of new endoscopic techniques in Lynch syndrome

    NARCIS (Netherlands)

    Haanstra, Jasmijn F.; Kleibeuker, Jan H.; Koornstra, Jan J.

    Lynch syndrome, or hereditary nonpolyposis colorectal cancer (HNPCC), is the most common hereditary condition predisposing for colorectal cancer. International guidelines recommend surveillance of the colorectum by colonoscopy every 1-2 years starting at the age of 20-25 years. This has been shown

  8. The identification of Lynch syndrome in Congolese colorectal cancer patients.

    Science.gov (United States)

    Poaty, Henriette; Aba Gandzion, Chandra; Soubeyran, Isabelle; Gassaye, Déby; Peko, Jean Félix; Nkoua Bon, Jean Bernard; Gombé Mbalawa, Charles

    2017-10-01

    We aimed to investigate the prevalence of Lynch syndrome as one of hereditary causes of colorectal cancer (CRC) among young Congolese individuals affected by the CRC, and to define methods for diagnosis in Congo Brazzaville. We conducted a transversal cohort study of 34 patients having a CRC with a family history for a period of eight years. They were selected among 89 CRCs of any type from the Bethesda guidelines criteria combined with pedigrees. Mismatch repair (MMR) genes alterations were researched by immunohistochemistry (IHC). We identified with the Bethesda criteria a total of 38.2% (34/89) patients having familial CRC with a confidence interval (CI) of 95%=[0.34-0.41]. Only 14.7% (5/34) 95% CI=[0.34-2.32] patients showed MMR immunodeficiency involving firstly MLH1 protein then MSH2 protein. These data account for 5.6% (5/89) 95% CI=[0.15-0.33] of patients affected by Lynch syndrome with an earlier median age of 35 years (range 20 to 47 years). The prevalence of Lynch syndrome found in Brazzaville is comparable to that is found in northern countries. The combined Bethesda guidelines, pedigree and IHC is an accessible and good alternative method for the positive diagnosis of Lynch syndrome in current practice in Congo. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  9. Aerosol impacts on California winter clouds and precipitation during CalWater 2011: local pollution vs. long-range transported dust

    Science.gov (United States)

    Fan, J.; Leung, L. R.; DeMott, P. J.; Comstock, J. M.; Singh, B.; Rosenfeld, D.; Tomlinson, J. M.; White, A.; Prather, K. A.; Minnis, P.; Ayers, J. K.; Min, Q.

    2013-07-01

    Mineral dust aerosols often observed over California in winter/spring, associated with long-range transport from Asia and Sahara, have been linked to enhanced precipitation based on observations. Local anthropogenic pollution, on the other hand, was shown in previous observational and modeling studies to reduce precipitation. Here we incorporate recent developments in ice nucleation parameterizations to link aerosols with ice crystal formation in a spectral-bin cloud microphysical model coupled with the Weather Research and Forecasting (WRF) model, to examine the relative and combined impacts of dust and local pollution particles on cloud properties and precipitation type and intensity. Simulations are carried out for two cloud cases with contrasting meteorology and cloud dynamics that occurred on 16 February (FEB16) and 2 March (MAR02) from the CalWater 2011 field campaign. In both cases, observations show the presence of dust or dust/biological particles in a relative pristine environment. The simulated cloud microphysical properties and precipitation show reasonable agreement with aircraft and surface measurements. Model sensitivity experiments indicate that in the pristine environment, the dust/biological aerosol layers increase the accumulated precipitation by 10-20% from the Central Valley to the Sierra Nevada Mountains for both FEB16 and MAR02 due to a 40% increase in snow formation, validating the observational hypothesis. Model results show that local pollution increases precipitation over the windward slope of the mountains by few percent due to increased snow formation when dust is present but reduces precipitation by 5-8% if dust is removed on FEB16. The effects of local pollution on cloud microphysics and precipitation strongly depend on meteorology including the strength of the Sierra Barrier Jet, and cloud dynamics. This study further underscores the importance of the interactions between local pollution, dust, and environmental conditions for

  10. Aerosol impacts on California winter clouds and precipitation during CalWater 2011: local pollution versus long-range transported dust

    Science.gov (United States)

    Fan, J.; Leung, L. R.; DeMott, P. J.; Comstock, J. M.; Singh, B.; Rosenfeld, D.; Tomlinson, J. M.; White, A.; Prather, K. A.; Minnis, P.; Ayers, J. K.; Min, Q.

    2014-01-01

    Mineral dust aerosols often observed over California in winter and spring, associated with long-range transport from Asia and the Sahara, have been linked to enhanced precipitation based on observations. Local anthropogenic pollution, on the other hand, was shown in previous observational and modeling studies to reduce precipitation. Here we incorporate recent developments in ice nucleation parameterizations to link aerosols with ice crystal formation in a spectral-bin cloud microphysical model coupled with the Weather Research and Forecasting (WRF) model in order to examine the relative and combined impacts of dust and local pollution particles on cloud properties and precipitation type and intensity. Simulations are carried out for two cloud cases (from the CalWater 2011 field campaign) with contrasting meteorology and cloud dynamics that occurred on 16 February (FEB16) and 2 March (MAR02). In both cases, observations show the presence of dust and biological particles in a relative pristine environment. The simulated cloud microphysical properties and precipitation show reasonable agreement with aircraft and surface measurements. Model sensitivity experiments indicate that in the pristine environment, the dust and biological aerosol layers increase the accumulated precipitation by 10-20% from the Central Valley to the Sierra Nevada for both FEB16 and MAR02 due to a ~40% increase in snow formation, validating the observational hypothesis. Model results show that local pollution increases precipitation over the windward slope of the mountains by a few percent due to increased snow formation when dust is present, but reduces precipitation by 5-8% if dust is removed on FEB16. The effects of local pollution on cloud microphysics and precipitation strongly depend on meteorology, including cloud dynamics and the strength of the Sierra Barrier Jet. This study further underscores the importance of the interactions between local pollution, dust, and environmental

  11. Colorectal Cancer Risk in Patients With Lynch Syndrome and Inflammatory Bowel Disease.

    Science.gov (United States)

    Derikx, Lauranne A A P; Smits, Lisa J T; van Vliet, Shannon; Dekker, Evelien; Aalfs, Cora M; van Kouwen, Mariëtte C A; Nagengast, Fokko M; Nagtegaal, Iris D; Hoogerbrugge, Nicoline; Hoentjen, Frank

    2017-03-01

    Lynch syndrome and inflammatory bowel diseases (IBD) are associated with an increased risk of colorectal cancer (CRC). However, it is not clear whether the risk of CRC is even higher for patients with a combination of Lynch syndrome and IBD. We investigated the risk for CRC in this subgroup by establishing a Lynch syndrome cohort from the Radboud University Medical Center (Nijmegen, The Netherlands) and the Academic Medical Center (Amsterdam, The Netherlands). Patients with heterozygous germline mutations in MLH1, MSH2 (and EPCAM deletion-mediated MSH2 methylation), MSH6, or PMS2 who were tested and/or treated from 1998 through 2014 were included. Patients who developed IBD were identified by linkage of this cohort to the Dutch nationwide Pathology Registry (PALGA). Subsequently, we compared the risk of CRC between Lynch syndrome patients with IBD and without IBD. Of 1046 patients with Lynch syndrome, 15 developed IBD (1.4%). Patients with Lynch syndrome and IBD were significantly younger (median age, 38.0 y) than patients with Lynch syndrome without IBD (median age, 52.0 y; P = .001). Nevertheless, a similar proportion of patients in each group developed CRC: 4 of the 15 patients (26.7%) with Lynch syndrome and IBD compared with 311 of the 1031 patients (30.2%) with Lynch syndrome without IBD. Patients with Lynch syndrome and IBD developed CRC at a younger age (median age, 36.0 y) than patients with Lynch syndrome without IBD (median age, 46.0 y; P = .045). However, the cumulative incidence of CRC was similar between groups (P = .121). All patients with Lynch syndrome and IBD who developed CRC had ulcerative colitis, producing a higher cumulative incidence of CRC for this IBD subgroup (P Lynch syndrome and IBD develop CRC risk at a younger age than patients without IBD; patients with ulcerative colitis are at especially high risk. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

  12. Henretta Creek reclamation project

    International Nuclear Information System (INIS)

    Pumphrey, J.F.

    2009-01-01

    Teck Coal Ltd. operates 6 open-pit coal mines, of which 5 are located in the Elk Valley in southeastern British Columbia. The Fording River Operations (FRO) began in 1971 in mining areas in Eagle Mountain, Turnbull Mountain and Henretta Valley. The recovery of approximately 5 million tons of coal from the Henretta Creek Valley posed significant challenges to mine planners, hydrologists and environmental experts because the coal had to be recovered from the valley flanks and also from under the main valley floor, on which the fish-bearing Henretta Creek runs. The Henretta Dragline Mining project was described along with the water control structures and fisheries management efforts for the cutthroat trout. A detailed Environmental Impact Assessment and Stage 1 mining report for the Henretta Valley area was completed in December 1990. FRO was granted a mining and reclamation permit in 1991. A temporary relocation of 1,270 metres was required in in April 1997 in order to enable mining on both sides and below the creek bed. Among the innovative construction techniques was a diversion of Henretta Creek through large diameter steel culverts and a specialized crossing of the creek to allow fish passage. The first water flowed through the reclaimed Henretta Creek channel in late 1998 and the first high flow occurred in the spring of 2000. Teck coal FRO then launched an annual fish and fish habitat monitoring program which focused on the Henretta Creek Reclaimed Channel and Henretta Lake. This document presented the results from the final year, 2006, and a summary of the 7 year aquatic monitoring program. It was concluded that from mining through to reclamation, the Henretta project shows the commitment and success of mining and reclamation practices at Teck Coal. Indicators of the project's success include riparian zone vegetation, fisheries re-establishment, aquatic communities and habitat utilization by terrestrial and avian species. 33 refs., 1 fig.

  13. Genetic anticipation in Swedish Lynch syndrome families.

    Directory of Open Access Journals (Sweden)

    Jenny von Salomé

    2017-10-01

    Full Text Available Among hereditary colorectal cancer predisposing syndromes, Lynch syndrome (LS caused by mutations in DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2 is the most common. Patients with LS have an increased risk of early onset colon and endometrial cancer, but also other tumors that generally have an earlier onset compared to the general population. However, age at first primary cancer varies within families and genetic anticipation, i.e. decreasing age at onset in successive generations, has been suggested in LS. Anticipation is a well-known phenomenon in e.g neurodegenerative diseases and several reports have studied anticipation in heritable cancer. The purpose of this study is to determine whether anticipation can be shown in a nationwide cohort of Swedish LS families referred to the regional departments of clinical genetics in Lund, Stockholm, Linköping, Uppsala and Umeå between the years 1990-2013. We analyzed a homogenous group of mutation carriers, utilizing information from both affected and non-affected family members. In total, 239 families with a mismatch repair gene mutation (96 MLH1 families, 90 MSH2 families including one family with an EPCAM-MSH2 deletion, 39 MSH6 families, 12 PMS2 families, and 2 MLH1+PMS2 families comprising 1028 at-risk carriers were identified among the Swedish LS families, of which 1003 mutation carriers had available follow-up information and could be included in the study. Using a normal random effects model (NREM we estimate a 2.1 year decrease in age of diagnosis per generation. An alternative analysis using a mixed-effects Cox proportional hazards model (COX-R estimates a hazard ratio of exp(0.171, or about 1.19, for age of diagnosis between consecutive generations. LS-associated gene-specific anticipation effects are evident for MSH2 (2.6 years/generation for NREM and hazard ratio of 1.33 for COX-R and PMS2 (7.3 years/generation and hazard ratio of 1.86. The estimated anticipation effects for MLH1

  14. Genetic anticipation in Swedish Lynch syndrome families.

    Science.gov (United States)

    von Salomé, Jenny; Boonstra, Philip S; Karimi, Masoud; Silander, Gustav; Stenmark-Askmalm, Marie; Gebre-Medhin, Samuel; Aravidis, Christos; Nilbert, Mef; Lindblom, Annika; Lagerstedt-Robinson, Kristina

    2017-10-01

    Among hereditary colorectal cancer predisposing syndromes, Lynch syndrome (LS) caused by mutations in DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2 is the most common. Patients with LS have an increased risk of early onset colon and endometrial cancer, but also other tumors that generally have an earlier onset compared to the general population. However, age at first primary cancer varies within families and genetic anticipation, i.e. decreasing age at onset in successive generations, has been suggested in LS. Anticipation is a well-known phenomenon in e.g neurodegenerative diseases and several reports have studied anticipation in heritable cancer. The purpose of this study is to determine whether anticipation can be shown in a nationwide cohort of Swedish LS families referred to the regional departments of clinical genetics in Lund, Stockholm, Linköping, Uppsala and Umeå between the years 1990-2013. We analyzed a homogenous group of mutation carriers, utilizing information from both affected and non-affected family members. In total, 239 families with a mismatch repair gene mutation (96 MLH1 families, 90 MSH2 families including one family with an EPCAM-MSH2 deletion, 39 MSH6 families, 12 PMS2 families, and 2 MLH1+PMS2 families) comprising 1028 at-risk carriers were identified among the Swedish LS families, of which 1003 mutation carriers had available follow-up information and could be included in the study. Using a normal random effects model (NREM) we estimate a 2.1 year decrease in age of diagnosis per generation. An alternative analysis using a mixed-effects Cox proportional hazards model (COX-R) estimates a hazard ratio of exp(0.171), or about 1.19, for age of diagnosis between consecutive generations. LS-associated gene-specific anticipation effects are evident for MSH2 (2.6 years/generation for NREM and hazard ratio of 1.33 for COX-R) and PMS2 (7.3 years/generation and hazard ratio of 1.86). The estimated anticipation effects for MLH1 and MSH6 are

  15. Vegetation - Pine Creek WA and Fitzhugh Creek WA [ds484

    Data.gov (United States)

    California Natural Resource Agency — This fine-scale vegetation classification and map of the Pine Creek and Fitzhugh Creek Wildlife Areas, Modoc County, California was created following FGDC and...

  16. DNA mismatch repair protein deficient non-neoplastic colonic crypts: a novel indicator of Lynch syndrome.

    Science.gov (United States)

    Pai, Rish K; Dudley, Beth; Karloski, Eve; Brand, Randall E; O'Callaghan, Neil; Rosty, Christophe; Buchanan, Daniel D; Jenkins, Mark A; Thibodeau, Stephen N; French, Amy J; Lindor, Noralane M; Pai, Reetesh K

    2018-06-08

    Lynch syndrome is the most common form of hereditary colorectal carcinoma. However, establishing the diagnosis of Lynch syndrome is challenging, and ancillary studies that distinguish between sporadic DNA mismatch repair (MMR) protein deficiency and Lynch syndrome are needed, particularly when germline mutation studies are inconclusive. The aim of this study was to determine if MMR protein-deficient non-neoplastic intestinal crypts can help distinguish between patients with and without Lynch syndrome. We evaluated the expression of MMR proteins in non-neoplastic intestinal mucosa obtained from colorectal surgical resection specimens from patients with Lynch syndrome-associated colorectal carcinoma (n = 52) and patients with colorectal carcinoma without evidence of Lynch syndrome (n = 70), including sporadic MMR protein-deficient colorectal carcinoma (n = 30), MMR protein proficient colorectal carcinoma (n = 30), and "Lynch-like" syndrome (n = 10). MMR protein-deficient non-neoplastic colonic crypts were identified in 19 of 122 (16%) patients. MMR protein-deficient colonic crypts were identified in 18 of 52 (35%) patients with Lynch syndrome compared to only 1 of 70 (1%) patients without Lynch syndrome (p Lynch-like" syndrome and harbored two MSH2-deficient non-neoplastic colonic crypts. MMR protein-deficient non-neoplastic colonic crypts were not identified in patients with sporadic MMR protein-deficient or MMR protein proficient colorectal carcinoma. Our findings suggest that MMR protein-deficient colonic crypts are a novel indicator of Lynch syndrome, and evaluation for MMR protein-deficient crypts may be a helpful addition to Lynch syndrome diagnostics.

  17. The genetic basis of Lynch syndrome and its implications for clinical practice and risk management

    Science.gov (United States)

    Cohen, Stephanie A; Leininger, Anna

    2014-01-01

    Lynch syndrome is the most common cause of hereditary colon cancer, and accounts for as much as 3% of all colon and endometrial cancers. The identification and management of individuals with Lynch syndrome have evolved over the past 20 years, yet the syndrome remains vastly underdiagnosed. It is important for clinicians to recognize individuals and families who are at risk in order to be able to manage them appropriately and reduce their morbidity and mortality from this condition. This review will touch on the history of Lynch syndrome, the current knowledge of genotype–phenotype correlations, the cancers associated with Lynch syndrome, and management of individuals who are gene carriers. PMID:25161364

  18. Metachronous Uterine Endometrioid Adenocarcinoma and Peritoneal Mesothelioma in Lynch Syndrome: A Case Report.

    Science.gov (United States)

    Lu, Yuxin; Milchgrub, Sara; Khatri, Gaurav; Gopal, Purva

    2017-05-01

    Lynch syndrome is a hereditary disease with germline mutation in a DNA mismatch repair gene, most often presenting with colorectal and/or endometrial carcinomas; however, the spectrum of Lynch syndrome-associated tumors is expanding. In this article, we report a case of a primary peritoneal epithelioid mesothelioma that developed in a Lynch syndrome patient 10 months after diagnosis of uterine endometrioid adenocarcinoma. To our knowledge, this is the first reported case of a Lynch syndrome patient with metachronous uterine endometrioid adenocarcinoma and primary peritoneal mesothelioma.

  19. Current Hypotheses on How Microsatellite Instability Leads to Enhanced Survival of Lynch Syndrome Patients

    Directory of Open Access Journals (Sweden)

    Kristen M. Drescher

    2010-01-01

    Full Text Available High levels of microsatellite instability (MSI-high are a cardinal feature of colorectal tumors from patients with Lynch Syndrome. Other key characteristics of Lynch Syndrome are that these patients experience fewer metastases and have enhanced survival when compared to patients diagnosed with microsatellite stable (MSS colorectal cancer. Many of the characteristics associated with Lynch Syndrome including enhanced survival are also observed in patients with sporadic MSI-high colorectal cancer. In this review we will present the current state of knowledge regarding the mechanisms that are utilized by the host to control colorectal cancer in Lynch Syndrome and why these same mechanisms fail in MSS colorectal cancers.

  20. Current hypotheses on how microsatellite instability leads to enhanced survival of Lynch Syndrome patients.

    Science.gov (United States)

    Drescher, Kristen M; Sharma, Poonam; Lynch, Henry T

    2010-01-01

    High levels of microsatellite instability (MSI-high) are a cardinal feature of colorectal tumors from patients with Lynch Syndrome. Other key characteristics of Lynch Syndrome are that these patients experience fewer metastases and have enhanced survival when compared to patients diagnosed with microsatellite stable (MSS) colorectal cancer. Many of the characteristics associated with Lynch Syndrome including enhanced survival are also observed in patients with sporadic MSI-high colorectal cancer. In this review we will present the current state of knowledge regarding the mechanisms that are utilized by the host to control colorectal cancer in Lynch Syndrome and why these same mechanisms fail in MSS colorectal cancers.

  1. Lynch Syndrome Caused by Germline PMS2 Mutations

    DEFF Research Database (Denmark)

    Ten Broeke, Sanne W; Brohet, Richard M; Tops, Carli M

    2015-01-01

    PURPOSE: The clinical consequences of PMS2 germline mutations are poorly understood compared with other Lynch-associated mismatch repair gene (MMR) mutations. The aim of this European cohort study was to define the cancer risk faced by PMS2 mutation carriers. METHODS: Data were collected from 98...... PMS2 families ascertained from family cancer clinics that included a total of 2,548 family members and 377 proven mutation carriers. To adjust for potential ascertainment bias, a modified segregation analysis model was used to calculate colorectal cancer (CRC) and endometrial cancer (EC) risks....... Standardized incidence ratios (SIRs) were calculated to estimate risks for other Lynch syndrome-associated cancers. RESULTS: The cumulative risk (CR) of CRC for male mutation carriers by age 70 years was 19%. The CR among female carriers was 11% for CRC and 12% for EC. The mean age of CRC development was 52...

  2. Ssk or Esw? -- the Bloor-Lynch Debate Revisited

    Science.gov (United States)

    Cheng, Kai-Yuan

    2014-03-01

    Philosophical discussions of rule-following in the later Wittgenstein (1953, 1967) are an important source of inspiration for the development of views on the social nature of scientific knowledge. Two major opposing views in this inquiry -- Bloor's sociology of scientific knowledge (SSK) (1983, 1991, 1992, 1997) and Lynch's (1992, 1993) ethnomethodological studies of work (ESW) -- represent two positions derived from two different readings of Wittgenstein's later writings on rule-following. The aim of this paper is two-fold. One is to re-examine the noted Bloor-Lynch debate by considering Kusch's (2004) recent discussion of this debate. Another is to show that a new semantic framework of rule-following ascriptions based on a cognitive approach to the study of generics can be provided such that SSK and ESW are compatible in it (Leslie, 2009; Cheng, 2011).

  3. Indsigter og udfordringer i danske Lynch-syndrom-familier

    DEFF Research Database (Denmark)

    Therkildsen, Christina; Timshel, Susanne; Nilbert, Mef

    2008-01-01

    The Danish Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Register is a national resource that registers families with hereditary colorectal cancer. HNPCC is the most common type of hereditary colorectal cancer and carries an increased risk of other tumor types. Genetic diagnostics has...... identified 88 unique mutations in 164 Danish families delineated as Lynch syndrome families. Predictive genetic diagnostics enables the identification of high risk individuals, who are offered participation in surveillance programmes that effectively reduce morbidity and mortality in colorectal cancer....

  4. Fertility and apparent genetic anticipation in Lynch syndrome.

    Science.gov (United States)

    Stupart, Douglas; Win, Aung Ko; Jenkins, Mark; Winship, Ingrid M; Goldberg, Paul; Ramesar, Rajkumar

    2014-09-01

    Genetic anticipation is the phenomenon in which age of onset of an inherited disorder decreases in successive generations. Inconsistent evidence suggests that this occurs in Lynch syndrome. A possible cause for apparent anticipation is fecundity bias, which occurs if the disease adversely affects fertility. The purpose of this study was to determine the effect of age of diagnosis of colorectal cancer (CRC) on lifetime fertility in Lynch syndrome, and whether this can falsely create the appearance of genetic anticipation. A computer model simulated age of diagnosis of CRC in hypothetical Lynch syndrome carriers and their offspring. The model assumed similar age distribution of CRC across generations (i.e. that there was no true anticipation). Age distribution of CRC diagnosis, and lifetime fertility rates (grouped by age of diagnosis of CRC) were determined from the Australasian Colorectal Cancer Family Registry (ACCFR). Apparent anticipation was calculated by comparing ages of diagnosis of CRC in affected parent-child pairs. A total of 1,088 patients with CRC were identified from the ACCFR. Total lifetime (cohort) fertility was related to age of diagnosis of CRC (correlation coefficient 0.13, P = 0.0001). In the simulation, apparent anticipation was 1.8 ± 0.54 years (P = 0.0044). Observed apparent anticipation in the ACCFR cohort was 4.8 ± 1.73 years (P = 0.0064). There was no difference in apparent anticipation between the simulate d and observed parent-child pairs (P = 0.89). The appearance of genetic anticipation in Lynch syndrome can be falsely created due to changes in fertility.

  5. Efficacy of b-lynch brace suture in postpartum haemorrhage

    International Nuclear Information System (INIS)

    Tarique, S.; Wazir, S.; Moeen, G.

    2011-01-01

    Massive uncontrolled haemorrhage after childbirth is the leading cause of maternal death in developing countries. Postpartum haemorrhage is traditionally defined as blood loss of more than 500 ml after vaginal delivery and more than 1000 ml after caesarean section, but intraoperative estimation of blood loss is inaccurate. Uterine atony alone accounts for 75 - 90% of PPH. To estimate the effectiveness and safety of B-Lynch brace Suture in the management of primary postpartum haemorrhage (PPH). (author)

  6. The mutational spectrum of Lynch syndrome in cyprus.

    Directory of Open Access Journals (Sweden)

    Maria A Loizidou

    Full Text Available Lynch syndrome is the most common form of hereditary colorectal cancer and is caused by germline mutations in the mismatch repair (MMR genes MLH1, MSH2, MSH6 and PMS2. Mutation carriers have an increased lifetime risk of developing colorectal cancer as well as other extracolonic tumours. The aim of the current study was to evaluate the frequency and distribution of mutations in the MLH1, MSH2 and MSH6 genes within a cohort of Cypriot families that fulfilled the revised Bethesda guidelines. The study cohort included 77 patients who fulfilled at least one of the revised Bethesda guidelines. Mutational analysis revealed the presence of 4 pathogenic mutations, 3 in the MLH1 gene and 1 in the MSH2 gene, in 5 unrelated individuals. It is noted that out of the 4 pathogenic mutations detected, one is novel (c.1610delG in exon 14 of the MLH1 and has been detected for the first time in the Cypriot population. Overall, the pathogenic mutation detection rate in our patient cohort was 7%. This percentage is relatively low but could be explained by the fact that the sole criterion for genetic screening was compliance to the revised Bethesda guidelines. Larger numbers of Lynch syndrome families and screening of the two additional predisposition genes, PMS2 and EPCAM, are needed in order to decipher the full spectrum of mutations associated with Lynch syndrome predisposition in Cyprus.

  7. Systematic immunohistochemical screening for Lynch syndrome in colorectal cancer: a single centre experience of 486 patients.

    Science.gov (United States)

    Zumstein, Valentin; Vinzens, Fabrizio; Zettl, Andreas; Heinimann, Karl; Koeberle, Dieter; von Flüe, Markus; Bolli, Martin

    2016-01-01

    Germline mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 cause autosomal dominantly inherited Lynch syndrome. Lynch syndrome patients and their families benefit from life-saving intensive cancer surveillance. Approximately one in 30 colorectal cancers arises in the setting of Lynch syndrome. The aim of this study was to assess the detection rate of Lynch syndrome at our institution after introduction of systematic immunohistochemical screening for MMR deficiency in colorectal cancers from 2011 to 2015. Following the recommendations by the Evaluation of Genomic Applications in Practice and Prevention working group all colorectal cancers were immunohistochemically stained for the presence of MMR proteins MLH1, PMS2, MSH2 and MSH6, independent of clinical criteria. In the case of loss of MLH1, the somatic BRAF mutation V600E was assessed with molecular testing and/or immunohistochemistry. Clinical follow-up of potential Lynch syndrome carriers (patients with tumours showing loss of MLH1 expression with absence of BRAFV600E, loss of PMS2, MSH2 or MSH6) was evaluated. Of all patients (n = 486), loss of MMR protein expression was found in 73 (15.0%) tumours. Twenty-eight (6.0%) were classified as potential Lynch syndrome carriers. Of the genetically tested potential Lynch syndrome carriers (10 out of 28 patients), 40% were first diagnosed with Lynch syndrome. Implementation of systematic immunohistochemistry screening for Lynch syndrome showed that 6% of colorectal cancers were potentially Lynch-syndrome related. Tumour board protocols should systematically contain information on MMR status of all colorectal cancers and, in MMR deficient cases, include clear recommendations for genetic counselling for all potential Lynch syndrome patients.

  8. [Colorectal Carcinoma with Suspected Lynch Syndrome: A Multidisciplinary Algorithm].

    Science.gov (United States)

    Schneider, R; Schneider, C; Büttner, R; Reinacher-Schick, A; Tannapfel, A; Fürst, A; Rüschoff, J; Jakobeit, C; Royer-Pokora, B; Möslein, G

    2015-12-01

    Lynch syndrome is the most frequent hereditary cancer syndrome, accounting for approximately 3-5 % of all colorectal cancers. In addition, it is the most frequent predisposing hereditary cause of endometrial cancer and is also associated with gastric cancer, ovarian cancer, cancer of the urinary tract as well as several other cancers. In clinical practise Lynch syndrome is frequently not detected and many clinicians admit uncertainties regarding diagnostic procedures. Also, counselling of patients is considered difficult regarding therapeutic - especially prophylactic surgical and chemopreventive options and recommendations. Based on a review of available literature we discuss optimized strategies for improved detection of suspected Lynch syndrome patients. The aim of this review is to establish a clinical algorithm of how to proceed on a diagnostic level and to discuss surgical options at the time of a colorectal cancer. In order to identify patients with Lynch syndrome, family history should be ascertained and evaluated in regards to fulfilment of the Amsterdam-II- and/or the revised Bethesda criteria. Subsequently immunohistochemical staining for the mismatch-repair-genes, BRAF testing for MLH1 loss of expression, as well as testing for microsatellite instability in some, followed by genetic counselling and mutation analysis when indicated, is recommended. Pathological identification of suspected Lynch syndrome is readily feasible and straightforward. However, the need of performing these analyses in the tumor biopsy at the time of (gastroenterological) diagnosis of CRC neoplasia is essential, in order to offer patients the option of a prophylactically extended surgery and - as recommended in the German S3 guidelines - to discuss the option of a merely prophylactical hysterectomy and oophorectomy (if postmenopausal) in women. Close cooperation between gastroenterologists, pathologists and surgeons is warranted, so that patients may benefit from options of

  9. Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome : a cohort study

    NARCIS (Netherlands)

    Kempers, Marlies J. E.; Kuiper, Roland P.; Ockeloen, Charlotte W.; Chappuis, Pierre O.; Hutter, Pierre; Rahner, Nils; Schackert, Hans K.; Steinke, Verena; Holinski-Feder, Elke; Morak, Monika; Kloor, Matthias; Buettner, Reinhard; Verwiel, Eugene T. P.; van Krieken, J. Han; Nagtegaal, Iris D.; Goossens, Monique; van der Post, Rachel S.; Niessen, Renee C.; Sijmons, Rolf H.; Kluijt, Irma; Hogervorst, Frans B. L.; Leter, Edward M.; Gille, Johan J. P.; Aalfs, Cora M.; Redeker, Egbert J. W.; Hes, Frederik J.; Tops, Carli M. J.; van Nesselrooij, Bernadette P. M.; van Gijn, Marielle E.; Garcia, Encarna B. Gomez; Eccles, Diana M.; Bunyan, David J.; Syngal, Sapna; Stoffel, Elena M.; Culver, Julie O.; Palomares, Melanie R.; Graham, Tracy; Velsher, Lea; Papp, Janos; Olah, Edith; Chan, Tsun L.; Leung, Suet Y.; van Kessel, Ad Geurts; Kiemeney, Lambertus A. L. M.; Hoogerbrugge, Nicoline; Ligtenberg, Marjolijn J. L.

    Background Lynch syndrome is caused by germline mutations in MSH2, MLH1, MSH6, and PMS2 mismatch-repair genes and leads to a high risk of colorectal and endometrial cancer. We previously showed that constitutional 3' end deletions of EPCAM can cause Lynch syndrome through epigenetic silencing of

  10. Small-bowel cancer in Lynch syndrome : is it time for surveillance?

    NARCIS (Netherlands)

    Koornstra, Jan J.; Kleibeuker, Jan H.; Vasen, Hans F. A.

    Small-bowel cancer is part of the tumour spectrum of Lynch syndrome. Lynch syndrome, or hereditary non-polyposis colorectal cancer, is caused by germline mutations in one of the mismatch repair genes. Mutation carriers have an estimated lifetime risk for the development of small-bowel cancer of

  11. Predicting the impact of Lynch syndrome-causing missense mutations from structural calculations

    DEFF Research Database (Denmark)

    Nielsen, Sofie V,; Stein, Amelie; Dinitzen, Alexander B.

    2017-01-01

    selected the human mismatch repair protein, MSH2, where missense variants are known to cause the hereditary cancer predisposition disease, known as Lynch syndrome. We show that the majority of disease-causing MSH2 mutations give rise to folding defects and proteasome-dependent degradation rather than...... and for diagnosis of Lynch syndrome, and perhaps other hereditary diseases....

  12. Colorectal Cancer Risk in Patients With Lynch Syndrome and Inflammatory Bowel Disease

    NARCIS (Netherlands)

    Derikx, L.A.A.P.; Smits, L.J.T.; Lent-van Vliet, S. van; Dekker, E.; Aalfs, C.M.; Kouwen, M.C.A. van; Nagengast, F.M.; Nagtegaal, I.D.; Hoogerbrugge, N.; Hoentjen, F.

    2017-01-01

    Lynch syndrome and inflammatory bowel diseases (IBD) are associated with an increased risk of colorectal cancer (CRC). However, it is not clear whether the risk of CRC is even higher for patients with a combination of Lynch syndrome and IBD. We investigated the risk for CRC in this subgroup by

  13. Lynch Syndrome-Related Clear Cell Carcinoma of the Cervix: A Case Report

    Science.gov (United States)

    Nakamura, Kohei; Nakayama, Kentaro; Minamoto, Toshiko; Ishibashi, Tomoka; Ohnishi, Kaori; Yamashita, Hitomi; Ono, Ruriko; Sasamori, Hiroki; Razia, Sultana; Hossain, Mohammad Mahmud; Kamrunnahar, Shanta; Ishikawa, Masako; Ishikawa, Noriyoshi; Kyo, Satoru

    2018-01-01

    Lynch syndrome, a hereditary cancer syndrome, occurs because of germline mutations in at least one of four DNA mismatch repair genes (MutL Homolog 1 (MLH1), MutS Homolog 2 (MSH2), MutS Homolog 6 (MSH6), and PMS1 Homolog 2 (PMS2)). The disorder is associated with colorectal, endometrial, and other epithelial malignancies, but not cervical cancer. We report a woman with Lynch syndrome with synchronous cervical cancer. This is the first report of Lynch syndrome-related clear cell carcinoma of the cervix, which indicates the possibility of an association between cervical cancer and Lynch syndrome. Suitable genetic tests are required to determine whether common genetics can account for synchronous or subsequent malignancies in Lynch syndrome patients and their families. Such knowledge will also enhance our understanding of the genetic mechanisms governing the development of apparently unrelated cancers. PMID:29587389

  14. Lynch Syndrome-Related Clear Cell Carcinoma of the Cervix: A Case Report

    Directory of Open Access Journals (Sweden)

    Kohei Nakamura

    2018-03-01

    Full Text Available Lynch syndrome, a hereditary cancer syndrome, occurs because of germline mutations in at least one of four DNA mismatch repair genes (MutL Homolog 1 (MLH1, MutS Homolog 2 (MSH2, MutS Homolog 6 (MSH6, and PMS1 Homolog 2 (PMS2. The disorder is associated with colorectal, endometrial, and other epithelial malignancies, but not cervical cancer. We report a woman with Lynch syndrome with synchronous cervical cancer. This is the first report of Lynch syndrome-related clear cell carcinoma of the cervix, which indicates the possibility of an association between cervical cancer and Lynch syndrome. Suitable genetic tests are required to determine whether common genetics can account for synchronous or subsequent malignancies in Lynch syndrome patients and their families. Such knowledge will also enhance our understanding of the genetic mechanisms governing the development of apparently unrelated cancers.

  15. Lynch Syndrome-Related Clear Cell Carcinoma of the Cervix: A Case Report.

    Science.gov (United States)

    Nakamura, Kohei; Nakayama, Kentaro; Minamoto, Toshiko; Ishibashi, Tomoka; Ohnishi, Kaori; Yamashita, Hitomi; Ono, Ruriko; Sasamori, Hiroki; Razia, Sultana; Hossain, Mohammad Mahmud; Kamrunnahar, Shanta; Ishikawa, Masako; Ishikawa, Noriyoshi; Kyo, Satoru

    2018-03-25

    Lynch syndrome, a hereditary cancer syndrome, occurs because of germline mutations in at least one of four DNA mismatch repair genes (MutL Homolog 1 ( MLH1 ), MutS Homolog 2 ( MSH2 ), MutS Homolog 6 ( MSH6 ), and PMS1 Homolog 2 ( PMS2 )). The disorder is associated with colorectal, endometrial, and other epithelial malignancies, but not cervical cancer. We report a woman with Lynch syndrome with synchronous cervical cancer. This is the first report of Lynch syndrome-related clear cell carcinoma of the cervix, which indicates the possibility of an association between cervical cancer and Lynch syndrome. Suitable genetic tests are required to determine whether common genetics can account for synchronous or subsequent malignancies in Lynch syndrome patients and their families. Such knowledge will also enhance our understanding of the genetic mechanisms governing the development of apparently unrelated cancers.

  16. Early onset of colorectal cancer in a 13-year-old girl with Lynch syndrome.

    Science.gov (United States)

    Ahn, Do Hee; Rho, Jung Hee; Tchah, Hann; Jeon, In-Sang

    2016-01-01

    Lynch syndrome is the most common inherited colon cancer syndrome. Patients with Lynch syndrome develop a range of cancers including colorectal cancer (CRC) and carry a mutation on one of the mismatched repair (MMR) genes. Although CRC usually occurs after the fourth decade in patients with Lynch syndrome harboring a heterozygous MMR gene mutation, it can occur in children with Lynch syndrome who have a compound heterozygous or homozygous MMR gene mutation. We report a case of CRC in a 13-year-old patient with Lynch syndrome and congenital heart disease. This patient had a heterozygous mutation in MLH1 (an MMR gene), but no compound MMR gene defects, and a K-RAS somatic mutation in the cancer cells.

  17. Pine Creek uranium province

    International Nuclear Information System (INIS)

    Bower, M.B.; Needham, R.S.; Page, R.W.; Stuart-Smith, P.G.; Wyborn, L.A.I.

    1985-01-01

    The objective of this project is to help establish a sound geological framework of the Pine Creek region through regional geological, geochemical and geophysical studies. Uranium ore at the Coronation Hill U-Au mine is confined to a wedge of conglomerate in faulted contact with altered volcanics. The uranium, which is classified as epigenetic sandstone type, is derived from a uranium-enriched felsic volcanic source

  18. Universal Point of Care Testing for Lynch Syndrome in Patients with Upper Tract Urothelial Carcinoma.

    Science.gov (United States)

    Metcalfe, Michael J; Petros, Firas G; Rao, Priya; Mork, Maureen E; Xiao, Lianchun; Broaddus, Russell R; Matin, Surena F

    2018-01-01

    Patients with Lynch syndrome are at risk for upper tract urothelial carcinoma. We sought to identify the incidence and most reliable means of point of care screening for Lynch syndrome in patients with upper tract urothelial carcinoma. A total of 115 consecutive patients with upper tract urothelial carcinoma without a history of Lynch syndrome were universally screened during followup from January 2013 through July 2016. We evaluated patient and family history using AMS (Amsterdam criteria) I and II, and tumor immunohistochemistry for mismatch repair proteins and microsatellite instability. Patients who were positive for AMS I/II, microsatellite instability or immunohistochemistry were classified as potentially having Lynch syndrome and referred for clinical genetic analysis and counseling. Patients with known Lynch syndrome served as positive controls. Of the 115 patients 16 (13.9%) screened positive for potential Lynch syndrome. Of these patients 7.0% met AMS II criteria, 11.3% had loss of at least 1 mismatch repair protein and 6.0% had high microsatellite instability. All 16 patients were referred for germline testing, 9 completed genetic analysis and counseling, and 6 were confirmed to have Lynch syndrome. All 7 patients with upper tract urothelial carcinoma who had a known history of Lynch syndrome were positive for AMS II criteria and at least a single mismatch repair protein loss while 5 of 6 had high microsatellite instability. We identified 13.9% of upper tract urothelial carcinoma cases as potential Lynch syndrome and 5.2% as confirmed Lynch syndrome at the point of care. These findings have important implications for universal screening of upper tract urothelial carcinoma, representing one of the highest rates of undiagnosed genetic disease in a urological cancer. Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  19. Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database

    OpenAIRE

    Moller, Pal; Seppala, Toni; Bernstein, Inge; Holinski-Feder, Elke; Sala, Paola; Evans, D. Gareth; Lindblom, Annika; Macrae, Finlay; Blanco, Ignacio; Sijmons, Rolf; Jeffries, Jacqueline; Vasen, Hans; Burn, John; Nakken, Sigve; Hovig, Eivind

    2017-01-01

    Objective Estimates of cancer risk and the effects of surveillance in Lynch syndrome have been subject to bias, partly through reliance on retrospective studies. We sought to establish more robust estimates in patients undergoing prospective cancer surveillance.\\ud \\ud Design We undertook a multicentre study of patients carrying Lynch syndrome-associated mutations affecting MLH1, MSH2, MSH6 or PMS2. Standardised information on surveillance, cancers and outcomes were collated in an Oracle rela...

  20. Is there a role for prophylactic colectomy in Lynch syndrome patients with inflammatory bowel disease?

    Science.gov (United States)

    McNamara, Kate L; Aronson, Melyssa D; Cohen, Zane

    2016-01-01

    Lynch syndrome and chronic inflammatory bowel disease are two important risk factors for colorectal cancer. It is unclear whether Lynch syndrome patients with inflammatory bowel disease are at sufficiently increased risk for colorectal cancer to warrant prophylactic colectomy. This study aims to identify all cases of Lynch syndrome and concurrent inflammatory bowel disease in a large familial gastrointestinal cancer registry, define incidence of colorectal cancer, and characterize mismatch repair protein gene mutation status and inflammatory bowel disease-associated colorectal cancer risk factors. We retrospectively identified and collected clinical data for all cases with confirmed diagnoses of Lynch syndrome and inflammatory bowel disease in the Familial Gastrointestinal Cancer Registry at Mount Sinai Hospital in Toronto, Canada. Twelve cases of confirmed Lynch syndrome, and concurrent inflammatory bowel disease were identified. Four cases developed colorectal cancer. An additional five cases had colectomy; one was performed for severe colitis, and four were performed for low-grade dysplasia. None of these surgical specimens contained malignancy or high-grade dysplasia. The presentation of Lynch syndrome with inflammatory bowel disease is uncommon and not well described in the literature. This small but important series of twelve cases is the largest reported to date. In this series, patients with Lynch syndrome and concurrent inflammatory bowel disease do not appear to have sufficiently increased risk for colorectal cancer to recommend prophylactic surgery. Therefore, the decision to surgery should continue to be guided by surgical indications for each disease. Further evaluation of this important area will require multi-institutional input.

  1. Universal Versus Targeted Screening for Lynch Syndrome: Comparing Ascertainment and Costs Based on Clinical Experience.

    Science.gov (United States)

    Erten, Mujde Z; Fernandez, Luca P; Ng, Hank K; McKinnon, Wendy C; Heald, Brandie; Koliba, Christopher J; Greenblatt, Marc S

    2016-10-01

    Strategies to screen colorectal cancers (CRCs) for Lynch syndrome are evolving rapidly; the optimal strategy remains uncertain. We compared targeted versus universal screening of CRCs for Lynch syndrome. In 2010-2011, we employed targeted screening (age Lynch syndrome and estimated the 5-year costs of preventing CRC by colonoscopy screening, using a system dynamics model. Using targeted screening, 51/175 (29 %) cancers fit criteria and were tested by immunohistochemistry; 15/51 (29 %, or 8.6 % of all CRCs) showed suspicious loss of ≥1 mismatch repair protein. Germline mismatch repair gene mutations were found in 4/4 cases sequenced (11 suspected cases did not have germline testing). Using universal screening, 17/292 (5.8 %) screened cancers had abnormal immunohistochemistry suspicious for Lynch syndrome. Germline mismatch repair mutations were found in only 3/10 cases sequenced (7 suspected cases did not have germline testing). The mean cost to identify Lynch syndrome probands was ~$23,333/case for targeted screening and ~$175,916/case for universal screening at our institution. Estimated costs to identify and screen probands and relatives were: targeted, $9798/case and universal, $38,452/case. In real-world Lynch syndrome management, incomplete clinical follow-up was the major barrier to do genetic testing. Targeted screening costs 2- to 7.5-fold less than universal and rarely misses Lynch syndrome cases. Future changes in testing costs will likely change the optimal algorithm.

  2. Judy Creek and beyond

    International Nuclear Information System (INIS)

    Kerr, S.A.

    1999-01-01

    The story of the Pengrowth Energy Trust, a company created in 1988 to provide investors with an opportunity to participate in the oil and gas industry without the higher investment risk associated with exploratory drilling is the vehicle used to provide an overview of the development of the Judy Creek oil field, an historical sketch of Imperial Oil Limited, and of the development of the community of Swan Hills shed, a town carved out of muskeg by early pioneers in 1957-1958. The book is replete with anecdotes and photographs, depicting the indomitable spirit of the people whose determination and faith made the development of the oil industry in Alberta possible

  3. Mismatch repair deficiency commonly precedes adenoma formation in Lynch Syndrome-Associated colorectal tumorigenesis.

    Science.gov (United States)

    Sekine, Shigeki; Mori, Taisuke; Ogawa, Reiko; Tanaka, Masahiro; Yoshida, Hiroshi; Taniguchi, Hirokazu; Nakajima, Takeshi; Sugano, Kokichi; Yoshida, Teruhiko; Kato, Mamoru; Furukawa, Eisaku; Ochiai, Atsushi; Hiraoka, Nobuyoshi

    2017-08-01

    Lynch syndrome is a cancer predisposition syndrome caused by germline mutations in mismatch repair (MMR) genes. MMR deficiency is a ubiquitous feature of Lynch syndrome-associated colorectal adenocarcinomas; however, it remains unclear when the MMR-deficient phenotype is acquired during tumorigenesis. To probe this issue, the present study examined genetic alterations and MMR statuses in Lynch syndrome-associated colorectal adenomas and adenocarcinomas, in comparison with sporadic adenomas. Among the Lynch syndrome-associated colorectal tumors, 68 of 86 adenomas (79%) and all adenocarcinomas were MMR-deficient, whereas all the sporadic adenomas were MMR-proficient, as determined by microsatellite instability testing and immunohistochemistry for MMR proteins. Sequencing analyses identified APC or CTNNB1 mutations in the majority of sporadic adenomas (58/84, 69%) and MMR-proficient Lynch syndrome-associated adenomas (13/18, 72%). However, MMR-deficient Lynch syndrome-associated adenomas had less APC or CTNNB1 mutations (25/68, 37%) and frequent frameshift RNF43 mutations involving mononucleotide repeats (45/68, 66%). Furthermore, frameshift mutations affecting repeat sequences constituted 14 of 26 APC mutations (54%) in MMR-deficient adenomas whereas these frameshift mutations were rare in MMR-proficient adenomas in patients with Lynch syndrome (1/12, 8%) and in sporadic adenomas (3/52, 6%). Lynch syndrome-associated adenocarcinomas exhibited mutation profiles similar to those of MMR-deficient adenomas. Considering that WNT pathway activation sufficiently drives colorectal adenoma formation, the distinct mutation profiles of WNT pathway genes in Lynch syndrome-associated adenomas suggest that MMR deficiency commonly precedes adenoma formation.

  4. Prevalence of Lynch syndrome and Lynch-like syndrome among patients with colorectal cancer in a Japanese hospital-based population.

    Science.gov (United States)

    Chika, Noriyasu; Eguchi, Hidetaka; Kumamoto, Kensuke; Suzuki, Okihide; Ishibashi, Keiichiro; Tachikawa, Tetsuhiko; Akagi, Kiwamu; Tamaru, Jun-Ichi; Okazaki, Yasushi; Ishida, Hideyuki

    2017-02-09

    We investigated the prevalence of Lynch syndrome and Lynch-like syndrome among Japanese colorectal cancer patients, as there have been no credible data from Japan. Immunohistochemical analyses for mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) were carried out in surgically resected, formalin-fixed paraffin-embedded specimens obtained from 1,234 newly diagnosed colorectal cancer patients between March 2005 and April 2014. The presence/absence of the BRAF V600E mutation and hypermethylation of the MLH1 promoter was analyzed where necessary. Genetic testing was finally undertaken in patients suspected as having Lynch syndrome. By the universal screening approach with immunohistochemical analysis for mismatch repair proteins followed by analyses for the BRAF V600E mutation and MLH1 promoter methylation status, 11 (0.9%) of the 1,234 patients were identified as candidates for genetic testing. Out of the 11 patients, 9 (0.7%) were finally diagnosed as having Lynch syndrome; the responsible genes included MLH1 (n = 1), MSH2 (n = 4), EPCAM (n = 1) and MSH6 (n = 3). The remaining two patients (0.2%) were regarded as having Lynch-like syndrome, since biallelic somatic deletion of the relevant mismatch repair genes was detected in the absence of germline mismatch repair alterations. None of the cases was identified as having germline MLH1 epimutation. The prevalence of Lynch syndrome among all newly diagnosed cases of colorectal cancer in Japan is in the same range as that recently reported by studies in Western population. The prevalence of Lynch-like syndrome seems to be extremely low. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

  5. A review of statistical methods for testing genetic anticipation: looking for an answer in Lynch syndrome

    DEFF Research Database (Denmark)

    Boonstra, Philip S; Gruber, Stephen B; Raymond, Victoria M

    2010-01-01

    the issue of multiplex ascertainment and its effect on the different methods. We then focus on exploring genetic anticipation in Lynch syndrome and analyze new data on the age of onset in affected parent-child pairs from families seen at the University of Michigan Cancer Genetics clinic with a mutation...... in one of the three main mismatch repair (MMR) genes. In contrast to the clinic-based population, we re-analyze data on a population-based Lynch syndrome cohort, derived from the Danish HNPCC-register. Both datasets indicate evidence of genetic anticipation in Lynch syndrome. We then expand our review...

  6. SNP association study in PMS2-associated Lynch syndrome.

    Science.gov (United States)

    Ten Broeke, Sanne W; Elsayed, Fadwa A; Pagan, Lisa; Olderode-Berends, Maran J W; Garcia, Encarna Gomez; Gille, Hans J P; van Hest, Liselot P; Letteboer, Tom G W; van der Kolk, Lizet E; Mensenkamp, Arjen R; van Os, Theo A; Spruijt, Liesbeth; Redeker, Bert J W; Suerink, Manon; Vos, Yvonne J; Wagner, Anja; Wijnen, Juul T; Steyerberg, E W; Tops, Carli M J; van Wezel, Tom; Nielsen, Maartje

    2017-11-17

    Lynch syndrome (LS) patients are at high risk of developing colorectal cancer (CRC). Phenotypic variability might in part be explained by common susceptibility loci identified in Genome Wide Association Studies (GWAS). Previous studies focused mostly on MLH1, MSH2 and MSH6 carriers, with conflicting results. We aimed to determine the role of GWAS SNPs in PMS2 mutation carriers. A cohort study was performed in 507 PMS2 carriers (124 CRC cases), genotyped for 24 GWAS SNPs, including SNPs at 11q23.1 and 8q23.3. Hazard ratios (HRs) were calculated using a weighted Cox regression analysis to correct for ascertainment bias. Discrimination was assessed with a concordance statistic in a bootstrap cross-validation procedure. Individual SNPs only had non-significant associations with CRC occurrence with HRs lower than 2, although male carriers of allele A at rs1321311 (6p21.31) may have increased risk of CRC (HR = 2.1, 95% CI 1.2-3.0). A polygenic risk score (PRS) based on 24 HRs had an HR of 2.6 (95% CI 1.5-4.6) for the highest compared to the lowest quartile, but had no discriminative ability (c statistic 0.52). Previously suggested SNPs do not modify CRC risk in PMS2 carriers. Future large studies are needed for improved risk stratification among Lynch syndrome patients.

  7. History, genetics, and strategies for cancer prevention in Lynch syndrome.

    Science.gov (United States)

    Kastrinos, Fay; Stoffel, Elena M

    2014-05-01

    Colorectal cancer (CRC) is the most common gastrointestinal malignancy and the third cause of cancer death in men and women in the United States. The majority of CRC cases diagnosed annually are due to sporadic events, but up to 6% are attributed to known monogenic disorders that confer a markedly increased risk for the development of CRC and multiple extracolonic malignancies. Lynch syndrome is the most common inherited CRC syndrome and is associated with mutations in DNA mismatch repair genes, mainly MLH1 and MSH2 but also MSH6, PMS2, and EPCAM. Although the risk of CRC and endometrial cancer may approach near 75% and 50%, respectively, in gene mutation carriers, the identification of these individuals and at-risk family members through predictive genetic testing provides opportunities for cancer prevention including specialized cancer screening, intensified surveillance, and/or prophylactic surgeries. This article will provide a review of the major advances in risk assessment, molecular genetics, DNA mutational analyses, and cancer prevention and management made since Lynch syndrome was first described 100 years ago. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

  8. “Silencio”: hearing loss in David Lynch's Mulholland Drive

    Directory of Open Access Journals (Sweden)

    Allister Mactaggart

    2014-11-01

    Full Text Available In a filmmaking career replete with extraordinary images and sounds, David Lynch's Mulholland Drive (2001 stands out for attention as a striking and seemingly inexhaustible resource for analysis. In this article, this film is used to examine the specific ways in which Lynch uses pre-existing pop songs to wrap the spectator within the filmic soundscape. Nowhere is the complexity and uncanniness of pop music made more explicit than in Rebekah Del Rio's stunning performance of “Llorando (Crying” in the Club Silencio scene. The split between the singer's powerful performance and her subsequent collapse with the sound of the voice left hanging in the air marks a pivotal point in the film. This scene, coupled with other examples of feminine jouissance, is contrasted with the deadening roar of the master's voice, which solely demands obedience but is deaf to any reply. At the core of this article is an analysis of the status of the voice (and the gaze as examples of the Lacanian object a and its relationship to Marx's concept of surplus value. Mulholland Drive provides a powerful demonstration of how these concepts can be seen, heard, and felt in relation to film, and how sound can reverberate into the spaces and silences beyond the screen.

  9. LYNCHING IN RUSSIAN COUNTRYSIDE (late XIX-early XX

    Directory of Open Access Journals (Sweden)

    Vladimir Borisovich Bezgin

    2013-08-01

    Full Text Available Research actuality is due to the frequent attempts of extrajudicial killings of criminals in the country as a result of the citizens' law enforcement distrust, their doubt of deserved retribution.Such phenomenon of legal life of the Russian countryside as a lynch mob is studied in the article on the basis of a wide range of archival and ethnographic sources. The author analyzes the crimes for which the perpetrators are arbitrarily subjected to massacre in the village. The role of the peasant community in the punishment implementation of criminals was found out. The causes of the stability of this tradition in rural society were set.Lynching played an effective means of suppression of unlawful acts of the peasants. The collective nature of the spontaneously created killings of criminals was the result of mutual responsibility of community members and rural solidarity preservation condition. According to farmers gathering verdict gave legal force to massacre and left no doubt about the justice of the decision.DOI: http://dx.doi.org/10.12731/2218-7405-2013-8-1

  10. Novel Implications in Molecular Diagnosis of Lynch Syndrome

    Directory of Open Access Journals (Sweden)

    Raffaella Liccardo

    2017-01-01

    Full Text Available About 10% of total colorectal cancers are associated with known Mendelian inheritance, as Familial Adenomatous Polyposis (FAP and Lynch syndrome (LS. In these cancer types the clinical manifestations of disease are due to mutations in high-risk alleles, with a penetrance at least of 70%. The LS is associated with germline mutations in the DNA mismatch repair (MMR genes. However, the mutation detection analysis of these genes does not always provide informative results for genetic counseling of LS patients. Very often, the molecular analysis reveals the presence of variants of unknown significance (VUSs whose interpretation is not easy and requires the combination of different analytical strategies to get a proper assessment of their pathogenicity. In some cases, these VUSs may make a more substantial overall contribution to cancer risk than the well-assessed severe Mendelian variants. Moreover, it could also be possible that the simultaneous presence of these genetic variants in several MMR genes that behave as low risk alleles might contribute in a cooperative manner to increase the risk of hereditary cancer. In this paper, through a review of the recent literature, we have speculated a novel inheritance model in the Lynch syndrome; this could pave the way toward new diagnostic perspectives.

  11. Lynch syndrome in South America: past, present and future.

    Science.gov (United States)

    Vaccaro, Carlos A; Sarroca, Carlos; Rossi, Benedito; Lopez-Kostner, Francisco; Dominguez, Mev; Calo, Natalia Causada; Cutait, Raul; Valle, Adriana Della; Nuñez, Lina; Neffa, Florencia; Alvarez, Karin; Gonzalez, Maria Laura; Kalfayan, Pablo; Lynch, Henry T; Church, James

    2016-07-01

    After decades of unawareness about Lynch syndrome, the medical community in South America is increasingly interested and informed. The visits and support of mentors like H. T. Lynch had been crucial to this awakening. Several countries have at least one registry with skilled personnel in genetic counseling and research. However, this only represents a very restricted resource for the region. According to the GETH, there are 27 hereditary cancer care centers in South America (21 in Brazil, 3 in Argentina, 1 in Uruguay, 1 in Chile and 1 in Peru). These registries differ in fundamental aspects of function, capabilities and funding, but are able to conduct high quality clinical, research and educational activities due to the dedication and personal effort of their members, and organizational support. More support from the governments as well as the participation of the community would boost the initiatives of people leading these groups. Meantime, the collaboration among the South American registries and the involvement of registries and leaders from developed countries will allow to maximize the efficiency in caring for affected patients and their families. The aim of this article is to describe how the knowledge of LS began to be spread in South America, how the first registries were organized and to summarize the current state of progress. In addition, we will provide an update of the clinical and molecular findings in the region.

  12. Ship Creek bioassessment investigations

    Energy Technology Data Exchange (ETDEWEB)

    Cushing, C.E.; Mueller, R.P.; Murphy, M.T.

    1995-06-01

    Pacific Northwest Laboratory (PNL) was asked by Elmendorf Air Force Base (EAFB) personnel to conduct a series of collections of macroinvertebrates and sediments from Ship Creek to (1) establish baseline data on these populations for reference in evaluating possible impacts from Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) activities at two operable units, (2) compare current population indices with those found by previous investigations in Ship Creek, and (3) determine baseline levels of concentrations of any contaminants in the sediments associated with the macroinvertebrates. A specific suite of indices established by the US Environmental Protection Agency (EPA) was requested for the macroinvertebrate analyses; these follow the Rapid Bioassessment Protocol developed by Plafkin et al. (1989) and will be described. Sediment sample analyses included a Microtox bioassay and chemical analysis for contaminants of concern. These analyses included, volatile organic compounds, total gasoline and diesel hydrocarbons (EPA method 8015, CA modified), total organic carbon, and an inductive-coupled plasma/mass spectrometry (ICP/MS) metals scan. Appendix A reports on the sediment analyses. The Work Plan is attached as Appendix B.

  13. The Failure of Lehman Brothers and Merril Lynch: A Lesson for the ...

    African Journals Online (AJOL)

    DR Nneka

    the United State America treasury securities market. Ahimie (2008) ... Thus, the above school of thought considered a bank failure as not when it ceases .... Lynch had further confirmed the historical fact that, no bank or financial institution is.

  14. Surveillance colonoscopy practice in Lynch syndrome in the Netherlands : A nationwide survey

    NARCIS (Netherlands)

    Koornstra, Jan J.; Vasen, Hans Fa

    2007-01-01

    Lynch syndrome, or hereditary nonpolyposis colorectal cancer (HNPCC), is the most common genetic disorder predisposing to colorectal cancer. As regular colonoscopic surveillance has been shown to reduce the incidence of colorectal cancer, this strategy is recommended worldwide. Recently, several

  15. A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome

    DEFF Research Database (Denmark)

    Clendenning, Mark; Senter, Leigha; Hampel, Heather

    2008-01-01

    BACKGROUND: When compared to the other mismatch repair genes involved in Lynch syndrome, the identification of mutations within PMS2 has been limited (Lynch syndrome cases...... on immunohistochemical analysis. RESULTS: We have identified a frequently occurring frame-shift mutation (c.736_741del6ins11) in 12 ostensibly unrelated Lynch syndrome patients (20% of patients we have identified with a deleterious mutation in PMS2, n=61). These individuals all display the rare allele (population...... and Swedish ancestry. We estimate that there are >10,000 carriers of this mutation in the United States alone. The identification of both the mutation and the common haplotype in one Swedish control sample (n = 225), along with evidence that Lynch syndrome associated cancers are rarer than expected...

  16. Distinct gene expression profiles in ovarian cancer linked to Lynch syndrome

    DEFF Research Database (Denmark)

    Jönsson, Jenny-Maria; Bartuma, Katarina; Dominguez-Valentin, Mev

    2014-01-01

    Ovarian cancer linked to Lynch syndrome represents a rare subset that typically presents at young age as early-stage tumors with an overrepresentation of endometrioid and clear cell histologies. We investigated the molecular profiles of Lynch syndrome-associated and sporadic ovarian cancer...... with the aim to identify key discriminators and central tumorigenic mechanisms in hereditary ovarian cancer. Global gene expression profiling using whole-genome c-DNA-mediated Annealing, Selection, extension, and Ligation was applied to 48 histopathologically matched Lynch syndrome-associated and sporadic...... ovarian cancers. Lynch syndrome-associated and sporadic ovarian cancers differed by 349 significantly deregulated genes, including PTPRH, BIRC3, SHH and TNFRSF6B. The genes involved were predominantly linked to cell growth, proliferation, and cell-to-cell signaling and interaction. When stratified...

  17. Upper tract urothelial carcinomas: frequency of association with mismatch repair protein loss and lynch syndrome.

    Science.gov (United States)

    Harper, Holly L; McKenney, Jesse K; Heald, Brandie; Stephenson, Andrew; Campbell, Steven C; Plesec, Thomas; Magi-Galluzzi, Cristina

    2017-01-01

    Increased risk for upper tract urothelial carcinoma is described in patients with Lynch syndrome, caused by germline mutations in mismatch repair genes. We aimed to identify the frequency of mismatch repair protein loss in upper tract urothelial carcinoma and its potential for identifying an association with Lynch syndrome. We queried our database to identify upper tract urothelial carcinomas. Patients were cross-referenced for history of colorectal carcinoma or other common Lynch syndrome-associated neoplasms to enrich for potential Lynch syndrome cases. Tumor histopathologic characteristics were reviewed and each case was analyzed for loss of mismatch repair proteins, MLH1, MSH2, MSH6, and PMS2, by immunohistochemistry. Of 444 patients with upper tract urothelial carcinoma, a subset of 215 (encompassing 30 with upper tract urothelial carcinoma and another common Lynch syndrome-associated neoplasm) was analyzed for loss of mismatch repair protein expression. Of 30 patients with Lynch syndrome-associated neoplasms, six had documented Lynch syndrome, including two with Muir-Torre syndrome. Mismatch repair protein loss was identified in 7% of total upper tract urothelial carcinomas and 30% of patients with Lynch syndrome-associated neoplasms (including all patients with Lynch syndrome/Muir-Torre syndrome). Of patients without history of Lynch syndrome-associated neoplasms, 5 of 184 (2.7%) had loss of mismatch repair protein expression. Twelve cases with mismatch repair protein loss demonstrated loss of MSH2 and MSH6, and 2 had isolated loss of MSH6. MLH1 and PMS2 expression were consistently retained. Although increased intratumoral lymphocytes, inverted growth, pushing tumor-stromal interface, and lack of nuclear pleomorphism were more commonly seen in cases with mismatch repair protein loss, only intratumoral lymphocytes and presence of pushing borders were statistically significant. MLH1 and PMS2 testing appear to have little utility in upper tract urothelial

  18. Bridge Creek IMW database - Bridge Creek Restoration and Monitoring Project

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The incised and degraded habitat of Bridge Creek is thought to be limiting a population of ESA-listed steelhead (Oncorhynchus mykiss). A logical restoration approach...

  19. Common mutations identified in the MLH1 gene in familial Lynch syndrome

    OpenAIRE

    Jisha Elias; Coral Karunakaran; Snigdha Majumder; Malini Manoharan; Rakshit Shah; Yogesh Mistry; Rajesh Ramanuj; Niraj Bhatt; Arati Khanna- Gupta

    2017-01-01

    Lynch syndrome (Hereditary Non Polyposis Colorectal Cancer, HNPCC) is one of the most common hereditary familial colorectal cancers (CRC) with an autosomal dominant pattern of inheritance. It accounts for 2-5% of the total CRCs reported worldwide. Although a lower incidence for CRCs have been observed in India, the last decade has shown a remarkable increase of CRC incidences (2-4 %). Features of Lynch syndrome associated colorectal cancer include early age of cancer onset, accelerated car...

  20. Distinct Gene Expression Signatures in Lynch Syndrome and Familial Colorectal Cancer Type X

    DEFF Research Database (Denmark)

    Valentin, Mev; Therkildsen, Christina; Veerla, Srinivas

    2013-01-01

    Heredity is estimated to cause at least 20% of colorectal cancer. The hereditary nonpolyposis colorectal cancer subset is divided into Lynch syndrome and familial colorectal cancer type X (FCCTX) based on presence of mismatch repair (MMR) gene defects.......Heredity is estimated to cause at least 20% of colorectal cancer. The hereditary nonpolyposis colorectal cancer subset is divided into Lynch syndrome and familial colorectal cancer type X (FCCTX) based on presence of mismatch repair (MMR) gene defects....

  1. Clinicopathological Features and Management of Cancers in Lynch Syndrome

    Directory of Open Access Journals (Sweden)

    Markku Aarnio

    2012-01-01

    Full Text Available Lynch syndrome (LS is characterized by an autosomal dominant inheritance of the early onset of colorectal cancer (CRC and endometrial cancer, as well as increased risk for several other cancers including gastric, urinary tract, ovarian, small bowel, biliary tract, and brain tumors. The syndrome is due to a mutation in one of the four DNA mismatch repair (MMR genes MLH1, MSH2, MSH6, or PMS2. The majority of LS patients and families can now be identified, and the underlying mutation detected using genetic diagnostics. Regular surveillance for CRC and endometrial cancer has proved beneficial for mutation carriers. However, screening for other tumors is also recommended even though experiences in the screening of these tumors is limited. Prophylactic colectomy, prophylactic hysterectomy, and bilateral salpingo-oophorectomy may be reasonable options for selected patients with LS. This paper describes the features and management of LS.

  2. Tidal Creek Sentinel Habitat Database

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Ecological Research, Assessment and Prediction's Tidal Creeks: Sentinel Habitat Database was developed to support the National Oceanic and Atmospheric...

  3. Big Bayou Creek and Little Bayou Creek Watershed Monitoring Program

    Energy Technology Data Exchange (ETDEWEB)

    Kszos, L.A.; Peterson, M.J.; Ryon; Smith, J.G.

    1999-03-01

    Biological monitoring of Little Bayou and Big Bayou creeks, which border the Paducah Site, has been conducted since 1987. Biological monitoring was conducted by University of Kentucky from 1987 to 1991 and by staff of the Environmental Sciences Division (ESD) at Oak Ridge National Laboratory (ORNL) from 1991 through March 1999. In March 1998, renewed Kentucky Pollutant Discharge Elimination System (KPDES) permits were issued to the US Department of Energy (DOE) and US Enrichment Corporation. The renewed DOE permit requires that a watershed monitoring program be developed for the Paducah Site within 90 days of the effective date of the renewed permit. This plan outlines the sampling and analysis that will be conducted for the watershed monitoring program. The objectives of the watershed monitoring are to (1) determine whether discharges from the Paducah Site and the Solid Waste Management Units (SWMUs) associated with the Paducah Site are adversely affecting instream fauna, (2) assess the ecological health of Little Bayou and Big Bayou creeks, (3) assess the degree to which abatement actions ecologically benefit Big Bayou Creek and Little Bayou Creek, (4) provide guidance for remediation, (5) provide an evaluation of changes in potential human health concerns, and (6) provide data which could be used to assess the impact of inadvertent spills or fish kill. According to the cleanup will result in these watersheds [Big Bayou and Little Bayou creeks] achieving compliance with the applicable water quality criteria.

  4. Thyroid cancer in a patient with Lynch syndrome - case report and literature review.

    Science.gov (United States)

    Fazekas-Lavu, Monika; Parker, Andrew; Spigelman, Allan D; Scott, Rodney J; Epstein, Richard J; Jensen, Michael; Samaras, Katherine

    2017-01-01

    Lynch syndrome describes a familial cancer syndrome comprising germline mutations in one of four DNA mismatch repair genes, MLH1 , MSH2 , MSH6 , and PMS2 and is characterized by colorectal, endometrial, and other epithelial malignancies. Thyroid cancer is not usually considered to be part of the constellation of Lynch syndrome cancers nor have Lynch syndrome tumor gene mutations been reported in thyroid malignancies. This study reports a woman with Lynch syndrome (colonic cancer and a DNA mismatch repair mutation in the MSH2 gene) with a synchronous papillary thyroid cancer. Six years later, she developed metachronous breast cancer. Metastatic bone disease developed after 3 years, and the disease burden was due to both breast and thyroid diseases. Despite multiple interventions for both metastatic breast and thyroid diseases, the patient's metastatic burden progressed and she died of leptomeningeal metastatic disease. Two prior case reports suggested thyroid cancer may be an extraintestinal malignancy of the Lynch syndrome cancer group. Hence, this study examined the genetic relationship between the patient's known Lynch syndrome and her thyroid cancer. The thyroid cancer tissue showed normal expression of MSH2 , suggesting that the tumor was not due to the oncogenic mutation of Lynch syndrome, and molecular analysis confirmed BRAF V600E mutation. Although in this case the thyroid cancer was sporadic, it raises the importance of considering cancer genetics in familial cancer syndromes when other cancers do not fit the criteria of the syndrome. Careful documentation of other malignancies in patients with thyroid cancer and their families would assist in better understanding of any potential association. Appropriate genetic testing will clarify whether a common pathogenic mechanism links seemingly unrelated cancers.

  5. Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance : first report from the prospective Lynch syndrome database

    NARCIS (Netherlands)

    Moller, Pal; Seppala, Toni; Bernstein, Inge; Holinski-Feder, Elke; Sala, Paola; Evans, D. Gareth; Lindblom, Annika; Macrae, Finlay; Blanco, Ignacio; Sijmons, Rolf; Jeffries, Jacqueline; Vasen, Hans; Burn, John; Nakken, Sigve; Hovig, Eivind; Rodland, Einar Andreas; Tharmaratnam, Kukatharmini; Cappel, Wouter H. de Vos Tot Nederveen; Hill, James; Wijnen, Juul; Green, Kate; Lalloo, Fiona; Sunde, Lone; Mints, Miriam; Bertario, Lucio; Pineda, Marta; Navarro, Matilde; Morak, Monika; Renkonen-Sinisalo, Laura; Frayling, Ian M.; Plazzer, John-Paul; Pylvanainen, Kirsi; Sampson, Julian R.; Capella, Gabriel; Mecklin, Jukka-Pekka; Moslein, Gabriela

    Objective Estimates of cancer risk and the effects of surveillance in Lynch syndrome have been subject to bias, partly through reliance on retrospective studies. We sought to establish more robust estimates in patients undergoing prospective cancer surveillance. Design We undertook a multicentre

  6. Pine creek geosyncline

    International Nuclear Information System (INIS)

    Needham, R.S.; Ewers, G.R.; Ferguson, J.

    1988-01-01

    The Pine Creek Geosyncline is a 66,000 km 2 inlier of Early Proterozoic metasediments, mafic and felsic intrusives and minor extrusives, surrounding small late Archaean granitic domes. Economic uranium occurrences cluster into three fields, with the Alligator Rivers field being the most significant. The metasediments are alluvial and reduced shallow-water pelites and psammites. Evaporitic carbonate developed on shallow shelves around Archaean islands. Basin development and sedimentation (c. 2000-1870 Ma) were related to gradual subsidence induced by crustal extension. Facies variations and volcanism were in places controlled by the extensional faults. The rocks were metamorphosed to lower the high grade, complexly folded, and intruded by numerous granitoids from c. 1870 to 1730 Ma. Late orogenic felsic volcanics accumulated in local rift systems. Middle Proterozoic sandstone was deposited on a peneplaned and deeply weathered surface from about 1650 Ma. Uranium is enriched in some Archaean and Proterozoic igneous rocks, but there is no local or regional enrichment of the metasedimentary hosts or of the unconformably overlying sandstone. There is no regional gravity, magnetic or radiometric character attributable to the region's significance as a uranium province; contrasts with surrounding sedimentary basins reflect expected differences in rock properties between a heterogeneous igneous/metamorphic region and relatively homogeneous undeformed and unmineralized sediments. Uranium-enriched Archaean and Proterozoic granitoids and felsic volcanics with labile U are likely though not exclusive source rocks. U was probably transported in oxidized low temperature solutions as uranyl complexes and precipitated in reduced, structurally controlled, low-pressure traps. All uranium occurrences are broadly classified as 'Proterozoic unconformity related'. Greatest potential for further discovery is offered in the Alligator Rivers field, where perhaps at least 3 to 5.5 times the

  7. TumorNext-Lynch-MMR: a comprehensive next generation sequencing assay for the detection of germline and somatic mutations in genes associated with mismatch repair deficiency and Lynch syndrome.

    Science.gov (United States)

    Gray, Phillip N; Tsai, Pei; Chen, Daniel; Wu, Sitao; Hoo, Jayne; Mu, Wenbo; Li, Bing; Vuong, Huy; Lu, Hsiao-Mei; Batth, Navanjot; Willett, Sara; Uyeda, Lisa; Shah, Swati; Gau, Chia-Ling; Umali, Monalyn; Espenschied, Carin; Janicek, Mike; Brown, Sandra; Margileth, David; Dobrea, Lavinia; Wagman, Lawrence; Rana, Huma; Hall, Michael J; Ross, Theodora; Terdiman, Jonathan; Cullinane, Carey; Ries, Savita; Totten, Ellen; Elliott, Aaron M

    2018-04-17

    The current algorithm for Lynch syndrome diagnosis is highly complex with multiple steps which can result in an extended time to diagnosis while depleting precious tumor specimens. Here we describe the analytical validation of a custom probe-based NGS tumor panel, TumorNext-Lynch-MMR, which generates a comprehensive genetic profile of both germline and somatic mutations that can accelerate and streamline the time to diagnosis and preserve specimen. TumorNext-Lynch-MMR can detect single nucleotide variants, small insertions and deletions in 39 genes that are frequently mutated in Lynch syndrome and colorectal cancer. Moreover, the panel provides microsatellite instability status and detects loss of heterozygosity in the five Lynch genes; MSH2 , MSH6 , MLH1 , PMS2 and EPCAM . Clinical cases are described that highlight the assays ability to differentiate between somatic and germline mutations, precisely classify variants and resolve discordant cases.

  8. Water quality study at the Congaree Swamp National monument of Myers Creek, Reeves Creek and Toms Creek. Technical report

    International Nuclear Information System (INIS)

    Rikard, M.

    1991-11-01

    The Congaree Swamp National Monument is one of the last significant near virgin tracts of bottom land hardwood forests in the Southeast United States. The study documents a water quality monitoring program on Myers Creek, Reeves Creek and Toms Creek. Basic water quality parameters were analyzed. High levels of aluminum and iron were found, and recommendations were made for further monitoring

  9. The Course of Law: State Intervention in Southern Lynch Mob Violence 1882–1930

    Directory of Open Access Journals (Sweden)

    Kinga Makovi

    2016-09-01

    Full Text Available Collective violence when framed by its perpetrators as "citizen" justice is inherently a challenge to state legitimacy. To properly account for such violence, it is necessary to consider an opportunity structure incorporating the actions of both vigilantes and agents of the state. The motivation and lethality of lynch mobs in the South cannot be understood without considering how the state reacted to the legitimacy challenges posed by lynching. We trace the shifting orientation of state agents to lynching attempts between the end of Reconstruction and the start of the Great Depression. Analyzing an inventory of more than 1,000 averted and completed lynching events in three Southern states, we model geographic and temporal patterns in the determinants of mob formation, state intervention, and intervention success. Opponents of lynching often pled with mobs to "let the law take its course." This article examines the course followed by the law itself, as state actors moved between encouraging, accommodating, and in many instances averting mob violence.

  10. How does genetic risk information for Lynch syndrome translate to risk management behaviours?

    Science.gov (United States)

    Steel, Emma; Robbins, Andrew; Jenkins, Mark; Flander, Louisa; Gaff, Clara; Keogh, Louise

    2017-01-01

    There is limited research on why some individuals who have undergone predictive genetic testing for Lynch syndrome do not adhere to screening recommendations. This study aimed to explore qualitatively how Lynch syndrome non-carriers and carriers translate genetic risk information and advice to decisions about risk managment behaviours in the Australian healthcare system. Participants of the Australasian Colorectal Cancer Family Registry who had undergone predictive genetic testing for Lynch syndrome were interviewed on their risk management behaviours. Transcripts were analysed thematically using a comparative coding analysis. Thirty-three people were interviewed. Of the non-carriers ( n  = 16), 2 reported having apparently unnecessary colonoscopies, and 6 were unsure about what population-based colorectal cancer screening entails. Of the carriers ( n  = 17), 2 reported they had not had regular colonoscopies, and spoke about their discomfort with the screening process and a lack of faith in the procedure's ability to reduce their risk of developing colorectal cancer. Of the female carriers ( n  = 9), 2 could not recall being informed about the associated risk of gynaecological cancers. Non-carriers and female carriers of Lynch syndrome could benefit from further clarity and advice about appropriate risk management options. For those carriers who did not adhere to colonoscopy screening, a lack of faith in both genetic test results and screening were evident. It is essential that consistent advice is offered to both carriers and non-carriers of Lynch syndrome.

  11. Asotin Creek Model Watershed Plan

    Energy Technology Data Exchange (ETDEWEB)

    Browne, D.; Holzmiller, J.; Koch, F.; Polumsky, S.; Schlee, D.; Thiessen, G.; Johnson, C.

    1995-04-01

    The Asotin Creek Model Watershed Plan is the first to be developed in Washington State which is specifically concerned with habitat protection and restoration for salmon and trout. The plan is consistent with the habitat element of the ``Strategy for Salmon``. Asotin Creek is similar in many ways to other salmon-bearing streams in the Snake River system. Its watershed has been significantly impacted by human activities and catastrophic natural events, such as floods and droughts. It supports only remnant salmon and trout populations compared to earlier years. It will require protection and restoration of its fish habitat and riparian corridor in order to increase its salmonid productivity. The watershed coordinator for the Asotin County Conservation District led a locally based process that combined local concerns and knowledge with technology from several agencies to produce the Asotin Creek Model Watershed Plan.

  12. Targeted Screening With Combined Age- and Morphology-Based Criteria Enriches Detection of Lynch Syndrome in Endometrial Cancer.

    Science.gov (United States)

    Lin, Douglas I; Hecht, Jonathan L

    2016-06-01

    Endometrial cancer is associated with Lynch syndrome in 2% to 6% of cases. Adequate screening may prevent of a second cancer and incident cancers in family members via risk-reducing strategies. The goal of the study was to evaluate the detection rate of Lynch syndrome via a targeted screening approach. In 2009, we incorporated targeted Lynch syndrome screening via immunohistochemistry for MLH1, PMS2, MSH2, and MSH6, followed by MLH1 promoter hypermethylation, in select cases of endometrial carcinoma. Criteria for patient selection included (1) all patients Lynch syndrome. Therefore, targeted screening with combined age and morphology based criteria enriches detection of Lynch syndrome in endometrial cancer. However, the detection rate is lower than the rates from published series that offer universal screening. © The Author(s) 2016.

  13. Gain of chromosomal region 20q and loss of 18 discriminates between Lynch syndrome and familial colorectal cancer

    DEFF Research Database (Denmark)

    Therkildsen, Christina; Jönsson, Göran; Dominguez-Valentin, Mev

    2013-01-01

    Lynch syndrome and familial colorectal cancer type X, FCCTX, represent the two predominant colorectal cancer syndromes. Whereas Lynch syndrome is clinically and genetically well defined, the genetic cause of FCCTX is unknown and genomic differences between Lynch syndrome and FCCTX tumours...... are largely unknown. We applied array-based comparative genomic hybridisation to 23 colorectal cancers from FCCTX with comparison to 23 Lynch syndrome tumours and to 45 sporadic colorectal cancers. FCCTX tumours showed genomic complexity with frequent gains on chromosomes 20q, 19 and 17 and losses of 18, 8p...... and 15. Gain of genetic material in two separate regions encompassing, 20q12-13.12 and 20q13.2-13.32, was identified in 65% of the FCCTX tumours. Gain of material on chromosome 20q and loss on chromosome 18 significantly discriminated colorectal cancers associated with FCCTX from Lynch syndrome, which...

  14. 33 CFR 117.331 - Snake Creek.

    Science.gov (United States)

    2010-07-01

    ... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Snake Creek. 117.331 Section 117.331 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS Specific Requirements Florida § 117.331 Snake Creek. The draw of the Snake Creek...

  15. Some aspects of molecular diagnostics in Lynch syndrome

    Directory of Open Access Journals (Sweden)

    Kurzawski Grzegorz

    2006-12-01

    Full Text Available Abstract This manuscript is composed of five parts which summarize five publications in succession. Essentially, they are concerned with molecular diagnostics of Lynch syndrome and are based on studies in 238 families. The finding that young age at diagnosis is the key feature in patients with MSH2 and MLH1 mutations (Part 1 has helped to define simple criteria for the preliminary diagnosis of this syndrome. A cheaper method for the detection of mutations has been developed (Part 2 and applied to study the types of mutations and their prevalence in Poland (Part 3 and the Baltic States (Part 4. A specific feature of these mutations, i.e. presence of recurrent mutations in the majority of affected families with mutations, has suggested the feasibility of effective diagnostics with a single test disclosing all of them. An attempt to reveal other causes of familial aggregation of colorectal cancer has ruled out any association with C insertion in the NOD2 gene (Part 5.

  16. Lynch syndrome in the 21st century: clinical perspectives.

    Science.gov (United States)

    Tiwari, A K; Roy, H K; Lynch, H T

    2016-03-01

    Lynch syndrome (LS) is the most common of all inherited cancer syndromes, associated with substantially elevated risks for colonic and extracolonic malignancies, earlier onset and high rates of multiple primary cancers. At the genetic level, it is caused by a defective mismatch repair (MMR) system due to presence of germline defects in at least one of the MMR genes- MLH1, MSH2, MSH6, PMS2 or EPCAM. An impaired MMR function during replication introduces infidelity in DNA sequence and leads to ubiquitous mutations at simple repetitive sequences (microsatellites), causing microsatellite instability (MSI). Although previously, clinicopathological criteria such as Amsterdam I/II and Revised Bethesda Guidelines were commonly used to identify suspected LS mutation carriers, there has been a recent push towards universally testing, especially in case of colorectal cancers (CRCs), through immunohistochemistry for expression of MMR proteins or through molecular tests (polymerase chain reaction, PCR) for MSI, in order to identify LS mutation carriers and subject them to genetic testing to ascertain the specific gene implicated. In this review, we have discussed the latest diagnostic strategies and the current screening and treatment guidelines for colonic and extracolonic cancers in clinically affected and at-risk individuals for LS. © The Author 2015. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  17. Same MSH2 Gene Mutation But Variable Phenotypes in 2 Families With Lynch Syndrome: Two Case Reports and Review of Genotype-Phenotype Correlation.

    Science.gov (United States)

    Liccardo, Raffaella; De Rosa, Marina; Duraturo, Francesca

    2018-01-01

    Lynch syndrome is an autosomal dominant syndrome that can be subdivided into Lynch syndrome I, or site-specific colonic cancer, and Lynch syndrome II, or extracolonic cancers, particularly carcinomas of the stomach, endometrium, biliary and pancreatic systems, and urinary tract. Lynch syndrome is associated with point mutations and large rearrangements in DNA MisMatch Repair ( MMR ) genes. This syndrome shows a variable phenotypic expression in people who carry pathogenetic mutations. So far, a correlation in genotype-phenotype has not been definitely established. In this study, we describe 2 Lynch syndrome cases presenting with the same genotype but different phenotypes and discuss possible reasons for this.

  18. A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome

    DEFF Research Database (Denmark)

    Clendenning, Mark; Senter, Leigha; Hampel, Heather

    2008-01-01

    BACKGROUND: When compared to the other mismatch repair genes involved in Lynch syndrome, the identification of mutations within PMS2 has been limited (Lynch syndrome cases...... on immunohistochemical analysis. RESULTS: We have identified a frequently occurring frame-shift mutation (c.736_741del6ins11) in 12 ostensibly unrelated Lynch syndrome patients (20% of patients we have identified with a deleterious mutation in PMS2, n=61). These individuals all display the rare allele (population...... are caused by PMS2. This disparity is primarily due to complications in the study of this gene caused by interference from pseudogene sequences. METHODS: Using a recently developed method for detecting PMS2 specific mutations, we have screened 99 patients who are likely candidates for PMS2 mutations based...

  19. Cancer risks and immunohistochemical profiles linked to the Danish MLH1 Lynch syndrome founder mutation

    DEFF Research Database (Denmark)

    Therkildsen, Christina; Isinger-Ekstrand, Anna; Ladelund, Steen

    2012-01-01

    Founder mutations with a large impact in distinct populations have been described in Lynch syndrome. In Denmark, the MLH1 c.1667+2_1667_+8TAAATCAdelinsATTT mutation accounts for 25 % of the MLH1 mutant families. We used the national Danish hereditary nonpolyposis colorectal cancer register...... to estimate the cumulative lifetime risks for Lynch syndrome-associated cancer in 16 founder mutation families with comparison to 47 other MLH1 mutant families. The founder mutation conferred comparable risks for colorectal cancer (relative risks, RR, of 0.99 for males and 0.79 for females) and lower risks...... in 68 % with extensive inter-tumor variability despite the same underlying germline mutation. In conclusion, the Danish MLH1 founder mutation that accounts for a significant proportion of Lynch syndrome and is associated with a lower risk for extracolonic cancers....

  20. Neuroendocrine-type prostatic adenocarcinoma with microsatellite instability in a patient with lynch syndrome.

    Science.gov (United States)

    Wagner, David G; Gatalica, Zoran; Lynch, Henry T; Kohl, Shane; Johansson, Sonny L; Lele, Subodh M

    2010-12-01

    Lynch syndrome is an autosomal-dominant cancer syndrome that can be identified with microsatellite instability molecular tests or immunohistochemical stains on pathologic material from patients who meet the Amsterdam Criteria II. The development of prostatic carcinoma in situ or invasive small cell carcinoma (SCC) of the prostate has not been previously reported in a patient with this syndrome. In this report, an 87-year-old White man with the Lynch syndrome had a prostate biopsy that revealed a mixed high-grade conventional adenocarcinoma and SCC of the prostate with high-grade prostatic intraepithelial neoplasia of the small cell neuroendocrine-type (HGPIN-NE), all showing MSH2 microsatellite instability and loss of MSH2 expression, a finding not previously published. These findings suggest that HGPIN-NE is a precursor of invasive SCC and also that prostatic SCC can develop in a patient with the Lynch syndrome.

  1. Genetic screens to identify pathogenic gene variants in the common cancer predisposition Lynch syndrome

    DEFF Research Database (Denmark)

    Drost, Mark; Lützen, Anne; van Hees, Sandrine

    2013-01-01

    In many individuals suspected of the common cancer predisposition Lynch syndrome, variants of unclear significance (VUS), rather than an obviously pathogenic mutations, are identified in one of the DNA mismatch repair (MMR) genes. The uncertainty of whether such VUS inactivate MMR, and therefore...... function. When a residue identified as mutated in an individual suspected of Lynch syndrome is listed as critical in such a reverse diagnosis catalog, there is a high probability that the corresponding human VUS is pathogenic. To investigate the applicability of this approach, we have generated....... Nearly half of these critical residues match with VUS previously identified in individuals suspected of Lynch syndrome. This aids in the assignment of pathogenicity to these human VUS and validates the approach described here as a diagnostic tool. In a wider perspective, this work provides a model...

  2. Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome

    DEFF Research Database (Denmark)

    Burn, John; Bishop, D Timothy; Mecklin, Jukka-Pekka

    2008-01-01

    BACKGROUND: Observational and epidemiologic data indicate that the use of aspirin reduces the risk of colorectal neoplasia; however, the effects of aspirin in the Lynch syndrome (hereditary nonpolyposis colon cancer) are not known. Resistant starch has been associated with an antineoplastic effect...... on the colon. METHODS: In a randomized, placebo-controlled trial, we used a two-by-two design to investigate the effects of aspirin, at a dose of 600 mg per day, and resistant starch (Novelose), at a dose of 30 g per day, in reducing the risk of adenoma and carcinoma among persons with the Lynch syndrome...... on the incidence of colorectal adenoma or carcinoma among carriers of the Lynch syndrome. (Current Controlled Trials number, ISRCTN59521990.)...

  3. Hereditary non-polyposis colorectal cancer/Lynch syndrome in three dimensions.

    Science.gov (United States)

    Kravochuck, Sara E; Church, James M

    2017-12-01

    Hereditary non-polyposis colorectal cancer (HNPCC) is defined by family history, and Lynch syndrome (LS) is defined genetically. However, universal tumour testing is now increasingly used to screen for patients with defective mismatch repair. This mixing of the results of family history, tumour testing and germline testing produces multiple permutations and combinations that can foster confusion. We wanted to clarify hereditary colorectal cancer using the three dimensions of classification: family history, tumour testing and germline testing. Family history (Amsterdam I or II criteria versus not Amsterdam criteria) was used to define patients and families with HNPCC. Tumour testing and germline testing were then performed to sub-classify patients and families. The permutations of these classifications are applied to our registry. There were 234 HNPCC families: 129 had LS of which 55 were three-dimensional Lynch (family history, tumour testing and germline testing), 66 were two-dimensional Lynch and eight were one-dimensional Lynch. A total of 10 families had tumour Lynch (tumours with microsatellite instability or loss of expression of a mismatch repair protein but an Amsterdam-negative family and negative germline testing), five were Lynch like (Amsterdam-positive family, tumours with microsatellite instability or loss of expression of a mismatch repair protein on immunohistochemistry but negative germline testing), 26 were familial colorectal cancer type X and 95 were HNPCC. Hereditary colorectal cancer can be confusing. Sorting families in three dimensions can clarify the confusion and may direct further testing and, ultimately, surveillance. © 2016 Royal Australasian College of Surgeons.

  4. Screening for Lynch syndrome using risk assessment criteria in patients with ovarian cancer.

    Science.gov (United States)

    Takeda, Takashi; Tsuji, Kosuke; Banno, Kouji; Yanokura, Megumi; Kobayashi, Yusuke; Tominaga, Eiichiro; Aoki, Daisuke

    2018-05-01

    Lynch syndrome is a cancer predisposition syndrome caused by germline mutation of DNA mismatch repair (MMR) genes. Lynch syndrome only causes about 0.4% of cases of ovarian cancer, which suggests that universal screening may not be cost-efficient. However, the frequency of Lynch syndrome in ovarian cancer is unclear in the Asian population. The goal of the study was to investigate a screening strategy using family history. The subjects were 129 patients with ovarian cancer. Clinical and family history were collected using a self-administered questionnaire, and Society of Gynecologic Oncology (SGO) criteria 2007 and PREMM₅ were used for risk assessment. Microsatellite instability, immunohistochemistry, and methylation of MMR genes were analyzed. Of the 129 cases, 25 (19.4%) met the SGO criteria, and 4 of these 25 had MSI-high and MMR deficiency. Two cases had loss of MSH2 and MSH6, indicating MSH2 mutation, and the other two had loss of MLH1 and PMS2, including one without MLH1 methylation indicating MLH1 mutation. These results show that screening using family history can detect Lynch syndrome in 12.0% (3/25) of ovarian cancer cases. The 3 cases were positive for PREMM₅, but negative for Amsterdam II criteria and revised Bethesda guidelines. Genetic testing in one case with MSH2 and MSH6 deficiency confirmed the diagnosis of Lynch syndrome with MSH2 mutation. This is the first study of screening for Lynch syndrome in ovarian cancer using clinical and family history in an Asian population. This approach may be effective for diagnosis in these patients. Copyright © 2018. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.

  5. General practitioner attitudes towards prescribing aspirin to carriers of Lynch Syndrome: findings from a national survey.

    Science.gov (United States)

    Smith, Samuel G; Foy, Robbie; McGowan, Jennifer; Kobayashi, Lindsay C; Burn, John; Brown, Karen; Side, Lucy; Cuzick, Jack

    2017-10-01

    A dose non-inferiority study comparing 100 mg, 300 mg and 600 mg of aspirin for cancer prevention among Lynch Syndrome carriers is underway (Colorectal Adenoma/Carcinoma Prevention Programme trial 3, CaPP3). To guide implementation of the findings, we investigated general practitioner (GP) attitudes towards aspirin prescribing for Lynch Syndrome carriers. We surveyed 1007 UK GPs (9.6% response rate). Using a within-subjects design, GPs read a statement on harms and benefits of aspirin and indicated their willingness to prescribe aspirin at three doses (100 mg, 300 mg, 600 mg). Approximately two-thirds (70.8%) of GPs had heard of Lynch Syndrome or its associated names, and among those 46.7% were aware of the cancer preventive effects of aspirin among carriers. Two-thirds (68.1%) of GPs reported feeling comfortable discussing harms and benefits of aspirin with a Lynch Syndrome patient. Willingness to prescribe was 91.3% at 100 mg, and declined to 81.8% at 300 mg and 62.3% at 600 mg (p Lynch Syndrome patient in practice (OR 1.44, 95% CI 1.01-2.05, p = 0.045). GPs report limited awareness of Lynch Syndrome and the preventive effects of aspirin among carriers. To ensure the optimal dose identified in the CaPP3 trial is readily available to patients, prescribing guidance and strategies to educate GPs should be developed.

  6. Laboratory Assays in Evaluation of Lynch Syndrome in Patients with Endometrial Carcinoma.

    Science.gov (United States)

    Djordjevic, Bojana; Broaddus, Russell R

    2016-06-01

    This article reviews the main tissue testing modalities for Lynch Syndrome in the pathology laboratory, such as immunohistochemistry and PCR based analyses, and discusses their routine application, interpretation pitfalls, and troubleshooting of common technical performance issues. Discrepancies between laboratory and genetic testing may arise, and are examined in the context of the complexity of molecular abnormalities associated with Lynch Syndrome. The merits of targeted versus universal screening in a changing healthcare climate are addressed. In the absence of comprehensive screening programs, specific tumor topography and histological features that may prompt pathologist-initiated molecular tumor testing are outlined. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.

    Science.gov (United States)

    Yurgelun, Matthew B; Allen, Brian; Kaldate, Rajesh R; Bowles, Karla R; Judkins, Thaddeus; Kaushik, Praveen; Roa, Benjamin B; Wenstrup, Richard J; Hartman, Anne-Renee; Syngal, Sapna

    2015-09-01

    Multigene panels are commercially available tools for hereditary cancer risk assessment that allow for next-generation sequencing of numerous genes in parallel. However, it is not clear if these panels offer advantages over traditional genetic testing. We investigated the number of cancer predisposition gene mutations identified by parallel sequencing in individuals with suspected Lynch syndrome. We performed germline analysis with a 25-gene, next-generation sequencing panel using DNA from 1260 individuals who underwent clinical genetic testing for Lynch syndrome from 2012 through 2013. All patients had a history of Lynch syndrome-associated cancer and/or polyps. We classified all identified germline alterations for pathogenicity and calculated the frequencies of pathogenic mutations and variants of uncertain clinical significance (VUS). We also analyzed data on patients' personal and family history of cancer, including fulfillment of clinical guidelines for genetic testing. Of the 1260 patients, 1112 met National Comprehensive Cancer Network (NCCN) criteria for Lynch syndrome testing (88%; 95% confidence interval [CI], 86%-90%). Multigene panel testing identified 114 probands with Lynch syndrome mutations (9.0%; 95% CI, 7.6%-10.8%) and 71 with mutations in other cancer predisposition genes (5.6%; 95% CI, 4.4%-7.1%). Fifteen individuals had mutations in BRCA1 or BRCA2; 93% of these met the NCCN criteria for Lynch syndrome testing and 33% met NCCN criteria for BRCA1 and BRCA2 analysis (P = .0017). An additional 9 individuals carried mutations in other genes linked to high lifetime risks of cancer (5 had mutations in APC, 3 had bi-allelic mutations in MUTYH, and 1 had a mutation in STK11); all of these patients met NCCN criteria for Lynch syndrome testing. A total of 479 individuals had 1 or more VUS (38%; 95% CI, 35%-41%). In individuals with suspected Lynch syndrome, multigene panel testing identified high-penetrance mutations in cancer predisposition genes, many

  8. An Analysis of Coordinated Observations from NOAA’s Ronald H. Brown Ship and G-IV Aircraft in a Landfalling Atmospheric River over the North Pacific during CalWater-2015

    Energy Technology Data Exchange (ETDEWEB)

    Neiman, Paul J. [Physical Sciences Division, NOAA/Earth System Research Laboratory, Boulder, Colorado; Gaggini, Natalie [Science and Technology Corporation, and NOAA/Earth System Research Laboratory, Boulder, Colorado; Fairall, Christopher W. [Physical Sciences Division, NOAA/Earth System Research Laboratory, Boulder, Colorado; Aikins, Joshua [Cooperative Institute for Research in the Environmental Sciences, and NOAA/Earth System Research Laboratory, Boulder, Colorado; Spackman, J. Ryan [Science and Technology Corporation, and NOAA/Earth System Research Laboratory, Boulder, Colorado; Leung, L. Ruby [Pacific Northwest National Laboratory, Richland, Washington; Fan, Jiwen [Pacific Northwest National Laboratory, Richland, Washington; Hardin, Joseph [Pacific Northwest National Laboratory, Richland, Washington; Nalli, Nicholas R. [I. M. Systems Group, NOAA/NESDIS/STAR, College Park, Maryland; White, Allen B. [Physical Sciences Division, NOAA/Earth System Research Laboratory, Boulder, Colorado

    2017-09-01

    Using a diverse suite of mobile observing platforms deployed on NOAA’s Ronald H. Brown (RHB) research vessel and G-IV research aircraft during the CalWater-2015 field campaign, this study describes the structure and evolution of a long-lived atmospheric river (AR) modulated by six frontal waves over the northeastern Pacific on 20-25 January 2015. Satellite observations and reanalysis diagnostics provided synoptic-scale context, illustrating the warm, moist southwesterly airstream within the quasi-stationary AR situated between an upper-level trough and ridge. The AR remained offshore of the U.S. West Coast but made landfall across British Columbia where heavy precipitation and high melting levels occurred, resulting in flooding. Forty-seven rawinsondes launched from the RHB provided a comprehensive thermodynamic and kinematic depiction of the AR, including an upward intrusion of strong water-vapor transport in the low-level moist southwesterly flow during the passage of frontal waves 2 through 6. A collocated 1290-MHz wind profiler showed an abrupt frontal transition from southwesterly to northerly flow below 1 km MSL coinciding with the tail-end of AR conditions. Shipborne radar and disdrometer observations in the AR uniquely captured key microphysical characteristics of shallow warm rain, convection, and deep mixed-phase precipitation. Continuous and novel observations of sea-surface fluxes documented persistent ocean-surface evaporation into the AR and sensible-heat transfer from the AR into the ocean. The G-IV aircraft coordinated with the RHB and flew directly over the ship. Dropsonde and radar spatial analyses complemented the temporal depictions of the AR from the RHB. The AR characteristics varied, depending on the location of the cross section through the frontal waves.

  9. Pain evaluation during gynaecological surveillance in women with Lynch syndrome.

    Science.gov (United States)

    Helder-Woolderink, Jorien; de Bock, Geertruida; Hollema, Harry; van Oven, Magda; Mourits, Marian

    2017-04-01

    To evaluate perceived pain during repetitive annual endometrial sampling at gynaecologic surveillance in asymptomatic women with Lynch syndrome (LS) over time and in addition to symptomatic women without LS, undergoing single endometrial sampling. In this prospective study, 52 women with LS or first degree relatives who underwent repetitive annual gynaecological surveillance including endometrial sampling of which 33 were evaluated twice or more and 50 symptomatic women without LS who had single endometrial sampling, were included. Pain intensity was registered with VAS scores. Differences in pain intensities between subsequent visits (in LS) and between the two groups were evaluated. The use of painkillers before endometrial sampling was registered. If women with LS decided for preventive surgery, the reason was recorded. The LS group reported a median VAS score of 5.0 (range 0-10) at the first surveillance (n = 52) and at the second visit (n = 24). Women who repeatedly underwent endometrial sampling more often used painkillers for this procedure. During the study period 7/52 (13 %) women with LS choose for preventive surgery, another 4/52 (8 %) refused further endometrial sampling. Painful endometrial sampling was mentioned as main reason to quit screening. The median VAS score of the 50 symptomatic women was 5.0 (range 1-9). Endometrial sampling, irrespective of indication, is a painful procedure, with a median VAS score of 5.0. During subsequent procedures in women with LS, the median pain score does not aggravate although one in five women chose an alternative for endometrial sampling.

  10. Elisa Alicia Lynch: a Dama de Aço do Paraguai * Elisa Alicia Lynch: the Steel ‘S Lady of Paraguay

    OpenAIRE

    Frota, Luciara Silveira de Aragão e

    2015-01-01

    Este trabalho mostra uma nova visão da irlandesa Elisa Alicia Lynch, longe da figura de prostituta manipuladora que incitou o Marechal Solano López no começo da Guerra do Paraguai. Dentro de uma corrente revisionista histórica, apoiada em Marc Bloch, propõe uma nova análise de seu papel na vida de Solano López e do Paraguai, comentando a literatura sobre o assunto.

  11. CTNNB1-mutant colorectal carcinomas with immediate invasive growth: a model of interval cancers in Lynch syndrome.

    Science.gov (United States)

    Ahadova, Aysel; von Knebel Doeberitz, Magnus; Bläker, Hendrik; Kloor, Matthias

    2016-10-01

    The implementation of regular colonoscopy programs has significantly decreased the mortality associated with colorectal cancer (CRC) in Lynch syndrome patients. However, interval CRCs in Lynch syndrome that remain undetected by colonoscopy still represent a substantial problem in the management of the syndrome. One possible reason of interval cancers could be a non-polypous pathway of cancer development. To examine the possibility of a non-polypous pathway of CRC development in Lynch syndrome, we analyzed the histological appearance of 46 Lynch syndrome-associated CRCs and compared them to 34 sporadic microsatellite unstable cancers. We observed that 25 (62.5 %) out of 40 assessable Lynch syndrome-associated carcinomas lacked evidence of polypous growth, compared to 17 (50 %) out of 34 sporadic MSI-H cancers. We detected CTNNB1 mutations in 8 (17.4 %) out of 46 Lynch syndrome-associated cancers compared to 0 out of 34 sporadic MSI-H cancers (p = 0.01). The majority of CTNNB1-mutant cancers presented with a histological appearance suggesting immediate invasive growth. Our results suggest that a distinct subgroup of CRCs in Lynch syndrome may in fact emerge from a non-polypous precursor, thus potentially explaining the phenomenon of interval cancers. Such a non-polypous precursor may be the recently described mismatch repair-deficient crypt focus, which remains invisible for the examiner during colonoscopy. This calls for considering the implementation of active, primary preventive measures in the management of Lynch syndrome. Future studies on pathogenic pathways and precursor lesions in Lynch syndrome are strongly encouraged, and the clinical efficacy of new prevention approaches should be evaluated in prospective clinical trials.

  12. Lynch, Urry and city marketing: Taking advantage of the city as a built and graphic image

    NARCIS (Netherlands)

    Hospers, G-J.

    2009-01-01

    City marketing is usually addressed from the perspective of marketing theory. This article follows an alternative approach by exploring city marketing from the viewpoint of urban planning and the sociology of tourism. In his classic ‘The Image of the City’ (1960), planner Kevin Lynch found that

  13. Dietary patterns and colorectal adenomas in Lynch syndrome: the GEOLynch cohort study

    NARCIS (Netherlands)

    Botma, A.; Vasen, H.F.; Duijnhoven, F.J.B. van; Kleibeuker, J.H.; Nagengast, F.M.; Kampman, E.

    2013-01-01

    BACKGROUND: Patients with Lynch syndrome (LS) have a high risk of developing colorectal cancer due to mutations in mismatch repair genes. Because dietary factors, alone and in combination, influence sporadic colorectal carcinogenesis, the association of dietary patterns with colorectal adenomas in

  14. Dietary Patterns and Colorectal Adenomas in Lynch Syndrome: The GEOLynch Cohort Study

    NARCIS (Netherlands)

    Botma, A.; Vasen, H.F.; Duijnhoven, van F.J.B.; Kleibeuker, J.H.; Nagengast, F.M.; Kampman, E.

    2013-01-01

    BACKGROUND: Patients with Lynch syndrome (LS) have a high risk of developing colorectal cancer due to mutations in mismatch repair genes. Because dietary factors, alone and in combination, influence sporadic colorectal carcinogenesis, the association of dietary patterns with colorectal adenomas in

  15. Dietary Patterns and Colorectal Adenomas in Lynch Syndrome The GEOLynch Cohort Study

    NARCIS (Netherlands)

    Botma, Akke; Vasen, Hans F. A.; van Duijnhoven, Franzel J. B.; Kleibeuker, Jan H.; Nagengast, Fokko M.; Kampman, Ellen

    2013-01-01

    BACKGROUND: Patients with Lynch syndrome (LS) have a high risk of developing colorectal cancer due to mutations in mismatch repair genes. Because dietary factors, alone and in combination, influence sporadic colorectal carcinogenesis, the association of dietary patterns with colorectal adenomas in

  16. Inflammatory potential of the diet and colorectal tumor risk in persons with Lynch syndrome

    NARCIS (Netherlands)

    Brouwer, Jesca G.M.; Makama, Maureen; Woudenbergh, Van Geertruida J.; Vasen, Hans F.A.; Nagengast, Fokko M.; Kleibeuker, Jan H.; Kampman, Ellen; Duijnhoven, Van Fränzel J.B.

    2017-01-01

    Background: Persons with Lynch syndrome (LS) have high lifetime risk of developing colorectal tumors (CRTs) because of a germline mutation in one of their mismatch repair (MMR) genes. An important process in the development of CRTs is inflammation, which has been shown to be modulated by diet.

  17. Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population

    DEFF Research Database (Denmark)

    Lagerstedt-Robinson, Kristina; Rohlin, Anna; Aravidis, Christos

    2016-01-01

    Lynch syndrome caused by constitutional mismatch‑repair defects is one of the most common hereditary cancer syndromes with a high risk for colorectal, endometrial, ovarian and urothelial cancer. Lynch syndrome is caused by mutations in the mismatch repair (MMR) genes i.e., MLH1, MSH2, MSH6 and PMS2...... Lynch syndrome families. These mutations affected MLH1 in 40%, MSH2 in 36%, MSH6 in 18% and PMS2 in 6% of the families. A large variety of mutations were identified with splice site mutations being the most common mutation type in MLH1 and frameshift mutations predominating in MSH2 and MSH6. Large...... deletions of one or several exons accounted for 21% of the mutations in MLH1 and MSH2 and 22% in PMS2, but were rare (4%) in MSH6. In 66% of the Lynch syndrome families the variants identified were private and the effect from founder mutations was limited and predominantly related to a Finnish founder...

  18. Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk

    NARCIS (Netherlands)

    Broeke, S.W. ten; Brohet, R.M.; Tops, C.M.; Klift, H.M. van der; Velthuizen, M.E.; Bernstein, I.; Capella Munar, G.; Garcia, E.; Hoogerbrugge, N.; Letteboer, T.G.; Menko, F.H.; Lindblom, A.; Mensenkamp, A.R.; Moller, P.; Os, T.A. van; Rahner, N.; Redeker, B.J.; Sijmons, R.H.; Spruijt, L.; Suerink, M.; Vos, Y.J.; Wagner, A.; Hes, F.J.; Vasen, H.F.A.; Nielsen, M.; Wijnen, J.T.

    2015-01-01

    PURPOSE: The clinical consequences of PMS2 germline mutations are poorly understood compared with other Lynch-associated mismatch repair gene (MMR) mutations. The aim of this European cohort study was to define the cancer risk faced by PMS2 mutation carriers. METHODS: Data were collected from 98

  19. Prevalence of small-bowel neoplasia in Lynch syndrome assessed by video capsule endoscopy

    NARCIS (Netherlands)

    Haanstra, Jasmijn F.; Al-Toma, Abdul; Dekker, Evelien; Vanhoutvin, Steven A. L. W.; Nagengast, Fokko M.; Mathus-Vliegen, Elisabeth M.; van Leerdam, Monique E.; de Vos tot Nederveen Cappel, Wouter H.; Sanduleanu, Silvia; Veenendaal, Roeland A.; Cats, Annemieke; Vasen, Hans F. A.; Kleibeuker, Jan H.; Koornstra, Jan J.

    2015-01-01

    The aim was to determine the prevalence of small-bowel neoplasia in asymptomatic patients with Lynch syndrome (LS) by video capsule endoscopy (VCE). After obtaining informed consent, asymptomatic proven gene mutation carriers aged 35-70 years were included in this prospective multicentre study in

  20. Lynch Syndrome Caused by Germline PMS2 Mutations: Delineating the Cancer Risk

    NARCIS (Netherlands)

    ten Broeke, Sanne W.; Brohet, Richard M.; Tops, Carli M.; van der Klift, Heleen M.; Velthuizen, Mary E.; Bernstein, Inge; Capellá Munar, Gabriel; Gomez Garcia, Encarna; Hoogerbrugge, Nicoline; Letteboer, Tom G. W.; Menko, Fred H.; Lindblom, Annika; Mensenkamp, Arjen R.; Moller, Pal; van Os, Theo A.; Rahner, Nils; Redeker, Bert J. W.; Sijmons, Rolf H.; Spruijt, Liesbeth; Suerink, Manon; Vos, Yvonne J.; Wagner, Anja; Hes, Frederik J.; Vasen, Hans F.; Nielsen, Maartje; Wijnen, Juul T.

    2015-01-01

    Purpose The clinical consequences of PMS2 germline mutations are poorly understood compared with other Lynch-associated mismatch repair gene (MMR) mutations. The aim of this European cohort study was to define the cancer risk faced by PMS2 mutation carriers. Methods Data were collected from 98 PMS2

  1. Prevalence of small-bowel neoplasia in Lynch syndrome assessed by video capsule endoscopy

    NARCIS (Netherlands)

    Haanstra, Jasmijn F.; Al-Toma, Abdul; Dekker, Evelien; Vanhoutvin, Steven A. L. W.; Nagengast, Fokko M.; Mathus-Vliegen, Elisabeth M.; van Leerdam, Monique E.; Cappel, Wouter H. de Vos tot Nederveen; Sanduleanu, Silvia; Veenendaal, Roeland A.; Cats, Annemieke; Vasen, Hans F. A.; Kleibeuker, Jan H.; Koornstra, Jan J.

    2015-01-01

    Objective The aim was to determine the prevalence of small-bowel neoplasia in asymptomatic patients with Lynch syndrome (LS) by video capsule endoscopy (VCE). Design After obtaining informed consent, asymptomatic proven gene mutation carriers aged 3570 years were included in this prospective

  2. Lynch Syndrome Caused by Germline PMS2 Mutations : Delineating the Cancer Risk

    NARCIS (Netherlands)

    ten Broeke, Sanne W.; Brohet, Richard M.; Tops, Carli M.; van der Klift, Heleen M.; Velthuizen, Mary E.; Bernstein, Inge; Capella Munar, Gabriel; Garcia, Encarna Gomez; Hoogerbrugge, Nicoline; Letteboer, Tom G. W.; Menko, Fred H.; Lindblom, Annika; Mensenkamp, Arjen R.; Moller, Pal; Van Os, Theo A.; Rahner, Nils; Redeker, Bert J. W.; Sijmons, Rolf H.; Spruijt, Liesbeth; Suerink, Manon; Vos, Yvonne J.; Wagner, Anja; Hes, Frederik J.; Vasen, Hans F.; Nielsen, Maartje; Wijnen, Juul T.

    2015-01-01

    Purpose The clinical consequences of PMS2 germline mutations are poorly understood compared with other Lynch-associated mismatch repair gene (MMR) mutations. The aim of this European cohort study was to define the cancer risk faced by PMS2 mutation carriers. Methods Data were collected from 98 PMS2

  3. Diagnostic Strategies for Early Lynch Syndrome Detection: From Molecular Testing to Economic Evaluation

    NARCIS (Netherlands)

    C.H.M. Leenen (Celine)

    2015-01-01

    markdownabstract__Abstract__ Lynch syndrome (LS) is an autosomal dominant inherited syndrome that predisposes to multiple malignancies, in particular colorectal cancer (CRC) and endometrial cancer (EC). The lifetime risk of developing CRC for a LS mutation carrier is 25 to 70%, while women

  4. Germline Hypermethylation of MLH1 and EPCAM Deletions Are a Frequent Cause of Lynch Syndrome

    NARCIS (Netherlands)

    Niessen, Renee C.; Hofstra, Robert M. W.; Westers, Helga; Ligtenberg, Marjolijn J. L.; Kooi, Krista; Jager, Paul O. J.; de Groote, Marloes L.; Dijkhuizen, Trijnie; Olderode-Berends, Maran J. W.; Hollema, Harry; Kleibeuker, Jan H.; Sijmons, Rolf H.

    It was shown that Lynch syndrome can be caused by germline hypermethylation of the MLH1 and MSH2 promoters. Furthermore, it has been demonstrated very recently that germline deletions of the 3' region of EPCAM cause transcriptional read-through which results in silencing of MSH2 by hypermethylation.

  5. Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome.

    NARCIS (Netherlands)

    Niessen, R.C.; Hofstra, R.M.; Westers, H.; Ligtenberg, M.J.L.; Kooi, K.; Jager, P.O.; Groote, M.L. de; Dijkhuizen, T.; Olderode-Berends, M.J.; Hollema, H.; Kleibeuker, J.H.; Sijmons, R.H.

    2009-01-01

    It was shown that Lynch syndrome can be caused by germline hypermethylation of the MLH1 and MSH2 promoters. Furthermore, it has been demonstrated very recently that germline deletions of the 3' region of EPCAM cause transcriptional read-through which results in silencing of MSH2 by hypermethylation.

  6. Lynch syndrome associated with two MLH1 promoter variants and allelic imbalance of MLH1 expression.

    Science.gov (United States)

    Hesson, Luke B; Packham, Deborah; Kwok, Chau-To; Nunez, Andrea C; Ng, Benedict; Schmidt, Christa; Fields, Michael; Wong, Jason W H; Sloane, Mathew A; Ward, Robyn L

    2015-06-01

    Lynch syndrome is a hereditary cancer syndrome caused by a constitutional mutation in one of the mismatch repair genes. The implementation of predictive testing and targeted preventative surveillance is hindered by the frequent finding of sequence variants of uncertain significance in these genes. We aimed to determine the pathogenicity of previously reported variants (c.-28A>G and c.-7C>T) within the MLH1 5'untranslated region (UTR) in two individuals from unrelated suspected Lynch syndrome families. We investigated whether these variants were associated with other pathogenic alterations using targeted high-throughput sequencing of the MLH1 locus. We also determined their relationship to gene expression and epigenetic alterations at the promoter. Sequencing revealed that the c.-28A>G and c.-7C>T variants were the only potentially pathogenic alterations within the MLH1 gene. In both individuals, the levels of transcription from the variant allele were reduced to 50% compared with the wild-type allele. Partial loss of expression occurred in the absence of constitutional epigenetic alterations within the MLH1 promoter. We propose that these variants may be pathogenic due to constitutional partial loss of MLH1 expression, and that this may be associated with intermediate penetrance of a Lynch syndrome phenotype. Our findings provide further evidence of the potential importance of noncoding variants in the MLH1 5'UTR in the pathogenesis of Lynch syndrome. © 2015 The Authors. **Human Mutation published by Wiley Periodicals, Inc.

  7. Expression defect size among unclassified MLH1 variants determines pathogenicity in Lynch syndrome diagnosis

    DEFF Research Database (Denmark)

    Hinrichsen, Inga; Brieger, Angela; Trojan, Jörg

    2013-01-01

    Lynch syndrome is caused by a germline mutation in a mismatch repair gene, most commonly the MLH1 gene. However, one third of the identified alterations are missense variants with unclear clinical significance. The functionality of these variants can be tested in the laboratory, but the results...

  8. Gene variants of unknown clinical significance in Lynch syndrome. An introduction for clinicians

    NARCIS (Netherlands)

    Sijmons, Rolf H.; Greenblatt, Marc S.; Genuardi, Maurizio

    Clinicians referring patients for genetic testing for Lynch syndrome will sooner or later receive results for DNA Mismatch Repair (MMR) genes reporting DNA changes that are unclear from a clinical point of view. These changes are referred to as variants of unknown, or unclear, clinical significance

  9. Determinants of adherence to recommendations for cancer prevention among Lynch Syndrome mutation carriers : A qualitative exploration

    NARCIS (Netherlands)

    Visser, Annemiek; Vrieling, Alina; Murugesu, Laxsini; Hoogerbrugge, Nicoline; Kampman, Ellen; Hoedjes, Meeke

    2017-01-01

    Background: Lynch Syndrome (LS) mutation carriers are at high risk for various cancer types, particularly colorectal cancer. Adherence to lifestyle and body weight recommendations for cancer prevention may lower this risk. To promote adherence to these recommendations, knowledge on determinants of

  10. Increasing awareness and knowledge of lifestyle recommendations for cancer prevention in Lynch syndrome carriers

    NARCIS (Netherlands)

    Vrieling, A.; Visser, A.; Hoedjes, Meeke; Hurks, H.M.H.; Gómez García, E.; Hoogerbrugge, N.; Kampman, E.

    2018-01-01

    Lynch syndrome (LS) mutation carriers may reduce their cancer risk by adhering to lifestyle recommendations for cancer prevention. This study tested the effect of providing LS mutation carriers with World Cancer Research Fund-the Netherlands (WCRF-NL) health promotion materials on awareness and

  11. Determinants of adherence to recommendations for cancer prevention among Lynch Syndrome mutation carriers: a qualitative exploration.

    NARCIS (Netherlands)

    Visser, A.; Vrieling, A.; Murugesu, L.; Hoogerbrugge, N.; Kampman, E.; Hoedjes, M.

    2017-01-01

    Background: Lynch Syndrome (LS) mutation carriers are at high risk for various cancer types, particularly colorectal cancer. Adherence to lifestyle and body weight recommendations for cancer prevention may lower this risk. To promote adherence to these recommendations, knowledge on determinants of

  12. Informing family members of individuals with Lynch syndrome: a guideline for clinical geneticists

    NARCIS (Netherlands)

    Menko, Fred H.; Aalfs, Cora M.; Henneman, Lidewij; Stol, Yrrah; Wijdenes, Miranda; Otten, Ellen; Ploegmakers, Marleen M. J.; Legemaate, Johan; Smets, Ellen M. A.; de Wert, Guido M. W. R.; Tibben, Aad

    2013-01-01

    The diagnosis of Lynch syndrome can lead to the prevention of colorectal cancer through periodic colonoscopies and removal of premalignant lesions in susceptible individuals. Therefore, predisposed individuals identified by mutation analysis are advised to inform their at-risk relatives about the

  13. What the physician needs to know about Lynch syndrome: an update.

    Science.gov (United States)

    Lynch, Henry T; Lynch, Jane F

    2005-04-01

    The Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]), is the most common form of hereditary colorectal cancer (CRC), accounting for 2% to 7% of all CRC cases. The next most common hereditary CRC syndrome is familial adenomatous polyposis (FAP), which accounts for less than 1% of all CRC. Lynch syndrome is of crucial clinical importance due to the fact that it predicts the lifetime risk for CRC and a litany of extra-CRC cancers (of the endometrium, ovary, stomach, small bowel, hepatobiliary tract, upper uroepithelial tract, and brain) through assessment of a well-orchestrated family history. A Lynch syndrome diagnosis is almost certain when a mutation in a mismatch repair gene--most commonly MSH2, MLHI, or, to a lesser degree, MSH6--is identified. Once diagnosed, the potential for significant reduction in cancer-related morbidity and mortality through highly targeted surveillance may be profound. Particularly important is colonoscopy initiated at an early age (ie, 25 years) and repeated annually due to accelerated carcinogenesis. In women, endometrial aspiration biopsy and transvaginal ultrasound are important given the extraordinarily high risk for endometrial and ovarian carcinoma. These cancer control strategies have a major impact on at-risk family members once they have been counseled and educated thoroughly about Lynch syndrome's natural history and their own hereditary cancer risk.

  14. Bayesian Modeling for Genetic Anticipation in Presence of Mutational Heterogeneity: A Case Study in Lynch Syndrome

    DEFF Research Database (Denmark)

    Boonstra, Philip S; Mukherjee, Bhramar; Taylor, Jeremy M G

    2011-01-01

    to cause hereditary nonpolyposis colorectal cancer, also called Lynch syndrome (LS). We find evidence for a decrease in AOO between generations in this article. Our model predicts family-level anticipation effects that are potentially useful in genetic counseling clinics for high-risk families....

  15. Assessing Genetic Variants of Uncertain Significance: The Example of Lynch Syndrome

    DEFF Research Database (Denmark)

    Rasmussen, Lene Juel; Heinen, Christopher D.

    2014-01-01

    cancer syndrome, Lynch syndrome, is used as an example. This challenge is addressed by illustrating the importance of combining genetic and functional data in future strategies to assess VUS. The proposed strategies combine clinical genetic, analytical, functional and in silico approaches....

  16. The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome

    DEFF Research Database (Denmark)

    Watson, Patrice; Vasen, Hans F A; Mecklin, Jukka-Pekka

    2008-01-01

    Persons with the Lynch syndrome (LS) are at high risk for cancer, including cancers of the small bowel, stomach, upper urologic tract (renal pelvis and ureter), ovary, biliary tract and brain tumors, in addition to the more commonly observed colorectal and endometrial cancers. Cancer prevention...

  17. Informing family members of individuals with Lynch syndrome : a guideline for clinical geneticists

    NARCIS (Netherlands)

    Menko, Fred H.; Aalfs, Cora M.; Henneman, Lidewij; Stol, Yrrah; Wijdenes, Miranda; Otten, Ellen; Ploegmakers, Marleen M. J.; Legemaate, Johan; Smets, Ellen M. A.; de Wert, Guido M. W. R.; Tibben, Aad

    The diagnosis of Lynch syndrome can lead to the prevention of colorectal cancer through periodic colonoscopies and removal of premalignant lesions in susceptible individuals. Therefore, predisposed individuals identified by mutation analysis are advised to inform their at-risk relatives about the

  18. Thyroid cancer in a patient with Lynch syndrome – case report and literature review

    Directory of Open Access Journals (Sweden)

    Fazekas-Lavu M

    2017-07-01

    Full Text Available Monika Fazekas-Lavu,1 Andrew Parker,2 Allan D Spigelman,3,4 Rodney J Scott,5 Richard J Epstein,6 Michael Jensen,7 Katherine Samaras1,8 1Department of Endocrinology, 2Department of Pathology, St Vincent’s Hospital, Darlinghurst, NSW, Australia; 3Hereditary Cancer Clinic, St Vincent’s Cancer Genetics Service, Darlinghurst, NSW, Australia; 4University of NSW, St Vincent’s Clinical School, Darlinghurst, NSW, Australia; 5Division of Molecular Medicine, Pathology North, John Hunter Hospital and The Hunter Medical Research Institute, Newcastle, NSW, Australia; 6Department of Oncology, 7Department of Oncological Surgery/General Surgery, St Vincent’s Hospital, Darlinghurst, NSW, Australia; 8Diabetes and Metabolism Research Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia Abstract: Lynch syndrome describes a familial cancer syndrome comprising germline mutations in one of four DNA mismatch repair genes, MLH1, MSH2, MSH6, and PMS2 and is characterized by colorectal, endometrial, and other epithelial malignancies. Thyroid cancer is not usually considered to be part of the constellation of Lynch syndrome cancers nor have Lynch syndrome tumor gene mutations been reported in thyroid malignancies. This study reports a woman with Lynch syndrome (colonic cancer and a DNA mismatch repair mutation in the MSH2 gene with a synchronous papillary thyroid cancer. Six years later, she developed metachronous breast cancer. Metastatic bone disease developed after 3 years, and the disease burden was due to both breast and thyroid diseases. Despite multiple interventions for both metastatic breast and thyroid diseases, the patient’s metastatic burden progressed and she died of leptomeningeal metastatic disease. Two prior case reports suggested thyroid cancer may be an extraintestinal malignancy of the Lynch syndrome cancer group. Hence, this study examined the genetic relationship between the patient’s known Lynch syndrome and her

  19. HEREDITARY NON-POLYPOSIS COLORECTAL CANCER (LYNCH SYNDROME PADA WANITA UMUR 16 TAHUN

    Directory of Open Access Journals (Sweden)

    Asril Zahari

    2011-09-01

    Full Text Available AbstrakKanker kolorektal menduduki peringkat ketiga jenis kanker yang paling sering terjadi di dunia. Sekitar 3% kasus kanker kolorektal merupakan jenis hereditary non polyposis colorectal cancer (HNPCC/Lynch syndrome, yang sering muncul pada usia muda. Dilaporkan satu kasus di rumah sakit Dr. M. Djamil Padang, wanita berumur 16 tahun dengan keluhan nyeri perut kanan bawah. Didapatkan riwayat penyakit serupa pada kakek, bibi pasien dan enam anggota keluarga yang lain. Pada pemeriksaan fisik abdomen teraba massa dengan konsistensi keras dan terfiksir. Pada kolonoskopi dan biopsi ditemukan tumor jenis adenocarcinoma colon moderatly differentiated di fleksura hepatika dan polip di kolon sigmoid. Berdasarkan kriteria Amsterdam pasien didiagnosa Lynch syndrome. Pada Pasien dilakukan subtotal kolektomi, anastomose ileorectal dan kemoterapi ajuvan. Identifikasi genetik sedang dikerjakan untuk melihat adanya kelainan genetik pada pasien. Pasien melakukan skrining berkala untuk mencegah kanker HNPCC jenis yang lain.Kata kunci : Hereditary non polyposis colorectal cancer, Lynch syndrome, Microsatellite instability, skrining.AbstractCarcinoma colorectal is the third most common type of cancer that occurs in the world. About 2% -3% of cases of colorectal cancer is hereditary non-polyposis colorectal cancer (HNPCC/Lynch syndrome, which often appear at a young age. Amsterdam and Bethesda criteria have been used to identify patients with Lynch syndrome.one case was reported at the Dr. M. Djamil Padang hospital, a 16-year-old girl with right lower abdominal pain. Obtained a history of similar disease in grandparents, aunts and six other family members. On physical examination found palpable fixed abdominal mass with hard consistency in the lower right abdomen. At colonoscopy and biopsy found a moderatly differentiated adenocarcinoma colon type at the hepatic flexure and the sigmoid colon polyp. Based on the Amsterdam criteria, patients diagnosed with HNPCC/Lynch

  20. The clinical phenotype of Lynch syndrome due to germline PMS2 mutations

    Science.gov (United States)

    Senter, Leigha; Clendenning, Mark; Sotamaa, Kaisa; Hampel, Heather; Green, Jane; Potter, John D.; Lindblom, Annika; Lagerstedt, Kristina; Thibodeau, Stephen N.; Lindor, Noralane M.; Young, Joanne; Winship, Ingrid; Dowty, James G.; White, Darren M.; Hopper, John L.; Baglietto, Laura; Jenkins, Mark A.; de la Chapelle, Albert

    2009-01-01

    Background and Aims Although the clinical phenotype of Lynch syndrome (also known as Hereditary Nonpolyposis Colorectal Cancer) has been well described, little is known about disease in PMS2 mutation carriers. Now that mutation detection methods can discern mutations in PMS2 from mutations in its pseudogenes, more mutation carriers have been identified. Information about the clinical significance of PMS2 mutations is crucial for appropriate counseling. Here, we report the clinical characteristics of a large series of PMS2 mutation carriers. Methods We performed PMS2 mutation analysis using long range PCR and MLPA for 99 probands diagnosed with Lynch syndrome-associated tumors showing isolated loss of PMS2 by immunohistochemistry. Penetrance was calculated using a modified segregation analysis adjusting for ascertainment. Results Germline PMS2 mutations were detected in 62% of probands (n = 55 monoallelic; 6 biallelic). Among families with monoallelic PMS2 mutations, 65.5% met revised Bethesda guidelines. Compared with the general population, in mutation carriers, the incidence of colorectal cancer was 5.2 fold higher and the incidence of endometrial cancer was 7.5 fold higher. In North America, this translates to a cumulative cancer risk to age 70 of 15–20% for colorectal cancer, 15% for endometrial cancer, and 25–32% for any Lynch syndrome-associated cancer. No elevated risk for non-Lynch syndrome-associated cancers was observed. Conclusions PMS2 mutations contribute significantly to Lynch syndrome but the penetrance for monoallelic mutation carriers appears to be lower than that for the other mismatch repair genes. Modified counseling and cancer surveillance guidelines for PMS2 mutation carriers are proposed. PMID:18602922

  1. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations.

    Science.gov (United States)

    Senter, Leigha; Clendenning, Mark; Sotamaa, Kaisa; Hampel, Heather; Green, Jane; Potter, John D; Lindblom, Annika; Lagerstedt, Kristina; Thibodeau, Stephen N; Lindor, Noralane M; Young, Joanne; Winship, Ingrid; Dowty, James G; White, Darren M; Hopper, John L; Baglietto, Laura; Jenkins, Mark A; de la Chapelle, Albert

    2008-08-01

    Although the clinical phenotype of Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer) has been well described, little is known about disease in PMS2 mutation carriers. Now that mutation detection methods can discern mutations in PMS2 from mutations in its pseudogenes, more mutation carriers have been identified. Information about the clinical significance of PMS2 mutations is crucial for appropriate counseling. Here, we report the clinical characteristics of a large series of PMS2 mutation carriers. We performed PMS2 mutation analysis using long-range polymerase chain reaction and multiplex ligation-dependent probe amplification for 99 probands diagnosed with Lynch syndrome-associated tumors showing isolated loss of PMS2 by immunohistochemistry. Penetrance was calculated using a modified segregation analysis adjusting for ascertainment. Germ-line PMS2 mutations were detected in 62% of probands (n = 55 monoallelic; 6 biallelic). Among families with monoallelic PMS2 mutations, 65.5% met revised Bethesda guidelines. Compared with the general population, in mutation carriers, the incidence of colorectal cancer was 5.2-fold higher, and the incidence of endometrial cancer was 7.5-fold higher. In North America, this translates to a cumulative cancer risk to age 70 years of 15%-20% for colorectal cancer, 15% for endometrial cancer, and 25%-32% for any Lynch syndrome-associated cancer. No elevated risk for non-Lynch syndrome-associated cancers was observed. PMS2 mutations contribute significantly to Lynch syndrome, but the penetrance for monoallelic mutation carriers appears to be lower than that for the other mismatch repair genes. Modified counseling and cancer surveillance guidelines for PMS2 mutation carriers are proposed.

  2. Immune Profiling of Premalignant Lesions in Patients With Lynch Syndrome.

    Science.gov (United States)

    Chang, Kyle; Taggart, Melissa W; Reyes-Uribe, Laura; Borras, Ester; Riquelme, Erick; Barnett, Reagan M; Leoni, Guido; San Lucas, F Anthony; Catanese, Maria T; Mori, Federica; Diodoro, Maria G; You, Y Nancy; Hawk, Ernest T; Roszik, Jason; Scheet, Paul; Kopetz, Scott; Nicosia, Alfredo; Scarselli, Elisa; Lynch, Patrick M; McAllister, Florencia; Vilar, Eduardo

    2018-04-16

    Colorectal carcinomas in patients with Lynch syndrome (LS) arise in a background of mismatch repair (MMR) deficiency, display a unique immune profile with upregulation of immune checkpoints, and response to immunotherapy. However, there is still a gap in understanding the pathogenesis of MMR-deficient colorectal premalignant lesions, which is essential for the development of novel preventive strategies for LS. To characterize the immune profile of premalignant lesions from a cohort of patients with LS. Whole-genome transcriptomic analysis using next-generation sequencing was performed in colorectal polyps and carcinomas of patients with LS. As comparator and model of MMR-proficient colorectal carcinogenesis, we used samples from patients with familial adenomatous polyposis (FAP). In addition, a total of 47 colorectal carcinomas (6 hypermutants and 41 nonhypermutants) were obtained from The Cancer Genome Atlas (TCGA) for comparisons. Samples were obtained from the University of Texas MD Anderson Cancer Center and "Regina Elena" National Cancer Institute, Rome, Italy. All diagnoses were confirmed by genetic testing. Polyps were collected at the time of endoscopic surveillance and tumors were collected at the time of surgical resection. The data were analyzed from October 2016 to November 2017. Assessment of the immune profile, mutational signature, mutational and neoantigen rate, and pathway enrichment analysis of neoantigens in LS premalignant lesions and their comparison with FAP premalignant lesions, LS carcinoma, and sporadic colorectal cancers from TCGA. The analysis was performed in a total of 28 polyps (26 tubular adenomas and 2 hyperplastic polyps) and 3 early-stage LS colorectal tumors from 24 patients (15 [62%] female; mean [SD] age, 48.12 [15.38] years) diagnosed with FAP (n = 10) and LS (n = 14). Overall, LS polyps presented with low mutational and neoantigen rates but displayed a striking immune activation profile characterized by CD4 T cells

  3. 75 FR 40034 - Northeastern Tributary Reservoirs Land Management Plan, Beaver Creek, Clear Creek, Boone, Fort...

    Science.gov (United States)

    2010-07-13

    ... TENNESSEE VALLEY AUTHORITY Northeastern Tributary Reservoirs Land Management Plan, Beaver Creek...-managed public land on Beaver Creek, Clear Creek, Boone, Fort Patrick Henry, South Holston, Watauga, and... Proposed Land Use Alternative) identified in the final environmental impact statement (FEIS). Under the...

  4. 78 FR 62616 - Salmon Creek Hydroelectric Company, Salmon Creek Hydroelectric Company, LLC; Notice of Transfer...

    Science.gov (United States)

    2013-10-22

    ... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Project No. 3730-005] Salmon Creek Hydroelectric Company, Salmon Creek Hydroelectric Company, LLC; Notice of Transfer of Exemption 1. By letter filed September 23, 2013, Salmon Creek Hydroelectric Company informed the Commission that they have...

  5. Limited impact on self-concept in individuals with Lynch syndrome; results from a national cohort study

    DEFF Research Database (Denmark)

    Petersen, Helle Vendel; Esplen, Mary Jane; Ladelund, Steen

    2011-01-01

    An increasing number of individuals seek genetic counseling and hereby learn about hereditary cancer in the family. Lynch syndrome is associated with an inherited high risk for colorectal and gynecological cancer, but knowledge about how family members at risk perceive their situation is limited....... We used the national Danish HNPCC register to collect data on self-concept from 413 individuals with Lynch syndrome. The recently developed Lynch syndrome self-concept scale contains 20 items within two subscales related to stigma-vulnerability and bowel symptom-related anxiety. Significantly higher...... more often reported by women (odds ratio 1.8) and by individuals with less education (OR 1.8). This study provides the first extended use of the Lynch syndrome self-concept scale and suggests that the majority of the Danish mutation carriers adapt well to the situation, though knowledge about...

  6. The B-Lynch uterine brace suture, and a bit of this and a bit of that...

    Science.gov (United States)

    Karoshi, Mahantesh

    2010-03-01

    The widespread application of the B-Lynch brace suture to control postpartum hemorrhage has sparked interest in a variety of adjunctive methods, used alone or in combination, to control uterine bleeding. Although the B-Lynch brace suture has been used with good results throughout the world, failures can and do occur in rare instances, especially when the suture is incorrectly placed for use for an inappropriate indication. Four reports of additional methods to control postpartum hemorrhage are published in this issue of IJGO. Three use the B-Lynch brace suture combined with other techniques. The need for additional techniques reminds the reader of the importance of proper suture application for proper indication. Potential reasons for failure of the B-Lynch suture are provided.

  7. Identification of MSH2 inversion of exons 1-7 in clinical evaluation of families with suspected Lynch syndrome.

    Science.gov (United States)

    Mork, Maureen E; Rodriguez, Andrea; Taggart, Melissa W; Rodriguez-Bigas, Miguel A; Lynch, Patrick M; Bannon, Sarah A; You, Y Nancy; Vilar, Eduardo

    2017-07-01

    Traditional germline sequencing and deletion/duplication analysis does not detect Lynch syndrome-causing mutations in all individuals whose colorectal or endometrial tumors demonstrate mismatch repair (MMR) deficiency. Unique inversions and other rearrangements of the MMR genes have been reported in families with Lynch syndrome. In 2014, a recurrent inversion of MSH2 exons 1-7 was identified in five families suspected to have Lynch syndrome. We aimed to describe our clinical experience in identifying families with this specific inversion. Four probands whose Lynch syndrome-associated tumors demonstrated absence of MSH2/MSH6 staining and who had negative MMR germline testing were evaluated for the MSH2 inversion of exons 1-7, offered during initial genetic workup or upon routine clinical follow-up. All four probands tested positive for the MSH2 inversion. Proband cancer diagnoses included colon and endometrial adenocarcinoma and sebaceous adenoma. A variety of Lynch syndrome-associated cancers were reported in the family histories, although only one family met Amsterdam II criteria. Thirteen at-risk relatives underwent predictive testing. MSH2 inversion of exons 1-7 was found in four probands previously suspected to have Lynch syndrome based on family history and tumor testing. This testing should be offered routinely to patients with tumors demonstrating loss of MSH2/MSH6 staining.

  8. Differential expression of CK20, β-catenin, and MUC2/5AC/6 in Lynch syndrome and familial colorectal cancer type X

    DEFF Research Database (Denmark)

    Haraldsson, Stefan; Klarskov, Louise; Nilbert, Mef

    2017-01-01

    BACKGROUND: Hereditary non-polyposis colorectal cancer comprises Lynch syndrome and familial colorectal cancer type X (FCCTX). Differences in genetics, demographics and histopathology have been extensively studied. The purpose of this study is to characterize their immunoprofile of markers other...... than MMR proteins. METHODS: We compared the expression patterns of cytokeratins (CK7 and CK20), mucins (MUC2/5 AC/6), CDX2 and β-catenin in Lynch syndrome and FCCTX. RESULTS: Differences were identified for CK20 and nuclear β-catenin, which were significantly more often expressed in FCCTX than in Lynch...... syndrome (p Lynch syndrome tumors compared with FCCTX tumors (p = 0.001,

  9. 33 CFR 117.917 - Battery Creek.

    Science.gov (United States)

    2010-07-01

    ... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Battery Creek. 117.917 Section 117.917 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS Specific Requirements South Carolina § 117.917 Battery Creek. The draw of...

  10. 33 CFR 117.543 - Bear Creek.

    Science.gov (United States)

    2010-07-01

    ... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Bear Creek. 117.543 Section 117.543 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS Specific Requirements Maryland § 117.543 Bear Creek. (a) The draws of the Baltimore...

  11. 27 CFR 9.211 - Swan Creek.

    Science.gov (United States)

    2010-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false Swan Creek. 9.211 Section 9.211 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT OF THE TREASURY LIQUORS AMERICAN VITICULTURAL AREAS Approved American Viticultural Areas § 9.211 Swan Creek. (a) Name. The name of the viticultural are...

  12. 33 CFR 117.231 - Brandywine Creek.

    Science.gov (United States)

    2010-07-01

    ... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Brandywine Creek. 117.231 Section 117.231 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS Specific Requirements Delaware § 117.231 Brandywine Creek. The draw of the...

  13. 33 CFR 117.841 - Smith Creek.

    Science.gov (United States)

    2010-07-01

    ... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Smith Creek. 117.841 Section 117.841 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS Specific Requirements North Carolina § 117.841 Smith Creek. The draw of the S117-S133...

  14. 33 CFR 117.324 - Rice Creek.

    Science.gov (United States)

    2010-07-01

    ... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Rice Creek. 117.324 Section 117.324 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS Specific Requirements Florida § 117.324 Rice Creek. The CSX Railroad Swingbridge, mile...

  15. Currents and siltation at Dharamtar creek, Bombay

    Digital Repository Service at National Institute of Oceanography (India)

    Swamy, G.N.; Kolhatkar, V.M.; Fernandes, A.A.

    Hydrographic data collected in Dharamtar Creek during 1976-77 have been analysed. This showed that the waters in the Creek are well mixed and the salinity varied with the tide. The tidal currents are found to be generally strong. The distribution...

  16. 33 CFR 117.335 - Taylor Creek.

    Science.gov (United States)

    2010-07-01

    ... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Taylor Creek. 117.335 Section 117.335 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS Specific Requirements Florida § 117.335 Taylor Creek. The draw of US441 bridge, mile 0...

  17. Buck Creek River Flow Analysis

    Science.gov (United States)

    Dhanapala, Yasas; George, Elizabeth; Ritter, John

    2009-04-01

    Buck Creek flowing through Springfield Ohio has a number of low-head dams currently in place that cause safety issues and sometimes make it impossible for recreational boaters to pass through. The safety issues include the back eddies created by the dams that are known as drowning machines and the hydraulic jumps. In this study we are modeling the flow of Buck Creek using topographical and flow data provided by the Geology Department of Wittenberg University. The flow is analyzed using Hydraulic Engineering Center - River Analysis System software (HEC-RAS). As the first step a model of the river near Snyder Park has been created with the current structure in place for validation purposes. Afterwards the low-head dam is replaced with four drop structures with V-notch overflow gates. The river bed is altered to reflect plunge pools after each drop structure. This analysis will provide insight to how the flow is going to behave after the changes are made. In addition a sediment transport analysis is also being conducted to provide information about the stability of these structures.

  18. Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance

    DEFF Research Database (Denmark)

    Møller, Pål; Seppälä, Toni; Bernstein, Inge

    2017-01-01

    study of patients carrying Lynch syndrome-associated mutations affecting MLH1, MSH2, MSH6 or PMS2. Standardised information on surveillance, cancers and outcomes were collated in an Oracle relational database and analysed by age, sex and mutated gene. RESULTS: 1942 mutation carriers without previous...... carriers. Among first cancer detected in each patient the colorectal cancer cumulative incidences at 70 years by gene were 46%, 35%, 20% and 10% for MLH1, MSH2, MSH6 and PMS2 mutation carriers, respectively. The equivalent cumulative incidences for endometrial cancer were 34%, 51%, 49% and 24......%; and for ovarian cancer 11%, 15%, 0% and 0%. Ten-year crude survival was 87% after any cancer, 91% if the first cancer was colorectal, 98% if endometrial and 89% if ovarian. CONCLUSIONS: The four Lynch syndrome-associated genes had different penetrance and expression. Colorectal cancer occurred frequently despite...

  19. Revised Bethesda Guidelines for Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) and Microsatellite Instability

    OpenAIRE

    Umar, Asad; Boland, C. Richard; Terdiman, Jonathan P.; Syngal, Sapna; de la Chapelle, Albert; Rüschoff, Josef; Fishel, Richard; Lindor, Noralane M.; Burgart, Lawrence J.; Hamelin, Richard; Hamilton, Stanley R.; Hiatt, Robert A.; Jass, Jeremy; Lindblom, Annika; Lynch, Henry T.

    2004-01-01

    Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is a common autosomal dominant syndrome characterized by early age at onset, neoplastic lesions, and microsatellite instability (MSI). Because cancers with MSI account for approximately 15% of all colorectal cancers and because of the need for a better understanding of the clinical and histologic manifestations of HNPCC, the National Cancer Institute hosted an international workshop on HNPCC in 1996, which led to...

  20. »Just cut them up like regular children.« : Eraserhead (USA 1977, David Lynch)

    OpenAIRE

    Höltgen, Stefan

    2010-01-01

    Zwischen 1970 und 1977 entsteht in fünfjähriger Dreharbeit mit Unterbrechungen und unter extrem schwierigen Produktionsbedingungen David Lynchs erster Spielfilm "Eraserhead". Vorbereitet wurde er in mehrfacher Hinsicht durch das Frühwerk des noch jungen Regisseurs. Seine kinetische Skulptur "Six Men getting sick", sowie seine Kurzfilme "The Alphabet" und "The Grandmother" verhalfen ihm nicht nur zu Stipendien (etwa der AFI für "The Grandmother"), sondern etablierten auch ein Motivinventar, au...

  1. Pancreatic non-functioning neuroendocrine tumor: a new entity genetically related to Lynch syndrome

    OpenAIRE

    Serracant Barrera, Anna; Serra Pla, Sheila; Blázquez Maña, Carmen María; Salas, Rubén Carrera; García Monforte, Neus; Bejarano González, Natalia; Romaguera Monzonis, Andreu; Andreu Navarro, Francisco Javier; Bella Cueto, Maria Rosa; Borobia, Francisco G.

    2017-01-01

    Some pancreatic neuroendocrine tumors (P-NETs) are associated with hereditary syndromes. An association between Lynch syndrome (LS) and P-NETs has been suggested, however it has not been confirmed to date. We describe the first case associating LS and P-NETs. Here we report a 65-year-old woman who in the past 20 years presented two colorectal carcinomas (CRC) endometrial carcinoma (EC), infiltrating ductal breast carcinoma, small intestine adenocarcinoma, two non-functioning P-NETs and seboma...

  2. Uncertainties in the Management of a Lynch Syndrome Patient: A Case Report

    OpenAIRE

    Campos, Sara; Amaro, Pedro; Cunha, Inês; Fraga, João; Cipriano, Maria Augusta; Tomé, Luís

    2017-01-01

    Introduction: Lynch syndrome (LS), the most common hereditary colorectal cancer syndrome, is characterized by mutations in mismatch repair (MMR) genes leading to an increased cancer risk, namely colorectal cancer. Case: In the context of surveillance colonoscopy, a 40-mm flat lesion (0-IIa+b, Paris classification) was identified and submitted to piecemeal mucosal endoscopic resection in a 64-year-old LS patient with an MLH1 germline mutation (262delATC) and two previous segmental resections d...

  3. Field performance of timber bridges. 8, Lynches Woods Park stress-laminated deck bridge

    Science.gov (United States)

    J. P. Wacker; M. A. Ritter; D. Conger

    The Lynches Woods Park bridge was constructed during the summer of 1990 in Newberry, South Carolina. It is a single-span, single-lane, stress-laminated deck superstructure that measures approximately 30 ft long, 16 ft wide, and 14 in. deep. The bridge is unique in that is one of the first known stress-laminated deck bridges to be constructed of Southern Pine lumber...

  4. Lynch syndrome: barriers to and facilitators of screening and disease management.

    Science.gov (United States)

    Watkins, Kathy E; Way, Christine Y; Fiander, Jacqueline J; Meadus, Robert J; Esplen, Mary Jane; Green, Jane S; Ludlow, Valerie C; Etchegary, Holly A; Parfrey, Patrick S

    2011-09-07

    Lynch syndrome is a hereditary cancer with confirmed carriers at high risk for colorectal (CRC) and extracolonic cancers. The purpose of the current study was to develop a greater understanding of the factors influencing decisions about disease management post-genetic testing. The study used a grounded theory approach to data collection and analysis as part of a multiphase project examining the psychosocial and behavioral impact of predictive DNA testing for Lynch syndrome. Individual and small group interviews were conducted with individuals from 10 families with the MSH2 intron 5 splice site mutation or exon 8 deletion. The data from confirmed carriers (n = 23) were subjected to re-analysis to identify key barriers to and/or facilitators of screening and disease management. Thematic analysis identified personal, health care provider and health care system factors as dominant barriers to and/or facilitators of managing Lynch syndrome. Person-centered factors reflect risk perceptions and decision-making, and enduring screening/disease management. The perceived knowledge and clinical management skills of health care providers also influenced participation in recommended protocols. The health care system barriers/facilitators are defined in terms of continuity of care and coordination of services among providers. Individuals with Lynch syndrome often encounter multiple barriers to and facilitators of disease management that go beyond the individual to the provider and health care system levels. The current organization and implementation of health care services are inadequate. A coordinated system of local services capable of providing integrated, efficient health care and follow-up, populated by providers with knowledge of hereditary cancer, is necessary to maintain optimal health.

  5. The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors

    Science.gov (United States)

    Medeiros, Fabiola; Lindor, Noralane M.; Couch, Fergus J.; Highsmith, W. Edward

    2013-01-01

    Missense variants discovered during sequencing of cancer susceptibility genes can be problematic for clinical interpretation. MLH1 K618A, which results from a 2-bp alteration (AAG→GCG) leading to a substitution of lysine to alanine in codon 618, has variously been interpreted as a pathogenic mutation, a variant of unknown significance, and a benign polymorphism. We evaluated the role of MLH1 K618A in predisposition to cancer by genotyping 1512 control subjects to assess its frequency in the general population. We also reviewed the literature concerning MLH1 K618A in families with colorectal cancer. The measured allele frequency of the K618A variant was 0.40%, which is remarkably close to the 0.44% summarized from 2491 control subjects in the literature. K618A was over-represented in families with suspected Lynch syndrome. In 1366 families, the allele frequency was 0.88% (OR = 2.1, 95% CI = 1.3 to 3.5; P = 0.006). In studies of sporadic cancers of the type associated with Lynch syndrome, K618A was over-represented in 1742 cases (allele frequency of 0.83) (OR = 2.0, 95% CI = 1.2 to 3.2; P = 0.008). We conclude that MLH1 K618A is not a fully penetrant Lynch syndrome mutation, although it is not without effect, appearing to increase the risk of Lynch syndrome-associated tumors approximately twofold. Our systematic assessment approach may be useful for variants in other genes. PMID:22426235

  6. Finding the needle in a haystack: identification of cases of Lynch syndrome with MLH1 epimutation.

    Science.gov (United States)

    Hitchins, Megan P

    2016-07-01

    Constitutional epimutation of the DNA mismatch repair gene, MLH1, represents a minor cause of Lynch syndrome. MLH1 epimutations are characterized by the soma-wide distribution of methylation of a single allele of the MLH1 promoter accompanied by constitutive allelic loss of transcription. 'Primary' MLH1 epimutations, considered pure epigenetic defects, tend to arise de novo in patients without a family history or any apparent genetic mutation. These demonstrate non-Mendelian inheritance. 'Secondary' MLH1 epimutations have a genetic basis and have been linked to non-coding genetic alterations in the vicinity of MLH1. These demonstrate autosomal dominant inheritance. Despite convincing evidence of their role in causing Lynch-type cancers, routine screening for MLH1 epimutations has not been widely adopted. Complicating factors may include: the need to perform additional methylation-based testing beyond the standard genetic screening for a germline mutation; the lack of a consensus algorithm for the selection of patients warranting MLH1 epimutation testing; overlapping molecular pathology features of MLH1 methylation and loss of MLH1 expression with more prevalent sporadic MSI cancers; the rarity of MLH1 epimutation; the variable inter-generational inheritance patterns; and the cost-effectiveness of screening. Nevertheless, a positive molecular diagnosis of MLH1 epimutation is clinically important because carriers have a high personal risk of developing metachronous Lynch-type cancers, and their relatives may also be at risk of carriage. Extending existing universal and clinic-based screening algorithms for Lynch syndrome to include an additional arm of selection criteria for cases warranting MLH1 epimutation testing could provide a cost-effective means of diagnosing these cases.

  7. Lynch syndrome: barriers to and facilitators of screening and disease management

    Directory of Open Access Journals (Sweden)

    Watkins Kathy E

    2011-09-01

    Full Text Available Abstract Background Lynch syndrome is a hereditary cancer with confirmed carriers at high risk for colorectal (CRC and extracolonic cancers. The purpose of the current study was to develop a greater understanding of the factors influencing decisions about disease management post-genetic testing. Methods The study used a grounded theory approach to data collection and analysis as part of a multiphase project examining the psychosocial and behavioral impact of predictive DNA testing for Lynch syndrome. Individual and small group interviews were conducted with individuals from 10 families with the MSH2 intron 5 splice site mutation or exon 8 deletion. The data from confirmed carriers (n = 23 were subjected to re-analysis to identify key barriers to and/or facilitators of screening and disease management. Results Thematic analysis identified personal, health care provider and health care system factors as dominant barriers to and/or facilitators of managing Lynch syndrome. Person-centered factors reflect risk perceptions and decision-making, and enduring screening/disease management. The perceived knowledge and clinical management skills of health care providers also influenced participation in recommended protocols. The health care system barriers/facilitators are defined in terms of continuity of care and coordination of services among providers. Conclusions Individuals with Lynch syndrome often encounter multiple barriers to and facilitators of disease management that go beyond the individual to the provider and health care system levels. The current organization and implementation of health care services are inadequate. A coordinated system of local services capable of providing integrated, efficient health care and follow-up, populated by providers with knowledge of hereditary cancer, is necessary to maintain optimal health.

  8. Phenotypic and genotypic heterogeneity of Lynch syndrome: a complex diagnostic challenge.

    Science.gov (United States)

    Lynch, Henry T; Lanspa, Stephen; Shaw, Trudy; Casey, Murray Joseph; Rendell, Marc; Stacey, Mark; Townley, Theresa; Snyder, Carrie; Hitchins, Megan; Bailey-Wilson, Joan

    2018-07-01

    Lynch syndrome is the hereditary disorder that most frequently predisposes to colorectal cancer as well as predisposing to a number of extracolonic cancers, most prominently endometrial cancer. It is caused by germline mutations in the mismatch repair genes. Both its phenotype and genotype show marked heterogeneity. This review gives a historical overview of the syndrome, its heterogeneity, its genomic landscape, and its implications for complex diagnosis, genetic counseling and putative implications for immunotherapy.

  9. A Systematic Review on the Existing Screening Pathways for Lynch Syndrome Identification

    OpenAIRE

    Tognetto, Alessia; Michelazzo, Maria Benedetta; Calabró, Giovanna Elisa; Unim, Brigid; Di Marco, Marco; Ricciardi, Walter; Pastorino, Roberta; Boccia, Stefania

    2017-01-01

    Background Lynch syndrome (LS) is the most common hereditary colon cancer syndrome, accounting for 3–5% of colorectal cancer (CRC) cases, and it is associated with the development of other cancers. Early detection of individuals with LS is relevant, since they can take advantage of life-saving intensive care surveillance. The debate regarding the best screening policy, however, is far from being concluded. This prompted us to conduct a systematic review of the existing screening pathways for ...

  10. Serum antibodies against frameshift peptides in microsatellite unstable colorectal cancer patients with Lynch syndrome.

    Science.gov (United States)

    Reuschenbach, Miriam; Kloor, Matthias; Morak, Monika; Wentzensen, Nicolas; Germann, Anja; Garbe, Yvette; Tariverdian, Mirjam; Findeisen, Peter; Neumaier, Michael; Holinski-Feder, Elke; von Knebel Doeberitz, Magnus

    2010-06-01

    High level microsatellite instability (MSI-H) occurs in about 15% of colorectal cancer (CRCs), either as sporadic cancers or in the context of hereditary non-polyposis cancer or Lynch syndrome. In MSI-H CRC, mismatch repair deficiency leads to insertion/deletion mutations at coding microsatellites and thus to the translation of frameshift peptides (FSPs). FSPs are potent inductors of T cell responses in vitro and in vivo. The present study aims at the identification of FSP-specific humoral immune responses in MSI-H CRC and Lynch syndrome. Sera from patients with history of MSI-H CRC (n = 69), healthy Lynch syndrome mutation carriers (n = 31) and healthy controls (n = 52) were analyzed for antibodies against FSPs using peptide ELISA. Reactivities were measured against FSPs derived from genes frequently mutated in MSI-H CRCs, AIM2, TGFBR2, CASP5, TAF1B, ZNF294, and MARCKS. Antibody reactivity against FSPs was significantly higher in MSI-H CRC patients than in healthy controls (P = 0.036, Mann-Whitney) and highest in patients with shortest interval between tumor resection and serum sampling. Humoral immune responses in patients were most frequently directed against FSPs derived from mutated TAF1B (11.6%, 8/69) and TGFBR2 (10.1%, 7/69). Low level FSP-specific antibodies were also detected in healthy mutation carriers. Our results show that antibody responses against FSPs are detectable in MSI-H CRC patients and healthy Lynch syndrome mutation carriers. Based on the high number of defined FSP antigens, measuring FSP-specific humoral immune responses is a highly promising tool for future diagnostic application in MSI-H cancer patients.

  11. Models for Immune Response and Immune Evasion in MSI Cancer and Lynch Syndrome

    OpenAIRE

    Özcan, Mine

    2017-01-01

    Microsatellite-unstable (MSI) cancers occurring in the context of the hereditary Lynch syndrome or as sporadic cancers elicit pronounced tumor-specific immune responses. The pronounced immune response was shown to be closely associated with frameshift peptides (FSP) that are generated as a result of deficiency in DNA mismatch repair system leading to insertion/deletion mutations in coding microsatellites (cMS). FSP neoantigens are long antigenic amino acid stretches that bear m...

  12. Serum antibodies against frameshift peptides in microsatellite unstable colorectal cancer patients with Lynch syndrome

    Science.gov (United States)

    Reuschenbach, Miriam; Kloor, Matthias; Morak, Monika; Wentzensen, Nicolas; Germann, Anja; Garbe, Yvette; Tariverdian, Mirjam; Findeisen, Peter; Neumaier, Michael; Holinski-Feder, Elke; Doeberitz, Magnus von Knebel

    2014-01-01

    High level microsatellite instability (MSI-H) occurs in about 15% of colorectal cancer (CRCs), either as sporadic cancers or in the context of hereditary non-polyposis cancer (HNPCC) or Lynch syndrome. In MSI-H CRC, mismatch repair deficiency leads to insertion/deletion mutations at coding microsatellites (cMS) and thus to the translation of frameshift peptides (FSPs). FSPs are potent inductors of T cell responses in vitro and in vivo. The present study aims at the identification of FSP-specific humoral immune responses in MSI-H CRC and Lynch syndrome. Sera from patients with history of MSI-H CRC (n=69), healthy Lynch syndrome mutation carriers (n=31) and healthy controls (n=52) were analyzed for antibodies against FSPs using peptide ELISA. Reactivities were measured against FSPs derived from genes frequently mutated in MSI-H CRCs, AIM2, TGFBR2, CASP5, TAF1B, ZNF294, and MARCKS. Antibody reactivity against FSPs was significantly higher in MSI-H CRC patients than in healthy controls (p=0.036, Mann-Whitney) and highest in patients with shortest interval between tumor resection and serum sampling. Humoral immune responses in patients were most frequently directed against FSPs derived from mutated TAF1B (11.6%, 8/69) and TGFBR2 (10.1%, 7/69). Low level FSP-specific antibodies were also detected in healthy mutation carriers. Our results show that antibody responses against FSPs are detectable in MSI-H CRC patients and healthy Lynch syndrome mutation carriers. Based on the high number of defined FSP antigens, measuring FSP-specific humoral immune responses is a highly promising tool for future diagnostic application in MSI-H cancer patients. PMID:19957108

  13. Using Social Media Data to Understand the Impact of Promotional Information on Laypeople's Discussions: A Case Study of Lynch Syndrome.

    Science.gov (United States)

    Bian, Jiang; Zhao, Yunpeng; Salloum, Ramzi G; Guo, Yi; Wang, Mo; Prosperi, Mattia; Zhang, Hansi; Du, Xinsong; Ramirez-Diaz, Laura J; He, Zhe; Sun, Yuan

    2017-12-13

    Social media is being used by various stakeholders among pharmaceutical companies, government agencies, health care organizations, professionals, and news media as a way of engaging audiences to raise disease awareness and ultimately to improve public health. Nevertheless, it is unclear what effects this health information has on laypeople. This study aimed to provide a detailed examination of how promotional health information related to Lynch syndrome impacts laypeople's discussions on a social media platform (Twitter) in terms of topic awareness and attitudes. We used topic modeling and sentiment analysis techniques on Lynch syndrome-related tweets to answer the following research questions (RQs): (1) what are the most discussed topics in Lynch syndrome-related tweets?; (2) how promotional Lynch syndrome-related information on Twitter affects laypeople's discussions?; and (3) what impact do the Lynch syndrome awareness activities in the Colon Cancer Awareness Month and Lynch Syndrome Awareness Day have on laypeople's discussions and their attitudes? In particular, we used a set of keywords to collect Lynch syndrome-related tweets from October 26, 2016 to August 11, 2017 (289 days) through the Twitter public search application programming interface (API). We experimented with two different classification methods to categorize tweets into the following three classes: (1) irrelevant, (2) promotional health information, and (3) laypeople's discussions. We applied a topic modeling method to discover the themes in these Lynch syndrome-related tweets and conducted sentiment analysis on each layperson's tweet to gauge the writer's attitude (ie, positive, negative, and neutral) toward Lynch syndrome. The topic modeling and sentiment analysis results were elaborated to answer the three RQs. Of all tweets (N=16,667), 87.38% (14,564/16,667) were related to Lynch syndrome. Of the Lynch syndrome-related tweets, 81.43% (11,860/14,564) were classified as promotional and 18

  14. Hydrology of the Johnson Creek Basin, Oregon

    Science.gov (United States)

    Lee, Karl K.; Snyder, Daniel T.

    2009-01-01

    The Johnson Creek basin is an important resource in the Portland, Oregon, metropolitan area. Johnson Creek forms a wildlife and recreational corridor through densely populated areas of the cities of Milwaukie, Portland, and Gresham, and rural and agricultural areas of Multnomah and Clackamas Counties. The basin has changed as a result of agricultural and urban development, stream channelization, and construction of roads, drains, and other features characteristic of human occupation. Flooding of Johnson Creek is a concern for the public and for water management officials. The interaction of the groundwater and surface-water systems in the Johnson Creek basin also is important. The occurrence of flooding from high groundwater discharge and from a rising water table prompted this study. As the Portland metropolitan area continues to grow, human-induced effects on streams in the Johnson Creek basin will continue. This report provides information on the groundwater and surface-water systems over a range of hydrologic conditions, as well as the interaction these of systems, and will aid in management of water resources in the area. High and low flows of Crystal Springs Creek, a tributary to Johnson Creek, were explained by streamflow and groundwater levels collected for this study, and results from previous studies. High flows of Crystal Springs Creek began in summer 1996, and did not diminish until 2000. Low streamflow of Crystal Springs Creek occurred in 2005. Flow of Crystal Springs Creek related to water-level fluctuations in a nearby well, enabling prediction of streamflow based on groundwater level. Holgate Lake is an ephemeral lake in Southeast Portland that has inundated residential areas several times since the 1940s. The water-surface elevation of the lake closely tracked the elevation of the water table in a nearby well, indicating that the occurrence of the lake is an expression of the water table. Antecedent conditions of the groundwater level and autumn

  15. A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome.

    Science.gov (United States)

    Clendenning, M; Senter, L; Hampel, H; Robinson, K Lagerstedt; Sun, S; Buchanan, D; Walsh, M D; Nilbert, M; Green, J; Potter, J; Lindblom, A; de la Chapelle, A

    2008-06-01

    When compared to the other mismatch repair genes involved in Lynch syndrome, the identification of mutations within PMS2 has been limited (PMS2. This disparity is primarily due to complications in the study of this gene caused by interference from pseudogene sequences. Using a recently developed method for detecting PMS2 specific mutations, we have screened 99 patients who are likely candidates for PMS2 mutations based on immunohistochemical analysis. We have identified a frequently occurring frame-shift mutation (c.736_741del6ins11) in 12 ostensibly unrelated Lynch syndrome patients (20% of patients we have identified with a deleterious mutation in PMS2, n = 61). These individuals all display the rare allele (population frequency 10 000 carriers of this mutation in the USA alone. The identification of both the mutation and the common haplotype in one Swedish control sample (n = 225), along with evidence that Lynch syndrome associated cancers are rarer than expected in the probands' families, would suggest that this is a prevalent mutation with reduced penetrance.

  16. Lynch syndrome patients' views of and preferences for return of results following whole exome sequencing.

    Science.gov (United States)

    Hitch, Kelly; Joseph, Galen; Guiltinan, Jenna; Kianmahd, Jessica; Youngblom, Janey; Blanco, Amie

    2014-08-01

    Whole exome sequencing (WES) uses next generation sequencing technology to provide information on nearly all functional, protein-coding regions in an individual's genome. Due to the vast amount of information and incidental findings that can be generated from this technology, patient preferences must be investigated to help clinicians consent and return results to patients. Patients (n = 19) who were previously clinically diagnosed with Lynch syndrome, but received uninformative negative Lynch syndrome genetic results through traditional molecular testing methods participated in semi-structured interviews after WES testing but before return of results to explore their views of WES and preferences for return of results. Analyses of interview results found that nearly all participants believed that the benefits of receiving all possible results generated from WES outweighed the undesirable effects. The majority of participants conveyed that relative to coping with a cancer diagnosis, information generated from WES would be manageable. Importantly, participants' experience with Lynch syndrome influenced their notions of genetic determinism, tolerance for uncertain results, and family communication plans. Participants would prefer to receive WES results in person from a genetic counselor or medical geneticist so that an expert could help explain the meaning and implications of the potentially large quantity and range of complicated results. These results underscore the need to study various populations with regard to the clinical use of WES in order to effectively and empathetically communicate the possible implications of this new technology and return results.

  17. Physical activity and the risk of colorectal cancer in Lynch syndrome.

    Science.gov (United States)

    Dashti, S Ghazaleh; Win, Aung Ko; Hardikar, Sheetal S; Glombicki, Stephen E; Mallenahalli, Sheila; Thirumurthi, Selvi; Peterson, Susan K; You, Y Nancy; Buchanan, Daniel D; Figueiredo, Jane C; Campbell, Peter T; Gallinger, Steven; Newcomb, Polly A; Potter, John D; Lindor, Noralane M; Le Marchand, Loic; Haile, Robert W; Hopper, John L; Jenkins, Mark A; Basen-Engquist, Karen M; Lynch, Patrick M; Pande, Mala

    2018-06-14

    Greater physical activity is associated with a decrease in risk of colorectal cancer for the general population; however, little is known about its relationship with colorectal cancer risk for people with Lynch syndrome, carriers of inherited pathogenic mutations in genes affecting DNA mismatch repair (MMR). We studied a cohort of 2,042 MMR gene mutations carriers (n=807, diagnosed with colorectal cancer), from the Colon Cancer Family Registry. Self-reported physical activity in three age-periods (20-29, 30-49, and ≥50 years) was summarized as average metabolic equivalent of task hours per week (MET-h/week) during the age-period of cancer diagnosis or censoring (near-term exposure), and across all age-periods preceding cancer diagnosis or censoring (long-term exposure). Weighted Cox regression was used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for the association between physical activity and colorectal cancer risk. Near-term physical activity was associated with a small reduction in the risk of colorectal cancer (HR ≥35 vs. Lynch syndrome, however, further confirmation is warranted. The potential modifying effect of physical activity on colorectal cancer risk for people with Lynch syndrome could be useful for risk prediction and support counseling advice for lifestyle modification to reduce cancer risk. This article is protected by copyright. All rights reserved. © 2018 UICC.

  18. Adrenocortical carcinoma, an unusual extracolonic tumor associated with Lynch II syndrome.

    Science.gov (United States)

    Medina-Arana, V; Delgado, L; González, L; Bravo, A; Díaz, H; Salido, E; Riverol, D; González-Aguilera, J J; Fernández-Peralta, A M

    2011-06-01

    Lynch syndrome (LS) is an autosomal dominant condition that predisposes to colorectal cancer and specific other tumors. Extracolonic tumors occur mainly in the endometrium, stomach, ovary, small intestine and urinary tract. The presence of rare tumors in patients belonging to families who have Lynch syndrome is always interesting, because the question arises whether these tumors should be considered as a coincidence or are related with the syndrome. In this last case, they are also the result of the defect in the mismatch repair system, opening the possibility of extending the tumor spectrum associated with the syndrome. Here we describe a patient from a Lynch syndrome family with a germline mutation c.2063T>G (p.M688R) in the MSH2 gene, who developed an adrenal cortical carcinoma, a tumor not usually associated with LS. We analyzed the adrenocortical tumour for microsatellite instability (MSI), LOH and the presence of the germline c.2063T>G (M688R) mutation. The adrenal cortical carcinoma showed the MSH2 mutation, loss of heterozygosity of the normal allele in the MSH2 gene and loss of immunohistochemical expression for MSH2 protein, but no microsatellite instability. Additionally, the adrenal cortical carcinoma did not harbour a TP53 mutation. The molecular study indicates that this adrenal cortical cancer is probably due to the mismatch repair defect.

  19. Utility of MLH1 methylation analysis in the clinical evaluation of Lynch Syndrome in women with endometrial cancer.

    Science.gov (United States)

    Bruegl, Amanda S; Djordjevic, Bojana; Urbauer, Diana L; Westin, Shannon N; Soliman, Pamela T; Lu, Karen H; Luthra, Rajyalakshmi; Broaddus, Russell R

    2014-01-01

    Clinical screening criteria, such as young age of endometrial cancer diagnosis and family history of signature cancers, have traditionally been used to identify women with Lynch Syndrome, which is caused by mutation of a DNA mismatch repair gene. Immunohistochemistry and microsatellite instability analysis have evolved as important screening tools to evaluate endometrial cancer patients for Lynch Syndrome. A complicating factor is that 15-20% of sporadic endometrial cancers have immunohistochemical loss of the DNA mismatch repair protein MLH1 and high levels of microsatellite instability due to methylation of MLH1. The PCR-based MLH1 methylation assay potentially resolves this issue, yet many clinical laboratories do not perform this assay. The objective of this study was to determine if clinical and pathologic features help to distinguish sporadic endometrial carcinomas with MLH1 loss secondary to MLH1 methylation from Lynch Syndrome-associated endometrial carcinomas with MLH1 loss and absence of MLH1 methylation. Of 337 endometrial carcinomas examined, 54 had immunohistochemical loss of MLH1. 40/54 had MLH1 methylation and were designated as sporadic, while 14/54 lacked MLH1 methylation and were designated as Lynch Syndrome. Diabetes and deep myometrial invasion were associated with Lynch Syndrome; no other clinical or pathological variable distinguished the 2 groups. Combining Society of Gynecologic Oncology screening criteria with these 2 features accurately captured all Lynch Syndrome cases, but with low specificity. In summary, no single clinical/pathologic feature or screening criteria tool accurately identified all Lynch Syndrome-associated endometrial carcinomas, highlighting the importance of the MLH1 methylation assay in the clinical evaluation of these patients.

  20. Universal tumor screening for Lynch syndrome: Assessment of the perspectives of patients with colorectal cancer regarding benefits and barriers.

    Science.gov (United States)

    Hunter, Jessica Ezzell; Zepp, Jamilyn M; Gilmore, Mari J; Davis, James V; Esterberg, Elizabeth J; Muessig, Kristin R; Peterson, Susan K; Syngal, Sapna; Acheson, Louise S; Wiesner, Georgia L; Reiss, Jacob A; Goddard, Katrina A B

    2015-09-15

    Universal tumor screening for Lynch syndrome, the most common form of hereditary colorectal cancer (CRC), has been recommended among all patients newly diagnosed with CRC. However, there is limited literature regarding patient perspectives of tumor screening for Lynch syndrome among patients with CRC who are not selected for screening based on family history criteria. A total of 145 patients aged 39 to 87 years were administered surveys assessing perceived risk, patient perspectives, and potential benefits of and barriers to tumor screening for Lynch syndrome. Associations between patient-specific and cancer-specific factors and survey responses were analyzed. The majority of participants perceived their risk of developing Lynch syndrome as being low, with 9 participants (6.2%) anticipating an abnormal screening result. However, most participants endorsed the potential benefits of screening for themselves and their families, with 84.8% endorsing ≥6 benefits and 50.3% endorsing all 8 benefits. Participants also endorsed few potential barriers to screening, with 89.4% endorsing ≤4 of 9 potential barriers. A common barrier was worry about the cost of additional testing and surveillance, which was endorsed by 54.5% of participants. The level of distress associated with tumor screening for Lynch syndrome, which was very low, was not associated with age or CRC stage. The results of the current study indicate that patients with CRC overall have a positive attitude toward tumor screening for Lynch syndrome, endorse the benefits of screening, and experience low levels of distress. These findings provide insight into patient attitudes toward tumor screening for Lynch syndrome among unselected patients with CRC to inform educational approaches that assist in patient decision-making and guide the successful implementation of screening programs. © 2015 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

  1. Worldwide Practice Patterns in Lynch Syndrome Diagnosis and Management, Based on Data From the International Mismatch Repair Consortium.

    Science.gov (United States)

    Pan, Jennifer Y; Haile, Robert W; Templeton, Allyson; Macrae, Finlay; Qin, FeiFei; Sundaram, Vandana; Ladabaum, Uri

    2018-04-24

    Families with a history of Lynch syndrome often do not adhere to guidelines for genetic testing and screening. We investigated practice patterns related to Lynch syndrome worldwide, to ascertain potential targets for research and public policy efforts. We collected data from the International Mismatch Repair Consortium (IMRC), which comprises major research and clinical groups engaged in the care of families with Lynch syndrome worldwide. IMRC institutions were invited to complete a questionnaire to characterize diagnoses of Lynch syndrome and management practice patterns. Fifty-five providers, representing 63 of 128 member institutions (49%) in 21 countries, completed the questionnaire. For case finding, 55% of respondents reported participating in routine widespread population tumor testing among persons with newly diagnosed Lynch syndrome-associated cancers, whereas 27% reported relying on clinical criteria with selective tumor and/or germline analyses. Most respondents (64%) reported using multigene panels for germline analysis, and only 28% reported testing tumors for biallelic mutations for cases in which suspected pathogenic mutations were not confirmed by germline analysis. Respondents reported relying on passive dissemination of information to at-risk family members, and there was variation in follow through of genetic testing recommendations. Reported risk management practices varied-nearly all programs (98%) recommended colonoscopy every 1 to 2 years, but only 35% recommended chemoprevention with aspirin. There is widespread heterogeneity in management practices for Lynch syndrome worldwide among IMRC member institutions. This may reflect the rapid pace of emerging technology, regional differences in resources, and the lack of definitive data for many clinical questions. Future efforts should focus on the large numbers of high-risk patients without access to state-of-the-art Lynch syndrome management. Copyright © 2018 AGA Institute. Published by

  2. 77 FR 10960 - Drawbridge Operation Regulation; Snake Creek, Islamorada, FL

    Science.gov (United States)

    2012-02-24

    ... Operation Regulation; Snake Creek, Islamorada, FL AGENCY: Coast Guard, DHS. ACTION: Notice of temporary... deviation from the regulation governing the operation of Snake Creek Bridge, mile 0.5, across Snake Creek... schedule of Snake Creek Bridge in Islamorada, Florida. This deviation will result in the bridge opening...

  3. Flood discharges and hydraulics near the mouths of Wolf Creek, Craig Branch, Manns Creek, Dunloup Creek, and Mill Creek in the New River Gorge National River, West Virginia

    Science.gov (United States)

    Wiley, J.B.

    1994-01-01

    The U.S. Geological Survey, in cooperation with the National Park Service, studied the frequency and magnitude of flooding near the mouths of five tributaries to the New River in the New River Gorge National River. The 100-year peak discharge at each tributary was determined from regional frequency equations. The 100-year discharge at Wolf Creek, Craig Branch, Manns Creek, Dunloup Creek, and Mill Creek was 3,400 cubic feet per second, 640 cubic feet per second, 8,200 cubic feet per second, 7,100 cubic feet per second, and 9,400 cubic feet per second, respectively. Flood elevations for each tributary were determined by application of a steady-state, one-dimensional flow model. Manning's roughness coefficients for the stream channels ranged from 0.040 to 0.100. Bridges that would be unable to contain the 100-year flood within the bridge opening included: the State Highway 82 bridge on Wolf Creek, the second Fayette County Highway 25 bridge upstream from the confluence with New River on Dunloup Creek, and an abandoned log bridge on Mill Creek.

  4. RNF43 is mutated less frequently in Lynch Syndrome compared with sporadic microsatellite unstable colorectal cancers.

    Science.gov (United States)

    Fennell, Lochlan J; Clendenning, Mark; McKeone, Diane M; Jamieson, Saara H; Balachandran, Samanthy; Borowsky, Jennifer; Liu, John; Kawamata, Futoshi; Bond, Catherine E; Rosty, Christophe; Burge, Matthew E; Buchanan, Daniel D; Leggett, Barbara A; Whitehall, Vicki L J

    2018-01-01

    The WNT signaling pathway is commonly altered during colorectal cancer development. The E3 ubiquitin ligase, RNF43, negatively regulates the WNT signal through increased ubiquitination and subsequent degradation of the Frizzled receptor. RNF43 has recently been reported to harbor frequent truncating frameshift mutations in sporadic microsatellite unstable (MSI) colorectal cancers. This study assesses the relative frequency of RNF43 mutations in hereditary colorectal cancers arising in the setting of Lynch syndrome. The entire coding region of RNF43 was Sanger sequenced in 24 colorectal cancers from 23 patients who either (i) carried a germline mutation in one of the DNA mismatch repair genes (MLH1, MSH6, MSH2, PMS2), or (ii) showed immunohistochemical loss of expression of one or more of the DNA mismatch repair proteins, was BRAF wild type at V600E, were under 60 years of age at diagnosis, and demonstrated no promoter region methylation for MLH1 in tumor DNA. A validation cohort of 44 colorectal cancers from mismatch repair germline mutation carriers from the Australasian Colorectal Cancer Family Registry (ACCFR) were sequenced for the most common truncating mutation hotspots (X117 and X659). RNF43 mutations were found in 9 of 24 (37.5%) Lynch syndrome colorectal cancers. The majority of mutations were frameshift deletions in the G659 G7 repeat tract (29%); 2 cancers (2/24, 8%) from the one patient harbored frameshift mutations at codon R117 (C6 repeat tract) within exon 3. In the ACCFR validation cohort, RNF43 hotspot mutations were identified in 19/44 (43.2%) of samples, which was not significantly different to the initial series. The proportion of mutant RNF43 in Lynch syndrome related colorectal cancers is significantly lower than the previously reported mutation rate found in sporadic MSI colorectal cancers. These findings identify further genetic differences between sporadic and hereditary colorectal cancers. This may be because Lynch Syndrome cancers

  5. CREEK Project's Internal Creek Habitat Survey for Eight Creeks in the North Inlet Estuary, South Carolina: January 1998.

    Data.gov (United States)

    Baruch Institute for Marine and Coastal Sciences, Univ of South Carolina — A group of eight intertidal creeks with high densities of oysters, Crassostrea virginica, in North Inlet Estuary, South Carolina, USA were studied using a replicated...

  6. Strategies to Identify the Lynch Syndrome Among Patients With Colorectal Cancer

    Science.gov (United States)

    Ladabaum, Uri; Wang, Grace; Terdiman, Jonathan; Blanco, Amie; Kuppermann, Miriam; Boland, C. Richard; Ford, James; Elkin, Elena; Phillips, Kathryn A.

    2013-01-01

    Background Testing has been advocated for all persons with newly diagnosed colorectal cancer to identify families with the Lynch syndrome, an autosomal dominant cancer-predisposition syndrome that is a paradigm for personalized medicine. Objective To estimate the effectiveness and cost-effectiveness of strategies to identify the Lynch syndrome, with attention to sex, age at screening, and differential effects for probands and relatives. Design Markov model that incorporated risk for colorectal, endometrial, and ovarian cancers. Data Sources Published literature. Target Population All persons with newly diagnosed colorectal cancer and their relatives. Time Horizon Lifetime. Perspective Third-party payer. Intervention Strategies based on clinical criteria, prediction algorithms, tumor testing, or up-front germline mutation testing, followed by tailored screening and risk-reducing surgery. Outcome Measures Life-years, cancer cases and deaths, costs, and incremental cost-effectiveness ratios. Results of Base-Case Analysis The benefit of all strategies accrued primarily to relatives with a mutation associated with the Lynch syndrome, particularly women, whose life expectancy could increase by approximately 4 years with hysterectomy and salpingo-oophorectomy and adherence to colorectal cancer screening recommendations. At current rates of germline testing, screening, and prophylactic surgery, the strategies reduced deaths from colorectal cancer by 7% to 42% and deaths from endometrial and ovarian cancer by 1% to 6%. Among tumor-testing strategies, immunohistochemistry followed by BRAF mutation testing was preferred, with an incremental cost-effectiveness ratio of $36 200 per life-year gained. Results of Sensitivity Analysis The number of relatives tested per proband was a critical determinant of both effectiveness and cost-effectiveness, with testing of 3 to 4 relatives required for most strategies to meet a threshold of $50 000 per life-year gained. Immunohistochemistry

  7. Comparison of clinical features between suspected familial colorectal cancer type X and Lynch syndrome in Japanese patients with colorectal cancer: a cross-sectional study conducted by the Japanese Society for Cancer of the Colon and Rectum.

    Science.gov (United States)

    Yamaguchi, Tatsuro; Furukawa, Yoichi; Nakamura, Yusuke; Matsubara, Nagahide; Ishikawa, Hideki; Arai, Masami; Tomita, Naohiro; Tamura, Kazuo; Sugano, Kokichi; Ishioka, Chikashi; Yoshida, Teruhiko; Moriya, Yoshihiro; Ishida, Hideyuki; Watanabe, Toshiaki; Sugihara, Kenichi

    2015-02-01

    The characteristics of familial colorectal cancer type X are poorly defined. Here we aimed to clarify the differences in clinical features between suspected familial colorectal cancer type X and Lynch syndrome in Japanese patients. We performed germline mutation analyses of mismatch repair genes in 125 patients. Patients who met the Amsterdam Criteria I but lacked mismatch repair gene mutations were diagnosed with suspected familial colorectal cancer type X. We identified 69 patients with Lynch syndrome and 25 with suspected familial colorectal cancer type X. The frequencies of gastric and extracolonic Lynch syndrome-associated cancers were lower with suspected familial colorectal cancer type X than with Lynch syndrome. The number of organs with Lynch syndrome-associated cancer was significantly lower with suspected familial colorectal cancer type X than with Lynch syndrome. The cumulative incidence of extracolonic Lynch syndrome-associated cancer was significantly lower with suspected familial colorectal cancer type X than with Lynch syndrome. We estimated that the median cancer risk in 60-year-old patients with Lynch syndrome was 89, 36 and 24% for colorectal, endometrial and gastric cancers, respectively. Analyses of family members, including probands, revealed that the median age at diagnosis of extracolonic Lynch syndrome-associated cancer was significantly older with suspected familial colorectal cancer type X than with Lynch syndrome. The frequency of extracolonic Lynch syndrome-associated cancer was significantly lower with suspected familial colorectal cancer type X than with Lynch syndrome. A significant difference in extracolonic Lynch syndrome-associated cancer was evident between suspected familial colorectal cancer type X and Lynch syndrome. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  8. Differential expression of CK20, β-catenin, and MUC2/5AC/6 in Lynch syndrome and familial colorectal cancer type X.

    Science.gov (United States)

    Haraldsson, Stefan; Klarskov, Louise; Nilbert, Mef; Bernstein, Inge; Bonde, Jesper; Holck, Susanne

    2017-01-01

    Hereditary non-polyposis colorectal cancer comprises Lynch syndrome and familial colorectal cancer type X (FCCTX). Differences in genetics, demographics and histopathology have been extensively studied. The purpose of this study is to characterize their immunoprofile of markers other than MMR proteins. We compared the expression patterns of cytokeratins (CK7 and CK20), mucins (MUC2/5 AC/6), CDX2 and β-catenin in Lynch syndrome and FCCTX. Differences were identified for CK20 and nuclear β-catenin, which were significantly more often expressed in FCCTX than in Lynch syndrome ( p  Lynch syndrome tumors compared with FCCTX tumors ( p  = 0.001, Lynch syndrome with a more sporadic-like profile in the former group and a more distinct profile with frequent MUC6 positivity in the latter group.

  9. Featured Partner: Saddle Creek Logistics Services

    Science.gov (United States)

    This EPA fact sheet spotlights Saddle Creek Logistics as a SmartWay partner committed to sustainability in reducing greenhouse gas emissions and air pollution caused by freight transportation, partly by growing its compressed natural gas (CNG) vehicles for

  10. Some Physicochemical Charateristics of Badagry Creek, Nigeria ...

    African Journals Online (AJOL)

    West African Journal of Applied Ecology ... Badagry Creek runs through Nigeria and Republic of Benin with access to the Atlantic Ocean. ... Colour, surface temperature, pH, salinity, turbidity, phenol, dissolved oxygen, biological oxygen ...

  11. Tritium at the Steel Creek Landing

    International Nuclear Information System (INIS)

    Arnett, M.; Heffner, J.D.; Fledderman, P.D.; Littrell, J.W.; Hayes, D.W.; Dodgen, M.S.

    1998-01-01

    In December 1997 and January 1998, the South Carolina Department of Health and Environmental Control (SCDHEC) collected routine weekly grab samples from the Savannah River near the Steel Creek Boat Landing

  12. Mercury in Thana creek, Bombay harbour

    Digital Repository Service at National Institute of Oceanography (India)

    Zingde, M.D.; Desai, B.N.

    weight) with marked increased from harbour to the creek region suggests substantial mercury input in the head region. Chemical extraction by hydrogen peroxide indicated that more than 70% of mercury was leachable and probably organically bound...

  13. Wolf Creek Generating Station containment model

    International Nuclear Information System (INIS)

    Nguyen, D.H.; Neises, G.J.; Howard, M.L.

    1995-01-01

    This paper presents a CONTEMPT-LT/28 containment model that has been developed by Wolf Creek Nuclear Operating Corporation (WCNOC) to predict containment pressure and temperature behavior during the postulated events at Wolf Creek Generating Station (WCGS). The model has been validated using data provided in the WCGS Updated Safety Analysis Report (USAR). CONTEMPT-LT/28 model has been used extensively at WCGS to support plant operations, and recently, to support its 4.5% thermal power uprate project

  14. Freshwater and Saline Loads of Dissolved Inorganic Nitrogen to Hood Canal and Lynch Cove, Western Washington

    Science.gov (United States)

    Paulson, Anthony J.; Konrad, Christopher P.; Frans, Lonna M.; Noble, Marlene; Kendall, Carol; Josberger, Edward G.; Huffman, Raegan L.; Olsen, Theresa D.

    2006-01-01

    Hood Canal is a long (110 kilometers), deep (175 meters) and narrow (2 to 4 kilometers wide) fjord of Puget Sound in western Washington. The stratification of a less dense, fresh upper layer of the water column causes the cold, saltier lower layer of the water column to be isolated from the atmosphere in the late summer and autumn, which limits reaeration of the lower layer. In the upper layer of Hood Canal, the production of organic matter that settles and consumes dissolved oxygen in the lower layer appears to be limited by the load of dissolved inorganic nitrogen (DIN): nitrate, nitrite, and ammonia. Freshwater and saline loads of DIN to Hood Canal were estimated from available historical data. The freshwater load of DIN to the upper layer of Hood Canal, which could be taken up by phytoplankton, came mostly from surface and ground water from subbasins, which accounts for 92 percent of total load of DIN to the upper layer of Hood Canal. Although DIN in rain falling on land surfaces amounts to about one-half of the DIN entering Hood Canal from subbasins, rain falling directly on the surface of marine waters contributed only 4 percent of the load to the upper layer. Point-source discharges and subsurface flow from shallow shoreline septic systems contributed less than 4 percent of the DIN load to the upper layer. DIN in saline water flowing over the sill into Hood Canal from Admiralty Inlet was at least 17 times the total load to the upper layer of Hood Canal. In September and October 2004, field data were collected to estimate DIN loads to Lynch Cove - the most inland marine waters of Hood Canal that routinely contain low dissolved-oxygen waters. Based on measured streamflow and DIN concentrations, surface discharge was estimated to have contributed about one-fourth of DIN loads to the upper layer of Lynch Cove. Ground-water flow from subbasins was estimated to have contributed about one-half of total DIN loads to the upper layer. In autumn 2004, the relative

  15. Sessile serrated polyps of the colorectum are rare in patients with Lynch syndrome and in familial colorectal cancer families

    DEFF Research Database (Denmark)

    Andersen, S H; Lykke, E; Folker, M B

    2008-01-01

    Whereas the generally accepted carcinogenesis pathway of the microsatellite instabile high (MSI-H) colorectal carcinoma (CRC) involves the traditional adenoma in patients with Lynch syndrome, a serrate pathway involving serrate adenomas (SA) and sessile serrate polyps (SSP) characterize...... the sporadic MSI-H counterpart. Recent studies have, however, challenged such simple one-pathway models, inviting the consideration of alternative, unexpected pathways. Here, the issue as to the possible role of SSP, primarily in the context of Lynch syndrome, but also in subjects from familial CRC families...... (FCF) is addressed. Polyps coded as hyperplastic polyps (HP) from subjects with Lynch syndrome and FCF enrolled in the HNPCC-register at the Hvidovre University Hospital as well as adenomas from this population were retrieved and reviewed for features of SSP. Ninety-eight polyps coded as HP and 41...

  16. Limited impact on self-concept in individuals with Lynch syndrome; results from a national cohort study

    DEFF Research Database (Denmark)

    Petersen, Helle Vendel; Esplen, Mary Jane; Ladelund, Steen

    2011-01-01

    . We used the national Danish HNPCC register to collect data on self-concept from 413 individuals with Lynch syndrome. The recently developed Lynch syndrome self-concept scale contains 20 items within two subscales related to stigma-vulnerability and bowel symptom-related anxiety. Significantly higher...... total scores, indicating a greater impact on self-concept, were reported by females and by individuals with experience from cancer in close relatives, whereas individuals with less formal education scored significantly higher on the stigma and vulnerability subscale. Scores in the upper quartile were...... more often reported by women (odds ratio 1.8) and by individuals with less education (OR 1.8). This study provides the first extended use of the Lynch syndrome self-concept scale and suggests that the majority of the Danish mutation carriers adapt well to the situation, though knowledge about...

  17. Cancer spectrum in DNA mismatch repair gene mutation carriers: results from a hospital based Lynch syndrome registry.

    Science.gov (United States)

    Pande, Mala; Wei, Chongjuan; Chen, Jinyun; Amos, Christopher I; Lynch, Patrick M; Lu, Karen H; Lucio, Laura A; Boyd-Rogers, Stephanie G; Bannon, Sarah A; Mork, Maureen E; Frazier, Marsha L

    2012-09-01

    The spectrum of cancers seen in a hospital based Lynch syndrome registry of mismatch repair gene mutation carriers was examined to determine the distribution of cancers and examine excess cancer risk. Overall there were 504 cancers recorded in 368 mutation carriers from 176 families. These included 236 (46.8 %) colorectal and 268 (53.2 %) extracolonic cancers. MLH1 mutation carriers had a higher frequency of colorectal cancers whereas MSH2, MSH6 and PMS2 mutation carriers had more extracolonic cancers although these differences were not statistically significant. Men had fewer extracolonic cancers than colorectal (45.3 vs. 54.7 %), whereas women had more extracolonic than colorectal cancers (59.0 vs. 41.0 %). The mean age at diagnosis overall for extracolonic cancers was older than for colorectal, 49.1 versus 44.8 years (P ≤ 0.001). As expected, the index cancer was colorectal in 58.1 % of patients and among the extracolonic index cancers, endometrial was the most common (13.8 %). A significant number of non-Lynch syndrome index cancers were recorded including breast (n = 5) prostate (n = 3), thyroid (n = 3), cervix (n = 3), melanoma (n = 3), and 1 case each of thymoma, sinus cavity, and adenocarcinoma of the lung. However, standardized incidence ratios calculated to assess excess cancer risk showed that only those cancers known to be associated with Lynch syndrome were significant in our sample. We found that Lynch syndrome patients can often present with cancers that are not considered part of Lynch syndrome. This has clinical relevance both for diagnosis of Lynch syndrome and surveillance for cancers of different sites during follow-up of these patients.

  18. Molecular changes preceding endometrial and ovarian cancer: a study of consecutive endometrial specimens from Lynch syndrome surveillance.

    Science.gov (United States)

    Niskakoski, Anni; Pasanen, Annukka; Lassus, Heini; Renkonen-Sinisalo, Laura; Kaur, Sippy; Mecklin, Jukka-Pekka; Bützow, Ralf; Peltomäki, Päivi

    2018-03-27

    Molecular alterations preceding endometrial and ovarian cancer and the sequence of events are unknown. Consecutive specimens from lifelong surveillance for Lynch syndrome provides a natural setting to address such questions. To molecularly define the multistep gynecological tumorigenesis, DNA mismatch repair gene mutation carriers with endometrial or ovarian carcinoma or endometrial hyperplasia were identified from a nation-wide registry and endometrial biopsy specimens taken from these individuals during 20 years of screening were collected. A total of 213 endometrial and ovarian specimens from Lynch syndrome individuals and 197 histology-matched (non-serous) samples from sporadic cases were available for this investigation. The specimens were profiled for markers linked to endometrial and ovarian tumorigenesis, including ARID1A protein expression, mismatch repair status, and tumor suppressor gene promoter methylation. In Lynch syndrome-associated endometrial and ovarian carcinomas, ARID1A protein was lost in 61-100% and mismatch repair was deficient in 97-100%, compared to 0-17% and 14-44% in sporadic cases (P = 0.000). ARID1A loss appeared in complex hyperplasia and deficient mismatch repair and tumor suppressor gene promoter methylation in histologically normal endometrium. Despite quantitative differences between Lynch syndrome and sporadic cases, ARID1A expression, mismatch repair, and tumor suppressor gene promoter methylation divided endometrial samples from both patient groups into three categories of increasing abnormality, comprising normal endometrium and simple hyperplasia (I), complex hyperplasia with or without atypia (II), and endometrial cancer (III). Complex hyperplasias without vs. with atypia were molecularly indistinguishable. In conclusion, surveillance specimens from Lynch syndrome identify mismatch repair deficiency, tumor suppressor gene promoter methylation, and ARID1A loss as early changes in tumor development. Our findings are

  19. Clinical problems of colorectal cancer and endometrial cancer cases with unknown cause of tumor mismatch repair deficiency (suspected Lynch syndrome

    Directory of Open Access Journals (Sweden)

    Buchanan DD

    2014-10-01

    Full Text Available Daniel D Buchanan,1,2 Christophe Rosty,1,3,4 Mark Clendenning,1 Amanda B Spurdle,5 Aung Ko Win2 1Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC, Australia; 2Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia; 3Envoi Specialist Pathologists, Herston, QLD, Australia; 4School of Medicine, University of Queensland, Herston, QLD, Australia; 5Molecular Cancer Epidemiology Laboratory, Genetics and Computational Biology Division, QIMR Berghofer Medical Research Institute, Herston, QLD, AustraliaAbstract: Carriers of a germline mutation in one of the DNA mismatch repair (MMR genes have a high risk of developing numerous different cancers, predominantly colorectal cancer and endometrial cancer (known as Lynch syndrome. MMR gene mutation carriers develop tumors with MMR deficiency identified by tumor microsatellite instability or immunohistochemical loss of MMR protein expression. Tumor MMR deficiency is used to identify individuals most likely to carry an MMR gene mutation. However, MMR deficiency can also result from somatic inactivation, most commonly methylation of the MLH1 gene promoter. As tumor MMR testing of all incident colorectal and endometrial cancers (universal screening is becoming increasingly adopted, a growing clinical problem is emerging for individuals who have tumors that show MMR deficiency who are subsequently found not to carry an MMR gene mutation after genetic testing using the current diagnostic approaches (Sanger sequencing and multiplex ligation-dependent probe amplification and who also show no evidence of MLH1 methylation. The inability to determine the underlying cause of tumor MMR deficiency in these "Lynch-like" or "suspected Lynch syndrome" cases has significant implications on the clinical management of these individuals and their relatives. When the

  20. Achieving behaviour change for detection of Lynch syndrome using the Theoretical Domains Framework Implementation (TDFI) approach: a study protocol.

    Science.gov (United States)

    Taylor, Natalie; Long, Janet C; Debono, Deborah; Williams, Rachel; Salisbury, Elizabeth; O'Neill, Sharron; Eykman, Elizabeth; Braithwaite, Jeffrey; Chin, Melvin

    2016-03-12

    Lynch syndrome is an inherited disorder associated with a range of cancers, and found in 2-5 % of colorectal cancers. Lynch syndrome is diagnosed through a combination of significant family and clinical history and pathology. The definitive diagnostic germline test requires formal patient consent after genetic counselling. If diagnosed early, carriers of Lynch syndrome can undergo increased surveillance for cancers, which in turn can prevent late stage cancers, optimise treatment and decrease mortality for themselves and their relatives. However, over the past decade, international studies have reported that only a small proportion of individuals with suspected Lynch syndrome were referred for genetic consultation and possible genetic testing. The aim of this project is to use behaviour change theory and implementation science approaches to increase the number and speed of healthcare professional referrals of colorectal cancer patients with a high-likelihood risk of Lynch syndrome to appropriate genetic counselling services. The six-step Theoretical Domains Framework Implementation (TDFI) approach will be used at two large, metropolitan hospitals treating colorectal cancer patients. Steps are: 1) form local multidisciplinary teams to map current referral processes; 2) identify target behaviours that may lead to increased referrals using discussion supported by a retrospective audit; 3) identify barriers to those behaviours using the validated Influences on Patient Safety Behaviours Questionnaire and TDFI guided focus groups; 4) co-design interventions to address barriers using focus groups; 5) co-implement interventions; and 6) evaluate intervention impact. Chi square analysis will be used to test the difference in the proportion of high-likelihood risk Lynch syndrome patients being referred for genetic testing before and after intervention implementation. A paired t-test will be used to assess the mean time from the pathology test results to referral for high

  1. Hoe Creek groundwater restoration, 1989

    Energy Technology Data Exchange (ETDEWEB)

    Renk, R.R.; Crader, S.E.; Lindblom, S.R.; Covell, J.R.

    1990-01-01

    During the summer of 1989, approximately 6.5 million gallons of contaminated groundwater were pumped from 23 wells at the Hoe Creek underground coal gasification site, near Gillette, Wyoming. The organic contaminants were removed using activated carbon before the water was sprayed on 15.4 acres at the sites. Approximately 2647 g (5.8 lb) of phenols and 10,714 g (23.6 lb) of benzene were removed from the site aquifers. Phenols, benzene, toluene, ethylbenzene, and naphthalene concentrations were measured in 43 wells. Benzene is the only contaminant at the site exceeds the federal standard for drinking water (5 {mu}g/L). Benzene leaches into the groundwater and is slow to biologically degrade; therefore, the benzene concentration has remained high in the groundwater at the site. The pumping operation affected groundwater elevations across the entire 80-acre site. The water levels rebounded quickly when the pumping operation was stopped on October 1, 1989. Removing contaminated groundwater by pumping is not an effective way to clean up the site because the continuous release of benzene from coal tars is slow. Benzene will continue to leach of the tars for a long time unless its source is removed or the leaching rate retarded through mitigation techniques. The application of the treated groundwater to the surface stimulated plant growth. No adverse effects were noted or recorded from some 60 soil samples taken from twenty locations in the spray field area. 20 refs., 52 figs., 8 tabs.

  2. Universal screening for Lynch syndrome in endometrial cancers: frequency of germline mutations and identification of patients with Lynch-like syndrome.

    Science.gov (United States)

    Dillon, Jessica L; Gonzalez, Jorge L; DeMars, Leslie; Bloch, Katarzyna J; Tafe, Laura J

    2017-12-01

    Lynch syndrome (LS) is an inherited clinical syndrome characterized by a high risk of colorectal, endometrial (lifetime risk of up to 60%), ovarian, and urinary tract cancers. The diagnosis is confirmed by identification of germline mutations in the DNA mismatch repair genes MLH1, PMS2, MSH2, MSH6, or EPCAM. In 2015, our institution implemented universal screening of endometrial cancer (EC) hysterectomy specimens by mismatch repair immunohistochemistry (IHC) with reflex MLH1 promoter hypermethylation analysis for tumors with loss of MLH1/PMS2 expression. Patients with tumors negative for MLH1 methylation and those with a loss of the heterodimer pair MSH2 and MSH6, or isolated loss of either PMS2 or MSH6 were referred to the Familial Cancer Program for genetic counseling and consideration of germline testing. Between May 2015 to Dec 2016, 233 EC patients were screened by IHC for LS with a median age of 63 years. Sixty tumors (27%) had abnormal IHC staining results. Fifty-one (22%) harbored heterodimeric loss of MLH1 and PMS2, 49 of which showed MLH1 promoter methylation (1 failure, 1 negative). One showed loss of MLH1/PMS2 and MSH6, 2 showed loss of MSH2/MSH6, and 6 had isolated loss of MSH6 only. Ten patients underwent genetic counseling, and germline testing was performed in 8; LS was confirmed in 5 patients (2.1%). In addition, 3 patients with negative germline testing and presumed Lynch-like syndrome were identified and offered additional somatic testing. Universal screening for LS in EC patients has yielded positive results for identification of patients at risk for this inherited syndrome. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Family history of cancer predicts endometrial cancer risk independently of Lynch Syndrome: Implications for genetic counselling.

    Science.gov (United States)

    Johnatty, Sharon E; Tan, Yen Y; Buchanan, Daniel D; Bowman, Michael; Walters, Rhiannon J; Obermair, Andreas; Quinn, Michael A; Blomfield, Penelope B; Brand, Alison; Leung, Yee; Oehler, Martin K; Kirk, Judy A; O'Mara, Tracy A; Webb, Penelope M; Spurdle, Amanda B

    2017-11-01

    To determine endometrial cancer (EC) risk according to family cancer history, including assessment by degree of relatedness, type of and age at cancer diagnosis of relatives. Self-reported family cancer history was available for 1353 EC patients and 628 controls. Logistic regression was used to quantify the association between EC and cancer diagnosis in ≥1 first or second degree relative, and to assess whether level of risk differed by degree of relationship and/or relative's age at diagnosis. Risk was also evaluated for family history of up to three cancers from known familial syndromes (Lynch, Cowden, hereditary breast and ovarian cancer) overall, by histological subtype and, for a subset of 678 patients, by EC tumor mismatch repair (MMR) gene expression. Report of EC in ≥1 first- or second-degree relative was associated with significantly increased risk of EC (P=3.8×10 -7 ), independent of lifestyle risk factors. There was a trend in increasing EC risk with closer relatedness and younger age at EC diagnosis in relatives (P Trend =4.43×10 -6 ), and with increasing numbers of Lynch cancers in relatives (P Trend ≤0.0001). EC risk associated with family history did not differ by proband tumor MMR status, or histological subtype. Reported EC in first- or second-degree relatives remained associated with EC risk after conservative correction for potential misreported family history (OR 2.0; 95% CI, 1.24-3.37, P=0.004). The strongest predictor of EC risk was closer relatedness and younger EC diagnosis age in ≥1 relative. Associations remained significant irrespective of proband MMR status, and after excluding MMR pathogenic variant carriers, indicating that Lynch syndrome genes do not fully explain familial EC risk. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Subtotal Colectomy for Colon Cancer Reduces the Need for Subsequent Surgery in Lynch Syndrome.

    Science.gov (United States)

    Renkonen-Sinisalo, Laura; Seppälä, Toni T; Järvinen, Heikki J; Mecklin, Jukka-Pekka

    2017-08-01

    The risk of metachronous colorectal cancer is high after surgical resection for first colon cancer in Lynch syndrome. This study aimed to examine whether extended surgery decreases the risk of subsequent colorectal cancer and improves long-term survival. This was a retrospective study. Data were collected from a nationwide registry. Two hundred forty-two Lynch syndrome pathogenic variant carriers who underwent surgery for a first colon cancer from 1984 to 2009 were included. Patients underwent standard segmental colectomy (n = 144) or extended colectomy (n = 98) for colon cancer. Patients were followed a median of 14.6 up to 25 years. Risk of subsequent colorectal cancer in either group, overall and disease-specific survival, and operative mortality were the primary outcomes measured. Subtotal colectomy decreased the risk of subsequent colorectal cancer (HR, 0.20; 95% CI, 0.08-0.52; p = 0.001), compared with segmental resection. Subsequent colorectal cancer decreased in MLH1 carriers. The MSH2 carriers showed no statistical difference, possibly because of their small number. Disease-specific and overall survival within 25 years did not differ between the standard and extended surgeries (82.7% vs 87.2%, p = 0.76 and 47.2% vs 41.4%, p = 0.83). The cumulative risk of subsequent colorectal cancer was 20% in 10 years and 47% within 25 years after standard resection and 4% and 9% after extended surgery. The cumulative risk of metachronous colorectal cancer was 7% within 25 years after subtotal colectomy with ileosigmoidal anastomosis. One patient died of postoperative septicemia within 30 days after segmental colectomy. Data on surgical procedures were primarily collected retrospectively. Lynch syndrome pathogenic variant carriers may undergo subtotal colectomy to manage first colon cancer and avoid repetitive abdominal surgery and to reduce the remaining bowel to facilitate easier endoscopic surveillance. It provides no survival benefit, compared with segmental colon

  5. Functional characterization of MLH1 missense variants identified in Lynch Syndrome patients

    DEFF Research Database (Denmark)

    Andersen, Sofie Dabros; Liberti, Sascha Emilie; Lützen, Anne

    2012-01-01

    Germline mutations in the human DNA mismatch repair (MMR) genes MSH2 and MLH1 are associated with the inherited cancer disorder Lynch Syndrome (LS), also known as Hereditary Nonpolyposis Colorectal Cancer or HNPCC. A proportion of MSH2 and MLH1 mutations found in suspected LS patients give rise...... localization and protein-protein interaction with the dimer partner PMS2 and the MMR-associated exonuclease 1. We show that a significant proportion of examined variant proteins have functional defects in either subcellular localization or protein-protein interactions, which is suspected to lead to the cancer...

  6. Validation of a Self-Concept Scale for Lynch Syndrome in Different Nationalities

    DEFF Research Database (Denmark)

    Petersen, Helle Vendel; Domanska, Katarina; Bendahl, Pär-Ola

    2011-01-01

    syndrome. We compared the performance of this scale in 591 mutation carriers from Denmark, Sweden and Canada. Principal component analysis identified two sets of linked statements-the first related to feeling different, isolated and labeled, and the second to concern and worry about bowel changes....... The scale performed consistently in the three countries. Minor differences were identified, with guilt about passing on a defective gene and feelings of losing one's privacy being more pronounced among Canadians, whereas Danes more often expressed worries about cancer. Validation of the Lynch syndrome self...

  7. 78 FR 64003 - Notice of Availability of the Final Environmental Impact Statement for the Jump Creek, Succor...

    Science.gov (United States)

    2013-10-25

    ...] Notice of Availability of the Final Environmental Impact Statement for the Jump Creek, Succor Creek, and... Field Office Jump Creek, Succor Creek and Cow Creek Watersheds grazing permit renewal, and by this... in the Federal Register. ADDRESSES: Copies of the Jump Creek, Succor Creek and Cow Creek Watersheds...

  8. 78 FR 26065 - Notice of Availability of the Draft Environmental Impact Statement for the Jump Creek, Succor...

    Science.gov (United States)

    2013-05-03

    ...] Notice of Availability of the Draft Environmental Impact Statement for the Jump Creek, Succor Creek, and... the Jump Creek, Succor Creek, and Cow Creek Watersheds Grazing Permit Renewal and by this notice is... receive written comments on the Draft EIS for the Jump Creek, Succor Creek, and Cow Creek Watersheds...

  9. A Peek into 'Alamogordo Creek'

    Science.gov (United States)

    2006-01-01

    [figure removed for brevity, see original site] [figure removed for brevity, see original site] [figure removed for brevity, see original site] Figure 1Figure 2Figure 3 On its 825th Martian day (May 20, 2006), NASA's Mars Exploration Rover Opportunity stopped for the weekend to place its instrument arm onto the soil target pictured here, dubbed 'Alamogordo Creek.' Two views from the panoramic camera, acquired at about noon local solar time, are at the top. Below them is a close-up view from the microscopic imager. At upper left, a false-color view emphasizes differences among materials in rocks and soil. It combines images taken through the panoramic camera's 753-nanometer, 535-nanometer and 432-nanometer filters. At upper right is an approximately true-color rendering made with the panoramic camera's 600-nanometer, 535-nanometer and 480-nanometer filters. The microscopic-imager frame covers the area outlined by the white boxes in the panoramic-camera views, a rectangle 3 centimeters (1.2 inches) across. As Opportunity traverses to the south, it is analyzing soil and rocks along the way for differences from those seen earlier. At this site, the soil contains abundant small spherical fragments, thought to be hematite-rich concretions, plus finer-grained basaltic sand. Most of the spherical fragments seen in the microscopic image are smaller than those first seen at the rover's landing site in 'Eagle Crater,' some five kilometers (3.1 miles) to the north. However, a few larger spherical fragments and other rock fragments can also be seen in the panoramic-camera images.

  10. Elevation - LiDAR Survey Minnehaha Creek, MN Watershed

    Data.gov (United States)

    Army Corps of Engineers, Department of the Army, Department of Defense — LiDAR Bare-Earth Grid - Minnehaha Creek Watershed District. The Minnehaha Creek watershed is located primarily in Hennepin County, Minnesota. The watershed covers...

  11. Preliminary Chemical and Biological Assessment of Ogbe Creek ...

    African Journals Online (AJOL)

    USER

    The study was aimed at assessing the quality of water from the Ogbe Creek ... indicated the impact of the perturbational stress on the organisms inhabiting the creek. ... experiences seasonal flooding which introduces a lot of detritus and ...

  12. Plankton biodiversity of Dharamtar creek adjoining Mumbai harbour

    Digital Repository Service at National Institute of Oceanography (India)

    Tiwari, L.R.; Nair, V.R.

    rich plankton community. However, recent industrial development along the banks of creek may pose the problem due to waste disposal into this creek system. Losses of marine life diversity are largely the results of conflicting uses, in particular...

  13. Steel Creek water quality: L-Lake/Steel Creek Biological Monitoring Program, November 1985--December 1991

    International Nuclear Information System (INIS)

    Bowers, J.A.; Kretchmer, D.W.; Chimney, M.J.

    1992-04-01

    The Savannah River Site (SRS) encompasses 300 sq mi of the Atlantic Coastal Plain in west-central South Carolina. The Savannah River forms the western boundary of the site. Five major tributaries of the Savannah River -- upper Three Runs Creek, Four Mile Creek, Pen Branch, Steel Creek, and Lower Three Runs Creek -- drain the site. All but Upper Three Runs Creek receive, or in the past received, thermal effluents from nuclear production reactors. In 1985, L Lake, a 400-hectare cooling reservoir, was built on the upper reaches of Steel Creek to receive effluent from the restart of L-Reactor, and protect the lower reaches from thermal impacts. The Steel Creek Biological Monitoring Program was designed to meet envirorunental regulatory requirements associated with the restart of L-Reactor and complements the Biological Monitoring Program for L Lake. This extensive program was implemented to address portions of Section 316(a) of the Clean Water Act. The Department of Energy (DOE) must demonstrate that the operation of L-Reactor will not significantly alter the established aquatic ecosystems

  14. A model-based assessment of the cost–utility of strategies to identify Lynch syndrome in early-onset colorectal cancer patients

    International Nuclear Information System (INIS)

    Snowsill, Tristan; Huxley, Nicola; Hoyle, Martin; Jones-Hughes, Tracey; Coelho, Helen; Cooper, Chris; Frayling, Ian; Hyde, Chris

    2015-01-01

    Lynch syndrome is an autosomal dominant cancer predisposition syndrome caused by mutations in the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2. Individuals with Lynch syndrome have an increased risk of colorectal cancer, endometrial cancer, ovarian and other cancers. Lynch syndrome remains underdiagnosed in the UK. Reflex testing for Lynch syndrome in early-onset colorectal cancer patients is proposed as a method to identify more families affected by Lynch syndrome and offer surveillance to reduce cancer risks, although cost-effectiveness is viewed as a barrier to implementation. The objective of this project was to estimate the cost–utility of strategies to identify Lynch syndrome in individuals with early-onset colorectal cancer in the NHS. A decision analytic model was developed which simulated diagnostic and long-term outcomes over a lifetime horizon for colorectal cancer patients with and without Lynch syndrome and for relatives of those patients. Nine diagnostic strategies were modelled which included microsatellite instability (MSI) testing, immunohistochemistry (IHC), BRAF mutation testing (methylation testing in a scenario analysis), diagnostic mutation testing and Amsterdam II criteria. Biennial colonoscopic surveillance was included for individuals diagnosed with Lynch syndrome and accepting surveillance. Prophylactic hysterectomy with bilateral salpingo-oophorectomy (H-BSO) was similarly included for women diagnosed with Lynch syndrome. Costs from NHS and Personal Social Services perspective and quality-adjusted life years (QALYs) were estimated and discounted at 3.5% per annum. All strategies included for the identification of Lynch syndrome were cost-effective versus no testing. The strategy with the greatest net health benefit was MSI followed by BRAF followed by diagnostic genetic testing, costing £5,491 per QALY gained over no testing. The effect of prophylactic H-BSO on health-related quality of life (HRQoL) is uncertain and could

  15. A model-based assessment of the cost-utility of strategies to identify Lynch syndrome in early-onset colorectal cancer patients.

    Science.gov (United States)

    Snowsill, Tristan; Huxley, Nicola; Hoyle, Martin; Jones-Hughes, Tracey; Coelho, Helen; Cooper, Chris; Frayling, Ian; Hyde, Chris

    2015-04-25

    Lynch syndrome is an autosomal dominant cancer predisposition syndrome caused by mutations in the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2. Individuals with Lynch syndrome have an increased risk of colorectal cancer, endometrial cancer, ovarian and other cancers. Lynch syndrome remains underdiagnosed in the UK. Reflex testing for Lynch syndrome in early-onset colorectal cancer patients is proposed as a method to identify more families affected by Lynch syndrome and offer surveillance to reduce cancer risks, although cost-effectiveness is viewed as a barrier to implementation. The objective of this project was to estimate the cost-utility of strategies to identify Lynch syndrome in individuals with early-onset colorectal cancer in the NHS. A decision analytic model was developed which simulated diagnostic and long-term outcomes over a lifetime horizon for colorectal cancer patients with and without Lynch syndrome and for relatives of those patients. Nine diagnostic strategies were modelled which included microsatellite instability (MSI) testing, immunohistochemistry (IHC), BRAF mutation testing (methylation testing in a scenario analysis), diagnostic mutation testing and Amsterdam II criteria. Biennial colonoscopic surveillance was included for individuals diagnosed with Lynch syndrome and accepting surveillance. Prophylactic hysterectomy with bilateral salpingo-oophorectomy (H-BSO) was similarly included for women diagnosed with Lynch syndrome. Costs from NHS and Personal Social Services perspective and quality-adjusted life years (QALYs) were estimated and discounted at 3.5% per annum. All strategies included for the identification of Lynch syndrome were cost-effective versus no testing. The strategy with the greatest net health benefit was MSI followed by BRAF followed by diagnostic genetic testing, costing £5,491 per QALY gained over no testing. The effect of prophylactic H-BSO on health-related quality of life (HRQoL) is uncertain and could outweigh

  16. An {sup 57}Fe Mössbauer study of the ordinary chondrite meteorite Lynch 001

    Energy Technology Data Exchange (ETDEWEB)

    Elewa, Nancy N., E-mail: nancy.elewa@student.unsw.edu.au; Cadogan, J. M. [The University of New South Wales at the Australian Defence Force Academy, School of Physical, Environmental and Mathematical Sciences (Australia)

    2017-11-15

    The Lynch 001 meteorite was found in the Nullarbor Plain region of Western Australia in 1977. This meteorite is classified as an ordinary chondrite of the petrologic group L5/6 that has undergone ‘minor to moderate’ terrestrial weathering. Here, we characterize the Fe-bearing phases in this chondrite using {sup 57}Fe Mössbauer spectroscopy carried out over the temperature range 13 K to room temperature (295 K). The paramagnetic doublets of olivine, pyroxene and a superparamagnetic ferric phase dominate the room temperature Mössbauer spectrum. On the basis of the room temperature quadrupole splitting of the olivine component, we estimate its composition to be Fa {sub 30(5)}. Besides the paramagnetic ferric component, accounting for ∼15 % of the spectral area at room temperature, magnetically ordered ferric phases were also detected. The total relative proportion of the Fe {sup 3+} components allows us to estimate the terrestrial age of Lynch 001 to be 6,500 ± 1,500 yr, consistent with the value of 6,700 ± 1,300 yr determined by {sup 14}C dating.

  17. Common mutations identified in the MLH1 gene in familial Lynch syndrome

    Directory of Open Access Journals (Sweden)

    Jisha Elias

    2017-12-01

    In this study we identified three families with Lynch syndrome from a rural cancer center in western India (KCHRC, Goraj, Gujarat, where 70-75 CRC patients are seen annually. DNA isolated from the blood of consented family members of all three families (8-10 members/family was subjected to NGS sequencing methods on an Illumina HiSeq 4000 platform. We identified unique mutations in the MLH1 gene in all three HNPCC family members. Two of the three unrelated families shared a common mutation (154delA and 156delA. Total 8 members of a family were identified as carriers for 156delA mutation of which 5 members were unaffected while 3 were affected (age of onset: 1 member <30yrs & 2 were>40yr. The family with 154delA mutation showed 2 affected members (>40yr carrying the mutations.LYS618DEL mutation found in 8 members of the third family showed that both affected and unaffected carried the mutation. Thus the common mutations identified in the MLH1 gene in two unrelated families had a high risk for lynch syndrome especially above the age of 40.

  18. Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk.

    Science.gov (United States)

    ten Broeke, Sanne W; Brohet, Richard M; Tops, Carli M; van der Klift, Heleen M; Velthuizen, Mary E; Bernstein, Inge; Capellá Munar, Gabriel; Gomez Garcia, Encarna; Hoogerbrugge, Nicoline; Letteboer, Tom G W; Menko, Fred H; Lindblom, Annika; Mensenkamp, Arjen R; Moller, Pal; van Os, Theo A; Rahner, Nils; Redeker, Bert J W; Sijmons, Rolf H; Spruijt, Liesbeth; Suerink, Manon; Vos, Yvonne J; Wagner, Anja; Hes, Frederik J; Vasen, Hans F; Nielsen, Maartje; Wijnen, Juul T

    2015-02-01

    The clinical consequences of PMS2 germline mutations are poorly understood compared with other Lynch-associated mismatch repair gene (MMR) mutations. The aim of this European cohort study was to define the cancer risk faced by PMS2 mutation carriers. Data were collected from 98 PMS2 families ascertained from family cancer clinics that included a total of 2,548 family members and 377 proven mutation carriers. To adjust for potential ascertainment bias, a modified segregation analysis model was used to calculate colorectal cancer (CRC) and endometrial cancer (EC) risks. Standardized incidence ratios (SIRs) were calculated to estimate risks for other Lynch syndrome-associated cancers. The cumulative risk (CR) of CRC for male mutation carriers by age 70 years was 19%. The CR among female carriers was 11% for CRC and 12% for EC. The mean age of CRC development was 52 years, and there was a significant difference in mean age of CRC between the probands (mean, 47 years; range, 26 to 68 years) and other family members with a PMS2 mutation (mean, 58 years; range, 31 to 86 years; P PMS2 mutation, and it should be noted that we observed a substantial variation in cancer phenotype within and between families, suggesting the influence of genetic modifiers and lifestyle factors on cancer risks. © 2014 by American Society of Clinical Oncology.

  19. [Management and Nursing care for a patient with Lynch syndrome: A case report].

    Science.gov (United States)

    Pacheco-Pérez, Luis Arturo; Guevara Valtier, Milton Carlos

    2016-01-01

    Colorectal cancer is one of the leading causes of death from cancer worldwide. Main interventions to reduce the impact are aimed to enhance prevention and early detection. Results of several studies show that tests such as the fecal occult blood test and colonoscopy are effective for early diagnosis. There are hereditary syndromes such as Lynch Syndrome that can lead to certain types of cancers, including bowel neoplasms, therefore early detection needs to be included as part of the treatment. In these cases, family genetic testing is recommended if the bowel cancer is diagnosed before 50 years old. A care plan including the NANDA (North American Nursing Diagnosis Association), NOC (Nursing Outcomes Classification) and NIC (Nursing Interventions Classification) was developed for a patient with suspected Lynch Syndrome. Nurses should be qualified to identify potential cases of cancer associated with this syndrome, and thus, reduce the likelihood that family members develop the disease, through genetic counseling and education of environmental risk factors. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  20. Predicting the impact of Lynch syndrome-causing missense mutations from structural calculations.

    Directory of Open Access Journals (Sweden)

    Sofie V Nielsen

    2017-04-01

    Full Text Available Accurate methods to assess the pathogenicity of mutations are needed to fully leverage the possibilities of genome sequencing in diagnosis. Current data-driven and bioinformatics approaches are, however, limited by the large number of new variations found in each newly sequenced genome, and often do not provide direct mechanistic insight. Here we demonstrate, for the first time, that saturation mutagenesis, biophysical modeling and co-variation analysis, performed in silico, can predict the abundance, metabolic stability, and function of proteins inside living cells. As a model system, we selected the human mismatch repair protein, MSH2, where missense variants are known to cause the hereditary cancer predisposition disease, known as Lynch syndrome. We show that the majority of disease-causing MSH2 mutations give rise to folding defects and proteasome-dependent degradation rather than inherent loss of function, and accordingly our in silico modeling data accurately identifies disease-causing mutations and outperforms the traditionally used genetic disease predictors. Thus, in conclusion, in silico biophysical modeling should be considered for making genotype-phenotype predictions and for diagnosis of Lynch syndrome, and perhaps other hereditary diseases.

  1. Comparison of extended colectomy and limited resection in patients with Lynch syndrome.

    Science.gov (United States)

    Natarajan, Nagendra; Watson, Patrice; Silva-Lopez, Edibaldo; Lynch, Henry T

    2010-01-01

    The purpose of the study was to determine the advantages and disadvantages of prophylactic/extended colectomy (subtotal colectomy) in patients with Lynch syndrome who manifest colorectal cancer. A retrospective cohort using Creighton University's hereditary cancer database was used to identify cases and controls. Cases are patients who underwent subtotal colectomy, either with no colorectal cancer diagnosis (prophylactic) or at diagnosis of first colorectal cancer; controls for these 2 types of cases were, respectively, patients who underwent no colon surgery or those having limited resection at time of diagnosis of first colorectal cancer. The Kaplan-Meier and proportional hazard regression models from the Statistical Analysis Software program was used to calculate the difference in survival, time to subsequent colorectal cancer, and subsequent abdominal surgery between cases and controls. The event-free survival of our study did not reach 50%, so we used the event-free survival at 5 years as our parameter to compare the 2 groups. The event-free survival for subsequent colorectal cancer, subsequent abdominal surgery, and death was 94%, 84%, and 93%, respectively, for cases and 74%, 63%, and 88%, respectively, for controls. Times to subsequent colorectal cancer and subsequent abdominal surgery were significantly shorter in the control group (P Lynch syndrome.

  2. Screening adherence and cancer risk perceptions in colorectal cancer survivors with Lynch-like syndrome.

    Science.gov (United States)

    Katz, L H; Burton-Chase, A M; Advani, S; Fellman, B; Polivka, K M; Yuan, Y; Lynch, P M; Peterson, S K

    2016-03-01

    Cancer screening recommendations for patients with Lynch-like syndrome (LLS) are not well defined. We evaluated adherence to Lynch syndrome (LS) screening recommendations, cancer risk perceptions, and communication within the families among colorectal cancer (CRC) survivors with LLS. Thirty-four participants with LLS completed a questionnaire about risk perception, adherence to LS screening recommendations, and communication with relatives. Clinical data were obtained from medical records. Most participants (76%) believed they should undergo colonoscopy every 1-2 years. Only 41% correctly interpreted their genetic tests as uninformative negative or as variant of unknown significance for LS. Less than half had had an upper gastrointestinal endoscopy for screening purpose. Among female participants, 86% had been screened for endometrial cancer (EC) and 71% for ovarian cancer. Most participants had informed relatives about the CRC diagnosis and advised them to undergo CRC screening, but only 50% advised female relatives to be screened for EC and only one-third advised relatives to have genetic counseling. Most CRC survivors with LLS follow the same cancer screening recommended for LS patients but do not understand the meaning of LLS. Greater care must be devoted to communicating the implications of nondiagnostic germline mutation testing among patients with LLS. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. Streamflow conditions along Soldier Creek, Northeast Kansas

    Science.gov (United States)

    Juracek, Kyle E.

    2017-11-14

    The availability of adequate water to meet the present (2017) and future needs of humans, fish, and wildlife is a fundamental issue for the Prairie Band Potawatomi Nation in northeast Kansas. Because Soldier Creek flows through the Prairie Band Potawatomi Nation Reservation, it is an important tribal resource. An understanding of historical Soldier Creek streamflow conditions is required for the effective management of tribal water resources, including drought contingency planning. Historical data for six selected U.S. Geological Survey (USGS) streamgages along Soldier Creek were used in an assessment of streamflow characteristics and trends by Juracek (2017). Streamflow data for the period of record at each streamgage were used to compute annual mean streamflow, annual mean base flow, mean monthly flow, annual peak flow, and annual minimum flow. Results of the assessment are summarized in this fact sheet.

  4. Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2

    Science.gov (United States)

    Haraldsdottir, Sigurdis; Rafnar, Thorunn; Frankel, Wendy L.; Einarsdottir, Sylvia; Sigurdsson, Asgeir; Hampel, Heather; Snaebjornsson, Petur; Masson, Gisli; Weng, Daniel; Arngrimsson, Reynir; Kehr, Birte; Yilmaz, Ahmet; Haraldsson, Stefan; Sulem, Patrick; Stefansson, Tryggvi; Shields, Peter G.; Sigurdsson, Fridbjorn; Bekaii-Saab, Tanios; Moller, Pall H.; Steinarsdottir, Margret; Alexiusdottir, Kristin; Hitchins, Megan; Pritchard, Colin C.; de la Chapelle, Albert; Jonasson, Jon G.; Goldberg, Richard M.; Stefansson, Kari

    2017-01-01

    Lynch syndrome, caused by germline mutations in the mismatch repair genes, is associated with increased cancer risk. Here using a large whole-genome sequencing data bank, cancer registry and colorectal tumour bank we determine the prevalence of Lynch syndrome, associated cancer risks and pathogenicity of several variants in the Icelandic population. We use colorectal cancer samples from 1,182 patients diagnosed between 2000–2009. One-hundred and thirty-two (11.2%) tumours are mismatch repair deficient per immunohistochemistry. Twenty-one (1.8%) have Lynch syndrome while 106 (9.0%) have somatic hypermethylation or mutations in the mismatch repair genes. The population prevalence of Lynch syndrome is 0.442%. We discover a translocation disrupting MLH1 and three mutations in MSH6 and PMS2 that increase endometrial, colorectal, brain and ovarian cancer risk. We find thirteen mismatch repair variants of uncertain significance that are not associated with cancer risk. We find that founder mutations in MSH6 and PMS2 prevail in Iceland unlike most other populations. PMID:28466842

  5. Lynch syndrome-associated extracolonic tumors are rare in two extended families with the same EPCAM deletion

    NARCIS (Netherlands)

    Lynch, H.T.; Riegert-Johnson, D.L.; Snyder, C.; Lynch, J.F.; Hagenkord, J.; Boland, C.R.; Rhees, J.; Thibodeau, S.N.; Boardman, L.A.; Davies, J.; Kuiper, R.P.; Hoogerbrugge, N.; Ligtenberg, M.J.L.

    2011-01-01

    OBJECTIVES: The Lynch syndrome (LS) is an inherited cancer syndrome showing a preponderance of colorectal cancer (CRC) in context with endometrial cancer and several other extracolonic cancers, which is due to pathogenic mutations in the mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2. Some

  6. Evaluation of current prediction models for Lynch syndrome: updating the PREMM5 model to identify PMS2 mutation carriers

    NARCIS (Netherlands)

    A. Goverde (Anne); M.C.W. Spaander (Manon); D. Nieboer (Daan); A.M.W. van den Ouweland (Ans); W.N.M. Dinjens (Winand); H.J. Dubbink (Erik Jan); C. Tops (Cmj); S.W. Ten Broeke (Sanne W.); M.J. Bruno (Marco); R.M.W. Hofstra (Robert); E.W. Steyerberg (Ewout); A. Wagner (Anja)

    2017-01-01

    textabstractUntil recently, no prediction models for Lynch syndrome (LS) had been validated for PMS2 mutation carriers. We aimed to evaluate MMRpredict and PREMM5 in a clinical cohort and for PMS2 mutation carriers specifically. In a retrospective, clinic-based cohort we calculated predictions for

  7. Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2.

    Science.gov (United States)

    Haraldsdottir, Sigurdis; Rafnar, Thorunn; Frankel, Wendy L; Einarsdottir, Sylvia; Sigurdsson, Asgeir; Hampel, Heather; Snaebjornsson, Petur; Masson, Gisli; Weng, Daniel; Arngrimsson, Reynir; Kehr, Birte; Yilmaz, Ahmet; Haraldsson, Stefan; Sulem, Patrick; Stefansson, Tryggvi; Shields, Peter G; Sigurdsson, Fridbjorn; Bekaii-Saab, Tanios; Moller, Pall H; Steinarsdottir, Margret; Alexiusdottir, Kristin; Hitchins, Megan; Pritchard, Colin C; de la Chapelle, Albert; Jonasson, Jon G; Goldberg, Richard M; Stefansson, Kari

    2017-05-03

    Lynch syndrome, caused by germline mutations in the mismatch repair genes, is associated with increased cancer risk. Here using a large whole-genome sequencing data bank, cancer registry and colorectal tumour bank we determine the prevalence of Lynch syndrome, associated cancer risks and pathogenicity of several variants in the Icelandic population. We use colorectal cancer samples from 1,182 patients diagnosed between 2000-2009. One-hundred and thirty-two (11.2%) tumours are mismatch repair deficient per immunohistochemistry. Twenty-one (1.8%) have Lynch syndrome while 106 (9.0%) have somatic hypermethylation or mutations in the mismatch repair genes. The population prevalence of Lynch syndrome is 0.442%. We discover a translocation disrupting MLH1 and three mutations in MSH6 and PMS2 that increase endometrial, colorectal, brain and ovarian cancer risk. We find thirteen mismatch repair variants of uncertain significance that are not associated with cancer risk. We find that founder mutations in MSH6 and PMS2 prevail in Iceland unlike most other populations.

  8. Ovarian cancer linked to lynch syndrome typically presents as early-onset, non-serous epithelial tumors

    DEFF Research Database (Denmark)

    Ketabi, Zohreh; Bartuma, Katarina; Bernstein, Inge

    2011-01-01

    . The underlying MMR gene mutations in these families affected MSH2 in 49%, MSH6 in 33% and MLH1 in 17%. Immunohistochemical loss of the corresponding MMR protein was demonstrated in 33/36 (92%) tumors analyzed. CONCLUSION: The combined data from our cohorts demonstrate that ovarian cancer associated with Lynch...

  9. Barriers and Motivators for Referral of Patients with Suspected Lynch Syndrome to Cancer Genetic Services: A Qualitative Study

    Science.gov (United States)

    Tan, Yen Y.; Fitzgerald, Lisa J.

    2014-01-01

    This article explores the views of general practitioners and specialists on their referral of patients with suspected Lynch syndrome to cancer genetic services. Using a purposive maximum variation sampling strategy, we conducted semi-structured interviews face-to-face with 28 general practitioners and specialists in public or private hospitals and specialist clinics between March and August 2011. General practitioners and specialists were recruited in a major metropolitan area in Australia. Interview transcripts were reviewed by two independent researchers, and thematic analysis was performed using NVivo10 software. The main barriers and motivators identified were: (1) clinician-related (e.g., familiarity with Lynch syndrome and family history knowledge); (2) patient-related (e.g., patients’ interests and personal experience with cancer); and (3) organizational-related (e.g., access to services, guidelines and referral pathway). Referral of patients with suspected Lynch syndrome to cancer genetic services is motivated and hindered by a range of individual, interpersonal and organizational factors. In order to improve the care and quality of life of patients and family with suspected Lynch syndrome, further research is needed to develop supportive tools for clinicians. PMID:25562140

  10. A rare case of choroid plexus carcinoma that led to the diagnosis of Lynch syndrome (hereditary nonpolyposis colorectal cancer).

    Science.gov (United States)

    Zhu, Viola W; Hinduja, Sanjay; Knezevich, Stevan R; Silveira, William R; DeLozier, Celia D

    2017-07-01

    Lynch syndrome (hereditary nonpolyposis colorectal cancer) is an autosomal dominant disorder characterized by a significant risk of colorectal and endometrial cancers. A variety of other epithelial cancers may be associated with this syndrome. Brian tumors are infrequent, but have been reported in series. Here, we report a case of a 34-year-old Caucasian woman with WHO grade III choroid plexus carcinoma (CPC). Comprehensive genomic profiling of the patient's resected brain tumor revealed mutations in six genes: PTEN, VHL, MSH6, NOTCH1, RB1, and TP53. Family history is significant for endometrial cancer in her mother and sister as well as colon cancer in her maternal grandfather suggestive of Lynch syndrome. Site-specific mutational analysis showed the MSH6 mutation (p.R482*) in peripheral lymphocytes. Subsequently we performed immunohistochemical staining of the tumor tissue which demonstrated widespread loss of MSH6 with intact MSH2, MLH1, and PMS2. The diagnosis of Lynch syndrome due to a mutation in MSH6 was therefore established. Our patient elected to have adjuvant radiation to the surgical bed only followed by prophylactic total abdominal hysterectomy and bilateral salpingo-oophorectomy and is doing very well. To our knowledge, this is the first case report of CPC in an adult patient with a germline MSH6 mutation. We believe our data have provided molecular evidence to suggest that CPC could potentially be part of the Lynch syndrome spectrum. Published by Elsevier B.V.

  11. Barriers and Motivators for Referral of Patients with Suspected Lynch Syndrome to Cancer Genetic Services: A Qualitative Study

    Directory of Open Access Journals (Sweden)

    Yen Y. Tan

    2014-02-01

    Full Text Available This article explores the views of general practitioners and specialists on their referral of patients with suspected Lynch syndrome to cancer genetic services. Using a purposive maximum variation sampling strategy, we conducted semi-structured interviews face-to-face with 28 general practitioners and specialists in public or private hospitals and specialist clinics between March and August 2011. General practitioners and specialists were recruited in a major metropolitan area in Australia. Interview transcripts were reviewed by two independent researchers, and thematic analysis was performed using NVivo10 software. The main barriers and motivators identified were: (1 clinician-related (e.g., familiarity with Lynch syndrome and family history knowledge; (2 patient-related (e.g., patients’ interests and personal experience with cancer; and (3 organizational-related (e.g., access to services, guidelines and referral pathway. Referral of patients with suspected Lynch syndrome to cancer genetic services is motivated and hindered by a range of individual, interpersonal and organizational factors. In order to improve the care and quality of life of patients and family with suspected Lynch syndrome, further research is needed to develop supportive tools for clinicians.

  12. Flood-inundation maps for Indian Creek and Tomahawk Creek, Johnson County, Kansas, 2014

    Science.gov (United States)

    Peters, Arin J.; Studley, Seth E.

    2016-01-25

    Digital flood-inundation maps for a 6.4-mile upper reach of Indian Creek from College Boulevard to the confluence with Tomahawk Creek, a 3.9-mile reach of Tomahawk Creek from 127th Street to the confluence with Indian Creek, and a 1.9-mile lower reach of Indian Creek from the confluence with Tomahawk Creek to just beyond the Kansas/Missouri border at State Line Road in Johnson County, Kansas, were created by the U.S. Geological Survey in cooperation with the city of Overland Park, Kansas. The flood-inundation maps, which can be accessed through the U.S. Geological Survey Flood Inundation Mapping Science Web site at http://water.usgs.gov/osw/flood_inundation/, depict estimates of the areal extent and depth of flooding corresponding to selected water levels (stages) at the U.S. Geological Survey streamgages on Indian Creek at Overland Park, Kansas; Indian Creek at State Line Road, Leawood, Kansas; and Tomahawk Creek near Overland Park, Kansas. Near real time stages at these streamgages may be obtained on the Web from the U.S. Geological Survey National Water Information System at http://waterdata.usgs.gov/nwis or the National Weather Service Advanced Hydrologic Prediction Service at http://water.weather.gov/ahps/, which also forecasts flood hydrographs at these sites.Flood profiles were computed for the stream reaches by means of a one-dimensional step-backwater model. The model was calibrated for each reach by using the most current stage-discharge relations at the streamgages. The hydraulic models were then used to determine 15 water-surface profiles for Indian Creek at Overland Park, Kansas; 17 water-surface profiles for Indian Creek at State Line Road, Leawood, Kansas; and 14 water-surface profiles for Tomahawk Creek near Overland Park, Kansas, for flood stages at 1-foot intervals referenced to the streamgage datum and ranging from bankfull to the next interval above the 0.2-percent annual exceedance probability flood level (500-year recurrence interval). The

  13. Clinical problems of colorectal cancer and endometrial cancer cases with unknown cause of tumor mismatch repair deficiency (suspected Lynch syndrome).

    Science.gov (United States)

    Buchanan, Daniel D; Rosty, Christophe; Clendenning, Mark; Spurdle, Amanda B; Win, Aung Ko

    2014-01-01

    Carriers of a germline mutation in one of the DNA mismatch repair (MMR) genes have a high risk of developing numerous different cancers, predominantly colorectal cancer and endometrial cancer (known as Lynch syndrome). MMR gene mutation carriers develop tumors with MMR deficiency identified by tumor microsatellite instability or immunohistochemical loss of MMR protein expression. Tumor MMR deficiency is used to identify individuals most likely to carry an MMR gene mutation. However, MMR deficiency can also result from somatic inactivation, most commonly methylation of the MLH1 gene promoter. As tumor MMR testing of all incident colorectal and endometrial cancers (universal screening) is becoming increasingly adopted, a growing clinical problem is emerging for individuals who have tumors that show MMR deficiency who are subsequently found not to carry an MMR gene mutation after genetic testing using the current diagnostic approaches (Sanger sequencing and multiplex ligation-dependent probe amplification) and who also show no evidence of MLH1 methylation. The inability to determine the underlying cause of tumor MMR deficiency in these "Lynch-like" or "suspected Lynch syndrome" cases has significant implications on the clinical management of these individuals and their relatives. When the data from published studies are combined, 59% (95% confidence interval [CI]: 55% to 64%) of colorectal cancers and 52% (95% CI: 41% to 62%) of endometrial cancers with MMR deficiency were identified as suspected Lynch syndrome. Recent studies estimated that colorectal cancer risk for relatives of suspected Lynch syndrome cases is lower than for relatives of those with MMR gene mutations, but higher than for relatives of those with tumor MMR deficiency resulting from methylation of the MLH1 gene promoter. The cause of tumor MMR deficiency in suspected Lynch syndrome cases is likely due to either unidentified germline MMR gene mutations, somatic cell mosaicism, or biallelic somatic

  14. The effectiveness of the double B-lynch suture as a modification in the treatment of intractable postpartum haemorrhage.

    Science.gov (United States)

    Şahin, Hanifi; Soylu Karapınar, Oya; Şahin, Eda Adeviye; Dolapçıoğlu, Kenan; Baloğlu, Ali

    2018-03-20

    A broader range of more effective compression techniques are needed in the patients who have an intractable postpartum haemorrhage due to uterine atony despite medical treatment and B-Lynch sutures. The aim of this study was to report the outcome of a series of patients with haemorrhage who were managed by double B-Lynch suture. Fourteen patients who were treated in a tertiary hospital between July 2010 and February 2015 were included in the study. The intractable haemorrhage rate was 0.35% over 5 years (14/4000 births). Bleeding was controlled in all the patients with a double B-Lynch suture. The mean age of the patients was 24 ± 3.4 years. The mean estimated blood loss was 1696 ± 272.075 mL, and the mean transfusion rate was 4.2 ± 2.5 units. Pregnancy was observed in five patients at follow up. The double B-Lynch suture seems to be an effective and reliable solution to an intractable postpartum haemorrhage resulting from uterine atony and has no unfavourable impacts on fertility. It should be considered before the use of any aggressive surgical techniques such as a hypogastric artery ligation or a hysterectomy. This the first study to investigate the effectiveness of the double B-Lynch suture, and we showed that the hysterectomy and/or hypogastric artery ligation rate can be decreased by adding a second B-Lynch suture in cases where the medical treatment or a single B-Lynch has failed. Impact statement What is already known on the subject? Uterine atony is the most common cause of a primary postpartum haemorrhage. When a simple massage of the uterus and medication failed to manage this condition, various surgical solutions have been sought, including uterine compression sutures, uterine artery ligation, devascularisation of the uterus, internal iliac artery ligation and, ultimately, a hysterectomy. The B-Lynch suturing technique is particularly useful because of its simplicity of application, life-saving potential, relative safety and capacity

  15. CREEK Project's Phytoplankton Pigment Monitoring Database for Eight Creeks in the North Inlet Estuary, South Carolina: 1997-1999

    Data.gov (United States)

    Baruch Institute for Marine and Coastal Sciences, Univ of South Carolina — The CREEK Project began in January of 1996 and was designed to help determine the role of oysters, Crassostrea virginica, in tidal creeks of the North Inlet Estuary,...

  16. 77 FR 5201 - Drawbridge Operation Regulation; Bear Creek, Dundalk, MD

    Science.gov (United States)

    2012-02-02

    ...-AA09 Drawbridge Operation Regulation; Bear Creek, Dundalk, MD AGENCY: Coast Guard, DHS. ACTION: Notice... operation of the Baltimore County highway bridge at Wise Avenue across Bear Creek, mile 3.4, between Dundalk... Avenue across Bear Creek, mile 3.4 between Dundalk and Sparrows Point, MD. This change would require the...

  17. Genetic variants in the cell cycle control pathways contribute to early onset colorectal cancer in Lynch syndrome.

    Science.gov (United States)

    Chen, Jinyun; Etzel, Carol J; Amos, Christopher I; Zhang, Qing; Viscofsky, Nancy; Lindor, Noralane M; Lynch, Patrick M; Frazier, Marsha L

    2009-11-01

    Lynch syndrome is an autosomal dominant syndrome of familial malignancies resulting from germ line mutations in DNA mismatch repair (MMR) genes. Our goal was to take a pathway-based approach to investigate the influence of polymorphisms in cell cycle-related genes on age of onset for Lynch syndrome using a tree model. We evaluated polymorphisms in a panel of cell cycle-related genes (AURKA, CDKN2A, TP53, E2F2, CCND1, TP73, MDM2, IGF1, and CDKN2B) in 220 MMR gene mutation carriers from 129 families. We applied a novel statistical approach, tree modeling (Classification and Regression Tree), to the analysis of data on patients with Lynch syndrome to identify individuals with a higher probability of developing colorectal cancer at an early age and explore the gene-gene interactions between polymorphisms in cell cycle genes. We found that the subgroup with CDKN2A C580T wild-type genotype, IGF1 CA-repeats >or=19, E2F2 variant genotype, AURKA wild-type genotype, and CCND1 variant genotype had the youngest age of onset, with a 45-year median onset age, while the subgroup with CDKN2A C580T wild-type genotype, IGF1 CA-repeats >or=19, E2F2 wild-type genotype, and AURKA variant genotype had the latest median age of onset, which was 70 years. Furthermore, we found evidence of a possible gene-gene interaction between E2F2 and AURKA genes related to CRC age of onset. Polymorphisms in these cell cycle-related genes work together to modify the age at the onset of CRC in patients with Lynch syndrome. These studies provide an important part of the foundation for development of a model for stratifying age of onset risk among those with Lynch syndrome.

  18. Patient-reported disease knowledge and educational needs in Lynch syndrome: findings of an interactive multidisciplinary patient conference.

    Science.gov (United States)

    Bannon, Sarah A; Mork, Maureen; Vilar, Eduardo; Peterson, Susan K; Lu, Karen; Lynch, Patrick M; Rodriguez-Bigas, Miguel A; You, Yiqian Nancy

    2014-02-05

    Patients with Lynch Syndrome, the most common hereditary colorectal cancer syndrome, benefit from genetic education and family counseling regarding diagnostic testing and cancer surveillance/prevention recommendations. Although genetic counseling is currently the most common venue where such education and counseling takes place, little is known about the level of disease knowledge and education needs as directly reported by patients and families with Lynch Syndrome. Furthermore, experiences with forums for larger-scale knowledge transfer have been limited in the current literature. We conducted a one-day interactive multidisciplinary patient conference, designed to complement individual genetic counseling for updating disease knowledge, supportive networking and needs assessment among Lynch Syndrome patients and their family members. The patient conference was designed utilizing the conceptual framework of action research. Paired pre- and post-conference surveys were administered to 44 conference participants anonymously to assess patient-reported disease knowledge and education needs. A multidisciplinary team of expert providers utilized a variety of educational formats during the one-day conference. Four main focus areas were: genetic testing, surveillance/prevention, living with Lynch Syndrome, and update on research. Thirty-two participants (73%) completed the pre-conference, and 28 (64%) participants completed the post-conference surveys. Nineteen respondents were affected and the remaining were unaffected. The scores of the disease-knowledge items significantly increased from 84% pre- to 92% post-conference (p = 0.012). Patients reported a high level of satisfaction and identified further knowledge needs in nutrition (71%), surveillance/prevention options (71%), support groups (36%), cancer risk assessment (32%), active role in medical care (32%), and research opportunities (5%). Our experience with a dedicated patient education conference focused on

  19. Sedimentation Study and Flume Investigation, Mission Creek, Santa Barbara, California; Corte Madera Creek, Marin County, California

    National Research Council Canada - National Science Library

    Copeland, Ronald

    2000-01-01

    .... An existing concrete-lined flood control channel on Corte Madera Creek in Marin County, California lacks a debris basin at its upstream terminus and carries significant bed load through a supercritical flow reach...

  20. CREEK Project's Oyster Biomass Database for Eight Creeks in the North Inlet Estuary, South Carolina

    Data.gov (United States)

    Baruch Institute for Marine and Coastal Sciences, Univ of South Carolina — A group of eight tidal creeks dominated by oysters, Crassostrea virginica, in North Inlet Estuary, South Carolina, USA were studied using a replicated BACI (Before -...

  1. Drywell corrosion stopped at Oyster Creek

    International Nuclear Information System (INIS)

    Lipford, B.L.; Flynn, J.C.

    1993-01-01

    This article describes the detection of corrosion on the drywell containment vessel of Oyster Creek Nuclear Plant and the application of a protective coating to repair the drywell. The topics of the article include drywell design features, identification of the problem, initial action, drywell corrosion, failure of cathodic protection, long-term repair, and repair results

  2. Geology of the Teakettle Creek watersheds

    Science.gov (United States)

    Robert S. LaMotte

    1937-01-01

    The Teakettle Creek Experimental Watersheds lie for the most part on quartzites of probable Triassic age. However one of the triplicate drainages has a considerable acreage developed on weathered granodiorite. Topography is relatively uniform and lends itself to triplicate watershed studies. Locations for dams are suitable if certain engineering precautions...

  3. Tidal mixing in Dahej creek waters

    Digital Repository Service at National Institute of Oceanography (India)

    Swamy, G.N.; Sarma, R.V.

    Mixing characteristics of a tidal inlet near Dahej at the mouth of Narmada River, Gujarat, India are examined in terms of tides, currents and bathymetry. The dilution potential of the Dahej Creek waters during a tidal march for a given rate...

  4. Species status of Mill Creek Elliptio

    Energy Technology Data Exchange (ETDEWEB)

    Davis, G.M. [Academy of Natural Sciences (United States); Mulvey, M. [Savannah River Ecology Lab., Aiken, SC (United States)

    1993-12-31

    This report discusses environmental effects of the Savannah River Plant on aqautic populations in Mill Creek and surrounding tributaries. Of particular concern was the status of Elliptio. Genetics and phenotypic characteristics have shown that the current classification system is not adequate for these populations. The appendices characterize genetic variability at different loci, electrophoretic data, allele frequencies, sympatric species, and anatomical characters.

  5. UTILIZING CREEKS FOR INTEGRATED RURAL COASTAL ...

    African Journals Online (AJOL)

    Osondu

    2013-02-09

    Feb 9, 2013 ... This study examines the Utilization of Creeks for Integrated Coastal Development of Ilaje ... utilization, poor fishing techniques, poor sources of water and navigation routes, and manual ... Ethiopian Journal of Environmental Studies and Management Vol. 6 No.3 .... together, implement, monitor and evaluate.

  6. Collaborative monitoring in Walnut Creek, California

    Science.gov (United States)

    Heidi Ballard; Ralph Kraetsch; Lynn Huntsinger

    2002-01-01

    In 1995 and 2000, a monitoring program was designed and implemented to track oak regeneration and native grass populations in target management areas in the four Open Space Preserves of the City of Walnut Creek, California. The program resulted from a collaboration of scientists at the University of California, Berkeley, a group of interested citizens known as the...

  7. Mutation spectrum and risk of colorectal cancer in African American families with Lynch syndrome.

    Science.gov (United States)

    Guindalini, Rodrigo Santa Cruz; Win, Aung Ko; Gulden, Cassandra; Lindor, Noralane M; Newcomb, Polly A; Haile, Robert W; Raymond, Victoria; Stoffel, Elena; Hall, Michael; Llor, Xavier; Ukaegbu, Chinedu I; Solomon, Ilana; Weitzel, Jeffrey; Kalady, Matthew; Blanco, Amie; Terdiman, Jonathan; Shuttlesworth, Gladis A; Lynch, Patrick M; Hampel, Heather; Lynch, Henry T; Jenkins, Mark A; Olopade, Olufunmilayo I; Kupfer, Sonia S

    2015-11-01

    African Americans (AAs) have the highest incidence of and mortality resulting from colorectal cancer (CRC) in the United States. Few data are available on genetic and nongenetic risk factors for CRC among AAs. Little is known about cancer risks and mutations in mismatch repair (MMR) genes in AAs with the most common inherited CRC condition, Lynch syndrome. We aimed to characterize phenotype, mutation spectrum, and risk of CRC in AAs with Lynch syndrome. We performed a retrospective study of AAs with mutations in MMR genes (MLH1, MSH2, MSH6, and PMS2) using databases from 13 US referral centers. We analyzed data on personal and family histories of cancer. Modified segregation analysis conditioned on ascertainment criteria was used to estimate age- and sex-specific CRC cumulative risk, studying members of the mutation-carrying families. We identified 51 AA families with deleterious mutations that disrupt function of the MMR gene product: 31 in MLH1 (61%), 11 in MSH2 (21%), 3 in MSH6 (6%), and 6 in PMS2 (12%); 8 mutations were detected in more than 1 individual, and 11 have not been previously reported. In the 920 members of the 51 families with deleterious mutations, the cumulative risks of CRC at 80 years of age were estimated to be 36.2% (95% confidence interval [CI], 10.5%-83.9%) for men and 29.7% (95% CI, 8.31%-76.1%) for women. CRC risk was significantly higher among individuals with mutations in MLH1 or MSH2 (hazard ratio, 13.9; 95% CI, 3.44-56.5). We estimate the cumulative risk for CRC in AAs with MMR gene mutations to be similar to that of individuals of European descent with Lynch syndrome. Two-thirds of mutations were found in MLH1, some of which were found in multiple individuals and some that have not been previously reported. Differences in mutation spectrum are likely to reflect the genetic diversity of this population. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

  8. Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome.

    Science.gov (United States)

    Burn, John; Bishop, D Timothy; Mecklin, Jukka-Pekka; Macrae, Finlay; Möslein, Gabriela; Olschwang, Sylviane; Bisgaard, Marie-Luise; Ramesar, Raj; Eccles, Diana; Maher, Eamonn R; Bertario, Lucio; Jarvinen, Heikki J; Lindblom, Annika; Evans, D Gareth; Lubinski, Jan; Morrison, Patrick J; Ho, Judy W C; Vasen, Hans F A; Side, Lucy; Thomas, Huw J W; Scott, Rodney J; Dunlop, Malcolm; Barker, Gail; Elliott, Faye; Jass, Jeremy R; Fodde, Ricardo; Lynch, Henry T; Mathers, John C

    2008-12-11

    Observational and epidemiologic data indicate that the use of aspirin reduces the risk of colorectal neoplasia; however, the effects of aspirin in the Lynch syndrome (hereditary nonpolyposis colon cancer) are not known. Resistant starch has been associated with an antineoplastic effect on the colon. In a randomized, placebo-controlled trial, we used a two-by-two design to investigate the effects of aspirin, at a dose of 600 mg per day, and resistant starch (Novelose), at a dose of 30 g per day, in reducing the risk of adenoma and carcinoma among persons with the Lynch syndrome. Among 1071 persons in 43 centers, 62 were ineligible to participate in the study, 72 did not enter the study, and 191 withdrew from the study. These three categories were equally distributed across the study groups. Over a mean period of 29 months (range, 7 to 74), colonic adenoma or carcinoma developed in 141 participants. Of 693 participants randomly assigned to receive aspirin or placebo, neoplasia developed in 66 participants receiving aspirin (18.9%), as compared with 65 receiving placebo (19.0%) (relative risk, 1.0; 95% confidence interval [CI], 0.7 to 1.4). There were no significant differences between the two groups with respect to the development of advanced neoplasia (7.4% and 9.9%, respectively; P=0.33). Among the 727 participants receiving resistant starch or placebo, neoplasia developed in 67 participants receiving starch (18.7%), as compared with 68 receiving placebo (18.4%) (relative risk, 1.0; 95% CI, 0.7 to 1.4). Advanced adenomas and colorectal cancers were evenly distributed in the two groups. The prevalence of serious adverse events was low, and the events were evenly distributed. The use of aspirin, resistant starch, or both for up to 4 years has no effect on the incidence of colorectal adenoma or carcinoma among carriers of the Lynch syndrome. (Current Controlled Trials number, ISRCTN59521990.) 2008 Massachusetts Medical Society

  9. Pine Creek Ranch, FY 2001 Annual Report.

    Energy Technology Data Exchange (ETDEWEB)

    Berry, Mark E.

    2001-11-01

    Pine Creek Ranch was purchased in 1999 by the Confederated Tribes of Warm Springs using Bonneville Power Administration Fish and Wildlife Habitat Mitigation funds. The 25,000 acre property will be managed in perpetuity for the benefit of fish and wildlife habitat. Major issues include: (1) Restoring quality spawning and rearing habitat for stealhead. Streams are incised and fish passage barriers exist from culverts and possibly beaver dams. In addition to stealhead habitat, the Tribes are interested in overall riparian recovery in the John Day River system for wildlife habitat, watershed values and other values such as recreation. (2) Future grazing for specific management purposes. Past grazing practices undoubtedly contributed to current unacceptable conditions. The main stem of Pine Creek has already been enrolled in the CREP program administered by the USDA, Natural Resource Conservation Service in part because of the cost-share for vegetation restoration in a buffer portion of old fields and in part because of rental fees that will help the Tribes to pay the property taxes. Grazing is not allowed in the riparian buffer for the term of the contract. (3) Noxious weeds are a major concern. (4) Encroachment by western juniper throughout the watershed is a potential concern for the hydrology of the creek. Mark Berry, Habitat Manager, for the Pine Creek Ranch requested the Team to address the following objectives: (1) Introduce some of the field staff and others to Proper Functioning Condition (PFC) assessments and concepts. (2) Do a PFC assessment on approximately 10 miles of Pine Creek. (3) Offer management recommendations. (4) Provide guidelines for monitoring.

  10. Thyroid cancer in a patient with a germline MSH2 mutation. Case report and review of the Lynch syndrome expanding tumour spectrum

    Directory of Open Access Journals (Sweden)

    Stulp Rein P

    2008-02-01

    Full Text Available Abstract Lynch syndrome (HNPCC is a dominantly inherited disorder characterized by germline defects in DNA mismatch repair (MMR genes and the development of a variety of cancers, predominantly colorectal and endometrial. We present a 44-year-old woman who was shown to carry the truncating MSH2 gene mutation that had previously been identified in her family. Recently, she had been diagnosed with an undifferentiated carcinoma of the thyroid and an adenoma of her coecum. Although the thyroid carcinoma was not MSI-high (1 out of 5 microsatellites instable, it did show complete loss of immunohistochemical expression for the MSH2 protein, suggesting that this tumour was not coincidental. Although the risks for some tumour types, including breast cancer, soft tissue sarcoma and prostate cancer, are not significantly increased in Lynch syndrome, MMR deficiency in the presence of a corresponding germline defect has been demonstrated in incidental cases of a growing range of tumour types, which is reviewed in this paper. Interestingly, the MSH2-associated tumour spectrum appears to be wider than that of MLH1 and generally the risk for most extra-colonic cancers appears to be higher for MSH2 than for MLH1 mutation carriers. Together with a previously reported case, our findings show that anaplastic thyroid carcinoma can develop in the setting of Lynch syndrome. Uncommon Lynch syndrome-associated tumour types might be useful in the genetic analysis of a Lynch syndrome suspected family if samples from typical Lynch syndrome tumours are unavailable.

  11. Germ-line variants identified by next generation sequencing in a panel of estrogen and cancer associated genes correlate with poor clinical outcome in Lynch syndrome patients.

    Science.gov (United States)

    Jóri, Balazs; Kamps, Rick; Xanthoulea, Sofia; Delvoux, Bert; Blok, Marinus J; Van de Vijver, Koen K; de Koning, Bart; Oei, Felicia Trups; Tops, Carli M; Speel, Ernst Jm; Kruitwagen, Roy F; Gomez-Garcia, Encarna B; Romano, Andrea

    2015-12-01

    The risk to develop colorectal and endometrial cancers among subjects testing positive for a pathogenic Lynch syndrome mutation varies, making the risk prediction difficult. Genetic risk modifiers alter the risk conferred by inherited Lynch syndrome mutations, and their identification can improve genetic counseling. We aimed at identifying rare genetic modifiers of the risk of Lynch syndrome endometrial cancer. A family based approach was used to assess the presence of genetic risk modifiers among 35 Lynch syndrome mutation carriers having either a poor clinical phenotype (early age of endometrial cancer diagnosis or multiple cancers) or a neutral clinical phenotype. Putative genetic risk modifiers were identified by Next Generation Sequencing among a panel of 154 genes involved in endometrial physiology and carcinogenesis. A simple pipeline, based on an allele frequency lower than 0.001 and on predicted non-conservative amino-acid substitutions returned 54 variants that were considered putative risk modifiers. The presence of two or more risk modifying variants in women carrying a pathogenic Lynch syndrome mutation was associated with a poor clinical phenotype. A gene-panel is proposed that comprehends genes that can carry variants with putative modifying effects on the risk of Lynch syndrome endometrial cancer. Validation in further studies is warranted before considering the possible use of this tool in genetic counseling.

  12. Bayesian Modeling for Genetic Anticipation in Presence of Mutational Heterogeneity: A Case Study in Lynch Syndrome

    DEFF Research Database (Denmark)

    Boonstra, Philip S; Mukherjee, Bhramar; Taylor, Jeremy M G

    2011-01-01

    Summary Genetic anticipation, described by earlier age of onset (AOO) and more aggressive symptoms in successive generations, is a phenomenon noted in certain hereditary diseases. Its extent may vary between families and/or between mutation subtypes known to be associated with the disease phenotype....... In this article, we posit a Bayesian approach to infer genetic anticipation under flexible random effects models for censored data that capture the effect of successive generations on AOO. Primary interest lies in the random effects. Misspecifying the distribution of random effects may result in incorrect...... to cause hereditary nonpolyposis colorectal cancer, also called Lynch syndrome (LS). We find evidence for a decrease in AOO between generations in this article. Our model predicts family-level anticipation effects that are potentially useful in genetic counseling clinics for high-risk families....

  13. A review of statistical methods for testing genetic anticipation: looking for an answer in Lynch syndrome

    DEFF Research Database (Denmark)

    Boonstra, Philip S; Gruber, Stephen B; Raymond, Victoria M

    2010-01-01

    Anticipation, manifested through decreasing age of onset or increased severity in successive generations, has been noted in several genetic diseases. Statistical methods for genetic anticipation range from a simple use of the paired t-test for age of onset restricted to affected parent-child pairs......, and this right truncation effect is more pronounced in children than in parents. In this study, we first review different statistical methods for testing genetic anticipation in affected parent-child pairs that address the issue of bias due to right truncation. Using affected parent-child pair data, we compare...... the issue of multiplex ascertainment and its effect on the different methods. We then focus on exploring genetic anticipation in Lynch syndrome and analyze new data on the age of onset in affected parent-child pairs from families seen at the University of Michigan Cancer Genetics clinic with a mutation...

  14. Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population

    DEFF Research Database (Denmark)

    Nilbert, Mef; Wikman, Friedrik P; Hansen, Thomas V O

    2009-01-01

    mutations in 164 families are considered pathogenic and an additional 50 variants from 76 families are considered to represent variants of unknown pathogenicity. The different MMR genes contribute to 40% (MSH2), 29% (MLH1), and 22% (MSH6) of the mutations and the Danish population thus shows a considerably...... higher frequency of MSH6 mutations than previously described. Although 69/88 (78%) pathogenic mutations were present in a single family, previously recognized recurrent/founder mutations were causative in 75/137 (55%) MLH1/MSH2 mutant families. In addition, the Danish MLH1 founder mutation c.1667......+2_1667_+8TAAATCAdelinsATTT was identified in 14/58 (24%) MLH1 mutant families. The Danish Lynch syndrome population thus demonstrates that MSH6 mutations and recurrent/founder mutations have a larger contribution than previously recognized, which implies that the MSH6 gene should be included in routine diagnostics...

  15. Structure of the human MLH1 N-terminus: implications for predisposition to Lynch syndrome

    International Nuclear Information System (INIS)

    Wu, Hong; Zeng, Hong; Lam, Robert; Tempel, Wolfram; Kerr, Iain D.; Min, Jinrong

    2015-01-01

    The crystal structure of the human MLH1 N-terminus is reported at 2.30 Å resolution. The overall structure is described along with an analysis of two clinically important mutations. Mismatch repair prevents the accumulation of erroneous insertions/deletions and non-Watson–Crick base pairs in the genome. Pathogenic mutations in the MLH1 gene are associated with a predisposition to Lynch and Turcot’s syndromes. Although genetic testing for these mutations is available, robust classification of variants requires strong clinical and functional support. Here, the first structure of the N-terminus of human MLH1, determined by X-ray crystallography, is described. The structure shares a high degree of similarity with previously determined prokaryotic MLH1 homologs; however, this structure affords a more accurate platform for the classification of MLH1 variants

  16. Gynecologic cancer screening and communication with health care providers in women with Lynch syndrome.

    Science.gov (United States)

    Burton-Chase, A M; Hovick, S R; Sun, C C; Boyd-Rogers, S; Lynch, P M; Lu, K H; Peterson, S K

    2014-08-01

    We evaluated knowledge of gynecologic cancer screening recommendations, screening behaviors, and communication with providers among women with Lynch syndrome (LS). Women aged ≥25 years who were at risk for LS-associated cancers completed a semi-structured interview and a questionnaire. Of 74 participants (mean age 40 years), 61% knew the appropriate age to begin screening, 75-80% correctly identified the recommended screening frequency, and 84% reported no previous screening endometrial biopsy. Women initiated discussions with their providers about their LS cancer risks, but many used nonspecific terms or relied on family history. Most were not offered high-risk screening options. While many women were aware of risk-appropriate LS screening guidelines, adherence was suboptimal. Improving communication between women and their providers regarding LS-related gynecologic cancer risk and screening options may help improve adherence. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Rare mutations in RINT1 predispose carriers to breast and Lynch Syndrome-spectrum cancers

    Science.gov (United States)

    Park, Daniel J.; Tao, Kayoko; Le Calvez-Kelm, Florence; Nguyen-Dumont, Tu; Robinot, Nivonirina; Hammet, Fleur; Odefrey, Fabrice; Tsimiklis, Helen; Teo, Zhi L.; Thingholm, Louise B.; Young, Erin L.; Voegele, Catherine; Lonie, Andrew; Pope, Bernard J.; Roane, Terrell C.; Bell, Russell; Hu, Hao; Shankaracharya; Huff, Chad D.; Ellis, Jonathan; Li, Jun; Makunin, Igor V.; John, Esther M.; Andrulis, Irene L.; Terry, Mary B.; Daly, Mary; Buys, Saundra S.; Snyder, Carrie; Lynch, Henry T.; Devilee, Peter; Giles, Graham G.; Hopper, John L.; Feng, Bing J.; Lesueur, Fabienne; Tavtigian, Sean V.; Southey, Melissa C.; Goldgar, David E.

    2014-01-01

    Approximately half of the familial aggregation of breast cancer remains unexplained. A multiple-case breast cancer family exome sequencing study identified three likely pathogenic mutations in RINT1 (NM_021930.4) not present in public sequencing databases: RINT1 c.343C>T (p.Q115X), c.1132_1134del (p.M378del) and c.1207G>T (p.D403Y). Based on this finding, a population-based case-control mutation-screening study was conducted and identified 29 carriers of rare (MAF Lynch syndrome-spectrum cancers (SIR 3.35, 95% CI 1.7-6.0; P=0.005), particularly for relatives diagnosed with cancer under age 60 years (SIR 10.9, 95%CI 4.7-21; P=0.0003). PMID:25050558

  18. HNPCC (Lynch Syndrome: Differential Diagnosis, Molecular Genetics and Management - a Review

    Directory of Open Access Journals (Sweden)

    Lynch Henry T

    2003-12-01

    Full Text Available Abstract HNPCC (Lynch syndrome is the most common form of hereditary colorectal cancer (CRC, wherein it accounts for between 2-7 percent of the total CRC burden. When considering the large number of extracolonic cancers integral to the syndrome, namely carcinoma of the endometrium, ovary, stomach, hepatobiliary system, pancreas, small bowel, brain tumors, and upper uroepithelial tract, these estimates of its frequency are likely to be conservative. The diagnosis is based upon its natural history in concert with a comprehensive cancer family history inclusive of all anatomic sites. In order for surveillance and management to be effective and, indeed, lifesaving, among these high-risk patients, the linchpin to cancer control would be the physician, who must be knowledgeable about hereditary cancer syndromes, their molecular and medical genetics, genetic counseling, and, most importantly, the natural history of the disorders, so that the entirety of this knowledge can be melded to highly-targeted management.

  19. Gynecologic cancer screening and communication with health care providers in women with Lynch syndrome

    Science.gov (United States)

    Burton-Chase, AM; Hovick, SR; Sun, CC; Boyd-Rogers, S; Lynch, PM; Lu, KH; Peterson, SK

    2014-01-01

    We evaluated knowledge of gynecologic cancer screening recommendations, screening behaviors, and communication with providers among women with Lynch syndrome (LS). Women aged ≥25 years who were at risk for LS-associated cancers completed a semi-structured interview and a questionnaire. Of 74 participants (mean age 40 years), 61% knew the appropriate age to begin screening, 75–80% correctly identified the recommended screening frequency, and 84% reported no previous screening endometrial biopsy. Women initiated discussions with their providers about their LS cancer risks, but many used nonspecific terms or relied on family history. Most were not offered high-risk screening options. While many women were aware of risk-appropriate LS screening guidelines, adherence was suboptimal. Improving communication between women and their providers regarding LS-related gynecologic cancer risk and screening options may help improve adherence. PMID:23906188

  20. Structure of the human MLH1 N-terminus: implications for predisposition to Lynch syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Hong; Zeng, Hong; Lam, Robert; Tempel, Wolfram [University of Toronto, 101 College Street, Toronto, ON M5G 1L7 (Canada); Kerr, Iain D., E-mail: ikerr@myriad.com [Myriad Genetic Laboratories Inc., 320 Wakara Way, Salt Lake City, UT 84108 (United States); Min, Jinrong, E-mail: ikerr@myriad.com [University of Toronto, 101 College Street, Toronto, ON M5G 1L7 (Canada); University of Toronto, Toronto, ON M5G 1L7 (Canada)

    2015-07-28

    The crystal structure of the human MLH1 N-terminus is reported at 2.30 Å resolution. The overall structure is described along with an analysis of two clinically important mutations. Mismatch repair prevents the accumulation of erroneous insertions/deletions and non-Watson–Crick base pairs in the genome. Pathogenic mutations in the MLH1 gene are associated with a predisposition to Lynch and Turcot’s syndromes. Although genetic testing for these mutations is available, robust classification of variants requires strong clinical and functional support. Here, the first structure of the N-terminus of human MLH1, determined by X-ray crystallography, is described. The structure shares a high degree of similarity with previously determined prokaryotic MLH1 homologs; however, this structure affords a more accurate platform for the classification of MLH1 variants.

  1. Revised Bethesda Guidelines for Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) and Microsatellite Instability

    Science.gov (United States)

    Umar, Asad; Boland, C. Richard; Terdiman, Jonathan P.; Syngal, Sapna; de la Chapelle, Albert; Rüschoff, Josef; Fishel, Richard; Lindor, Noralane M.; Burgart, Lawrence J.; Hamelin, Richard; Hamilton, Stanley R.; Hiatt, Robert A.; Jass, Jeremy; Lindblom, Annika; Lynch, Henry T.; Peltomaki, Païvi; Ramsey, Scott D.; Rodriguez-Bigas, Miguel A.; Vasen, Hans F. A.; Hawk, Ernest T.; Barrett, J. Carl; Freedman, Andrew N.; Srivastava, Sudhir

    2010-01-01

    Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is a common autosomal dominant syndrome characterized by early age at onset, neoplastic lesions, and microsatellite instability (MSI). Because cancers with MSI account for approximately 15% of all colorectal cancers and because of the need for a better understanding of the clinical and histologic manifestations of HNPCC, the National Cancer Institute hosted an international workshop on HNPCC in 1996, which led to the development of the Bethesda Guidelines for the identification of individuals with HNPCC who should be tested for MSI. To consider revision and improvement of the Bethesda Guidelines, another HNPCC workshop was held at the National Cancer Institute in Bethesda, MD, in 2002. In this commentary, we summarize the Workshop presentations on HNPCC and MSI testing; present the issues relating to the performance, sensitivity, and specificity of the Bethesda Guidelines; outline the revised Bethesda Guidelines for identifying individuals at risk for HNPCC; and recommend criteria for MSI testing. PMID:14970275

  2. HNPCC (Lynch Syndrome): Differential Diagnosis, Molecular Genetics and Management - a Review

    Science.gov (United States)

    2003-01-01

    HNPCC (Lynch syndrome) is the most common form of hereditary colorectal cancer (CRC), wherein it accounts for between 2-7 percent of the total CRC burden. When considering the large number of extracolonic cancers integral to the syndrome, namely carcinoma of the endometrium, ovary, stomach, hepatobiliary system, pancreas, small bowel, brain tumors, and upper uroepithelial tract, these estimates of its frequency are likely to be conservative. The diagnosis is based upon its natural history in concert with a comprehensive cancer family history inclusive of all anatomic sites. In order for surveillance and management to be effective and, indeed, lifesaving, among these high-risk patients, the linchpin to cancer control would be the physician, who must be knowledgeable about hereditary cancer syndromes, their molecular and medical genetics, genetic counseling, and, most importantly, the natural history of the disorders, so that the entirety of this knowledge can be melded to highly-targeted management.

  3. Association of Mismatch Repair Mutation With Age at Cancer Onset in Lynch Syndrome: Implications for Stratified Surveillance Strategies.

    Science.gov (United States)

    Ryan, Neil A J; Morris, Julie; Green, Kate; Lalloo, Fiona; Woodward, Emma R; Hill, James; Crosbie, Emma J; Evans, D Gareth

    2017-12-01

    Lynch syndrome is caused by dominantly inherited germline mutations that predispose individuals to colorectal, endometrial, ovarian, and other cancers through inactivation of the cellular mismatch repair system. Lynch syndrome–associated cancers are amenable to surveillance strategies that may improve survival. The age at which surveillance should start is disputed. To determine whether mutated gene and type of mutation influence age at onset of Lynch syndrome–associated cancers. A retrospective cohort study of individuals with Lynch syndrome–associated colorectal, endometrial, and/or ovarian cancers whose medical records were included in the clinical database of a large quaternary referral center for genomic medicine in the Northwest of England. Mutated gene (MLH1, MSH2, MSH6, and/or PMS2) and type of mutation (truncating, splicing, or large rearrangement). Age at cancer diagnosis. A total of 1063 individuals with proven Lynch syndrome were included, 495 male and 568 female (mean age 52 years; age range, 10-93 years [children were included in the database, but no children developed cancer]). There were 546 men and women with colorectal cancer, 162 women with endometrial cancer, and 49 women with ovarian cancer; mean follow-up was 68.2 months. Among MLH1 mutation carriers, mutations in MLH1 were associated with colorectal cancer in 249 (61%) of 409 men and women; endometrial cancer in 53 of 196 (27%) women; and ovarian cancer in 15 (8%) of 196 women. Among MSH2 mutation carriers, mutations in MSH2 (the most prevalent mutations overall) were most commonly associated with female-specific cancers: endometrial cancer in 83 (30%) of 279 women; ovarian cancer in 28 (10%) of 279 women; and colorectal cancer in 239 (50%) 479 men and women. Mutations in MSH6 were less prevalent, and MSH6 mutation carriers presented with colorectal and endometrial cancer at later ages than carriers of mutations in MSH2 or MLH1. When stratified by mutation type, women with truncating

  4. Dietary patterns and colorectal adenomas in Lynch syndrome: the GEOLynch cohort study.

    Science.gov (United States)

    Botma, Akke; Vasen, Hans F A; van Duijnhoven, Fränzel J B; Kleibeuker, Jan H; Nagengast, Fokko M; Kampman, Ellen

    2013-02-01

    Patients with Lynch syndrome (LS) have a high risk of developing colorectal cancer due to mutations in mismatch repair genes. Because dietary factors, alone and in combination, influence sporadic colorectal carcinogenesis, the association of dietary patterns with colorectal adenomas in LS patients was assessed. In the GEOLynch cohort of 486 persons with LS, dietary information was collected, using a food frequency questionnaire. Dietary pattern scores were obtained by principal components analysis. Hazard ratios (HR) between dietary patterns and colorectal adenomas were calculated using Cox regression models. Robust sandwich variance estimates were used to control for dependency within families. Final models were adjusted for age, sex, smoking habits, colorectal adenoma history, and extent of colon resection. During a median follow-up of 20 months, colorectal adenomas were detected in 58 persons. Four dietary patterns were identified: a "Prudent," "Meat," "Snack," and "Cosmopolitan" pattern. Individuals within the highest tertile of the "Prudent" pattern had a HR of 0.73 (95% confidence interval [CI], 0.32-1.66) for colorectal adenomas, compared with the lowest tertile. Those with high "Meat" pattern scores had a HR of 1.70 (95% CI, 0.83-3.52). A high "Snack" pattern was associated with an increased risk of colorectal adenomas (HR, 2.16; 95% CI, 1.03-4.49). A HR of 1.25 (95% CI, 0.61-2.55) was observed for persons in the highest tertile of the "Cosmopolitan" pattern. These findings suggest that dietary patterns may be associated with development of colorectal adenoma in patients with Lynch syndrome. The directions of these findings are corroborative with those observed in studies investigating sporadic colorectal cancer. Copyright © 2012 American Cancer Society.

  5. Whole Gene Capture Analysis of 15 CRC Susceptibility Genes in Suspected Lynch Syndrome Patients.

    Science.gov (United States)

    Jansen, Anne M L; Geilenkirchen, Marije A; van Wezel, Tom; Jagmohan-Changur, Shantie C; Ruano, Dina; van der Klift, Heleen M; van den Akker, Brendy E W M; Laros, Jeroen F J; van Galen, Michiel; Wagner, Anja; Letteboer, Tom G W; Gómez-García, Encarna B; Tops, Carli M J; Vasen, Hans F; Devilee, Peter; Hes, Frederik J; Morreau, Hans; Wijnen, Juul T

    2016-01-01

    Lynch Syndrome (LS) is caused by pathogenic germline variants in one of the mismatch repair (MMR) genes. However, up to 60% of MMR-deficient colorectal cancer cases are categorized as suspected Lynch Syndrome (sLS) because no pathogenic MMR germline variant can be identified, which leads to difficulties in clinical management. We therefore analyzed the genomic regions of 15 CRC susceptibility genes in leukocyte DNA of 34 unrelated sLS patients and 11 patients with MLH1 hypermethylated tumors with a clear family history. Using targeted next-generation sequencing, we analyzed the entire non-repetitive genomic sequence, including intronic and regulatory sequences, of 15 CRC susceptibility genes. In addition, tumor DNA from 28 sLS patients was analyzed for somatic MMR variants. Of 1979 germline variants found in the leukocyte DNA of 34 sLS patients, one was a pathogenic variant (MLH1 c.1667+1delG). Leukocyte DNA of 11 patients with MLH1 hypermethylated tumors was negative for pathogenic germline variants in the tested CRC susceptibility genes and for germline MLH1 hypermethylation. Somatic DNA analysis of 28 sLS tumors identified eight (29%) cases with two pathogenic somatic variants, one with a VUS predicted to pathogenic and LOH, and nine cases (32%) with one pathogenic somatic variant (n = 8) or one VUS predicted to be pathogenic (n = 1). This is the first study in sLS patients to include the entire genomic sequence of CRC susceptibility genes. An underlying somatic or germline MMR gene defect was identified in ten of 34 sLS patients (29%). In the remaining sLS patients, the underlying genetic defect explaining the MMRdeficiency in their tumors might be found outside the genomic regions harboring the MMR and other known CRC susceptibility genes.

  6. Role of microsatellite instability-low as a diagnostic biomarker of Lynch syndrome in colorectal cancer.

    Science.gov (United States)

    Vilar, Eduardo; Mork, Maureen E; Cuddy, Amanda; Borras, Ester; Bannon, Sarah A; Taggart, Melissa W; Ying, Jun; Broaddus, Russell R; Luthra, Rajyalakshmi; Rodriguez-Bigas, Miguel A; Lynch, Patrick M; You, Yi-Qian Nancy

    2014-01-01

    Lynch syndrome is the most common Mendelian disorder predisposing persons to hereditary colorectal cancer. Carriers of MSH6 mutations constitute less than 10% of the total of cases with Lynch syndrome and present with a weaker clinical phenotype, including low levels of microsatellite instability (MSI-L) in colorectal tumors. The frequency of MSH6 mutation carriers among patients presenting with MSI-L colorectal cancer has yet to be determined, as has the appropriate genetic workup in this context. We have reviewed here the clinicopathologic characteristics, immunohistochemistry, and genetic testing results for 71 patients at a single institution diagnosed with MSI-L colorectal cancers. Of 71 patients with MSI-L tumors, 21 underwent genetic testing for MSH6 mutations, three of whom presented with loss of staining of MSH6 and only one of whom carried a pathogenic germline MSH6 mutation in exon 4 (c.2677_2678delCT; p.Leu893Alafs*6). This latter patient had a significant family history of cancer and had a rectal primary tumor that showed instability only in mononucleotide markers. In this cohort of MSI-L patients, we detected no notable clinicopathologic or molecular characteristic that would help to distinguish a group most likely to harbor germline MSH6 mutations. Therefore, we conclude that the prevalence of MSH6 mutations among patients with MSI-L tumors is very low. Microsatellite instability analysis combined with immunohistochemistry of mismatch repair proteins adequately detects potential MSH6 mutation carriers among MSI-L colorectal cancers. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. The Use of Social Media to Recruit Participants With Rare Conditions: Lynch Syndrome as an Example.

    Science.gov (United States)

    Burton-Chase, Allison M; Parker, Wendy M; Hennig, Kelsey; Sisson, Faith; Bruzzone, Linda L

    2017-01-23

    Social media is increasingly being used as a means of recruiting participants, particularly for investigators whose areas of interest involve rare conditions or hard-to-reach populations. However, much of the literature to date has focused on paid advertisement recruitment. We used Lynch syndrome (LS), a rare hereditary cancer syndrome, as a model to demonstrate the successful partnership between researchers and a Web-based patient education and advocacy organization to facilitate participant recruitment. Recruitment was undertaken in partnership with Lynch Syndrome International (LSI), an advocacy organization with a strong social media presence. After LSI published our study information, participants followed up via email or phone call. Following prescreening and consent, interested and eligible participants were then sent a secure survey link. Within 36 hours of a single Facebook post by the site administrators for LSI, over 150 individuals responded via phone or email. Sixty-five individuals were sent the survey link and 57 individuals completed the survey (88% response rate). Of note, these 57 individuals were geographically diverse within the Unites States, representing LS patients from 26 different states. This approach has several advantages, including recruitment through a trusted source outside of a clinical setting, higher response rates, and cost-effectiveness with a small research team in a relatively short amount of time. Overall, social media recruitment with a trusted online partner can be highly effective in hard-to-reach clinical populations, such as patients with LS. However, this approach requires additional effort for eligibility screening. ©Allison M Burton-Chase, Wendy M Parker, Kelsey Hennig, Faith Sisson, Linda L Bruzzone. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 23.01.2017.

  8. Lynch Syndrome

    Science.gov (United States)

    ... be affected by your diagnosis, such as: Your privacy. The results of your genetic test will be listed in your medical record, ... to tell family members that you're having genetic testing and what that the results mean. By Mayo Clinic ... Conditions and Privacy Policy linked below. Terms and Conditions Privacy Policy ...

  9. Summer food habits and trophic overlap of roundtail chub and creek chub in Muddy Creek, Wyoming

    Science.gov (United States)

    Quist, M.C.; Bower, M.R.; Hubert, W.A.

    2006-01-01

    Native fishes of the Upper Colorado River Basin have experienced substantial declines in abundance and distribution, and are extirpated from most of Wyoming. Muddy Creek, in south-central Wyoming (Little Snake River watershed), contains sympatric populations of native roundtail chub (Gila robusta), bluehead sucker, (Catostomus discobolus), and flannelmouth sucker (C. tatipinnis), and represents an area of high conservation concern because it is the only area known to have sympatric populations of all 3 species in Wyoming. However, introduced creek chub (Semotilus atromaculatus) are abundant and might have a negative influence on native fishes. We assessed summer food habits of roundtail chub and creek chub to provide information on the ecology of each species and obtain insight on potential trophic overlap. Roundtail chub and creek chub seemed to be opportunistic generalists that consumed a diverse array of food items. Stomach contents of both species were dominated by plant material, aquatic and terrestrial insects, and Fishes, but also included gastropods and mussels. Stomach contents were similar between species, indicating high trophic, overlap. No length-related patterns in diet were observed for either species. These results suggest that creek chubs have the potential to adversely influence the roundtail chub population through competition for food and the native fish assemblage through predation.

  10. Lynch Syndrome Associated Colon Adenocarcinoma Resembling Lymphoma on Fluoro-Deoxyglucose-Positron Emission Tomography/Computed Tomography

    International Nuclear Information System (INIS)

    Aparici, Carina Mari; Win, Aung Zaw

    2015-01-01

    The patient was a 46-year-old Asian male diagnosed with lynch syndrome associated colon adenocarcinoma in the right ascending colon. A presurgical staging 18-fluoro-deoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) found increased metabolic activity in the cervical, axillary, mediastinal, supraclavicular, para-aortic and mesenteric lymph nodes. This pattern of metastasis was very unusual for lynch syndrome associated colon adenocarcinoma and the involvement of those lymph nodes resembles the pattern of spread of lymphoma. He underwent right hemicolectomy and he was subsequently treated with 12 cycles of folinic acid (leucovorin), fluorouracil (5-FU), irinotecan. A restaging FDG-PET/CT at the end of the chemotherapy showed interval decrease in size and metabolic activity in the affected lymph nodes. FDG-PET/CT is a useful imaging modality in following-up the treatment response in colon adenocarcinoma

  11. The macroinvertebrates of Magela Creek, Northern Territory

    International Nuclear Information System (INIS)

    Marchant, R.

    1982-04-01

    The littoral zones of five permanent billabongs in Magela Creek were sampled monthly for macroinvertebrates. Greatest numbers of taxa and individuals were caught in the late wet season and early dry season in the shallow billabongs; in the deep billabongs, seasonal variations were not so marked. These changes appeared to be associated with the development of macrophytes, which offered food and shelter to the invertebrate fauna. The dominant groups were the Chironomidae, Oligochaetae and Ephemeroptera. The seasonal patterns of the catches were sufficiently consistent for future samples to be able to be compared with these initial ones with some confidence that any changes are real. This work is part of a larger study into the biota and water quality of Magela Creek designed to provide data on aquatic communities before mining of the Ranger uranium deposit starts

  12. Mathematical modelling of flooding at Magela Creek

    International Nuclear Information System (INIS)

    Vardavas, I.

    1989-01-01

    The extent and frequency of the flooding at Magela Creek can be predicted from a mathematical/computer model describing the hydrological phases of surface runoff. Surface runoff involves complex water transfer processes over very inhomogeneous terrain. A simple mathematical model of these has been developed which includes the interception of rainfall by the plant canopy, evapotranspiration, infiltration of surface water into the soil, the storage of water in surface depressions, and overland and subsurface water flow. The rainfall-runoff model has then been incorporated into a more complex computer model to predict the amount of water that enters and leaves the Magela Creek flood plain, downstream of the mine. 2 figs., ills

  13. Clean Coal Power at Toms Creek

    International Nuclear Information System (INIS)

    Schmid, M.R.

    1993-01-01

    On October 20, 1992 the US Department of Energy (DOE), through the Morgantown Energy Technology Center, entered into Cooperative Agreement DE-FC-21-93MC92444 with TAMCO Power Partners to implement the Toms Creek Integrated Gasification Combined - Cycle Demonstration Project. The process design is proceeding as scheduled, and a draft Environmental Information Volume has been produced. The overall project schedule, however, may have to be adjusted when the Power Sales Agreement has been finalized

  14. Final Environmental Assessment, Horse Creek Bridge Replacement

    Science.gov (United States)

    2010-10-01

    existing bridge pipes that have failed and replace the failed structure with a new, prefabricated pedestrian bridge within the original bridge footprint...vehicles, nor designed for support of standard passenger vehicle loads. The bridge would be a single prefabricated unit consisting of a steel grate...placed on new concrete abutments built on the existing foundations on the creek banks, and put in place by a crane operating from the vehicle parking

  15. Channel stability of Turkey Creek, Nebraska

    Science.gov (United States)

    Rus, David L.; Soenksen, Philip J.

    1998-01-01

    Channelization on Turkey Creek and its receiving stream, the South Fork Big Nemaha River, has disturbed the equilibrium of Turkey Creek and has led to channel-stability problems, such as degradation and channel widening, which pose a threat to bridges and land adjacent to the stream. As part of a multiagency study, the U.S. Geological Survey assessed channel stability at two bridge sites on upper and middle portions of Turkey Creek by analyzing streambed-elevation data for gradation changes, comparing recent cross-section surveys and historic accounts, identifying bank-failure blocks, and analyzing tree-ring samples. These results were compared to gradation data and trend results for a U.S. Geological Survey streamflow-gaging station near the mouth of Turkey Creek from a previous study. Examination of data on streambed elevations reveals that degradation has occurred. The streambed elevation declined 0.5 m at the upper site from 1967-97. The streambed elevation declined by 3.2 m at the middle site from 1948-97 and exposed 2 m of the pilings of the Nebraska Highway 8 bridge. Channel widening could not be verified at the two sites from 1967-97, but a historic account indicates widening at the middle site to be two to three times that of the 1949 channel width. Small bank failures were evident at the upper site and a 4-m-wide bank failure occurred at the middle site in 1987 according to tree ring analyses. Examination of streambed-elevation data from a previous study at the lower site reveals a statistically significant aggrading trend from 1958-93. Further examination of these data suggests minor degradation occurred until 1975, followed by aggradation.

  16. Steel Creek primary producers: Periphyton and seston, L-Lake/Steel Creek Biological Monitoring Program, January 1986--December 1991

    Energy Technology Data Exchange (ETDEWEB)

    Bowers, J.A. [Westinghouse Savannah River Co., Aiken, SC (United States); Toole, M.A.; van Duyn, Y. [Normandeau Associates Inc., New Ellenton, SC (United States)

    1992-02-01

    The Savannah River Site (SRS) encompasses 300 sq mi of the Atlantic Coastal Plain in west-central South Carolina. Five major tributaries of the Savannah River -- Upper Three Runs Creek, Four Mile Creek, Pen Branch, Steel Creek, and Lower Three Runs Creek -- drain the site. In 1985, L Lake, a 400-hectare cooling reservoir, was built on the upper reaches of Steel Creek to receive effluent from the restart of L-Reactor and to protect the lower reaches from thermal impacts. The Steel Creek Biological Monitoring Program was designed to assess various components of the system and identify and changes due to the operation of L-Reactor or discharge from L Lake. An intensive ecological assessment program prior to the construction of the lake provided baseline data with which to compare data accumulated after the lake was filled and began discharging into the creek. The Department of Energy must demonstrate that the operation of L-Reactor will not significantly alter the established aquatic ecosystems. This report summarizes the results of six years` data from Steel Creek under the L-Lake/Steel Creek Monitoring Program. L Lake is discussed separately from Steel Creek in Volumes NAI-SR-138 through NAI-SR-143.

  17. Steel Creek primary producers: Periphyton and seston, L-Lake/Steel Creek Biological Monitoring Program, January 1986--December 1991

    International Nuclear Information System (INIS)

    Bowers, J.A.; Toole, M.A.; van Duyn, Y.

    1992-02-01

    The Savannah River Site (SRS) encompasses 300 sq mi of the Atlantic Coastal Plain in west-central South Carolina. Five major tributaries of the Savannah River -- Upper Three Runs Creek, Four Mile Creek, Pen Branch, Steel Creek, and Lower Three Runs Creek -- drain the site. In 1985, L Lake, a 400-hectare cooling reservoir, was built on the upper reaches of Steel Creek to receive effluent from the restart of L-Reactor and to protect the lower reaches from thermal impacts. The Steel Creek Biological Monitoring Program was designed to assess various components of the system and identify and changes due to the operation of L-Reactor or discharge from L Lake. An intensive ecological assessment program prior to the construction of the lake provided baseline data with which to compare data accumulated after the lake was filled and began discharging into the creek. The Department of Energy must demonstrate that the operation of L-Reactor will not significantly alter the established aquatic ecosystems. This report summarizes the results of six years' data from Steel Creek under the L-Lake/Steel Creek Monitoring Program. L Lake is discussed separately from Steel Creek in Volumes NAI-SR-138 through NAI-SR-143

  18. Contiguous gene deletion of chromosome 2p16.3-p21 as a cause of Lynch syndrome.

    Science.gov (United States)

    Salo-Mullen, Erin E; Lynn, Patricio B; Wang, Lu; Walsh, Michael; Gopalan, Anuradha; Shia, Jinru; Tran, Christina; Man, Fung Ying; McBride, Sean; Schattner, Mark; Zhang, Liying; Weiser, Martin R; Stadler, Zsofia K

    2018-01-01

    Lynch syndrome is an autosomal dominant condition caused by pathogenic mutations in the DNA mismatch repair (MMR) genes. Although commonly associated with clinical features such as intellectual disability and congenital anomalies, contiguous gene deletions may also result in cancer predisposition syndromes. We report on a 52-year-old male with Lynch syndrome caused by deletion of chromosome 2p16.3-p21. The patient had intellectual disability and presented with a prostatic adenocarcinoma with an incidentally identified synchronous sigmoid adenocarcinoma that exhibited deficient MMR with an absence of MSH2 and MSH6 protein expression. Family history was unrevealing. Physical exam revealed short stature, brachycephaly with a narrow forehead and short philtrum, brachydactyly of the hands, palmar transverse crease, broad and small feet with hyperpigmentation of the soles. The patient underwent total colectomy with ileorectal anastomosis for a pT3N1 sigmoid adenocarcinoma. Germline genetic testing of the MSH2, MSH6, and EPCAM genes revealed full gene deletions. SNP-array based DNA copy number analysis identified a deletion of 4.8 Mb at 2p16.3-p21. In addition to the three Lynch syndrome associated genes, the deleted chromosomal section encompassed genes including NRXN1, CRIPT, CALM2, FBXO11, LHCGR, MCFD2, TTC7A, EPAS1, PRKCE, and 15 others. Contiguous gene deletions have been described in other inherited cancer predisposition syndromes, such as Familial Adenomatous Polyposis. Our report and review of the literature suggests that contiguous gene deletion within the 2p16-p21 chromosomal region is a rare cause of Lynch syndrome, but presents with distinct phenotypic features, highlighting the need for recognition and awareness of this syndromic entity.

  19. Family perspectives in lynch syndrome becoming a family at risk, patterns of communication and influence on relations

    Directory of Open Access Journals (Sweden)

    Bartuma Katarina

    2012-05-01

    Full Text Available Abstract Background A growing number of individuals are diagnosed with hereditary cancer. Though increased levels of anxiety and depression have been demonstrated around the time of genetic counselling, most individuals handle life at increased risk well. Data have, however, been collected on individual basis, which led us to focus on family perspectives of hereditary cancer. Methods Lynch syndrome represents a major type of hereditary colorectal and gynaecological cancer. We preformed open-ended interviews with 27 informants from 9 Lynch syndrome families. Inductive content analysis revealed three major themes: transition to a risk family, patterns of communication and influence on family relations and individual roles. Results Family members described how learning about Lynch syndrome shifted focus from daily issues to concerns about cancer. Changes in communication related to difficulties in talking to children about heredity and informing new family members and distant relatives about an increased risk of cancer. Influence on relations was exemplified by family members taking on different roles, e.g. females often being responsible for coordinating information about heredity and providing support. Families in which members had experienced cancer at young age typically informed children soon after learning about heredity and at young age, whereas families with experience of cancer at higher age postponed information and thereby also genetic counselling. Conclusions Three major family perspectives are described in Lynch syndrome families; becoming a risk family, patterns of communication and influence on family relations. Since these issues are central, our findings suggests that such family perspectives should be considered during genetic counselling in order to contribute to information spread, help family members cope with the increased risk, and motivate family members at risk to undergo surveillance.

  20. Using Social Media Data to Understand the Impact of Promotional Information on Laypeople’s Discussions: A Case Study of Lynch Syndrome

    Science.gov (United States)

    Salloum, Ramzi G; Guo, Yi; Wang, Mo; Prosperi, Mattia; Zhang, Hansi; Du, Xinsong; Ramirez-Diaz, Laura J; He, Zhe

    2017-01-01

    Background Social media is being used by various stakeholders among pharmaceutical companies, government agencies, health care organizations, professionals, and news media as a way of engaging audiences to raise disease awareness and ultimately to improve public health. Nevertheless, it is unclear what effects this health information has on laypeople. Objective This study aimed to provide a detailed examination of how promotional health information related to Lynch syndrome impacts laypeople’s discussions on a social media platform (Twitter) in terms of topic awareness and attitudes. Methods We used topic modeling and sentiment analysis techniques on Lynch syndrome–related tweets to answer the following research questions (RQs): (1) what are the most discussed topics in Lynch syndrome–related tweets?; (2) how promotional Lynch syndrome–related information on Twitter affects laypeople’s discussions?; and (3) what impact do the Lynch syndrome awareness activities in the Colon Cancer Awareness Month and Lynch Syndrome Awareness Day have on laypeople’s discussions and their attitudes? In particular, we used a set of keywords to collect Lynch syndrome–related tweets from October 26, 2016 to August 11, 2017 (289 days) through the Twitter public search application programming interface (API). We experimented with two different classification methods to categorize tweets into the following three classes: (1) irrelevant, (2) promotional health information, and (3) laypeople’s discussions. We applied a topic modeling method to discover the themes in these Lynch syndrome–related tweets and conducted sentiment analysis on each layperson’s tweet to gauge the writer’s attitude (ie, positive, negative, and neutral) toward Lynch syndrome. The topic modeling and sentiment analysis results were elaborated to answer the three RQs. Results Of all tweets (N=16,667), 87.38% (14,564/16,667) were related to Lynch syndrome. Of the Lynch syndrome–related tweets, 81

  1. Biallelic MLH1 SNP cDNA expression or constitutional promoter methylation can hide genomic rearrangements causing Lynch syndrome.

    Science.gov (United States)

    Morak, Monika; Koehler, Udo; Schackert, Hans Konrad; Steinke, Verena; Royer-Pokora, Brigitte; Schulmann, Karsten; Kloor, Matthias; Höchter, Wilhelm; Weingart, Josef; Keiling, Cortina; Massdorf, Trisari; Holinski-Feder, Elke

    2011-08-01

    A positive family history, germline mutations in DNA mismatch repair genes, tumours with high microsatellite instability, and loss of mismatch repair protein expression are the hallmarks of hereditary non-polyposis colorectal cancer (Lynch syndrome). However, in ~10-15% of cases of suspected Lynch syndrome, no disease-causing mechanism can be detected. Oligo array analysis was performed to search for genomic imbalances in patients with suspected mutation-negative Lynch syndrome with MLH1 deficiency in their colorectal tumours. A deletion in the LRRFIP2 (leucine-rich repeat flightless-interacting protein 2) gene flanking the MLH1 gene was detected, which turned out to be a paracentric inversion on chromosome 3p22.2 creating two new stable fusion transcripts between MLH1 and LRRFIP2. A single-nucleotide polymorphism in MLH1 exon 8 was expressed from both alleles, initially pointing to appropriate MLH1 function at least in peripheral cells. In a second case, an inherited duplication of the MLH1 gene region resulted in constitutional MLH1 promoter methylation. Constitutional MLH1 promoter methylation may therefore in rare cases be a heritable disease mechanism and should not be overlooked in seemingly sporadic patients.

  2. Contribution of Large Genomic Rearrangements in Italian Lynch Syndrome Patients: Characterization of a Novel Alu-Mediated Deletion

    Directory of Open Access Journals (Sweden)

    Francesca Duraturo

    2013-01-01

    Full Text Available Lynch syndrome is associated with germ-line mutations in the DNA mismatch repair (MMR genes, mainly MLH1 and MSH2. Most of the mutations reported in these genes to date are point mutations, small deletions, and insertions. Large genomic rearrangements in the MMR genes predisposing to Lynch syndrome also occur, but the frequency varies depending on the population studied on average from 5 to 20%. The aim of this study was to examine the contribution of large rearrangements in the MLH1 and MSH2 genes in a well-characterised series of 63 unrelated Southern Italian Lynch syndrome patients who were negative for pathogenic point mutations in the MLH1, MSH2, and MSH6 genes. We identified a large novel deletion in the MSH2 gene, including exon 6 in one of the patients analysed (1.6% frequency. This deletion was confirmed and localised by long-range PCR. The breakpoints of this rearrangement were characterised by sequencing. Further analysis of the breakpoints revealed that this rearrangement was a product of Alu-mediated recombination. Our findings identified a novel Alu-mediated rearrangement within MSH2 gene and showed that large deletions or duplications in MLH1 and MSH2 genes are low-frequency mutational events in Southern Italian patients with an inherited predisposition to colon cancer.

  3. Prospective Study of Combined Colon and Endometrial Cancer Screening in Women With Lynch Syndrome: A Patient-Centered Approach

    Science.gov (United States)

    Huang, Marilyn; Sun, Charlotte; Boyd-Rogers, Stephanie; Burzawa, Jennifer; Milbourne, Andrea; Keeler, Elizabeth; Yzquierdo, Rebecca; Lynch, Patrick; Peterson, Susan K.; Lu, Karen

    2011-01-01

    Background: Endometrial and colorectal cancers are the most common cancers in Lynch syndrome. Consensus guidelines recommend annual endometrial biopsy (EMB) and regular colonoscopies. We assessed the feasibility of concurrently performing EMB and colonoscopy and evaluated women's perception of pain, satisfaction, and acceptability. Methods: From July 2002 to December 2009, women who had a gene mutation for Lynch syndrome, met the Amsterdam II criteria, or had a high-risk situation that required screening were prospectively enrolled. After conscious sedation, the procedures were sequentially performed. Patients completed pre- and postprocedure questionnaires assessing pain, level of satisfaction, and acceptability. The Wilcoxon rank test and Mann-Whitney test were used to compare pain scores. Results: Forty-two women completed the study. Median age was 37 years (range, 25 to 73). Nineteen had previously had an EMB in the office setting. Women reported significantly lower median levels of pain in the combined procedure compared with previous office setting biopsies (P Lynch syndrome screening recommendations. PMID:21532810

  4. Interval colon cancer in a Lynch syndrome patient under annual colonoscopic surveillance: a case for advanced imaging techniques?

    Directory of Open Access Journals (Sweden)

    Oxentenko Amy S

    2012-05-01

    Full Text Available Abstract Background Lynch syndrome confers increased risk for various malignancies, including colorectal cancer. Colonoscopic surveillance programs have led to reduced incidence of colorectal cancer and reduced mortality from colorectal cancer. Colonoscopy every 1–2 years beginning at age 20–25, or 10 years earlier than the first diagnosis of colorectal cancer in a family, with annual colonoscopy after age 40, is the recommended management for mutation carriers. Screening programs have reduced colon cancer mortality, but interval cancers may occur. Case presentation We describe a 48-year-old woman with Lynch syndrome who was found to have an adenoma with invasive colorectal cancer within one year after a normal colonoscopy. Conclusion Our patient illustrates two current concepts about Lynch syndrome: 1 adenomas are the cancer precursor and 2 such adenomas may be “aggressive,” in the sense that the adenoma progresses more readily and more rapidly to carcinoma in this setting compared to usual colorectal adenomas. Our patient’s resected tumor invaded only into submucosa and all lymph nodes were negative; in that sense, she represents a success for annual colonoscopic surveillance. Still, this case does raise the question of whether advanced imaging techniques are advisable for surveillance colonoscopy in these high-risk patients.

  5. Lynch syndrome-associated endometrial carcinoma with MLH1 germline mutation and MLH1 promoter hypermethylation: a case report and literature review.

    Science.gov (United States)

    Yokoyama, Takanori; Takehara, Kazuhiro; Sugimoto, Nao; Kaneko, Keika; Fujimoto, Etsuko; Okazawa-Sakai, Mika; Okame, Shinichi; Shiroyama, Yuko; Yokoyama, Takashi; Teramoto, Norihiro; Ohsumi, Shozo; Saito, Shinya; Imai, Kazuho; Sugano, Kokichi

    2018-05-21

    Lynch syndrome is an autosomal dominant inherited disease caused by germline mutations in mismatch repair genes. Analysis for microsatellite instability (MSI) and immunohistochemistry (IHC) of protein expressions of disease-associated genes is used to screen for Lynch syndrome in endometrial cancer patients. When losses of both MLH1 and PMS2 proteins are observed by IHC, MLH1 promoter methylation analysis is conducted to distinguish Lynch syndrome-associated endometrial cancer from sporadic cancer. Here we report a woman who developed endometrial cancer at the age of 49 years. She had a family history of colorectal cancer (first-degree relative aged 52 years) and stomach cancer (second-degree relative with the age of onset unknown). No other family history was present, and she failed to meet the Amsterdam II criteria for the diagnosis of Lynch syndrome. Losses of MLH1 and PMS2, but not MSH2 and MSH6, proteins were observed by IHC in endometrial cancer tissues. Because MLH1 promoter hypermethylation was detected in endometrial cancer tissue samples, the epigenetic silencing of MLH1 was suspected as the cause of the protein loss. However, because of the early onset of endometrial cancer and the positive family history, a diagnosis of Lynch syndrome was also suspected. Therefore, we provided her with genetic counseling. After obtaining her consent, MLH1 promoter methylation testing and genetic testing of peripheral blood were performed. MLH1 promoter methylation was not observed in peripheral blood. However, genetic testing revealed a large deletion of exon 5 in MLH1; thus, we diagnosed the presence of Lynch syndrome. Both MLH1 germline mutation and MLH1 promoter hypermethylation may be observed in endometrial cancer. Therefore, even if MLH1 promoter hypermethylation is detected, a diagnosis of Lynch syndrome cannot be excluded.

  6. Initiation of universal tumor screening for Lynch syndrome in colorectal cancer patients as a model for the implementation of genetic information into clinical oncology practice.

    Science.gov (United States)

    Cohen, Stacey A; Laurino, Mercy; Bowen, Deborah J; Upton, Melissa P; Pritchard, Colin; Hisama, Fuki; Jarvik, Gail; Fichera, Alessandro; Sjoding, Britta; Bennett, Robin L; Naylor, Lorraine; Jacobson, Angela; Burke, Wylie; Grady, William M

    2016-02-01

    Lynch syndrome confers a hereditary predisposition to colorectal and other cancers. Universal tumor screening (UTS) for Lynch syndrome is recommended by several professional societies, but the implementation can be complex. This article describes the evaluation, process development, and initiation of Lynch syndrome UTS at a tertiary referral cancer center. A multidisciplinary team developed the new process design. Issues in 5 themes were noted: timing, funding, second-opinion patients, result processing, and the role of genetics providers. A committee approach was used to examine each issue for process-improvement development. The issues related to testing were addressed individually for the successful implementation of UTS at the institutional level. In the conventional-care period, 9 of 30 cases (30%) received Lynch syndrome screening, and 4 cases were referred to medical genetics. During the 6 months following the implementation of UTS, 32 of 44 patients (73%) received Lynch syndrome screening. The 13 unscreened patients all had identified reasons for nonscreening (eg, financial limitations). Ten patients were referred to medical genetics, which identified no new cases of Lynch syndrome, but a low-risk adenomatous polyposis coli (APC) variant was detected in 1 individual. The implementation of effective Lynch syndrome UTS can feasibly alter practice at the institutional level. This experience with the assessment and management of issues relevant to the successful implementation of a new clinical care paradigm based on emerging technology has implications for the uptake of advances across molecular oncology into clinical practice, and this is highly relevant in the current era of rapidly evolving genomic technology. © 2015 American Cancer Society.

  7. Efficient molecular screening of Lynch syndrome by specific 3' promoter methylation of the MLH1 or BRAF mutation in colorectal cancer with high-frequency microsatellite instability.

    Science.gov (United States)

    Nakagawa, Hitoshi; Nagasaka, Takeshi; Cullings, Harry M; Notohara, Kenji; Hoshijima, Naoko; Young, Joanne; Lynch, Henry T; Tanaka, Noriaki; Matsubara, Nagahide

    2009-06-01

    It is sometimes difficult to diagnose Lynch syndrome by the simple but strict clinical criteria, or even by the definitive genetic testing for causative germline mutation of mismatch repair genes. Thus, some practical and efficient screening strategy to select highly possible Lynch syndrome patients is exceedingly desirable. We performed a comprehensive study to evaluate the methylation status of whole MLH1 promoter region by direct bisulfite sequencing of the entire MLH1 promoter regions on Lynch and non-Lynch colorectal cancers (CRCs). Then, we established a convenient assay to detect methylation in key CpG islands responsible for the silencing of MLH1 expression. We studied the methylation status of MLH1 as well as the CpG island methylator phenotype (CIMP) and immunohistochemical analysis of mismatch repair proteins on 16 cases of Lynch CRC and 19 cases of sporadic CRCs with high-frequency microsatellite instability (MSI-H). Sensitivity to detect Lynch syndrome by MLH1 (CCAAT) methylation was 88% and the specificity was 84%. Positive likelihood ratio (PLR) was 5.5 and negative likelihood ratio (NLR) was 0.15. Sensitivity by mutational analysis of BRAF was 100%, specificity was 84%, PLR was 6.3 and NLR was zero. By CIMP analysis; sensitivity was 88%, specificity was 79%, PLR was 4.2, and NLR was 0.16. BRAF mutation or MLH1 methylation analysis combined with MSI testing could be a good alternative to screen Lynch syndrome patients in a cost effective manner. Although the assay for CIMP status also showed acceptable sensitivity and specificity, it may not be practical because of its rather complicated assay.

  8. The Patroon Creek Contamination Migration Investigation

    International Nuclear Information System (INIS)

    Dufek, K.; Zafran, A.; Moore, J.T.

    2006-01-01

    Shaw performed a Site Investigation (SI) for sediment within the Unnamed Tributary of the Patroon Creek, a section of the Patroon Creek, and the Three Mile Reservoir as part of the overall contract with the United States Army Corps of Engineers (USACE) to remediate the Colonie Formerly Utilized Sites Remedial Action Program (FUSRAP) Site. The Unnamed Tributary formerly flowed through the former Patroon Lake, which was located on the main site property and was used as a landfill for radiological and chemical wastes. The objective of the investigation was to determine the absence/presence of radioactive contamination within the three Areas of Concern (AOC). In order to accomplish this objective, Shaw assembled a team to produce a Technical Memorandum that provided an in-depth understanding of the environmental conditions related to the Patroon Creek. Upon completion and analysis of the Technical Memorandum, a Conceptual Site Model (CSM) was constructed and a Technical Planning Program (TPP) was held to develop a Sediment Investigation Work Plan and Sediment Investigation Sampling and Analysis Plan. A total of 32 sample locations were analyzed using on-site direct gamma scans with a Pancake Geiger-Mueller (PGM) instrument for screening purposes and samples were analyzed at on-site and off-site laboratories. The highest interval from each core scan was selected for on-site analysis utilizing a High Purity Germanium (HPGe) detector. Eight of these samples were sent off-site for gamma/alpha spectroscopy confirmation. The data collected during the SI indicated that the U-238 cleanup criterion was exceeded in sediment samples collected from two locations within the Unnamed Tributary but not in downstream sections of Patroon Creek or Three Mile Reservoir. Future actions for impacted sediment in the Unnamed Tributary will be further evaluated. Concentrations of U-238 and Th-232 in all other off-site sediment samples collected from the Unnamed Tributary, Patroon Creek, and

  9. 75 FR 16728 - Beaver Creek Landscape Management Project, Ashland Ranger District, Custer National Forest...

    Science.gov (United States)

    2010-04-02

    ... DEPARTMENT OF AGRICULTURE Forest Service Beaver Creek Landscape Management Project, Ashland Ranger... manner that increases resiliency of the Beaver Creek Landscape Management Project area ecosystem to... requirements to require. The Beaver Creek Landscape Management Project includes treatments previously proposed...

  10. The natural channel of Brandywine Creek, Pennsylvania

    Science.gov (United States)

    Wolman, M.G.

    1955-01-01

    This study of the channel of Brandy wine Creek, Pennsylvania, consists of three parts. The first is an analysis of the changes which take place in the width, depth, velocity, slope of the water surface, suspended load, and roughness factor with changing discharge below the bankfull stage at each of several widely separated cross sections of the channel. Expressed as functions of the discharge, it is found that the variables behave systematically. In every section studied, as the discharge increases, the velocity increases to about the 0.6 power, depth to the 0.4, and load to the 2.0 power of the discharge. The roughness decreases to the 0.2 power of the discharge. The relative magnitudes and the direction of these variations are similar to those which have been observed in other rivers in the United States, primarily in the West. Some modifications of the hypotheses applicable to the western rivers are probably required because on Brandywine Creek the difference between the materials on the bed and in the banks is considerably greater than it is on most of the western rivers studied. In the second part of the paper the progressive changes of the same variables in the downstream direction with increasing discharge at a given frequency are described. Despite the disorderly appearance of the stream, it is found that the variables display a progressive, orderly change in the downstream direction when traced from the headwater tributaries through the trunk stream of Brandywine Creek. At a given frequency of flow, width increases with discharge to about the 0.5 power. Depth increases downstream somewhat less rapidly, while the slope and roughness both decrease in the downstream direction. Despite a decrease in the size of the material on the bed, both the mean velocity and the mean bed velocity increase downstream. The rates of change of these variables are in close accord with the changes observed on rivers flowing in alluvium and in stable irrigation canals. These

  11. Subsurface geology of the Cold Creek syncline

    International Nuclear Information System (INIS)

    Meyers, C.W.; Price, S.M.

    1981-07-01

    Bedrock beneath the Hanford Site is being evaluated by the Basalt Waste Isolation Project (BWIP) for possible use by the US Department of Energy as a geologic repository for nuclear waste storage. Initial BWIP geologic and hydrologic studies served to determine that the central Hanford Site contains basalt flows with thick, dense interiors that have low porosities and permeabilities. Furthermore, within the Cold Creek syncline, these flows appear to be nearly flat lying across areas in excess of tens of square kilometers. Such flows have been identified as potential repository host rock candidates. The Umtanum flow, which lies from 900 to 1150 m beneath the surface, is currently considered the leading host rock candidate. Within the west-central Cold Creek syncline, a 47-km 2 area designated as the reference repository location (RRL) is currently considered the leading candidate site. The specific purpose of this report is to present current knowledge of stratigraphic, lithologic, and structural factors that directly relate to the suitability of the Umtanum flow within the Cold Creek syncline for use as a nuclear waste repository host rock. The BWIP geologic studies have concentrated on factors that might influence groundwater transport of radionuclides from this flow. These factors include: (1) intraflow structures within the interiors of individual lava flows, (2) interflow zones and flow fronts between adjacent lava flows, and (3) bedrock structures. Data have been obtained primarily through coring and geophysical logging of deep boreholes, petrographic, paleomagnetic, and chemical analysis, seismic-reflection, gravity, and magnetic (ground and multilevel airborne) surveys, and surface mapping. Results included in this document comprise baseline data which will be utilized to prepare a Site Characterization Report as specified by the US Nuclear Regulatory Commission

  12. Bear Creek Project. Final environmental statement

    International Nuclear Information System (INIS)

    1977-06-01

    The Bear Creek Project consists of certain mining and milling operations involving uranium ore deposits located in Converse County, Wyoming. Mining of uranium from nine known ore bodies will take place over a period of ten years (estimated); a mill with a nominal capacity of 1000 tons per day of ore will be constructed and operated as long as ore is available. The waste material (tailings) from the mill, also produced at a rate of about 1000 tons per day, will be stored onsite in an impoundment. Environmental impacts and adverse effects are summarized

  13. 75 FR 8036 - Monitor-Hot Creek Rangeland Project

    Science.gov (United States)

    2010-02-23

    ... DEPARTMENT OF AGRICULTURE Forest Service Monitor-Hot Creek Rangeland Project AGENCY: Forest... Rangeland Project area. The analysis will determine if a change in management direction for livestock grazing is needed to move existing resource conditions within the Monitor-Hot Creek Rangeland Project area...

  14. 75 FR 57766 - Ryckman Creek Resources, LLC; Notice of Petition

    Science.gov (United States)

    2010-09-22

    ... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. CP10-498-000] Ryckman Creek Resources, LLC; Notice of Petition September 15, 2010. Take notice that on September 3, 2010, Ryckman Creek..., a petition for an Exemption of Temporary Acts and Operations and Request for Expedited Approval...

  15. 33 CFR 117.1001 - Cat Point Creek.

    Science.gov (United States)

    2010-07-01

    ... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Cat Point Creek. 117.1001 Section 117.1001 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS Specific Requirements Virginia § 117.1001 Cat Point Creek. The draw of the...

  16. 33 CFR 117.800 - Mill Neck Creek.

    Science.gov (United States)

    2010-07-01

    ... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Mill Neck Creek. 117.800 Section 117.800 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS Specific Requirements New York § 117.800 Mill Neck Creek. The draw of the...

  17. 33 CFR 117.705 - Beaver Dam Creek.

    Science.gov (United States)

    2010-07-01

    ... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Beaver Dam Creek. 117.705 Section 117.705 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY BRIDGES DRAWBRIDGE OPERATION REGULATIONS Specific Requirements New Jersey § 117.705 Beaver Dam Creek. The draw of the...

  18. Hydrology of Bishop Creek, California: An Isotopic Analysis

    Science.gov (United States)

    Michael L. Space; John W. Hess; Stanley D. Smith

    1989-01-01

    Five power generation plants along an eleven kilometer stretch divert Bishop Creek water for hydro-electric power. Stream diversion may be adversely affecting the riparian vegetation. Stable isotopic analysis is employed to determine surface water/ground-water interactions along the creek. surface water originates primarily from three headwater lakes. Discharge into...

  19. 78 FR 76750 - Drawbridge Operation Regulation; Chambers Creek, Steilacoom, WA

    Science.gov (United States)

    2013-12-19

    ... operating schedule that governs the Burlington Northern Santa Fe (BNSF) Chambers Creek Railway Bridge across... performing lift bridge maintenance and upgrades for the BNSF Chambers Creek Railway Bridge across Chambers... maintenance and upgrade items to this vertical lift bridge in support of Positive Train Control requirements...

  20. Causes of Cancer Death Among First-Degree Relatives in Japanese Families with Lynch Syndrome.

    Science.gov (United States)

    Tanakaya, Kohji; Yamaguchi, Tatsuro; Ishikawa, Hideki; Hinoi, Takao; Furukawa, Yoichi; Hirata, Keiji; Saida, Yoshihisa; Shimokawa, Mototsugu; Arai, Masami; Matsubara, Nagahide; Tomita, Naohiro; Tamura, Kazuo; Sugano, Kokichi; Ishioka, Chikashi; Yoshida, Teruhiko; Ishida, Hideyuki; Watanabe, Toshiaki; Sugihara, Kenichi

    2016-04-01

    To elucidate the causes of cancer death in Japanese families with Lynch syndrome (LS). The distributions of cancer deaths in 485 individuals from 67 families with LS (35, 30, and two families with MutL homologue 1 (MLH1), MSH2, and MSH6 gene mutations, respectively), obtained from the Registry of the Japanese Society for Cancer of the Colon and Rectum were analyzed. Among 98 cancer deaths of first-degree relatives of unknown mutation status, 53%, 19%, 13% (among females), 7% (among females) and 5% were due to colorectal, gastric, uterine, ovarian, and hepatobiliary cancer, respectively. The proportion of deaths from extra-colonic cancer was significantly higher in families with MSH2 mutation than in those with MLH1 mutation (p=0.003). In addition to colonic and uterine cancer, management and surveillance targeting gastric, ovarian and hepatobiliary cancer are considered important for Japanese families with LS. Extra-colonic cancer in families with MSH2 mutation might require for more intensive surveillance. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  1. Novel Mutations in MLH1 and MSH2 Genes in Mexican Patients with Lynch Syndrome

    Directory of Open Access Journals (Sweden)

    Jose Miguel Moreno-Ortiz

    2016-01-01

    Full Text Available Background. Lynch Syndrome (LS is characterized by germline mutations in the DNA mismatch repair (MMR genes MLH1, MSH2, MSH6, and PMS2. This syndrome is inherited in an autosomal dominant pattern and is characterized by early onset colorectal cancer (CRC and extracolonic tumors. The aim of this study was to identify mutations in MMR genes in three Mexican patients with LS. Methods. Immunohistochemical analysis was performed as a prescreening method to identify absent protein expression. PCR, Denaturing High Performance Liquid Chromatography (dHPLC, and Sanger sequencing complemented the analysis. Results. Two samples showed the absence of nuclear staining for MLH1 and one sample showed loss of nuclear staining for MSH2. The mutations found in MLH1 gene were c.2103+1G>C in intron 18 and compound heterozygous mutants c.1852_1854delAAG (p.K618del and c.1852_1853delinsGC (p.K618A in exon 16. In the MSH2 gene, we identified mutation c.638dupT (p.L213fs in exon 3. Conclusions. This is the first report of mutations in MMR genes in Mexican patients with LS and these appear to be novel.

  2. Uncertainties in the Management of a Lynch Syndrome Patient: A Case Report

    Science.gov (United States)

    Campos, Sara; Amaro, Pedro; Cunha, Inês; Fraga, João; Cipriano, Maria Augusta; Tomé, Luís

    2017-01-01

    Introduction Lynch syndrome (LS), the most common hereditary colorectal cancer syndrome, is characterized by mutations in mismatch repair (MMR) genes leading to an increased cancer risk, namely colorectal cancer. Case In the context of surveillance colonoscopy, a 40-mm flat lesion (0-IIa+b, Paris classification) was identified and submitted to piecemeal mucosal endoscopic resection in a 64-year-old LS patient with an MLH1 germline mutation (262delATC) and two previous segmental resections due to metachronous colorectal cancer. Pathology raised the suspicion of superficial submucosal invasive carcinoma with poor differentiation. Immunochemistry showed heterogeneous MLH1 expression and PMS2 loss. In a short-term follow-up colonoscopy, another 30-mm advanced carcinoma was identified. The patient was referred to surgery. Conclusion This case raises several issues: (1) the potentially fast tumorigenesis and progression to carcinoma in LS and implications for endoscopic screening and surveillance; (2) pitfalls in the interpretation of MMR proteins immunochemistry; (3) the role of endoscopic resection in LS. PMID:29255760

  3. Molecular profile of the Lynch Syndrome in the Republic of Macedonia

    Directory of Open Access Journals (Sweden)

    Marija Hiljadnikova-Bajro

    2012-12-01

    Full Text Available The most frequent type of hereditary colorectal cancer, the one occurring in the setting of the Lynch syndrome (LS is considered a phenotypic manifestation of a germline defect in the mismatch repair mechanism i.e. in the MLH1, MSH2, MSH6 or PMS2 gene. Aiming towards establishment of a standardized protocol involving molecular analyses for diagnosis of this syndrome and developing a unique national register of families with hereditary colorectal cancer syndromes in the Republic of Macedonia, we began a prospective study to reveal the genetic defects among Macedonian patients with colorectal cancer (CRC and identifying families with hereditary CRC. A total of 53 patients fulfilling the revised Bethesda criteria for MSI-genetic testing were compared to 350 patients with sporadic CRC. The results reveal significant differences in age at diagnosis (p=0.03, involvement of microsatellite instability (pG nonsense mutation with a possible founder effect in the Macedonian population, the MLH1 ex.3-12 deletion, as well as the c.244A>G mutation, IVS14- 19A>G and IVS4+65A>C changes in MLH1 without confirmed pathological significance. The observed high frequency (87.5% of the Ile219Val (c.655A>G variant in MLH1 among the LS suspects prompts further analyses to evaluate its involvement in the development of hereditary CRC by itself or as a risk modifying factor among the patients from the Republic of Macedonia.

  4. Uncertainties in the Management of a Lynch Syndrome Patient: A Case Report

    Directory of Open Access Journals (Sweden)

    Sara Campos

    2017-03-01

    Full Text Available Introduction: Lynch syndrome (LS, the most common hereditary colorectal cancer syndrome, is characterized by mutations in mismatch repair (MMR genes leading to an increased cancer risk, namely colorectal cancer. Case: In the context of surveillance colonoscopy, a 40-mm flat lesion (0-IIa+b, Paris classification was identified and submitted to piecemeal mucosal endoscopic resection in a 64-year-old LS patient with an MLH1 germline mutation (262delATC and two previous segmental resections due to metachronous colorectal cancer. Pathology raised the suspicion of superficial submucosal invasive carcinoma with poor differentiation. Immunochemistry showed heterogeneous MLH1 expression and PMS2 loss. In a short-term follow-up colonoscopy, another 30-mm advanced carcinoma was identified. The patient was referred to surgery. Conclusion: This case raises several issues: (1 the potentially fast tumorigenesis and progression to carcinoma in LS and implications for endoscopic screening and surveillance; (2 pitfalls in the interpretation of MMR proteins immunochemistry; (3 the role of endoscopic resection in LS.

  5. The changing landscape of Lynch syndrome due to PMS2 mutations.

    Science.gov (United States)

    Blount, J; Prakash, A

    2018-07-01

    DNA repair pathways are essential for cellular survival as our DNA is constantly under assault from both exogenous and endogenous DNA damaging agents. Five major mammalian DNA repair pathways exist within a cell to maintain genomic integrity. Of these, the DNA mismatch repair (MMR) pathway is highly conserved among species and is well documented in bacteria. In humans, the importance of MMR is underscored by the discovery that a single mutation in any 1 of 4 genes within the MMR pathway (MLH1, MSH2, MSH6 and PMS2) results in Lynch syndrome (LS). LS is a autosomal dominant condition that predisposes individuals to a higher incidence of many malignancies including colorectal, endometrial, ovarian, and gastric cancers. In this review, we discuss the role of PMS2 in the MMR pathway, the evolving testing criteria used to identify variants in the PMS2 gene, the LS phenotype as well as the autosomal recessive condition called constitutional mismatch repair deficiency syndrome, and current methods used to elucidate the clinical impact of PMS2 mutations. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. High incidence of large deletions in the PMS2 gene in Spanish Lynch syndrome families.

    Science.gov (United States)

    Brea-Fernández, A J; Cameselle-Teijeiro, J M; Alenda, C; Fernández-Rozadilla, C; Cubiella, J; Clofent, J; Reñé, J M; Anido, U; Milá, M; Balaguer, F; Castells, A; Castellvi-Bel, S; Jover, R; Carracedo, A; Ruiz-Ponte, C

    2014-06-01

    Lynch syndrome (LS) is caused by germline mutations in one of the four mismatch repair (MMR) genes. Defects in this pathway lead to microsatellite instability (MSI) in DNA tumors, which constitutes the molecular hallmark of this disease. Selection of patients for genetic testing in LS is usually based on fulfillment of diagnostic clinical criteria (i.e. Amsterdam criteria or the revised Bethesda guidelines). However, following these criteria PMS2 mutations have probably been underestimated as their penetrances appear to be lower than those of the other MMR genes. The use of universal MMR study-based strategies, using MSI testing and immunohistochemical (IHC) staining, is being one proposed alternative. Besides, germline mutation detection in PMS2 is complicated by the presence of highly homologous pseudogenes. Nevertheless, specific amplification of PMS2 by long-range polymerase chain reaction (PCR) and the improvement of the analysis of large deletions/duplications by multiplex ligation-dependent probe amplification (MLPA) overcome this difficulty. By using both approaches, we analyzed 19 PMS2-suspected carriers who have been selected by clinical or universal strategies and found five large deletions and one frameshift mutation in PMS2 in six patients (31%). Owing to the high incidence of large deletions found in our cohort, we recommend MLPA analysis as the first-line method for searching germline mutations in PMS2. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Constitutional mismatch repair deficiency and Lynch syndrome among consecutive Arab Bedouins with colorectal cancer in Israel.

    Science.gov (United States)

    Abu Freha, Naim; Leibovici Weissman, Yaara; Fich, Alexander; Barnes Kedar, Inbal; Halpern, Marisa; Sztarkier, Ignacio; Behar, Doron M; Arbib Sneh, Orly; Vilkin, Alex; Baris, Hagit N; Gingold, Rachel; Lejbkowicz, Flavio; Niv, Yaron; Goldberg, Yael; Levi, Zohar

    2018-01-01

    We assessed the molecular characteristics and the frequency of mutations in mismatch-repair genes among Bedouin patients with colorectal cancer (CRC) in Israel. Bedouin patients with a diagnosis of CRC at a major hospital in the southern part of Israel were deemed eligible for this study. The primary screening method was immunohistochemical staining for mismatch-repair proteins (MLH1, MSH2, MSH6, and PMS2). For subjects with abnormal immunohistochemical staining, we performed microsatellite instability (MSI) analyses, and for tumors with a loss of MLH1 expression we also performed BRAF testing. In MSI high cases we searched further for germline mutations. Of the 24 patients enrolled, four subjects (16.7%) had MSI high tumors: one subject was found to harbor a biallelic PMS2 mutation, one subject had Lynch syndrome (LS) with MSH6 mutation and two subjects had a loss of MLH1/PMS2 proteins/BRAF wild type /normal MLH1 sequence. Ten patients (41.7%) were younger than 50 at the time of diagnosis and none had first degree relatives with CRC. In conclusion, in this cohort of 24 consecutive Arab Bedouins with CRC, one patient was found to harbor a constitutional mismatch repair deficiency, one patient had LS with MSH6 mutation, and two patients had unresolved loss of MLH1/PMS2 proteins/BRAF wild type phenotype.

  8. Patients with colorectal cancer associated with Lynch syndrome and MLH1 promoter hypermethylation have similar prognoses.

    Science.gov (United States)

    Haraldsdottir, Sigurdis; Hampel, Heather; Wu, Christina; Weng, Daniel Y; Shields, Peter G; Frankel, Wendy L; Pan, Xueliang; de la Chapelle, Albert; Goldberg, Richard M; Bekaii-Saab, Tanios

    2016-09-01

    Mismatch repair-deficient (dMMR) colorectal cancer (CRC) is caused by Lynch syndrome (LS) in 3% and sporadic inactivation of MLH1 by hypermethylation (MLH1-hm) in 12% of cases. It is not clear whether outcomes between LS-associated and MLH1-hm CRC differ. The objective of this study was to explore differences in clinical factors and outcomes in these two groups. Patients with dMMR CRC identified by immunohistochemistry staining and treated at a single institution from 1998 to 2012 were included. MLH1-hm was established with BRAF mutational analysis or hypermethylation testing. Patients' charts were accessed for information on pathology, germ-line MMR mutation testing, and clinical course. A total of 143 patients had CRC associated with LS (37 patients, 26%) or MLH1-hm (106 patients, 74%). Patients with LS were younger, more often male, presented more often with stage III disease, and had more metachronous disease than patients with MLH1-hm tumors. There was no difference in cancer-specific survival (CSS) between the groups; overall survival was longer in patients with LS, but this difference was minimal after adjusting for age and stage at diagnosis. CSS did not differ in LS-associated CRC compared with MLH1-hm CRC, suggesting that they carry a similar prognosis.Genet Med 18 9, 863-868.

  9. Constitutional MLH1 methylation presenting with colonic polyposis syndrome and not Lynch syndrome.

    Science.gov (United States)

    Kidambi, Trilokesh D; Blanco, Amie; Van Ziffle, Jessica; Terdiman, Jonathan P

    2016-04-01

    At least one-third of patients meeting clinical criteria for Lynch syndrome will have no germline mutation and constitutional epimutations leading to promoter methylation of MLH1 have been identified in a subset of these patients. We report the first case of constitutional MLH1 promoter methylation associated with a colonic polyposis syndrome in a 39 year-old man with a family history of colorectal cancer (CRC) and a personal history of 21 polyps identified over 8 years as well as the development of two synchronous CRCs over 16 months who was evaluated for a hereditary cancer syndrome. Immunohistochemistry (IHC) of multiple tumors showed absent MLH1 and PMS2 expression, though germline testing with Sanger sequencing and multiplex ligation-dependent probe amplification of these mismatch repair genes (MMR) genes was negative. A next generation sequencing panel of 29 genes also failed to identify a pathogenic mutation. Hypermethylation was identified in MLH1 intron 1 in tumor specimens along with buccal cells and peripheral white blood cells, confirming the diagnosis of constitutional MLH1 promoter methylation. This case highlights that constitutional MLH1 methylation should be considered in the differential diagnosis for a polyposis syndrome if IHC staining shows absent MMR gene expression.

  10. Spectrum of mismatch repair gene mutations and clinical presentation of Hispanic individuals with Lynch syndrome.

    Science.gov (United States)

    Sunga, Annette Y; Ricker, Charité; Espenschied, Carin R; Castillo, Danielle; Melas, Marilena; Herzog, Josef; Bannon, Sarah; Cruz-Correa, Marcia; Lynch, Patrick; Solomon, Ilana; Gruber, Stephen B; Weitzel, Jeffrey N

    2017-04-01

    Lynch syndrome (LS), the most common hereditary colorectal cancer syndrome, is caused by mismatch repair (MMR) gene mutations. However, data about MMR mutations in Hispanics are limited. This study aims to describe the spectrum of MMR mutations in Hispanics with LS and explore ancestral origins. This case series involved an IRB-approved retrospective chart review of self-identified Hispanic patients (n = 397) seen for genetic cancer risk assessment at four collaborating academic institutions in California, Texas, and Puerto Rico who were evaluated by MMR genotyping and/or tumor analysis. A literature review was conducted for all mutations identified. Of those who underwent clinical genetic testing (n = 176), 71 had MMR gene mutations. Nine mutations were observed more than once. One third (3/9) of recurrent mutations and two additional mutations (seen only once) were previously reported in Spain, confirming the influence of Spanish ancestry on MMR mutations in Hispanic populations. The recurrent mutations identified (n = 9) included both previously reported mutations as well as unique mutations not in the literature. This is the largest report of Hispanic MMR mutations in North America; however, a larger sample and haplotype analyses are needed to better understand recurrent MMR mutations in Hispanic populations. Copyright © 2017. Published by Elsevier Inc.

  11. Recognition of Lynch Syndrome Amongst Newly Diagnosed Colorectal Cancers at St. Paul’s Hospital

    Directory of Open Access Journals (Sweden)

    Steven Pi

    2017-01-01

    Full Text Available Background. Lynch Syndrome (LS is the most common cause of inherited colorectal cancer (CRC. In British Columbia, most centres still use clinical criteria (Amsterdam II, Revised Bethesda, or the BC Cancer Agency’s criteria to determine who should undergo further first-line testing in the form of microsatellite instability or immunohistochemistry staining. Given the limitations with this strategy, LS is thought to be underrecognized. Objective. To investigate whether LS is truly underrecognized when compared to the reported prevalence. Methods. A retrospective chart review of all CRC cases diagnosed at St. Paul’s Hospital from 2010 to 2013 was conducted. Results. 246 patients met inclusion criteria. 76% (83/109 with a family history of malignancy were unable to recall the specific malignancy or age of diagnosis. 18% (43/235 were only asked about a history of gastrointestinal related malignancy and 26% (65/246 met at least one of the three criteria but only 21% (13/63 received further investigation. Only 1.6% (4/246 had LS compared to the reported prevalence of 2–5% of all CRC cases. Conclusion. This data supports our hypothesis that LS is underrecognized. Issues at the patient, physician, and systems level need to be evaluated to determine where the limitations preventing appropriate testing are occurring.

  12. Prevalence of Lynch syndrome among patients with newly diagnosed endometrial cancers.

    Directory of Open Access Journals (Sweden)

    Cecilia Egoavil

    Full Text Available Lynch syndrome (LS is a hereditary condition that increases the risk for endometrial and other cancers. The identification of endometrial cancer (EC patients with LS has the potential to influence life-saving interventions. We aimed to study the prevalence of LS among EC patients in our population.Universal screening for LS was applied for a consecutive series EC. Tumor testing using microsatellite instability (MSI, immunohistochemistry (IHC for mismatch-repair (MMR protein expression and MLH1-methylation analysis, when required, was used to select LS-suspicious cases. Sequencing of corresponding MMR genes was performed.One hundred and seventy-three EC (average age, 63 years were screened. Sixty-one patients (35% had abnormal IHC or MSI results. After MLH1 methylation analysis, 27 cases were considered suspicious of LS. From these, 22 were contacted and referred for genetic counseling. Nineteen pursued genetic testing and eight were diagnosed of LS. Mutations were more frequent in younger patients (<50 yrs. Three cases had either intact IHC or MSS and reinforce the need of implement the EC screening with both techniques.The prevalence of LS among EC patients was 4.6% (8/173; with a predictive frequency of 6.6% in the Spanish population. Universal screening of EC for LS is recommended.

  13. Novel germline MSH2 mutation in lynch syndrome patient surviving multiple cancers

    Directory of Open Access Journals (Sweden)

    Janavicius Ramunas

    2012-01-01

    Full Text Available Abstract Lynch syndrome (LS individuals are predisposed to a variety of cancers, most commonly colorectal, uterine, urinary tract, ovarian, small bowel, stomach and biliary tract cancers. The risk of extracolonic manifestations appears to be highest in MSH2 mutations carriers. We present a carrier case with a novel MSH2 gene mutation that clearly demonstrates the broad extent of LS phenotypic expression and highlights several important clinical aspects. Current evidence suggests that colorectal tumors from LS patients tend to have better prognoses than their sporadic counterparts, however survival benefits for other cancers encountered in LS are unclear. In this article we describe a family with a novel protein truncating mutation of c.2388delT in the MSH2 gene, particularly focusing on one individual carrier affected with multiple primary cancers who is surviving 25 years on. Our report of multiple primary tumors occurring in the 12-25 years interval might suggest these patients do not succumb to other extracolonic cancers, provided they are regularly followed-up.

  14. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications

    Science.gov (United States)

    Lynch, HT; Lynch, PM; Lanspa, SJ; Snyder, CL; Lynch, JF; Boland, CR

    2010-01-01

    More than one million patients will manifest colorectal cancer (CRC) this year of which, conservatively, approximately 3% (~30,700 cases) will have Lynch syndrome (LS), the most common hereditary CRC predisposing syndrome. Each case belongs to a family with clinical needs that require genetic counseling, DNA testing for mismatch repair genes (most frequently MLH1 or MSH2) and screening for CRC. Colonoscopy is mandated, given CRC’s proximal occurrence (70–80% proximal to the splenic flexure). Due to its early age of onset (average 45 years of age), colonoscopy needs to start by age 25, and because of its accelerated carcinogenesis, it should be repeated every 1 to 2 years through age 40 and then annually thereafter. Should CRC occur, subtotal colectomy may be necessary, given the marked frequency of synchronous and metachronous CRC. Because 40–60% of female patients will manifest endometrial cancer, tailored management is essential. Additional extracolonic cancers include ovary, stomach, small bowel, pancreas, hepatobiliary tract, upper uroepithelial tract, brain (Turcot variant) and sebaceous adenomas/carcinomas (Muir-Torre variant). LS explains only 10–25% of familial CRC. PMID:19659756

  15. Suspected Lynch syndrome associated MSH6 variants: A functional assay to determine their pathogenicity.

    Directory of Open Access Journals (Sweden)

    Hellen Houlleberghs

    2017-05-01

    Full Text Available Lynch syndrome (LS is a hereditary cancer predisposition caused by inactivating mutations in DNA mismatch repair (MMR genes. Mutations in the MSH6 DNA MMR gene account for approximately 18% of LS cases. Many LS-associated sequence variants are nonsense and frameshift mutations that clearly abrogate MMR activity. However, missense mutations whose functional implications are unclear are also frequently seen in suspected-LS patients. To conclusively diagnose LS and enroll patients in appropriate surveillance programs to reduce morbidity as well as mortality, the functional consequences of these variants of uncertain clinical significance (VUS must be defined. We present an oligonucleotide-directed mutagenesis screen for the identification of pathogenic MSH6 VUS. In the screen, the MSH6 variant of interest is introduced into mouse embryonic stem cells by site-directed mutagenesis. Subsequent selection for MMR-deficient cells using the DNA damaging agent 6-thioguanine (6TG allows the identification of MMR abrogating VUS because solely MMR-deficient cells survive 6TG exposure. We demonstrate the efficacy of the genetic screen, investigate the phenotype of 26 MSH6 VUS and compare our screening results to clinical data from suspected-LS patients carrying these variant alleles.

  16. Las cartas privadas de Wanda Morla Lynch: entre género discursivo y fuente documental

    Directory of Open Access Journals (Sweden)

    Carolina Miranda

    2016-11-01

    Full Text Available This essay is an approach to the private letters of Wanda Morla Lynch, a Chilean woman from the early XX century. This approach considers the epistolary genre as a complex and often contradictory genre, propitious to describe a feminine intimacy, feelings and subjectivity, due to the relationship of complicity between the letters and the historically acquired status of subordination, imposed by the patriarchal society. In this sense, this epistolary corpus will allow us establishing a characterization of these private letters as they have a formal/discursive singularity in relation to other genres that conform the corpus of autobiographic writing, as well as exploring and rescuing the value of those letters as a documentary source as they unveil the voice of a woman, who was a privileged witness of the changes that took place in Paris in the 1920’s, epicenter of the modernist avant-garde of the time. Regarding this last consideration, Wanda Morla Lynch’s letters can be also described as a “journey diary” (historically known as a particularly masculine experience, giving us the possibility of reading these letters as a secretly transgressor gesture towards the social conventions of an era.

  17. Hoe Creek 1990 quarterly sampling cumulative report

    Energy Technology Data Exchange (ETDEWEB)

    Crader, S.E.; Huntington, G.S.

    1991-03-01

    Groundwater samples were collected and analyzed for benzene and for total phenols three times during 1990. This report summarizes the results of these sampling events and compares the results with those obtained in previous years. Possible further options for remediation of the Hoe Creek site was addressed. Three underground coal gasification (UCG) burns were performed by Lawrence Livermore National Laboratory for the US Department of Energy in 1976, 1977, and 1979 at the Hoe Creek site, which is about 20 miles south of Gillette, Wyoming. As a result of these burns, there has been considerable contamination of groundwater by various organic compounds. There have been three efforts at remediating this situation. In 1986 and again in 1987, contaminated water was pumped out, treated, and reinjected. In 1989, the water was pumped, treated, and sprayed into the atmosphere. Benzene and total phenols have been monitored at various monitoring wells as the site during 1990. The highest detected benzene concentration in 1990 was 220 {mu}g/L, and the highest total phenols concentration was 430 {mu}g/L. It is apparent that contamination is still above baseline levels, although the concentration of total phenols is far less than immediately after the burns. The burned coal seams are still releasing organic compounds into the groundwater that passes through them.

  18. Considerations and management of a patient with three metachronous cancers in association with Lynch syndrome and ileal Crohn’s disease: A case report

    Directory of Open Access Journals (Sweden)

    Kaleb Lourensz

    2015-01-01

    Conclusion: The surgical treatment of patients with Lynch syndrome requires a sound knowledge of the possible neoplastic conditions that can arise in the syndrome. Early detection is paramount, either by implementation of evidence based surveillance programs or at least by a heightened clinical awareness of the features of this disease. Ideally this will result in both reduced surgical morbidity and improved oncologic outcome. Furthermore, the medical treatment of Crohn’s disease in a patient with tumors arising from Lynch syndrome must be undertaken with at least a consideration of the possibility that the use of immunosuppressive medication might increase the risk of cancer recurrence.

  19. Sources of baseflow for the Minnehaha Creek Watershed, Minnesota, US

    Science.gov (United States)

    Nieber, J. L.; Moore, T. L.; Gulliver, J. S.; Magner, J. A.; Lahti, L. B.

    2013-12-01

    Minnehaha Creek is among the most valued surface water features in the Minneapolis, MN metro area, with a waterfall as it enters the Minnehaha Creek park. Flow in Minnehaha Creek is heavily dependent on discharge from the stream's origin, Lake Minnetonka, the outlet of which is closed during drought periods to maintain water elevations in the lake resulting in low- (or no-) flow conditions in the creek. Stormwater runoff entering directly to the creek from the creek's largely urbanized watershed exacerbates extremes in flow conditions. Given the cultural and ecological value of this stream system, there is great interest in enhancing the cultural and ecosystem services provided by Minnehaha Creek through improvements in streamflow regime by reducing flashiness and sustaining increased low-flows. Determining the potential for achieving improvements in flow requires first that the current sources of water contributing to low-flows in the creek be identified and quantified. Work on this source identification has involved a number of different approaches, including analyses of the streamflow record using a hydrologic system model framework, examination of the Quaternary and bedrock geology of the region, estimation of groundwater-surface water exchange rates within the channel using hyporheic zone temperature surveys and flux meter measurements, and analyses of the stable isotopes of oxygen and hydrogen in samples of stream water, groundwater, and rainfall. Analysis of baseflow recessions using the method of Brutsaert and Nieber (1977) indicates that only a small portion of the catchment, probably the riparian zone, contributes to baseflows. This result appears to be supported by the observation that the limestone/shale bedrock layer underlying the surficial aquifer has a non-zero permeability, and in a significant portion of the watershed the layer has been eroded away leaving the surficial aquifer ';bottomless' and highly susceptible to vertical (down) water loss

  20. Contribution of MLH1 constitutional methylation for Lynch syndrome diagnosis in patients with tumor MLH1 downregulation.

    Science.gov (United States)

    Pinto, Diana; Pinto, Carla; Guerra, Joana; Pinheiro, Manuela; Santos, Rui; Vedeld, Hege Marie; Yohannes, Zeremariam; Peixoto, Ana; Santos, Catarina; Pinto, Pedro; Lopes, Paula; Lothe, Ragnhild; Lind, Guro Elisabeth; Henrique, Rui; Teixeira, Manuel R

    2018-02-01

    Constitutional epimutation of the two major mismatch repair genes, MLH1 and MSH2, has been identified as an alternative mechanism that predisposes to the development of Lynch syndrome. In the present work, we aimed to investigate the prevalence of MLH1 constitutional methylation in colorectal cancer (CRC) patients with abnormal expression of the MLH1 protein in their tumors. In a series of 38 patients who met clinical criteria for Lynch syndrome genetic testing, with loss of MLH1 expression in the tumor and with no germline mutations in the MLH1 gene (35/38) or with tumors presenting the BRAF p.Val600Glu mutation (3/38), we screened for constitutional methylation of the MLH1 gene promoter using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) in various biological samples. We found four (4/38; 10.5%) patients with constitutional methylation in the MLH1 gene promoter. RNA studies demonstrated decreased MLH1 expression in the cases with constitutional methylation when compared with controls. We could infer the mosaic nature of MLH1 constitutional hypermethylation in tissues originated from different embryonic germ layers, and in one family we could show that it occurred de novo. We conclude that constitutional MLH1 methylation occurs in a significant proportion of patients who have loss of MLH1 protein expression in their tumors and no MLH1 pathogenic germline mutation. Furthermore, we provide evidence that MLH1 constitutional hypermethylation is the molecular mechanism behind about 3% of Lynch syndrome families diagnosed in our institution, especially in patients with early onset or multiple primary tumors without significant family history. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  1. A tailored approach to BRAF and MLH1 methylation testing in a universal screening program for Lynch syndrome.

    Science.gov (United States)

    Adar, Tomer; Rodgers, Linda H; Shannon, Kristen M; Yoshida, Makoto; Ma, Tianle; Mattia, Anthony; Lauwers, Gregory Y; Iafrate, Anthony J; Chung, Daniel C

    2017-03-01

    To determine the correlation between BRAF genotype and MLH1 promoter methylation in a screening program for Lynch syndrome (LS), a universal screening program for LS was established in two medical centers. Tumors with abnormal MLH1 staining were evaluated for both BRAF V600E genotype and MLH1 promoter methylation. Tumors positive for both were considered sporadic, and genetic testing was recommended for all others. A total 1011 colorectal cancer cases were screened for Lynch syndrome, and 148 (14.6%) exhibited absent MLH1 immunostaining. Both BRAF and MLH1 methylation testing were completed in 126 cases. Concordant results (both positive or both negative) were obtained in 86 (68.3%) and 16 (12.7%) cases, respectively, with 81% concordance overall. The positive and negative predictive values for a BRAF mutation in predicting MLH1 promoter methylation were 98.9% and 41%, respectively, and the negative predictive value fell to 15% in patients ≥70 years old. Using BRAF genotyping as a sole test to evaluate cases with absent MLH1 staining would have increased referral rates for genetic testing by 2.3-fold compared with MLH1 methylation testing alone (31% vs 13.5%, respectively, PMLH1 methylation testing for BRAF wild-type cases only would significantly decrease the number of methylation assays performed and reduce the referral rate for genetic testing to 12.7%. A BRAF mutation has an excellent positive predictive value but poor negative predictive value in predicting MLH1 promoter methylation. A hybrid use of these tests may reduce the number of low-risk patients referred to genetic counseling and facilitate wider implementation of Lynch syndrome screening programs.

  2. Simulation of Water Quality in the Tull Creek and West Neck Creek Watersheds, Currituck Sound Basin, North Carolina and Virginia

    Science.gov (United States)

    Garcia, Ana Maria

    2009-01-01

    A study of the Currituck Sound was initiated in 2005 to evaluate the water chemistry of the Sound and assess the effectiveness of management strategies. As part of this study, the Soil and Water Assessment Tool (SWAT) model was used to simulate current sediment and nutrient loadings for two distinct watersheds in the Currituck Sound basin and to determine the consequences of different water-quality management scenarios. The watersheds studied were (1) Tull Creek watershed, which has extensive row-crop cultivation and artificial drainage, and (2) West Neck Creek watershed, which drains urban areas in and around Virginia Beach, Virginia. The model simulated monthly streamflows with Nash-Sutcliffe model efficiency coefficients of 0.83 and 0.76 for Tull Creek and West Neck Creek, respectively. The daily sediment concentration coefficient of determination was 0.19 for Tull Creek and 0.36 for West Neck Creek. The coefficient of determination for total nitrogen was 0.26 for both watersheds and for dissolved phosphorus was 0.4 for Tull Creek and 0.03 for West Neck Creek. The model was used to estimate current (2006-2007) sediment and nutrient yields for the two watersheds. Total suspended-solids yield was 56 percent lower in the urban watershed than in the agricultural watershed. Total nitrogen export was 45 percent lower, and total phosphorus was 43 percent lower in the urban watershed than in the agricultural watershed. A management scenario with filter strips bordering the main channels was simulated for Tull Creek. The Soil and Water Assessment Tool model estimated a total suspended-solids yield reduction of 54 percent and total nitrogen and total phosphorus reductions of 21 percent and 29 percent, respectively, for the Tull Creek watershed.

  3. A novel heterozygous germline deletion in MSH2 gene in a five generation Chinese family with Lynch syndrome

    OpenAIRE

    Wu, Bin; Ji, Wuyang; Liang, Shengran; Ling, Chao; You, Yan; Xu, Lai; Zhong, Min-Er; Xiao, Yi; Qiu, Hui-Zhong; Lu, Jun-Yang; Banerjee, Santasree

    2017-01-01

    Lynch syndrome (LS) is one of the most common familial forms of colorectal cancer predisposing syndrome with an autosomal dominant mode of inheritance. LS is caused by the germline mutations in DNA mismatch repair (MMR) genes including MSH2, MLH1, MSH6 and PMS2. Clinically, LS is characterized by high incidence of early-onset colorectal cancer as well as endometrial, small intestinal and urinary tract cancers, usually occur in the third to fourth decade of the life. Here we describe a five ge...

  4. Biochemical characterization of MLH3 missense mutations does not reveal an apparent role of MLH3 in Lynch syndrome

    DEFF Research Database (Denmark)

    Ou, Jianghua; Rasmussen, Merete; Westers, Helga

    2009-01-01

    for eight of these MLH3 UVs identified in suspected Lynch syndrome patients, we performed several biochemical tests. We determined the protein expression and stability, protein localization and interaction of the mutant MLH3 proteins with wildtype MLH1. All eight MLH3 UVs gave protein expression levels...... comparable with wildtype MLH3. Furthermore, the UV-containing proteins, in contrast to previous studies, were all localized normally in the nucleus and they interacted normally with wildtype MLH1. Our different biochemical assays yielded no evidence that the eight MLH3 UVs tested are the cause of hereditary...

  5. 75 FR 3195 - Ochoco National Forest, Lookout Mountain Ranger District; Oregon; Mill Creek; Allotment...

    Science.gov (United States)

    2010-01-20

    ...; Oregon; Mill Creek; Allotment Management Plans EIS AGENCY: Forest Service, USDA. ACTION: Notice of intent... allotments on the Lookout Mountain Ranger District. These four allotments are: Cox, Craig, Mill Creek, and..., Mill Creek and Old Dry Creek allotments. The responsible official will also decide how to mitigate...

  6. Prevalence of Lynch syndrome in a Middle Eastern population with colorectal cancer.

    Science.gov (United States)

    Siraj, Abdul K; Prabhakaran, Sarita; Bavi, Prashant; Bu, Rong; Beg, Shaham; Hazmi, Mohsen Al; Al-Rasheed, Maha; Al-Assiri, Mohammed; Sairafi, Rami; Al-Dayel, Fouad; Al-Sanea, Nasser; Uddin, Shahab; Al-Kuraya, Khawla S

    2015-06-01

    Lynch syndrome (LS; hereditary nonpolyposis colorectal cancer) is a common cause of hereditary colorectal cancer (CRC). CRC is the most common cancer diagnosed among males in Saudi Arabia but to the authors' knowledge there is a lack of data regarding the prevalence of LS in patients with CRC. There currently are no clear guidelines for the selection criteria for these patients to screen for LS. A comprehensive molecular characterization was performed in a cohort of 807 CRC cases by immunohistochemical and microsatellite analysis using polymerase chain reaction. BRAF mutation screening, high CpG island methylator phenotype, and analysis for germline mutations were performed in 425 CRC samples. These were all high microsatellite instability (MSI-H) samples (91 cases), all low MSI samples (143 cases), and selected cases from the microsatellite stable group (191 cases) that met revised Bethesda guidelines. Polymerase chain reaction identified 91 MSI-H cases (11.3%) and sequencing revealed mismatch repair germline mutations in 8 CRC cases only. Of the total of 807 CRC cases, these 8 cases (0.99%) were MSI-H, met the revised Bethesda guidelines, and did not harbor BRAF mutations. The results of the current study confirmed cases of LS in approximately 1.0% of CRC samples and reflects the efficacy of screening among MSI-H cases that lack BRAF mutations. This comprehensive study from Saudi Arabia will help in implementing a universal screening/reflex testing strategy in a clinical setting in Saudi Arabia and in conducting a national screening program that benefits both patients and their relatives. © 2015 American Cancer Society.

  7. Concomitant mutation and epimutation of the MLH1 gene in a Lynch syndrome family.

    Science.gov (United States)

    Cini, Giulia; Carnevali, Ileana; Quaia, Michele; Chiaravalli, Anna Maria; Sala, Paola; Giacomini, Elisa; Maestro, Roberta; Tibiletti, Maria Grazia; Viel, Alessandra

    2015-04-01

    Lynch syndrome (LS) is an inherited predisposition cancer syndrome, typically caused by germline mutations in the mismatch repair genes MLH1, MSH2, MSH6 and PMS2. In the last years, a role for epimutations of the same genes has also been reported. MLH1 promoter methylation is a well known mechanism of somatic inactivation in tumors, and more recently, several cases of constitutional methylation have been identified. In four subjects affected by multiple tumors and belonging to a suspected LS family, we detected a novel secondary MLH1 gene epimutation. The methylation of MLH1 promoter was always linked in cis with a 997 bp-deletion (c.-168_c.116+713del), that removed exon 1 and partially involved the promoter of the same gene. Differently from cases with constitutional primary MLH1 inactivation, this secondary methylation was allele-specific and CpGs of the residual promoter region were totally methylated, leading to complete allele silencing. In the colon tumor of the proband, MLH1 and PMS2 expression was completely lost as a consequence of a pathogenic somatic point mutation (MLH1 c.199G>A, p.Gly67Arg) that also abrogated local methylation by destroying a CpG site. The evidences obtained highlight how MLH1 mutations and epimutations can reciprocally influence each other and suggest that an altered structure of the MLH1 locus results in epigenetic alteration. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  8. Tumour MLH1 promoter region methylation testing is an effective prescreen for Lynch Syndrome (HNPCC).

    Science.gov (United States)

    Newton, K; Jorgensen, N M; Wallace, A J; Buchanan, D D; Lalloo, F; McMahon, R F T; Hill, J; Evans, D G

    2014-12-01

    Lynch syndrome (LS) patients have DNA mismatch repair deficiency and up to 80% lifetime risk of colorectal cancer (CRC). Screening of mutation carriers reduces CRC incidence and mortality. Selection for constitutional mutation testing relies on family history (Amsterdam and Bethesda Guidelines) and tumour-derived biomarkers. Initial biomarker analysis uses mismatch repair protein immunohistochemistry and microsatellite instability. Abnormalities in either identify mismatch repair deficiency but do not differentiate sporadic epigenetic defects, due to MLH1 promoter region methylation (13% of CRCs) from LS (4% of CRCs). A diagnostic biomarker capable of making this distinction would be valuable. This study compared two biomarkers in tumours with mismatch repair deficiency; quantification of methylation of the MLH1 promoter region using a novel assay and BRAF c.1799T>A, p.(Val600Glu) mutation status in the identification of constitutional mutations. Tumour DNA was extracted (formalin fixed, paraffin embedded, FFPE tissue) and pyrosequencing used to test for MLH1 promoter methylation and presence of the BRAF c.1799T>A, p.(Val600Glu) mutation 71 CRCs from individuals with pathogenic MLH1 mutations and 73 CRCs with sporadic MLH1 loss. Specificity and sensitivity was compared. Unmethylated MLH1 promoter: sensitivity 94.4% (95% CI 86.2% to 98.4%), specificity 87.7% (95% CI 77.9% to 94.2%), Wild-type BRAF (codon 600): sensitivity 65.8% (95% CI 53.7% to 76.5%), specificity 98.6% (95% CI 92.4% to 100.0%) for the identification of those with pathogenic MLH1 mutations. Quantitative MLH1 promoter region methylation using pyrosequencing is superior to BRAF codon 600 mutation status in identifying constitutional mutations in mismatch repair deficient tumours. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  9. Combined colonoscopy and endometrial biopsy cancer screening results in women with Lynch syndrome.

    Science.gov (United States)

    Nebgen, Denise R; Lu, Karen H; Rimes, Sue; Keeler, Elizabeth; Broaddus, Russell; Munsell, Mark F; Lynch, Patrick M

    2014-10-01

    Endometrial biopsy (EMBx) and colonoscopy performed under the same sedation is termed combined screening and has been shown to be feasible and to provide a less painful and more satisfactory experience for women with Lynch syndrome (LS). However, clinical results of these screening efforts have not been reported. The purpose of this study was to evaluate the long-term clinical outcomes and patient compliance with serial screenings over the last 10.5 years. We retrospectively analyzed the data for 55 women with LS who underwent combined screening every 1-2 years between 2002 and 2013. Colonoscopy and endometrial biopsy were performed by a gastroenterologist and a gynecologist, with the patient under conscious sedation. Out of 111 screening visits in these 55 patients, endometrial biopsies detected one simple hyperplasia, three complex hyperplasia, and one endometrioid adenocarcinoma (FIGO Stage 1A). Seventy-one colorectal polyps were removed in 29 patients, of which 29 were tubular adenomas. EMBx in our study detected endometrial cancer in 0.9% (1/111) of surveillance visits, and premalignant hyperplasia in 3.6% (4/111) of screening visits. No interval endometrial or colorectal cancers were detected. Combined screening under sedation is feasible and less painful than EMBx alone. Our endometrial pathology detection rates were comparable to yearly screening studies. Our results indicate that screening of asymptomatic LS women with EMBx every 1-2 years, rather than annually, is effective in the early detection of (pre)cancerous lesions, leading to their prompt definitive management, and potential reduction in endometrial cancer. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. A Systematic Review on the Existing Screening Pathways for Lynch Syndrome Identification

    Directory of Open Access Journals (Sweden)

    Alessia Tognetto

    2017-09-01

    Full Text Available BackgroundLynch syndrome (LS is the most common hereditary colon cancer syndrome, accounting for 3–5% of colorectal cancer (CRC cases, and it is associated with the development of other cancers. Early detection of individuals with LS is relevant, since they can take advantage of life-saving intensive care surveillance. The debate regarding the best screening policy, however, is far from being concluded. This prompted us to conduct a systematic review of the existing screening pathways for LS.MethodsWe performed a systematic search of MEDLINE, ISI Web of Science, and SCOPUS online databases for the existing screening pathways for LS. The eligibility criteria for inclusion in this review required that the studies evaluated a structured and permanent screening pathway for the identification of LS carriers. The effectiveness of the pathways was analyzed in terms of LS detection rate.ResultsWe identified five eligible studies. All the LS screening pathways started from CRC cases, of which three followed a universal screening approach. Concerning the laboratory procedures, the pathways used immunohistochemistry and/or microsatellite instability testing. If the responses of the tests indicated a risk for LS, the genetic counseling, performed by a geneticist or a genetic counselor, was mandatory to undergo DNA genetic testing. The overall LS detection rate ranged from 0 to 5.2%.ConclusionThis systematic review reported different existing pathways for the identification of LS patients. Although current clinical guidelines suggest to test all the CRC cases to identify LS cases, the actual implementation of pathways for LS identification has not been realized. Large-scale screening programs for LS have the potential to reduce morbidity and mortality for CRC, but coordinated efforts in educating all key stakeholders and addressing public needs are still required.

  11. The Risk of Extra-colonic, Extra-endometrial Cancer in the Lynch Syndrome

    Science.gov (United States)

    Watson, Patrice; Vasen, Hans F.A.; Mecklin, Jukka-Pekka; Bernstein, Inge; Aarnio, Markku; Järvinen, Heikki J.; Myrhøj, Torben; Sunde, Lone; Wijnen, Juul T.; Lynch, Henry T.

    2009-01-01

    Persons with the Lynch syndrome (LS) are at high risk for cancer, including cancers of the small bowel, stomach, upper urologic tract (renal pelvis and ureter), ovary, biliary tract, and brain tumors, in addition to the more commonly observed colorectal and endometrial cancers. Cancer prevention strategies for these less-common cancers require accurate, age-specific risk estimation. We pooled data from four LS research centers in a retrospective cohort study, to produce absolute incidence estimates for these cancer types, and to evaluate several potential risk modifiers. After elimination of 135 persons missing crucial information, cohort included 6041 members of 261 families with LS-associated MLH1 or MSH2 mutations. All were either mutation carriers by test, probable mutation carriers (endometrial/colorectal cancer-affected), or first-degree relatives of these. Among mutation carriers and probable carriers, urologic tract cancer (N=98) had an overall lifetime risk (to age 70) of 8.4% (95%CI: 6.6–10.8); risks were higher in males (p<0.02) and members of MSH2 families (p<0.0001). Ovarian cancer (N=72) had an lifetime risk of 6.7% (95%CI: 5.3–9.1); risks were higher in women born after the median year of birth (p<0.008) and in members of MSH2 families (p<0.006). Brain tumors and cancers of the small bowel, stomach, breast, and biliary tract were less common. Urologic tract cancer and ovarian cancer occur frequently enough in some LS subgroups to justify trials to evaluate promising prevention interventions. Other cancer types studied occur too infrequently to justify strenuous cancer control interventions. PMID:18398828

  12. A comparison between Lynch syndrome and sporadic colorectal cancer survivors' satisfaction with their healthcare providers.

    Science.gov (United States)

    Burton-Chase, Allison M; Parker, Wendy M; Polivka, Katrina M; Gritz, Ellen R; Amos, Christopher I; Lu, Karen H; Lynch, Patrick M; Rodriguez-Bigas, Miguel A; Nancy You, Y; Peterson, Susan K

    2017-03-01

    This study evaluated provider satisfaction in a sample of colorectal cancer (CRC) survivors with and without Lynch syndrome (LS). Participants were case-case-matched CRC survivors with (n = 75) or without (n = 75) LS (mean age of 55; range: 27-93). Participants completed a mailed questionnaire assessing demographics, clinical characteristics, healthcare utilization, psychosocial variables, and provider satisfaction. LS CRC survivors reported lower provider satisfaction scores on three subscales of the Primary Care Assessment Survey: communication (78.14 vs. 83.96; P < 0.05), interpersonal treatment (78.58 vs. 85.30; P < 0.05), and knowledge of the patient (60.34 vs. 69.86; P < 0.01). Among LS CRC survivors, predictors for mean communication and trust subscale scores were location of treatment and socioeconomic status. Higher mean depression scores also were associated with trust, while social support predicted higher satisfaction with communication. Sporadic CRC survivor satisfaction is driven largely by age (communication, interpersonal treatment) and patient anxiety (communication), while seeing a provider more often was associated with increased satisfaction with knowledge of the patient. LS CRC survivors reported lower levels of provider satisfaction than sporadic CRC survivors. LS survivors who received care at The University of Texas MD Anderson Cancer Center, a comprehensive cancer center (CCC), reported higher satisfaction than those receiving care at other institutions. Depressive symptoms and socioeconomic status may impact provider satisfaction ratings. Exploration of other potential predictors of provider satisfaction should be examined in this population. Additionally, further research is needed to examine the potential impact of provider satisfaction on adherence to medical recommendations in LS CRC survivors, particularly those being treated outside of CCCs. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  13. Bereavement rituals in the Muscogee Creek tribe.

    Science.gov (United States)

    Walker, Andrea C; Balk, David E

    2007-08-01

    A qualitative, collective case study explores bereavement rituals in the Muscogee Creek tribe. Data from interviews with 27 participants, all adult members of the tribe, revealed consensus on participation in certain bereavement rituals. Common rituals included: (a) conducting a wake service the night before burial; (b) never leaving the body alone before burial; (c) enclosing personal items and food in the casket; (d) digging graves by hand; (e) each individual throwing a handful of dirt into the grave before covering, called giving a "farewell handshake"; (f) covering the grave completely by hand; (g) building a house over the grave; (h) waiting 4 days before burial; (i) using medicine/purification; and (j) adhering to socialized mourning period. Cultural values of family, community, religion, importance of the number 4, Indian medicine, and the meaning of death contributed to the development of these rituals.

  14. Bear Creek Project. Draft environmental statement

    International Nuclear Information System (INIS)

    1977-01-01

    The Bear Creek Project consists of mining and milling operations involving uranium ore deposits located in Converse County, Wyoming. Mining of uranium from six known ore bodies will take place over ten years; a 1000 tons ore/day will be constructed and operated as long as ore is available. The tailings will be stored onsite in an impoundment. The project would convert 2700 acres from grazing use to mining/milling activities for about ten years. Mining would disturb a total of 1600 acres but, because of reclamation, the max acreage disturbed at any one time would be about 1000 acres, the average being about 650 acres. Dose rates were computed for an individual in a ranch house at the nearest ranch. Conditions for the protection of the environment are proposed. Possible environmental impacts evaluated cover air, land, water, soil, vegetation, wildlife, and community. A benefit-cost analysis is made

  15. Hydrogen sulfide concentration in Beaver Dam Creek

    International Nuclear Information System (INIS)

    Kiser, D.L.

    1979-01-01

    Concentration-time profiles calculated with LODIPS for various hypothetical releases of hydrogen sulfide from the heavy water extraction facility predict lethal conditions for swamp fish from releases as small as 568 kg discharged over a period of 30 minutes or from releases of 1818 kg discharged over a period of 6 hours or less. The necessary volatilization and oxidation coefficients for LODIPS were derived from field measurements following planned releases of H 2 S. Upsets in the operation of the wastewater strippers in the Girdler-Sulfide (GS) heavy water extraction facility in D Area have released significant amounts of dissolved H 2 S to Beaver Dam Creek. Because H 2 S is toxic to fish in concentrations as low as 1 mg/liter, the downstream environmental impact of H 2 S releases from D Area was evaluated

  16. Ground water in Creek County, Oklahoma

    Science.gov (United States)

    Cady, Richard Carlysle

    1937-01-01

    Creek County has been designated as a problem area by the Land Use Planning Section of the Resettlement Administration. Some of the earliest oil fields to brought into production were situated in and near this county, and new fields have been opened from time to time during the ensuing years. The production of the newer fields, however, has not kept pace with the exhaustion of the older fields, and the county now presents an excellent picture of the problems involved in adjusting a population to lands that are nearly depleted of their mineral wealth. Values of land have been greatly depressed; tax collection is far in arrears; tenancy is widespread; and in addition more people will apparently be forced to depend on the income from agriculture than the land seems capable of supporting. The county as a whole is at best indifferently suitable for general farming. The Land Use planning Section proposes to study the present and seemingly immanent maladjustments of population to the resources of the land, and make recommendations for their correction. The writer was detailed to the Land Use Planning Section of Region VIII for the purposes of making studies of ground water problems in the region. In Creek County two investigations were made. In September, 1936, the writer spent about ten days investigating the availability of ground water for the irrigation of garden crops during drouths. If it proved feasible to do this generally throughout the county, the Land Use Planning Section might be able to encourage this practice. The second investigation made by the writer was in regard to the extent to which ground water supplies have been damaged by oil well brines. He was in county for four days late in January 1937, and again in March, 1937. During part of the second field trip he was accompanied by R.M. Dixon, sanitary engineer of the Water Utilization Unit of the Resettlement Administration. (available as photostat copy only)

  17. Endoscopic detection rate of sessile serrated lesions in Lynch syndrome patients is comparable with an age- and gender-matched control population: case-control study with expert pathology review.

    Science.gov (United States)

    Vleugels, Jasper L A; Sahin, Husna; Hazewinkel, Yark; Koens, Lianne; van den Berg, Jose G; van Leerdam, Monique E; Dekker, Evelien

    2018-05-01

    Carcinogenesis in Lynch syndrome involves fast progression of adenomas to colorectal cancer (CRC) because of microsatellite instability. The role of sessile serrated lesions (SSLs) and the serrated neoplasia pathway in these patients is unknown. The aim of this matched case-control study was to compare endoscopic detection rates and distribution of SSLs in Lynch syndrome patients with a matched control population. We collected data of Lynch syndrome patients with a proven germline mutation who underwent colonoscopy between January 2011 and April 2016 in 2 tertiary referral hospitals. Control subjects undergoing elective colonoscopy from 2011 and onward for symptoms or surveillance were selected from a prospectively collected database. Patients were matched 1:1 for age, gender, and index versus surveillance colonoscopy. An expert pathology review of serrated polyps was performed. The primary outcomes included the detection rates and distribution of SSLs. We identified 321 patients with Lynch syndrome who underwent at least 1 colonoscopy. Of these, 223 Lynch syndrome patients (mean age, 49.3; 59% women; index colonoscopy, 56%) were matched to 223 control subjects. SSLs were detected in 7.6% (95% confidence interval, 4.8-11.9) of colonoscopies performed in Lynch syndrome patients and in 6.7% (95% confidence interval, 4.1-10.8) of control subjects (P = .86). None of the detected SSLs in Lynch syndrome patients contained dysplasia. The detection rate of SSLs in Lynch syndrome patients undergoing colonoscopy is comparable with a matched population. These findings suggest that the role of the serrated neoplasia pathway in CRC development in Lynch syndrome seems to be comparable with that in the general population. Copyright © 2018 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.

  18. Big Canyon Creek Ecological Restoration Strategy.

    Energy Technology Data Exchange (ETDEWEB)

    Rasmussen, Lynn; Richardson, Shannon

    2007-10-01

    He-yey, Nez Perce for steelhead or rainbow trout (Oncorhynchus mykiss), are a culturally and ecologically significant resource within the Big Canyon Creek watershed; they are also part of the federally listed Snake River Basin Steelhead DPS. The majority of the Big Canyon Creek drainage is considered critical habitat for that DPS as well as for the federally listed Snake River fall chinook (Oncorhynchus tshawytscha) ESU. The Nez Perce Soil and Water Conservation District (District) and the Nez Perce Tribe Department of Fisheries Resources Management-Watershed (Tribe), in an effort to support the continued existence of these and other aquatic species, have developed this document to direct funding toward priority restoration projects in priority areas for the Big Canyon Creek watershed. In order to achieve this, the District and the Tribe: (1) Developed a working group and technical team composed of managers from a variety of stakeholders within the basin; (2) Established geographically distinct sub-watershed areas called Assessment Units (AUs); (3) Created a prioritization framework for the AUs and prioritized them; and (4) Developed treatment strategies to utilize within the prioritized AUs. Assessment Units were delineated by significant shifts in sampled juvenile O. mykiss (steelhead/rainbow trout) densities, which were found to fall at fish passage barriers. The prioritization framework considered four aspects critical to determining the relative importance of performing restoration in a certain area: density of critical fish species, physical condition of the AU, water quantity, and water quality. It was established, through vigorous data analysis within these four areas, that the geographic priority areas for restoration within the Big Canyon Creek watershed are Big Canyon Creek from stream km 45.5 to the headwaters, Little Canyon from km 15 to 30, the mainstem corridors of Big Canyon (mouth to 7km) and Little Canyon (mouth to 7km). The District and the Tribe

  19. Insertion of an SVA element, a nonautonomous retrotransposon, in PMS2 intron 7 as a novel cause of Lynch syndrome.

    Science.gov (United States)

    van der Klift, Heleen M; Tops, Carli M; Hes, Frederik J; Devilee, Peter; Wijnen, Juul T

    2012-07-01

    Heterozygous germline mutations in the mismatch repair gene PMS2 predispose carriers for Lynch syndrome, an autosomal dominant predisposition to cancer. Here, we present a LINE-1-mediated retrotranspositional insertion in PMS2 as a novel mutation type for Lynch syndrome. This insertion, detected with Southern blot analysis in the genomic DNA of the patient, is characterized as a 2.2 kb long 5' truncated SVA_F element. The insertion is not detectable by current diagnostic testing limited to MLPA and direct Sanger sequencing on genomic DNA. The molecular nature of this insertion could only be resolved in RNA from cultured lymphocytes in which nonsense-mediated RNA decay was inhibited. Our report illustrates the technical problems encountered in the detection of this mutation type. Especially large heterozygous insertions will remain unnoticed because of preferential amplification of the smaller wild-type allele in genomic DNA, and are probably underreported in the mutation spectra of autosomal dominant disorders. © 2012 Wiley Periodicals, Inc.

  20. Efficacy of proximal colectomy for surgical management of right-sided first colorectal cancer in Lynch Syndrome mutation carriers.

    Science.gov (United States)

    Hiatt, Molly J; Casey, Murray Joseph; Lynch, Henry T; Snyder, Carrie L; Stacey, Mark; Walters, Ryan W

    2017-11-08

    This study analyzes the occurrence of colorectal cancer (CRC) in Lynch syndrome (LS) mutation carriers, interval until diagnosis of metachronous CRC, and survival after proximal colectomy (PC) compared with total (TC) and subtotal colectomy (STC) for right-sided first CRC in LS mutation carriers. Sixty-four LS mutation carriers with right-sided first CRC treated with PC or TC + STC were confirmed by clinical records. Bivariate analyses were examined for significance and life tables were generated for risk of metachronous CRC and survival estimates following surgery. One of 16 (6.3%) mutation carriers treated with TC + STC developed subsequent CRC compared with 13/48 (27%) treated by PC. There was no significant difference in survival estimates between PC compared with TC + STC through 25 years after surgery. Risk of subsequent CRC and survival estimates following PC and TC + STC should be considered in surgical management of right-sided first CRC in LS mutation carriers. Lynch syndrome mutation carriers are still at 27% risk for metachronous colorectal cancer after proximal colectomy for right-sided first colorectal cancers, but this study found no difference in survival through 25 years follow-up compared with those treated with total and subtotal colectomy. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. La mujer en el radiador en Cabeza borradora (Eraserhead, 1972-1976) de David Lynch: disección utópica del ojo

    OpenAIRE

    Villaplana Ruiz, Virginia

    1998-01-01

    Villaplana, V. (1998). La mujer en el radiador en Cabeza borradora (Eraserhead, 1972-1976) de David Lynch: disección utópica del ojo. Banda aparte. (11):29-31. http://hdl.handle.net/10251/43165. 29 31 11

  2. Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency Syndrome

    NARCIS (Netherlands)

    Klift, H.M. van der; Mensenkamp, A.R.; Drost, M.; Bik, E.C.; Vos, Y.J.; Gille, H.J.; Redeker, B.E.; Tiersma, Y.; Zonneveld, J.B.; Garcia, E.G.; Letteboer, T.G.; Olderode-Berends, M.J.; Hest, L.P. van; Os, T.A. van; Verhoef, S.; Wagner, A.; Asperen, C.J. van; Broeke, S.W. ten; Hes, F.J.; Wind, N. de; Nielsen, M.; Devilee, P.; Ligtenberg, M.J.L.; Wijnen, J.T.; Tops, C.M.

    2016-01-01

    Monoallelic PMS2 germline mutations cause 5%-15% of Lynch syndrome, a midlife cancer predisposition, whereas biallelic PMS2 mutations cause approximately 60% of constitutional mismatch repair deficiency (CMMRD), a rare childhood cancer syndrome. Recently improved DNA- and RNA-based strategies are

  3. Development of in vitro and in vivo functional assays to enable diagnosis of Variants of Uncertain Significance in the common cancer predisposition Lynch syndrome

    NARCIS (Netherlands)

    Drost, Mark

    2014-01-01

    Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair (MMR) genes and is the most prevalent hereditary colorectal cancer syndrome. A significant proportion of variants identified in MMR and other common cancer susceptibility genes are missense or noncoding changes whose

  4. Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency Syndrome

    NARCIS (Netherlands)

    van der Klift, Heleen M.; Mensenkamp, Arjen R.; Drost, Mark; Bik, Elsa C.; Vos, Yvonne J.; Gille, Hans J. J. P.; Redeker, Bert E. J. W.; Tiersma, Yvonne; Zonneveld, Jose B. M.; Garcia, Encarna Gomez; Letteboer, Tom G. W.; Olderode-Berends, Maran J. W.; van Hest, Liselotte P.; van Os, Theo A.; Verhoef, Senno; Wagner, Anja; van Asperen, Christi J.; ten Broeke, Sanne W.; Hes, Frederik J.; de Wind, Niels; Nielsen, Maartje; Devilee, Peter; Ligtenberg, Marjolijn J. L.; Wijnen, Juul T.; Tops, Carli M. J.

    Monoallelic PMS2 germline mutations cause 5%-15% of Lynch syndrome, a midlife cancer predisposition, whereas biallelic PMS2 mutations cause approximately 60% of constitutional mismatch repair deficiency (CMMRD), a rare childhood cancer syndrome. Recently improved DNA- and RNA-based strategies are

  5. Quantification of sequence exchange events between PMS2 and PMS2CL provides a basis for improved mutation scanning of Lynch syndrome patients.

    NARCIS (Netherlands)

    Klift, H.M. van der; Tops, C.M.; Bik, E.C.; Boogaard, M.W.; Borgstein, A.M.; Hansson, K.B.; Ausems, M.G.E.M.; Gomez Garcia, E.; Green, A.; Hes, F.J.; Izatt, L.; Hest, L.P. van; Alonso, A.M.; Vriends, A.H.; Wagner, A.; Zelst-Stams, W.A.G. van; Vasen, H.F.; Morreau, H.; Devilee, P.; Wijnen, J.T.

    2010-01-01

    Heterozygous mutations in PMS2 are involved in Lynch syndrome, whereas biallelic mutations are found in Constitutional mismatch repair-deficiency syndrome patients. Mutation detection is complicated by the occurrence of sequence exchange events between the duplicated regions of PMS2 and PMS2CL. We

  6. Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency (CMMRD) Syndrome

    NARCIS (Netherlands)

    van der Klift, Heleen M; Mensenkamp, Arjen R; Drost, Mark; Bik, Elsa C; Vos, Yvonne J; Gille, Hans J J P; Redeker, Bert E J W; Tiersma, Yvonne; Zonneveld, José B M; García, Encarna Gómez; Letteboer, Tom G W; Olderode-Berends, Maran J W; van Hest, Liselotte P; van Os, Theo A; Verhoef, Senno; Wagner, Anja; van Asperen, Christi J; Ten Broeke, Sanne W; Hes, Frederik J; de Wind, Niels; Nielsen, Maartje; Devilee, Peter; Ligtenberg, Marjolijn J L; Wijnen, Juul T; Tops, Carli M J

    2016-01-01

    Monoallelic PMS2 germline mutations cause 5-15% of Lynch syndrome, a midlife cancer predisposition, whereas biallelic PMS2 mutations cause approximately 60% of constitutional MMR deficiency (CMMRD), a rare childhood cancer syndrome. Recently improved DNA and RNA-based strategies are applied to

  7. Ovarian metastasis from uveal melanoma with MLH1/PMS2 protein loss in a patient with germline MLH1 mutated Lynch syndrome: consequence or coincidence?

    Science.gov (United States)

    Lobo, João; Pinto, Carla; Freitas, Micaela; Pinheiro, Manuela; Vizcaino, Rámon; Oliva, Esther; Teixeira, Manuel R; Jerónimo, Carmen; Bartosch, Carla

    2017-03-01

    Currently, uveal melanoma is not considered within the Lynch syndrome tumor spectrum. However, there are studies suggesting a contribution of microsatellite instability in sporadic uveal melanoma tumorigenesis. We report a 45-year-old woman who was referred for genetic counseling due to a family history of Lynch syndrome caused by a MLH1 mutation. She originally underwent enucleation of the right eye secondary to a uveal spindle cell melanoma diagnosed at age 25. The tumor recurred 22 years later presenting as an ovarian metastasis and concurrently a microscopic endometrial endometrioid carcinoma, grade 1/3 was diagnosed. Subsequent studies highlighted that the uveal melanoma showed high microsatellite instability and loss of MLH1 and PMS2 protein expression, with no MLH1 promoter methylation or BRAF mutation. Additionally, a GNAQ mutation was found. We conclude that our patient's uveal melanoma is most likely related to MLH1 germline mutation and thus Lynch syndrome related. To the best of our knowledge, this is the first report of uveal melanoma showing MLH1/PMS2 protein loss in the context of Lynch syndrome.

  8. A novel deletion in the splice donor site of MLH1 exon 6 in a Japanese colon cancer patient with Lynch syndrome.

    Science.gov (United States)

    Yamaguchi, Junya; Sato, Yuri; Kita, Mizuho; Nomura, Sachio; Yamamoto, Noriko; Kato, Yo; Ishikawa, Yuichi; Arai, Masami

    2015-10-01

    Lynch syndrome is an autosomal dominantly inherited disease that is characterized by a predisposition to cancers, mainly colorectal cancer. Germline mutations of DNA mismatch repair genes such as MLH1, MSH2, MSH6 and PMS2 have been described in patients with Lynch syndrome. Here, we report deletion of 2 bp in the splice donor site of the MLH1 exon 6 (c.545+4_545+5delCA) in a 48-year-old Japanese woman with Lynch syndrome. RT-PCR direct sequencing analysis revealed that this mutation led to an increase in the level of an MLH1 transcript in which exon 6 was skipped, and may cause a frameshift (p.E153FfsX8). Therefore, this mutation appears to be pathogenic and is responsible for Lynch syndrome. Additionally, analysis of the patient's tumor cells indicated microsatellite instability high phenotype and loss of the MLH1 and PMS2 proteins. To our knowledge, this is a germline splice site mutation of MLH1 that has not been reported previously. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  9. A putative Lynch syndrome family carrying MSH2 and MSH6 variants of uncertain significance-functional analysis reveals the pathogenic one

    DEFF Research Database (Denmark)

    Kantelinen, Jukka; Hansen, Thomas V O; Kansikas, Minttu

    2011-01-01

    Inherited pathogenic mutations in the mismatch repair (MMR) genes, MSH2, MLH1, MSH6, and PMS2 predispose to Lynch syndrome (LS). However, the finding of a variant or variants of uncertain significance (VUS) in affected family members complicates the risk assessment. Here, we describe a putative LS...

  10. Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer : a report from the prospective Lynch syndrome database

    NARCIS (Netherlands)

    Møller, Pål; Seppälä, Toni; Bernstein, Inge; Holinski-Feder, Elke; Sala, Paola; Evans, D Gareth; Lindblom, Annika; Macrae, Finlay; Blanco, Ignacio; Sijmons, Rolf; Jeffries, Jacqueline; Vasen, Hans; Burn, John; Nakken, Sigve; Hovig, Eivind; Rødland, Einar Andreas; Tharmaratnam, Kukatharmini; de Vos Tot Nederveen Cappel, Wouter H; Hill, James; Wijnen, Juul; Jenkins, Mark; Green, Kate; Lalloo, Fiona; Sunde, Lone; Mints, Miriam; Bertario, Lucio; Pineda, Marta; Navarro, Matilde; Morak, Monika; Renkonen-Sinisalo, Laura; Frayling, Ian M; Plazzer, John-Paul; Pylvanainen, Kirsi; Genuardi, Maurizio; Mecklin, Jukka-Pekka; Möslein, Gabriela; Sampson, Julian R; Capella, Gabriel

    2016-01-01

    Objective Today most patients with Lynch syndrome (LS) survive their first cancer. There is limited information on the incidences and outcome of subsequent cancers. The present study addresses three questions: (i) what is the cumulative incidence of a subsequent cancer; (ii) in which organs do

  11. Dietary B vitamin and methionine intake and MTHFR C677T genotype on risk of colorectal tumors in Lynch syndrome: the GEOLynch cohort study

    NARCIS (Netherlands)

    Jung, A.Y.; van Duijnhoven, F.J.B.; Nagengast, F.M.; Botma, A.; Heine-Broring, R.C.; Kleibeuker, J.H.; Vasen, H.F.A.; Harryvan, J.L.; Winkels, R.M.; Kampman, E.

    2014-01-01

    Purpose: Dietary intake of B vitamins and methionine, essential components of DNA synthesis and methylation pathways, may influence colorectal tumor (CRT) development. The impact of B vitamins on colorectal carcinogenesis in individuals with Lynch syndrome (LS) is unknown but is important given

  12. Prospective, Multi-center Randomized Intermediate Biomarker Study of Oral Contraceptive vs. Depo-Provera for Prevention of Endometrial Cancer in Women with Lynch Syndrome

    Science.gov (United States)

    Lu, Karen H.; Loose, David S.; Yates, Melinda S.; Nogueras-Gonzalez, Graciela M.; Munsell, Mark F.; Chen, Lee-may; Lynch, Henry; Cornelison, Terri; Boyd-Rogers, Stephanie; Rubin, Mary; Daniels, Molly S.; Conrad, Peggy; Milbourne, Andrea; Gershenson, David M.; Broaddus, Russell R.

    2013-01-01

    Women with Lynch syndrome have a 40–60% lifetime risk for developing endometrial cancer, a cancer associated with estrogen imbalance. The molecular basis for endometrial-specific tumorigenesis is unclear. Progestins inhibit estrogen-driven proliferation, and epidemiologic studies have demonstrated that progestin-containing oral contraceptives (OCP) reduce the risk of endometrial cancer by 50% in women at general population risk. It is unknown if they are effective in women with Lynch syndrome. Asymptomatic women age 25–50 with Lynch syndrome were randomized to receive the progestin compounds depo-Provera (depoMPA) or OCP for three months. An endometrial biopsy and transvaginal ultrasound were performed before and after treatment. Endometrial proliferation was evaluated as the primary endpoint. Histology and a panel of surrogate endpoint biomarkers were evaluated for each endometrial biopsy as secondary endpoints. A total of 51 women were enrolled, and 46 completed treatment. Two of the 51 women had complex hyperplasia with atypia at the baseline endometrial biopsy and were excluded from the study. Overall, both depoMPA and OCP induced a dramatic decrease in endometrial epithelial proliferation and microscopic changes in the endometrium characteristic of progestin action. Transvaginal ultrasound measurement of endometrial stripe was not a useful measure of endometrial response or baseline hyperplasia. These results demonstrate that women with Lynch syndrome do show an endometrial response to short term exogenous progestins, suggesting that OCP and depoMPA may be reasonable chemopreventive agents in this high-risk patient population. PMID:23639481

  13. Prospective multicenter randomized intermediate biomarker study of oral contraceptive versus depo-provera for prevention of endometrial cancer in women with Lynch syndrome.

    Science.gov (United States)

    Lu, Karen H; Loose, David S; Yates, Melinda S; Nogueras-Gonzalez, Graciela M; Munsell, Mark F; Chen, Lee-May; Lynch, Henry; Cornelison, Terri; Boyd-Rogers, Stephanie; Rubin, Mary; Daniels, Molly S; Conrad, Peggy; Milbourne, Andrea; Gershenson, David M; Broaddus, Russell R

    2013-08-01

    Women with Lynch syndrome have a 40% to 60% lifetime risk for developing endometrial cancer, a cancer associated with estrogen imbalance. The molecular basis for endometrial-specific tumorigenesis is unclear. Progestins inhibit estrogen-driven proliferation, and epidemiologic studies have shown that progestin-containing oral contraceptives (OCP) reduce the risk of endometrial cancer by 50% in women at general population risk. It is unknown whether they are effective in women with Lynch syndrome. Asymptomatic women ages 25 to 50 with Lynch syndrome were randomized to receive the progestin compounds Depo-Provera (depo-MPA) or OCP for three months. An endometrial biopsy and transvaginal ultrasound were conducted before and after treatment. Endometrial proliferation was evaluated as the primary endpoint. Histology and a panel of surrogate endpoint biomarkers were evaluated for each endometrial biopsy as secondary endpoints. A total of 51 women were enrolled, and 46 completed treatment. Two of the 51 women had complex hyperplasia with atypia at the baseline endometrial biopsy and were excluded from the study. Overall, both depo-MPA and OCP induced a dramatic decrease in endometrial epithelial proliferation and microscopic changes in the endometrium characteristic of progestin action. Transvaginal ultrasound measurement of endometrial stripe was not a useful measure of endometrial response or baseline hyperplasia. These results show that women with Lynch syndrome do show an endometrial response to short-term exogenous progestins, suggesting that OCP and depo-MPA may be reasonable chemopreventive agents in this high-risk patient population.

  14. Tidal flow characteristics at Kasheli (Kalwa/ Bassein creek), Bombay

    Digital Repository Service at National Institute of Oceanography (India)

    Swamy, G.N.; Suryanarayana, A.

    Tidal flow characteristics of waters at Kasheli, connected to the sea through Thane and Bassein Creeks in Bombay, Maharashtra, India are investigated based on tide and current observations carried out in 1980-81. The results establish that the tidal...

  15. Ecology of phytoplankton from Dharmatar Creek, west coast of India

    Digital Repository Service at National Institute of Oceanography (India)

    Tiwari, L.R.; Nair, V.R.

    Phytoplankton pigment, cell count and species diversity wee studied at five locations in Dharamtar Creek during September 1984 to November 1985. Chemical parameters indicated a healthy system free of any environmental stress. The water...

  16. Missing link between the Hayward and Rodgers Creek faults.

    Science.gov (United States)

    Watt, Janet; Ponce, David; Parsons, Tom; Hart, Patrick

    2016-10-01

    The next major earthquake to strike the ~7 million residents of the San Francisco Bay Area will most likely result from rupture of the Hayward or Rodgers Creek faults. Until now, the relationship between these two faults beneath San Pablo Bay has been a mystery. Detailed subsurface imaging provides definitive evidence of active faulting along the Hayward fault as it traverses San Pablo Bay and bends ~10° to the right toward the Rodgers Creek fault. Integrated geophysical interpretation and kinematic modeling show that the Hayward and Rodgers Creek faults are directly connected at the surface-a geometric relationship that has significant implications for earthquake dynamics and seismic hazard. A direct link enables simultaneous rupture of the Hayward and Rodgers Creek faults, a scenario that could result in a major earthquake ( M = 7.4) that would cause extensive damage and loss of life with global economic impact.

  17. Zooplankton composition in Dharamtar creek adjoining Bombay harbour

    Digital Repository Service at National Institute of Oceanography (India)

    Tiwari, L.R.; Nair, V.R.

    bedoti was the true inhabitant. In general zooplankton production indicated 1.5 fold increase towards the upper reaches of the creek where salinity variations were drastic. A more diversified faunal assemblage of oceanic and neritic species characterised...

  18. Water quality of the Swatara Creek Basin, PA

    Science.gov (United States)

    McCarren, Edward F.; Wark, J.W.; George, J.R.

    1964-01-01

    The Swatara Creek of the Susquehanna River Basin is the farthest downstream sub-basin that drains acid water (pH of 4.5 or less) from anthracite coal mines. The Swatara Creek drainage area includes 567 square miles of parts of Schuylkill, Berks, Lebanon, and Dauphin Counties in Pennsylvania.To learn what environmental factors and dissolved constituents in water were influencing the quality of Swatara Creek, a reconnaissance of the basin was begun during the summer of 1958. Most of the surface streams and the wells adjacent to the principal tributaries of the Creek were sampled for chemical analysis. Effluents from aquifers underlying the basin were chemically analyzed because ground water is the basic source of supply to surface streams in the Swatara Creek basin. When there is little runoff during droughts, ground water has a dominating influence on the quality of surface water. Field tests showed that all ground water in the basin was non-acidic. However, several streams were acidic. Sources of acidity in these streams were traced to the overflow of impounded water in unworked coal mines.Acidic mine effluents and washings from coal breakers were detected downstream in Swatara Creek as far as Harper Tavern, although the pH at Harper Tavern infrequently went below 6.0. Suspended-sediment sampling at this location showed the mean daily concentration ranged from 2 to 500 ppm. The concentration of suspended sediment is influenced by runoff and land use, and at Harper Tavern it consisted of natural sediments and coal wastes. The average daily suspended-sediment discharge there during the period May 8 to September 30, 1959, was 109 tons per day, and the computed annual suspended-sediment load, 450 tons per square mile. Only moderate treatment would be required to restore the quality of Swatara Creek at Harper Tavern for many uses. Above Ravine, however, the quality of the Creek is generally acidic and, therefore, of limited usefulness to public supplies, industries and

  19. Community Practice Implementation of a Self-administered Version of PREMM1,2,6 to Assess Risk for Lynch Syndrome.

    Science.gov (United States)

    Luba, Daniel G; DiSario, James A; Rock, Colleen; Saraiya, Devki; Moyes, Kelsey; Brown, Krystal; Rushton, Kristen; Ogara, Maydeen M; Raphael, Mona; Zimmerman, Dayna; Garrido, Kimmie; Silguero, Evelyn; Nelson, Jonathan; Yurgelun, Matthew B; Kastrinos, Fay; Wenstrup, Richard J; Syngal, Sapna

    2018-01-01

    Lynch syndrome is a genetic disorder that greatly increases risk for colorectal and other cancers, although it is underdiagnosed. Prediction of MLH1, MSH2, and MSH6 (PREMM 1,2,6 ) is a web-based tool that analyzes individuals' personal/family histories of cancer to quantify their likelihood of carrying a germline mutation associated with Lynch syndrome. We investigated the feasibility of systematic risk assessment for Lynch syndrome in a community gastroenterology practice using a patient-completed version of PREMM 1,2,6 . PREMM 1,2,6 was adapted into a computer tablet version designed for self-administration by patients. Individuals presenting to a community gastroenterology office and endoscopy facility in California completed the PREMM 1,2,6 assessment before their visit (n = 3134). The total study duration (8 months) comprised a 2-month initiation period (May 1-June 30, 2013) and a 6-month study period (July 1-December 31, 2013). Genetic counseling and germline analysis for mutations in genes associated with Lynch syndrome (MLH1, MSH2, MSH6, PMS2, and EPCAM) were offered to individuals with PREMM 1,2,6 scores of 5% or higher. Patients and providers completed surveys to evaluate the feasibility and satisfaction with the process. Of the 3134 individuals assessed by PREMM 1,2,6 during the 6-month study period, 177 individuals (5.6%) had scores of 5% or higher. Of these, 146 individuals underwent genetic testing, along with 28 additional participants recruited nonconsecutively during the initiation period. Mutations associated with Lynch syndrome were detected in 3 of the 146 individuals (2.1%) with PREMM 1,2,6 scores of 5% or higher who underwent germline testing, and 3 of the 28 patients (10.7%) recruited during study initiation with PREMM 1,2,6 scores of 5% or higher. Of the participants who underwent genetic analysis, 98.6% stated that they understood the information provided to them. All of the surveyed providers stated that they were satisfied with the

  20. Exploring clinicians' attitudes about using aspirin for risk reduction in people with Lynch Syndrome with no personal diagnosis of colorectal cancer.

    Science.gov (United States)

    Chen, Yanni; Peate, Michelle; Kaur, Rajneesh; Meiser, Bettina; Wong, Tim; Kirk, Judy; Ward, Robyn L; Goodwin, Annabel; Macrae, Finlay; Hiller, Janet; Trainer, Alison H; Mitchell, Gillian

    2017-01-01

    Recent research has shown that aspirin reduces the risk of cancers associated with Lynch Syndrome. However, uncertainty exists around the optimal dosage, treatment duration and whether the benefits of aspirin as a risk-reducing medication (RRM) outweigh adverse medication related side-effects. Little is known about clinicians' attitudes, current practice, and perceived barriers to recommending aspirin as a RRM. To explore the attitudes of clinicians who discuss risk management options with patients with Lynch Syndrome towards using aspirin as a RRM. Clinicians were invited through professional organisations to complete an online survey. Topics included their clinical experience with Lynch Syndrome, views and practice of recommending aspirin as a RRM, and knowledge about clinical risk management guidelines for Lynch Syndrome. Comparison of attitudes was made between three professional groups. 181 respondents were included in the analysis: 59 genetics professionals (genetic counsellors and clinical geneticists, medical oncologists with specialist training in familial cancer), 49 gastroenterologists and 73 colorectal surgeons. Most clinicians (76 %) considered aspirin to be an effective RRM and most (72 %) were confident about discussing it. In all professional categories, those who were confident about discussing aspirin with patients perceived it to be an effective RRM (OR = 2.8 [95 % CI = 1.8-4.2], p Lynch Syndrome patients compared to 69 % of gastroenterologists and 68 % of colorectal surgeons. Those who considered aspirin as an effective RRM or who felt confident in their knowledge of the aspirin literature were more likely (OR = 10 [95 % CI = 1.5-65], p = 0.010, OR = 6 [95 % CI = 2.2-16], p Lynch Syndrome per year were more likely to be confident in their knowledge of the aspirin literature and discussing it with patients (OR = 4.1 [95 % CI = 1.6-10.2], p = 0.003). Explicit recommendations to take aspirin, was reported by 65

  1. Results of the 2000 Creek Plantation Swamp Survey

    International Nuclear Information System (INIS)

    Fledderman, P.D.

    2000-01-01

    This report is a survey of the Creek Plantation located along the Savannah River and borders the southeast portion of the Savannah River Site. The land is primarily undeveloped and agricultural; its purpose is to engage in equestrian-related operations. A portion of Creek Plantation along the Savannah River is a low-lying swamp, known as the Savannah River Swamp, which is uninhabited and not easily accessible

  2. A mangrove creek restoration plan utilizing hydraulic modeling.

    Science.gov (United States)

    Marois, Darryl E; Mitsch, William J

    2017-11-01

    Despite the valuable ecosystem services provided by mangrove ecosystems they remain threatened around the globe. Urban development has been a primary cause for mangrove destruction and deterioration in south Florida USA for the last several decades. As a result, the restoration of mangrove forests has become an important topic of research. Using field sampling and remote-sensing we assessed the past and present hydrologic conditions of a mangrove creek and its connected mangrove forest and brackish marsh systems located on the coast of Naples Bay in southwest Florida. We concluded that the hydrology of these connected systems had been significantly altered from its natural state due to urban development. We propose here a mangrove creek restoration plan that would extend the existing creek channel 1.1 km inland through the adjacent mangrove forest and up to an adjacent brackish marsh. We then tested the hydrologic implications using a hydraulic model of the mangrove creek calibrated with tidal data from Naples Bay and water levels measured within the creek. The calibrated model was then used to simulate the resulting hydrology of our proposed restoration plan. Simulation results showed that the proposed creek extension would restore a twice-daily flooding regime to a majority of the adjacent mangrove forest and that there would still be minimal tidal influence on the brackish marsh area, keeping its salinity at an acceptable level. This study demonstrates the utility of combining field data and hydraulic modeling to aid in the design of mangrove restoration plans.

  3. Surface-water resources of Polecat Creek basin, Oklahoma

    Science.gov (United States)

    Laine, L.L.

    1956-01-01

    A compilation of basic data on surface waters in Polecat Creek basin is presented on a monthly basis for Heyburn Reservoir and for Polecat Creek at Heyburn, Okla. Chemical analyses are shown for five sites in the basin. Correlation of runoff records with those for nearby basins indicates that the average annual runoff of the basin above gaging station at Heyburn is 325 acre-feet per square mile. Estimated duration curves of daily flow indicate that under natural conditions there would be no flow in Polecat Creek at Heyburn (drainage area, 129 square miles) about 16 percent of the time on an average, and that the flow would be less than 3 cubic feet per second half of the time. As there is no significant base flow in the basin, comparable low flows during dry-weather periods may be expected in other parts of the basin. During drought periods Heyburn Reservoir does not sustain a dependable low-water flow in Polecat Creek. Except for possible re-use of the small sewage effluent from city of Sapulpa, dependable supplies for additional water needs on the main stem will require development of supplemental storage. There has been no regular program for collection of chemical quality data in the basin, but miscellaneous analyses indicate a water of suitable quality for municipal and agricultural uses in Heyburn Reservoir and Polecat Creek near Heyburn. One recent chemical analysis indicates the possibility of a salt pollution problem in the Creek near Sapulpa. (available as photostat copy only)

  4. Differences in histological features and PD-L1 expression between sporadic microsatellite instability and Lynch-syndrome-associated disease in Japanese patients with colorectal cancer.

    Science.gov (United States)

    Yamada, Rin; Yamaguchi, Tatsuro; Iijima, Takeru; Wakaume, Rika; Takao, Misato; Koizumi, Koichi; Hishima, Tsunekazu; Horiguchi, Shin-Ichiro

    2018-06-01

    The field of immunotherapy has recently focused on cancers with microsatellite instability (MSI). These cancers include both Lynch-syndrome-associated tumors, which are caused by mismatch repair (MMR) germline mutations, and sporadic MSI tumors, which are mainly attributed to MLH1 promoter methylation. The present study aimed to clarify differences in the histological and PD-L1 expression profiles between these two types of MSI cancers in Japanese patients. Among 908 cases of colorectal cancer treated via surgical resection from 2008 to 2014, we identified 64 MSI cancers, including 36 sporadic MSI and 28 Lynch-syndrome-associated cancers, using a BRAF V600E mutation analysis and MLH1 methylation analysis. Of the latter subgroup, 21 (75%) harbored MMR germline mutations. The following were more frequent with sporadic MSI than with Lynch syndrome associated cancers: poor differentiation (50.0 vs. 7.1%, P = 0.0002), especially solid type (30.6 vs. 3.6%, P = 0.0061); medullary morphology (19.4 and 0%, P = 0.015), Crohn-like lymphoid reaction (50.0 vs. 25.0%, P = 0.042), and PD-L1 expression (25.0 vs. 3.6%, P = 0.034). However, the groups did not differ in terms of the mean invasive front and intratumoral CD8-positive cell densities. In a logistic regression analysis, PD-L1 expression correlated with poor differentiation (odds ratio: 7.65, 95% confidence interval: 1.55-37.7, P = 0.012), but not with the difference between sporadic MSI cancer and Lynch-syndrome-associated cancer (odds ratio: 4.74, 95% confidence interval: 0.50-45.0, P = 0.176). Therefore, compared with Lynch-syndrome-associated cancers, sporadic MSI cancers are more frequently solid, poorly differentiated medullary cancers that express PD-L1.

  5. Characterization of a rare variant (c.2635-2A>G) of the MSH2 gene in a family with Lynch syndrome.

    Science.gov (United States)

    Cariola, Filomena; Disciglio, Vittoria; Valentini, Anna M; Lotesoriere, Claudio; Fasano, Candida; Forte, Giovanna; Russo, Luciana; Di Carlo, Antonio; Guglielmi, Floranna; Manghisi, Andrea; Lolli, Ivan; Caruso, Maria L; Simone, Cristiano

    2018-04-01

    Lynch syndrome is caused by germline mutations in one of the mismatch repair genes ( MLH1, MSH2, MSH6, and PMS2) or in the EPCAM gene. Lynch syndrome is defined on the basis of clinical, pathological, and genetic findings. Accordingly, the identification of predisposing genes allows for accurate risk assessment and tailored screening protocols. Here, we report a family case with three family members manifesting the Lynch syndrome phenotype, all of which harbor the rare variant c.2635-2A>G affecting the splice site consensus sequence of intron 15 of the MSH2 gene. This mutation was previously described only in one family with Lynch syndrome, in which mismatch repair protein expression in tumor tissues was not assessed. In this study, we report for the first time the molecular characterization of the MSH2 c.2635-2A>G variant through in silico prediction analysis, microsatellite instability, and mismatch repair protein expression experiments on tumor tissues of Lynch syndrome patients. The potential effect of the splice site variant was revealed by three splicing prediction bioinformatics tools, which suggested the generation of a new cryptic splicing site. The potential pathogenic role of this variant was also revealed by the presence of microsatellite instability and the absence of MSH2/MSH6 heterodimer protein expression in the tumor cells of cancer tissues of the affected family members. We provide compelling evidence in favor of the pathogenic role of the MSH2 variant c.2635-2A>G, which could induce an alteration of the canonical splice site and consequently an aberrant form of the protein product (MSH2).

  6. 33 CFR 207.170d - Taylor Creek, navigation lock (S-193) across the entrance to Taylor Creek at Lake Okeechobee...

    Science.gov (United States)

    2010-07-01

    ... 33 Navigation and Navigable Waters 3 2010-07-01 2010-07-01 false Taylor Creek, navigation lock (S-193) across the entrance to Taylor Creek at Lake Okeechobee, Okeechobee, Fla.; use, administration..., DEPARTMENT OF THE ARMY, DEPARTMENT OF DEFENSE NAVIGATION REGULATIONS § 207.170d Taylor Creek, navigation lock...

  7. CREEK Project's Nekton Database for Eight Creeks in the North Inlet Estuary, South Carolina: 1997-1998.

    Data.gov (United States)

    Baruch Institute for Marine and Coastal Sciences, Univ of South Carolina — A group of eight intertidal creeks with high densities of oysters, Crassostrea virginica, in North Inlet Estuary, South Carolina, USA were studied using a replicated...

  8. CREEK Project's Microzooplankton Seasonal Monitoring Database for Eight Creeks in the North Inlet Estuary, South Carolina: 1997-1999

    Data.gov (United States)

    Baruch Institute for Marine and Coastal Sciences, Univ of South Carolina — A group of eight intertidal creeks with high densities of oysters, Crassostrea virginica, in North Inlet Estuary, South Carolina, USA were studied using a replicated...

  9. Puente Willow Creek en Monterrey, California

    Directory of Open Access Journals (Sweden)

    Editorial, Equipo

    1965-09-01

    Full Text Available Of the 10 awards given every year by the Prestressed Concrete Institute for the most outstanding prestressed concrete projects, two have been awarded in California this year, one of them to the Willow Creek bridge, near Monterrey. The prestressed, double T girders of this bridge were made at a workshop, a great distance from the bridge site. These are 24 m long, 1.35 m high, and are stabilized by transversal diaphragms, 20 cm in thickness. The table deck is of reinforced concrete, being 8.85 m wide and 20 cm thick. The structure is straightforward, slender, and adapts itself pleasantly to the background. It has seven spans and crosses over a secondary road, in addition to bridging the Willow stream. The supporting piles are hollow, of rectangular cross section, and over them a cross beam carries the five girders and the deck itself. The end abutments consist of vertical reinforced concrete walls, and supporting, soil filled, structures. The above information was supplied by the California Road Department.De los diez premios que anualmente concede el Prestressed Concrete Institute para las obras de hormigón pretensado más notables, dos han correspondido a California y uno de ellos al puente de Willow Creek, situado en la región de Monterrey. Las vigas de hormigón pretensado, con sección en forma de doble T, se prefabricaron en un taller situado a gran distancia del puente. Tienen 24 m de longitud y 1,35 m de canto, estando arriostradas con diafragmas transversales de 20 cm de espesor. La losa del tablero, de hormigón armado, tiene 8,85 m de anchura y 20 cm de espesor. La estructura es sencilla, esbelta y armoniza perfectamente con el paisaje que la circunda. Tiene siete tramos y salva un paso inferior secundario y el arroyo Willow. Los soportes, se apoyan sobre pilotes, algunos de gran altura; son huecos, de sección rectangular y terminan en una cruceta que sirve de sostén a las cinco vigas que soportan la losa del tablero. Los estribos

  10. Clinical and Molecular Characterization of Brazilian Patients Suspected to Have Lynch Syndrome.

    Directory of Open Access Journals (Sweden)

    Felipe Carneiro da Silva

    Full Text Available Lynch syndrome (LS accounts for 3-5% of all colorectal cancers (CRC and is inherited in an autosomal dominant fashion. This syndrome is characterized by early CRC onset, high incidence of tumors in the ascending colon, excess of synchronous/metachronous tumors and extra-colonic tumors. Nowadays, LS is regarded of patients who carry deleterious germline mutations in one of the five mismatch repair genes (MMR, mostly in MLH1 and MSH2, but also in MSH6, PMS1 and PMS2. To comprehensively characterize 116 Brazilian patients suspected for LS, we assessed the frequency of germline mutations in the three minor genes MSH6, PMS1 and PMS2 in 82 patients negative for point mutations in MLH1 and MSH2. We also assessed large genomic rearrangements by MLPA for detecting copy number variations (CNVs in MLH1, MSH2 and MSH6 generating a broad characterization of MMR genes. The complete analysis of the five MMR genes revealed 45 carriers of pathogenic mutations, including 25 in MSH2, 15 in MLH1, four in MSH6 and one in PMS2. Eleven novel pathogenic mutations (6 in MSH2, 4 in MSH6 and one in PMS2, and 11 variants of unknown significance (VUS were found. Mutations in the MLH1 and MSH2 genes represented 89% of all mutations (40/45, whereas the three MMR genes (MSH6, PMS1 and PMS2 accounted for 11% (5/45. We also investigated the MLH1 p.Leu676Pro VUS located in the PMS2 interaction domain and our results revealed that this variant displayed no defective function in terms of cellular location and heterodimer interaction. Additionally, we assessed the tumor phenotype of a subset of patients and also the frequency of CRC and extra-colonic tumors in 2,365 individuals of the 116 families, generating the first comprehensive portrait of the genetic and clinical aspects of patients suspected of LS in a Brazilian cohort.

  11. Cost-Effectiveness Analysis of Different Genetic Testing Strategies for Lynch Syndrome in Taiwan.

    Directory of Open Access Journals (Sweden)

    Ying-Erh Chen

    Full Text Available Patients with Lynch syndrome (LS have a significantly increased risk of developing colorectal cancer (CRC and other cancers. Genetic screening for LS among patients with newly diagnosed CRC aims to identify mutations in the disease-causing genes (i.e., the DNA mismatch repair genes in the patients, to offer genetic testing for relatives of the patients with the mutations, and then to provide early prevention for the relatives with the mutations. Several genetic tests are available for LS, such as DNA sequencing for MMR genes and tumor testing using microsatellite instability and immunohistochemical analyses. Cost-effectiveness analyses of different genetic testing strategies for LS have been performed in several studies from different countries such as the US and Germany. However, a cost-effectiveness analysis for the testing has not yet been performed in Taiwan. In this study, we evaluated the cost-effectiveness of four genetic testing strategies for LS described in previous studies, while population-specific parameters, such as the mutation rates of the DNA mismatch repair genes and treatment costs for CRC in Taiwan, were used. The incremental cost-effectiveness ratios based on discounted life years gained due to genetic screening were calculated for the strategies relative to no screening and to the previous strategy. Using the World Health Organization standard, which was defined based on Taiwan's Gross Domestic Product per capita, the strategy based on immunohistochemistry as a genetic test followed by BRAF mutation testing was considered to be highly cost-effective relative to no screening. Our probabilistic sensitivity analysis results also suggest that the strategy has a probability of 0.939 of being cost-effective relative to no screening based on the commonly used threshold of $50,000 to determine cost-effectiveness. To the best of our knowledge, this is the first cost-effectiveness analysis for evaluating different genetic testing

  12. Regional geology of the Pine Creek Geosyncline

    International Nuclear Information System (INIS)

    Needham, R.S.; Crick, I.H.; Stuart-Smith, P.G.

    1980-01-01

    The Pine Creek Geosyncline comprises about 14km of chronostratigraphic mainly pelitic and psammitic Lower Proterozoic sediments with interlayered tuff units, resting on granitic late Archaean complexes exposed as three small domes. Sedimentation took place in one basin, and most stratigraphic units are represented throughout the basin. The sediments were regionally deformed and metamorphosed at 1800Ma. Tightly folded greenschist facies strata in the centre grade into isoclinally deformed amphibolite facies metamorphics in the west and northeast. Pre and post-orogenic continental tholeiites, and post-orogenic granite diapirs intrude the Lower Proterozoic metasediments, and the granites are surrounded by hornfels zones up to 10km wide in the greenschist facies terrane. Cover rocks of Carpentarian (Middle Proterozoic) and younger ages rest on all these rocks unconformably and conceal the original basin margins. The Lower Proterozoic metasediments are mainly pelites (about 75 percent) which are commonly carbonaceous, lesser psammites and carbonates (about 10 percent each), and minor rudites (about 5 percent). Volcanic rocks make up about 10 percent of the total sequence. The environment of deposition ranges from shallow-marine to supratidal and fluviatile for most of the sequence, and to flysch in the topmost part. Poor exposure and deep weathering over much of the area hampers correlation of rock units; the correlation preferred by the authors is presented, and possible alternatives are discussed. Regional geological observations pertinent to uranium ore genesis are described. (author)

  13. Pine Creek Geosyncline, N.T

    International Nuclear Information System (INIS)

    Ewers, G.R.; Ferguson, J.; Needham, R.S.; Donnelly, T.H.

    1984-01-01

    The Pine Creek Geosyncline comprises about 14 km of chronostratigraphic mainly pelitic and psammitic Early Proterozoic sediments with interlayered tuff units, resting on granitic late Archaean complexes exposed as small domes. Sedimentation took place in one basin, and most stratigraphic units are represented throughout the basin. The sediments were regionally deformed and metamorphosed at 1800 Ma. Tightly folded greenschist facies strata in the centre grade into isoclinally deformed amphibolite facies metamorphics in the west and northeast, granulites are present in the extreme northeast. Pre and post-orogenic continental tholeiites, and post-orogenic granite diapirs intrude the Early Proterozoic metasediments, and the granites are surrounded by hornfels zones up to 10 km wide in the greenschist facies terrane. Cover rocks of Carpentarian (Middle Proterozoic) and younger ages rest on all these rocks unconformably and conceal the original basin margins. The uranium deposits post-date the approx. 1800 Ma regional metamorphic event; isotopic dating of uraninite and galena in the ore bodies indicates ages of mineralisation at approx. 1600 Ma, approx. 900 Ma and approx. 500 Ma. The ore bodies are stratabound, located within breccia zones, are of a shallow depth, and occur immediately below the Early/Middle Proterozoic unconformity

  14. Ecological effects of contaminants and remedial actions in Bear Creek

    Energy Technology Data Exchange (ETDEWEB)

    Southworth, G.R.; Loar, J.M.; Ryon, M.G.; Smith, J.G.; Stewart, A.J. (Oak Ridge National Lab., TN (United States)); Burris, J.A. (C. E. Environmental, Inc., Tallahassee, FL (United States))

    1992-01-01

    Ecological studies of the Bear Creek watershed, which drains the area surrounding several Oak Ridge Y-12 Plant waste disposal facilities, were initiated in May 1984 and are continuing at present. These studies consisted of an initial, detailed characterization of the benthic invertebrate and fish communities in Bear Creek, and they were followed by a presently ongoing monitoring phase that involves reduced sampling intensities. The characterization phase utilized two approaches: (1) instream sampling of benthic invertebrate and fish communities in Bear Creek to identify spatial and temporal patterns in distribution and abundance and (2) laboratory bioassays on water samples from Bear Creek and selected tributaries to identify potential sources of toxicity to biota. The monitoring phase of the ecological program relates to the long-term goals of identifying and prioritizing contaminant sources and assessing the effectiveness of remedial actions. It continues activities of the characterization phase at less frequent intervals. The Bear Greek Valley is a watershed that drains the area surrounding several closed Oak Ridge Y-12 Plant waste disposal facilities. Past waste disposal practices in Bear Creek Valley resulted in contamination of Bear Creek and consequent ecological damage. Extensive remedial actions have been proposed at waste sites, and some of the have been implemented or are now underway. The proposed study plan consists of an initial, detailed characterization of the benthic invertebrate and fish communities in Bear Creek in the first year followed by a reduction in sampling intensity during the monitoring phase of the plan. The results of sampling conducted from May 1984 through early 1989 are presented in this report.

  15. Ecological effects of contaminants and remedial actions in Bear Creek

    International Nuclear Information System (INIS)

    Southworth, G.R.; Loar, J.M.; Ryon, M.G.; Smith, J.G.; Stewart, A.J.; Burris, J.A.

    1992-01-01

    Ecological studies of the Bear Creek watershed, which drains the area surrounding several Oak Ridge Y-12 Plant waste disposal facilities, were initiated in May 1984 and are continuing at present. These studies consisted of an initial, detailed characterization of the benthic invertebrate and fish communities in Bear Creek, and they were followed by a presently ongoing monitoring phase that involves reduced sampling intensities. The characterization phase utilized two approaches: (1) instream sampling of benthic invertebrate and fish communities in Bear Creek to identify spatial and temporal patterns in distribution and abundance and (2) laboratory bioassays on water samples from Bear Creek and selected tributaries to identify potential sources of toxicity to biota. The monitoring phase of the ecological program relates to the long-term goals of identifying and prioritizing contaminant sources and assessing the effectiveness of remedial actions. It continues activities of the characterization phase at less frequent intervals. The Bear Greek Valley is a watershed that drains the area surrounding several closed Oak Ridge Y-12 Plant waste disposal facilities. Past waste disposal practices in Bear Creek Valley resulted in contamination of Bear Creek and consequent ecological damage. Extensive remedial actions have been proposed at waste sites, and some of the have been implemented or are now underway. The proposed study plan consists of an initial, detailed characterization of the benthic invertebrate and fish communities in Bear Creek in the first year followed by a reduction in sampling intensity during the monitoring phase of the plan. The results of sampling conducted from May 1984 through early 1989 are presented in this report

  16. Från outsiderfilmmakare till etablerad indieregissör : David Lynch, Jim Jarmusch och Steven Soderbergh

    OpenAIRE

    Simberg, Maximilian

    2014-01-01

    Det här arbetet behandlar kreativ frihet och konstnärligt oberoende i filmskapande, utgående från begreppet independent film och regissörerna David Lynch, Jim Jarmusch och Steven Soderbergh. Den centrala frågeställningen är hur det har varit möjligt för en filmkonstnär att uppnå konstnärligt oberoende och samtidigt ha en långlivad och framgångsrik karriär. Arbetets fokus ligger på de tre regissörernas genombrottsfilmer; Eraserhead, Stranger Than Paradise och sex, lies, and videotape, och förs...

  17. FIDDLER CREEK POLYMER AUGMENTATION PROJECT; TOPICAL

    International Nuclear Information System (INIS)

    Lyle A. Johnson, Jr.

    2001-01-01

    The Fiddler Creek field is in Weston County, Wyoming, and was discovered in 1948. Secondary waterflooding recovery was started in 1955 and terminated in the mid-1980s with a fieldwide recovery of approximately 40%. The West Fiddler Creek Unit, the focus of this project, had a lower recovery and therefore has the most remaining oil. Before the project this unit was producing approximately 85 bbl of oil per day from 20 pumping wells and 17 swab wells. The recovery process planned for this project involved adapting two independent processes, the injection of polymer as a channel blocker or as a deep-penetrating permeability modifier, and the stabilization of clays and reduction of the residual oil saturation in the near-wellbore area around the injection wells. Clay stabilization was not conducted because long-term fresh water injection had not severely reduced the injectivity. It was determined that future polymer injection would not be affected by the clay. For the project, two adjoining project patterns were selected on the basis of prior reservoir studies and current well availability and production. The primary injection well of Pattern 1 was treated with a small batch of MARCIT gel to create channel blocking. The long-term test was designed for three phases: (1) 77 days of injection of a 300-mg/l cationic polyacrylamide, (2) 15 days of injection of a 300-mg/l anionic polymer to ensure injectivity of the polymer, and (3) 369 days of injection of the 300-mg/l anionic polymer and a 30:1 mix of the crosslinker. Phases 1 and 2 were conducted as planned. Phase 3 was started in late March 1999 and terminated in May 2001. In this phase, a crosslinker was added with the anionic polymer. Total injection for Phase 3 was 709,064 bbl. To maintain the desired injection rate, the injection pressure was slowly increased from 1,400 psig to 2,100 psig. Early in the application of the polymer, it appeared that the sweep improvement program was having a positive effect on Pattern 1

  18. Investigating the Maya Polity at Lower Barton Creek Cayo, Belize

    Science.gov (United States)

    Kollias, George Van, III

    The objectives of this research are to determine the importance of Lower Barton Creek in both time and space, with relation to other settlements along the Belize River Valley. Material evidence recovered from field excavations and spatial information developed from Lidar data were employed in determining the socio-political nature and importance of this settlement, so as to orient its existence within the context of ancient socio-political dynamics in the Belize River Valley. Before the investigations detailed in this thesis no archaeological research had been conducted in the area, the site of Lower Barton Creek itself was only recently identified via the 2013 West-Central Belize LiDAR Survey (WCBLS 2013). Previously, the southern extent of the Barton Creek area represented a major break in our knowledge not only of the Barton Creek area, but the southern extent of the Belize River Valley. Conducting research at Lower Barton Creek has led to the determination of the polity's temporal existence and allowed for a greater and more complex understanding of the Belize River Valley's interaction with regions abutting the Belize River Valley proper.

  19. Molecular Background of Colorectal Tumors From Patients with Lynch Syndrome Associated With Germline Variants in PMS2.

    Science.gov (United States)

    Ten Broeke, S W; van Bavel, T C; Jansen, A M L; Gómez-García, E; Hes, F J; van Hest, L P; Letteboer, T G W; Olderode-Berends, M J W; Ruano, D; Spruijt, L; Suerink, M; Tops, C M; van Eijk, R; Morreau, H; van Wezel, T; Nielsen, M

    2018-05-11

    Germline variants in the mismatch repair genes MLH1, MSH2 (EPCAM), MSH6, or PMS2 cause Lynch syndrome. Patients with these variants have an increased risk of developing colorectal cancers (CRCs) that differ from sporadic CRCs in genetic and histologic features. It has been a challenge to study CRCs associated with PMS2 variants (PMS2-associated CRCs) because these develop less frequently and in patients of older ages than colorectal tumors with variants in the other mismatch repair genes. We analyzed 20 CRCs associated with germline variants in PMS2, 22 sporadic CRCs, 18 CRCs with germline variants in MSH2, and 24 CRCs from patients with germline variants in MLH1. Tumor tissue blocks were collected from Dutch pathology departments in 2017. After extraction of tumor DNA, we used a platform designed to detect approximately 3000 somatic hotspot variants in 55 genes (including KRAS, APC, CTNNB1, and TP53). Somatic variant frequencies were compared using the Fisher's exact test. None of the PMS2-associated CRCs contained any somatic variants in the catenin beta 1 gene (CTNNB1), which encodes β-catenin, whereas 14/24 MLH1-associated CRCs (58%) contained variants in CTNNB1. Half of PMS2-associated CRCs contained KRAS variants, but only 20% of these were in hotspots that encoded G12D or G13D. These hotspot variants occurred more frequently in CRCs associated with variants in MLH1 (37.5%, P=.44) and MSH2 (and 71.4%, P=.035) than with variants in PMS2. In a genetic analysis of 84 colorectal tumors, we found tumors from patients with PMS2-associated Lynch syndrome to be distinct from colorectal tumors associated with defects in other mismatch repair genes. This might account for differences in development and less frequent occurrence. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

  20. Tumour MLH1 promoter region methylation testing is an effective pre-screen for Lynch Syndrome (HNPCC)

    Science.gov (United States)

    Newton, K; Jorgensen, NM; Wallace, AJ; Buchanan, DD; Lalloo, F; McMahon, RFT; Hill, J; Evans, DG

    2016-01-01

    Background & Aims Lynch syndrome patients have DNA mismatch repair deficiency and up to 80% life-time risk of colorectal cancer. Screening of mutation carriers reduces colorectal cancer incidence and mortality. Selection for constitutional mutation testing relies on family history (Amsterdam and Bethesda Guidelines) and tumour derived biomarkers. Initial biomarker analysis uses mismatch repair protein immunohistochemistry and microsatellite instability. Abnormalities in either identify mismatch repair deficiency but do not differentiate sporadic epigenetic defects, due to MLH1 promoter region methylation (13% of CRCs) from Lynch Syndrome (4% of CRCs). A diagnostic biomarker capable of making this distinction would be valuable. This study compared two biomarkers in tumours with mismatch repair deficiency; quantification of methylation of the MLH1 promoter region using a novel assay and BRAF c.1799T>A, p.(Val600Glu) mutation status in the identification of constitutional mutations. Methods Tumour DNA was extracted (FFPE tissue) and pyrosequencing used to test for MLH1 promoter methylation and presence of the BRAF c.1799T>A, p.(Val600Glu) mutation 71 CRCs from individuals with pathogenic MLH1 mutations and 73 CRCs with sporadic MLH1 loss. Specificity and sensitivity was compared. Findings Unmethylated MLH1 promoter: sensitivity 94.4% (95% CI 86.2–98.4%), specificity 87.7% (95% CI 77.9–94.2%), Wild-type BRAF (codon 600): sensitivity 65.8% (95% CI 53.7–76.5%), specificity 98.6% (95% CI 92.4–100.0%) for the identification of those with pathogenic MLH1 mutations. Conclusions Quantitative MLH1 promoter region methylation using pyrosequencing is superior to BRAF codon 600 mutation status in identifying constitutional mutations in mismatch repair deficient tumours. PMID:25280751

  1. Sherman Creek Hatchery, annual report 2000

    International Nuclear Information System (INIS)

    2001-01-01

    The Sherman Creek Hatchery (SCH) was designed to rear 1.7 million kokanee fry for acclimation and imprinting during the spring and early summer. Additionally, it was designed to trap all available returning adult kokanee during the fall for broodstock operations and evaluations. Since the start of this program, the operations on Lake Roosevelt have been modified to better achieve program goals. These strategic changes have been the result of recommendations through the Lake Roosevelt Hatcheries Coordination Team (LRHCT) and were done to enhance imprinting, improve survival and operate the two kokanee facilities more effectively. The primary changes have been to replace the kokanee fingerling program with a yearling (post smolt) program of up to 1,000,000 fish. To construct and operate twenty net pens to handle the increased production. The second significant change was to rear 200,000 rainbow trout fingerling at SCH from July through October, for stocking into the volunteer net pens. This enables the Spokane Tribal Hatchery (STH) to rear additional kokanee to further the enhancement efforts on Lake Roosevelt. Monitoring and evaluation is preformed by the Lake Roosevelt Fisheries Monitoring Program. From 1988 to 1998, the principle sport fishery on Lake Roosevelt has shifted from walleye to include rainbow trout and kokanee salmon (Underwood et al. 1997, Tilson and Scholz 1997). The angler use, harvest rates for rainbow and kokanee and the economic value of the fishery has increased substantially during this 10-year period. The most recent information from the monitoring program also suggests that the hatchery and net pen rearing programs have been beneficial to enhancing the Lake Roosevelt fishery while not negatively impacting wild and native stocks within the lake

  2. A systematic review and economic evaluation of diagnostic strategies for Lynch syndrome.

    Science.gov (United States)

    Snowsill, Tristan; Huxley, Nicola; Hoyle, Martin; Jones-Hughes, Tracey; Coelho, Helen; Cooper, Chris; Frayling, Ian; Hyde, Chris

    2014-09-01

    Lynch syndrome (LS) is an inherited autosomal dominant disorder characterised by an increased risk of colorectal cancer (CRC) and other cancers, and caused by mutations in the deoxyribonucleic acid (DNA) mismatch repair genes. To evaluate the accuracy and cost-effectiveness of strategies to identify LS in newly diagnosed early-onset CRC patients (aged strategies for individuals in whom LS is identified. Systematic reviews were conducted of the test accuracy of microsatellite instability (MSI) testing or immunohistochemistry (IHC) in individuals with CRC at risk of LS, and of economic evidence relating to diagnostic strategies for LS. Reviews were carried out in April 2012 (test accuracy); and in February 2012, repeated in February 2013 (economic evaluations). Databases searched included MEDLINE (1946 to April week 3, 2012), EMBASE (1980 to week 17, 2012) and Web of Science (inception to 30 April 2012), and risk of bias for test accuracy was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) quality appraisal tool. A de novo economic model of diagnostic strategies for LS was developed. Inconsistencies in study designs precluded pooling of diagnostic test accuracy results from a previous systematic review and nine subsequent primary studies. These were of mixed quality, with significant methodological concerns identified for most. IHC and MSI can both play a part in diagnosing LS but neither is gold standard. No UK studies evaluated the cost-effectiveness of diagnosing and managing LS, although studies from other countries generally found some strategies to be cost-effective compared with no testing. The de novo model demonstrated that all strategies were cost-effective compared with no testing at a threshold of £20,000 per quality-adjusted life-year (QALY), with the most cost-effective strategy utilising MSI and BRAF testing [incremental cost-effectiveness ratio (ICER) = £5491 per QALY]. The maximum health benefit to the

  3. NPDES Permit for Soap Creek Associates Wastewater Treatment Facility in Montana

    Science.gov (United States)

    Under National Pollutant Discharge Elimination System permit number MT-0023183, Soap Creek Associates, Inc. is authorized to discharge from its wastewater treatment facility located in West, Bighorn County, Montana, to Soap Creek.

  4. 75 FR 66077 - Mahoning Creek Hydroelectric Company, LLC; Notice of Availability of Supplemental Environmental...

    Science.gov (United States)

    2010-10-27

    ... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Project No. 12555-004-PA] Mahoning Creek Hydroelectric Company, LLC; Notice of Availability of Supplemental Environmental Assessment... Energy Projects has reviewed the application for an original license for the Mahoning Creek Hydroelectric...

  5. Marine ecological habitat: A case study on projected thermal power plant around Dharamtar creek, India

    Digital Repository Service at National Institute of Oceanography (India)

    Kulkarni, V.A.; Naidu, V.S.; Jagtap, T.G.

    Estuaries and tidal creeks, harboring mangroves particularly, face tremendous anthropogenic pressures. Expansion of mega cities and the thermal power plants are generally proposed in the vicinity of estuaries and creek, due to the feasibility...

  6. 76 FR 8728 - Bear Creek Hydro Associates, LLC; Notice of Preliminary Permit Application Accepted for Filing...

    Science.gov (United States)

    2011-02-15

    ... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Project No. 13951-000] Bear Creek Hydro..., Motions To Intervene, and Competing Applications On December 22, 2010, the Bear Creek Hydro Associates... (FPA), proposing to study the [[Page 8729

  7. Phytoplankton characteristics in a polluted Bombay Harbour-Thana-Bassein creek estuarine complex

    Digital Repository Service at National Institute of Oceanography (India)

    Ramaiah, Neelam; Ramaiah, N.; Nair, V.R.

    Annual variations in phytoplankton characteristics were studied from Bombay Harbour-Thana creek-Bassein creek (BHTCBC) estuarine confluence to assess the levels of pigment concentration, productivity and, qualitative and qunatitative nature...

  8. 78 FR 26063 - Central Utah Project Completion Act; East Hobble Creek Restoration Project Final Environmental...

    Science.gov (United States)

    2013-05-03

    ...-100-00-0-0, CUPCA00] Central Utah Project Completion Act; East Hobble Creek Restoration Project Final... Creek Restoration Project. These two agencies have determined that the proposed [[Page 26064

  9. Stream sediment detailed geochemical survey for Date Creek Basin, Arizona

    International Nuclear Information System (INIS)

    Butz, T.R.; Tieman, D.J.; Grimes, J.G.; Bard, C.S.; Helgerson, R.N.; Pritz, P.M.; Wolf, D.A.

    1981-01-01

    The purpose of the Date Creek Supplement is to characterize the chemistry of sediment samples representing stream basins in which the Anderson Mine (and related prospects) occur. Once characterized, the chemistry is then used to delineate other areas within the Date Creek Basin where stream sediment chemistry resembles that of the Anderson Mine area. This supplementary report examines more closely the data from sediment samples taken in 239 stream basins collected over a total area of approximately 900 km 2 (350 mi 2 ). Cluster and discriminant analyses are used to characterize the geochemistry of the stream sediment samples collected in the Date Creek Basin. Cluster and discriminant analysis plots are used to delineate areas having a potential for uranium mineralization similar to that of the Anderson Mine

  10. Simulation of effects of wastewater discharges on Sand Creek and lower Caddo Creek near Ardmore, Oklahoma

    Science.gov (United States)

    Wesolowski, Edwin A.

    1999-01-01

    A streamflow and water-quality model was developed for reaches of Sand and Caddo Creeks in south-central Oklahoma to simulate the effects of wastewater discharge from a refinery and a municipal treatment plant.The purpose of the model was to simulate conditions during low streamflow when the conditions controlling dissolved-oxygen concentrations are most severe. Data collected to calibrate and verify the streamflow and water-quality model include continuously monitored streamflow and water-quality data at two gaging stations and three temporary monitoring stations; wastewater discharge from two wastewater plants; two sets each of five water-quality samples at nine sites during a 24-hour period; dye and propane samples; periphyton samples; and sediment oxygen demand measurements. The water-quality sampling, at a 6-hour frequency, was based on a Lagrangian reference frame in which the same volume of water was sampled at each site. To represent the unsteady streamflows and the dynamic water-quality conditions, a transport modeling system was used that included both a model to route streamflow and a model to transport dissolved conservative constituents with linkage to reaction kinetics similar to the U.S. Environmental Protection Agency QUAL2E model to simulate nonconservative constituents. These model codes are the Diffusion Analogy Streamflow Routing Model (DAFLOW) and the branched Lagrangian transport model (BLTM) and BLTM/QUAL2E that, collectively, as calibrated models, are referred to as the Ardmore Water-Quality Model.The Ardmore DAFLOW model was calibrated with three sets of streamflows that collectively ranged from 16 to 3,456 cubic feet per second. The model uses only one set of calibrated coefficients and exponents to simulate streamflow over this range. The Ardmore BLTM was calibrated for transport by simulating dye concentrations collected during a tracer study when streamflows ranged from 16 to 23 cubic feet per second. Therefore, the model is expected to

  11. Towards gene-and gender-based risk estimates in Lynch syndrome; Age-specific incidences for 13 extra-colorectal cancer types

    DEFF Research Database (Denmark)

    Therkildsen, Christina; Ladelund, Steen; Smith-Hansen, Lars

    2017-01-01

    Background:In Lynch syndrome, inherited mismatch repair (MMR) defects predispose to colorectal cancer and to a wide spectrum of extra-colorectal tumours. Utilising a cohort study design, we aimed to determine the risk of extra-colorectal cancer and to identify yet unrecognised tumour types...... were identified for 13 cancer types with differences related to gender, age and disease-predisposing gene. The different cancer types showed variable peak age incidence rates (IRs) with the highest IRs for ovarian cancer at age 30-49 years, for endometrial cancer, breast cancer, renal cell cancer...... and brain tumours at age 50-69 years, and for urothelial cancer, small bowel cancer, gastric cancer, pancreatic cancer and skin tumours after age 70.Conclusions:The broad spectrum of tumour types that develop at an increased incidence defines Lynch syndrome as a multi-tumour syndrome. The variable...

  12. Identification and characterization of wetlands in the Bear Creek watershed

    International Nuclear Information System (INIS)

    Rosensteel, B.A.; Trettin, C.C.

    1993-10-01

    The primary objective of this study was to identify, characterize, and map the wetlands in the Bear Creek watershed. A preliminary wetland categorization system based on the Cowardin classification system (Cowardin et al. 1979) with additional site-specific topographic, vegetation, and disturbance characteristic modifiers was developed to characterize the type of wetlands that exist in the Bear Creek watershed. An additional objective was to detect possible relationships among site soils, hydrology, and the occurrence of wetlands in the watershed through a comparison of existing data with the field survey. Research needs are discussed in the context of wetland functions and values and regulatory requirements for wetland impact assessment and compensatory mitigation

  13. 76 FR 62758 - Wallowa-Whitman and Umatilla National Forests, Oregon Granite Creek Watershed Mining Plans

    Science.gov (United States)

    2011-10-11

    ... environmental analyses for proposed mining Plans in the portions of the Granite Creek Watershed under their... Granite Creek Watershed Mining Plans analysis area that meets the Purpose of and Need for Action. It is... Granite Creek Watershed Mining Plans AGENCY: Forest Service, USDA. ACTION: Notice of intent to prepare an...

  14. 78 FR 25484 - License Amendment for Anadarko Petroleum Corporation, Bear Creek Facility, Converse County, Wyoming

    Science.gov (United States)

    2013-05-01

    ... Petroleum Corporation, Bear Creek Facility, Converse County, Wyoming AGENCY: Nuclear Regulatory Commission.... 47 for its Bear Creek Uranium Mill facility in Converse County, Wyoming. The NRC has prepared an... INFORMATION: I. Background The Bear Creek Uranium Mill operated from September 1977 until January 1986, and...

  15. 76 FR 13344 - Beaver Creek Landscape Management Project, Ashland Ranger District, Custer National Forest...

    Science.gov (United States)

    2011-03-11

    ... DEPARTMENT OF AGRICULTURE Forest Service Beaver Creek Landscape Management Project, Ashland Ranger... Impact Statement for the Beaver Creek Landscape Management Project was published in the Federal Register... Responsible Official for the Beaver Creek Landscape Management Project. DATES: The Final Environmental Impact...

  16. 76 FR 65118 - Drawbridge Operation Regulation; Bear Creek, Sparrows Point, MD

    Science.gov (United States)

    2011-10-20

    ...-AA09 Drawbridge Operation Regulation; Bear Creek, Sparrows Point, MD AGENCY: Coast Guard, DHS. ACTION... regulation. The Baltimore County Revenue Authority (Dundalk Avenue) highway toll drawbridge across Bear Creek... applicable or necessary. Basis and Purpose The drawbridge across Bear Creek, mile 1.5 was removed and...

  17. 75 FR 31418 - Intermountain Region, Payette National Forest, Council Ranger District; Idaho; Mill Creek-Council...

    Science.gov (United States)

    2010-06-03

    ... Ranger District; Idaho; Mill Creek--Council Mountain Landscape Restoration Project AGENCY: Forest Service... the Mill Creek--Council Mountain Landscape Restoration Project. The approximate 51,900 acre project area is located about two miles east of Council, Idaho. The Mill Creek--Council Mountain Landscape...

  18. 75 FR 68780 - Cedar Creek Wind Energy, LLC; Notice of Filing

    Science.gov (United States)

    2010-11-09

    ... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. RC11-1-000] Cedar Creek Wind Energy, LLC; Notice of Filing November 2, 2010. Take notice that on October 27, 2010, Cedar Creek Wind Energy, LLC (Cedar Creek) filed an appeal with the Federal Energy Regulatory Commission (Commission) of...

  19. La representación de los personajes monstruosos en el cine de David Lynch: Cabeza Borradora y El Hombre Elefante

    OpenAIRE

    Suñer Royo, Iris

    2015-01-01

    Treball final de Grau en Comunicació Audiovisual. Codi: CA0932. Curs acadèmic 2014-2015 El universo creado por David Lynch es prácticamente inabarcable, sin embargo, con cada producto que realiza incorpora nuevas estrategias expresivas y formales que podemos desglosar y analizar para entender cada vez mejor como su mente y creatividad se desarrollan. Para ello hemos empezado desde el principio, por sus dos primeros largometrajes, los cuales son los únicos filmados en blanco ...

  20. MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer.

    Science.gov (United States)

    Talseth-Palmer, Bente A; McPhillips, Mary; Groombridge, Claire; Spigelman, Allan; Scott, Rodney J

    2010-05-21

    Approximately 10% of Lynch syndrome families have a mutation in MSH6 and fewer families have a mutation in PMS2. It is assumed that the cancer incidence is the same in families with mutations in MSH6 as in families with mutations in MLH1/MSH2 but that the disease tends to occur later in life, little is known about families with PMS2 mutations. This study reports on our findings on mutation type, cancer risk and age of diagnosis in MSH6 and PMS2 families. A total of 78 participants (from 29 families) with a mutation in MSH6 and 7 participants (from 6 families) with a mutation in PMS2 were included in the current study. A database of de-identified patient information was analysed to extract all relevant information such as mutation type, cancer incidence, age of diagnosis and cancer type in this Lynch syndrome cohort. Cumulative lifetime risk was calculated utilising Kaplan-Meier survival analysis. MSH6 and PMS2 mutations represent 10.3% and 1.9%, respectively, of the pathogenic mutations in our Australian Lynch syndrome families. We identified 26 different MSH6 and 4 different PMS2 mutations in the 35 families studied. We report 15 novel MSH6 and 1 novel PMS2 mutations. The estimated cumulative risk of CRC at age 70 years was 61% (similar in males and females) and 65% for endometrial cancer in MSH6 mutation carriers. The risk of developing CRC is different between males and females at age 50 years, which is 34% for males and 21% for females. Novel MSH6 and PMS2 mutations are being reported and submitted to the current databases for identified Lynch syndrome mutations. Our data provides additional information to add to the genotype-phenotype spectrum for both MSH6 and PMS2 mutations.

  1. MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer

    Directory of Open Access Journals (Sweden)

    Talseth-Palmer Bente A

    2010-05-01

    Full Text Available Abstract Background Approximately 10% of Lynch syndrome families have a mutation in MSH6 and fewer families have a mutation in PMS2. It is assumed that the cancer incidence is the same in families with mutations in MSH6 as in families with mutations in MLH1/MSH2 but that the disease tends to occur later in life, little is known about families with PMS2 mutations. This study reports on our findings on mutation type, cancer risk and age of diagnosis in MSH6 and PMS2 families. Methods A total of 78 participants (from 29 families with a mutation in MSH6 and 7 participants (from 6 families with a mutation in PMS2 were included in the current study. A database of de-identified patient information was analysed to extract all relevant information such as mutation type, cancer incidence, age of diagnosis and cancer type in this Lynch syndrome cohort. Cumulative lifetime risk was calculated utilising Kaplan-Meier survival analysis. Results MSH6 and PMS2 mutations represent 10.3% and 1.9%, respectively, of the pathogenic mutations in our Australian Lynch syndrome families. We identified 26 different MSH6 and 4 different PMS2 mutations in the 35 families studied. We report 15 novel MSH6 and 1 novel PMS2 mutations. The estimated cumulative risk of CRC at age 70 years was 61% (similar in males and females and 65% for endometrial cancer in MSH6 mutation carriers. The risk of developing CRC is different between males and females at age 50 years, which is 34% for males and 21% for females. Conclusion Novel MSH6 and PMS2 mutations are being reported and submitted to the current databases for identified Lynch syndrome mutations. Our data provides additional information to add to the genotype-phenotype spectrum for both MSH6 and PMS2 mutations.

  2. Isolated loss of PMS2 immunohistochemical expression is frequently caused by heterogeneous MLH1 promoter hypermethylation in Lynch syndrome screening for endometrial cancer patients

    OpenAIRE

    Kato, Aya; Sato, Naoki; Sugawara, Tae; Takahashi, Kazue; Kito, Masahiko; Makino, Kenichi; Sato, Toshiharu; Shimizu, Dai; Shirasawa, Hiromitu; Miura, Hiroshi; Sato, Wataru; Kumazawa, Yukiyo; Sato, Akira; Kumagai, Jin; Terada, Yukihiro

    2016-01-01

    Lynch syndrome (LS) is an autosomal dominant inherited disorder mainly caused by a germline mutation in the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) and is associated with increased risk of various cancers, particularly colorectal cancer and endometrial cancer (EC). Women with LS account for 2–6% of EC patients; it is clinically important to identify LS in such individuals for predicting and/or preventing additional LS-associated cancers. PMS2 germline mutation ...

  3. The Uterine Sandwich Method for Placenta Previa Accreta in Mullerian Anomaly: Combining the B-Lynch Compression Suture and an Intrauterine Gauze Tampon

    Directory of Open Access Journals (Sweden)

    Mustafa Kaplanoğlu

    2013-01-01

    Full Text Available Mullerian duct anomalies may cause obstetric complications, such as postpartum hemorrhage (PPH and placental adhesion anomalies. Uterine compression suture may be useful for controlling PPH (especially atony. In recent studies, uterine compression sutures have been used in placenta accreta. We report a case of PPH, a placenta accreta accompanying a large septae, treated with B-Lynch suture and intrauterine gauze tampon.

  4. Functional analysis in mouse embryonic stem cells reveals wild-type activity for three MSH6 variants found in suspected Lynch syndrome patients.

    Directory of Open Access Journals (Sweden)

    Eva A L Wielders

    Full Text Available Lynch syndrome confers an increased risk to various types of cancer, in particular early onset colorectal and endometrial cancer. Mutations in mismatch repair (MMR genes underlie Lynch syndrome, with the majority of mutations found in MLH1 and MSH2. Mutations in MSH6 have also been found but these do not always cause a clear cancer predisposition phenotype and MSH6-defective tumors often do not show the standard characteristics of MMR deficiency, such as microsatellite instability. In particular, the consequences of MSH6 missense mutations are challenging to predict, which further complicates genetic counseling. We have previously developed a method for functional characterization of MSH2 missense mutations of unknown significance. This method is based on endogenous gene modification in mouse embryonic stem cells using oligonucleotide-directed gene targeting, followed by a series of functional assays addressing the MMR functions. Here we have adapted this method for the characterization of MSH6 missense mutations. We recreated three MSH6 variants found in suspected Lynch syndrome families, MSH6-P1087R, MSH6-R1095H and MSH6-L1354Q, and found all three to behave like wild type MSH6. Thus, despite suspicion for pathogenicity from clinical observations, our approach indicates these variants are not disease causing. This has important implications for counseling of mutation carriers.

  5. Effect of low B-Lynch suture on menstrual cycle recovery and sex hormone levels in patients after cesarean section for placenta previa

    Directory of Open Access Journals (Sweden)

    Su-Lan Zhang

    2016-03-01

    Full Text Available Objective: To explore the effect of low B-Lynch suture on the menstrual cycle recovery and sex hormone levels in patients after cesarean section for placenta previa. Methods: A total of 40 patients who were admitted in our hospital from August, 2013 to August, 2015 for cesarean section due to placenta previa were included in the study and randomized into the observation group and the control group. The patients in the observation group were given low B-lynch suture, while in the control group, yarns were plugged in the uterus. The bleeding during operation and 24 h after operation, the postpartum lochia duration, and menstrual cycle recovery in the two groups were observed. The postpartum FSH, E2, and LH levels in the two groups were determined. Results: The amount of bleeding during operation and 24 h after operation in the observation group was significantly less than that in the control group (P0.05. The comparison of FSH, E2, and LH levels between the two groups was not statistically significant (P>0.05. Conclusions: Low B-Lynch suture can effectively reduce the amount of bleeding after cesarean section for placenta previa, and has no effect on the menstrual recovery and ovarian function with a simple operation and less postoperative complications; therefore, it deserves to be widely recommended in the clinic.

  6. Smoking and colorectal cancer in Lynch syndrome: Results from the Colon Cancer Family Registry and The University of Texas M. D. Anderson Cancer Center

    Science.gov (United States)

    Pande, Mala; Lynch, Patrick M.; Hopper, John L.; Jenkins, Mark A.; Gallinger, Steve; Haile, Robert W.; LeMarchand, Loic; Lindor, Noralane M.; Campbell, Peter T.; Newcomb, Polly A.; Potter, John D.; Baron, John A.; Frazier, Marsha L.; Amos, Christopher I.

    2009-01-01

    Purpose Lynch syndrome family members with inherited germline mutations in DNA mismatch repair (MMR) genes have a high risk of colorectal cancer (CRC) and cases typically have tumors that exhibit a high level of microsatellite instability (MSI). There is some evidence that smoking is a risk factor for CRCs with high MSI, but the association of smoking with CRC among those with Lynch syndrome is unknown. Experimental Design A multicentered retrospective cohort of 752 carriers of pathogenic MMR gene mutations was analyzed, using a weighted Cox regression analysis, adjusting for sex, ascertainment source, the specific mutated gene, year of birth, and familial clustering. Results Compared with never smokers, current smokers had a significantly increased CRC risk (adjusted hazard ratio [HR] = 1.62; 95% CI, 1.01 – 2.57) and former smokers who had quit smoking for 2 or more years were at decreased risk (HR = 0.53; 95% CI, 0.35 – 0.82). CRC risk did not vary according to age at starting. However, light smoking (Lynch syndrome may be at increased risk of CRC if they smoke regularly. Although our data suggest that former smokers, short-term and light smokers are at decreased CRC risk, these findings need further confirmation, preferably using prospective designs. PMID:20145170

  7. Cell cycle–related genes as modifiers of age of onset of colorectal cancer in Lynch syndrome: a large-scale study in non-Hispanic white patients

    Science.gov (United States)

    Chen, Jinyun; Pande, Mala

    2013-01-01

    Heterogeneity in age of onset of colorectal cancer in individuals with mutations in DNA mismatch repair genes (Lynch syndrome) suggests the influence of other lifestyle and genetic modifiers. We hypothesized that genes regulating the cell cycle influence the observed heterogeneity as cell cycle–related genes respond to DNA damage by arresting the cell cycle to provide time for repair and induce transcription of genes that facilitate repair. We examined the association of 1456 single nucleotide polymorphisms (SNPs) in 128 cell cycle–related genes and 31 DNA repair–related genes in 485 non-Hispanic white participants with Lynch syndrome to determine whether there are SNPs associated with age of onset of colorectal cancer. Genotyping was performed on an Illumina GoldenGate platform, and data were analyzed using Kaplan–Meier survival analysis, Cox regression analysis and classification and regression tree (CART) methods. Ten SNPs were independently significant in a multivariable Cox proportional hazards regression model after correcting for multiple comparisons (P Lynch syndrome. PMID:23125224

  8. Changes in screening behaviors and attitudes toward screening from pre-test genetic counseling to post-disclosure in Lynch syndrome families

    Science.gov (United States)

    Burton-Chase, Allison M.; Hovick, Shelly R.; Peterson, Susan K.; Marani, Salma K.; Vernon, Sally W.; Amos, Christopher I.; Frazier, Marsha L.; Lynch, Patrick M.; Gritz, Ellen R.

    2013-01-01

    Purpose This study examined colonoscopy adherence and attitudes towards colorectal cancer (CRC) screening in individuals who underwent Lynch syndrome genetic counseling and testing. Methods We evaluated changes in colonoscopy adherence and CRC screening attitudes in 78 cancer-unaffected relatives of Lynch syndrome mutation carriers before pre-test genetic counseling (baseline) and at 6 and 12 months post-disclosure of test results (52 mutation-negative, 26 mutation-positive). Results While both groups were similar at baseline, at 12 months post-disclosure, a greater number of mutation-positive individuals had had a colonoscopy compared with mutation-negative individuals. From baseline to 12 months post-disclosure, the mutation-positive group demonstrated an increase in mean scores on measures of colonoscopy commitment, self-efficacy, and perceived benefits of CRC screening, and a decrease in mean scores for perceived barriers to CRC screening. Mean scores on colonoscopy commitment decreased from baseline to 6 months in the mutation-negative group. Conclusion Adherence to risk-appropriate guidelines for CRC surveillance improved after genetic counseling and testing for Lynch syndrome. Mutation-positive individuals reported increasingly positive attitudes toward CRC screening after receiving genetic test results, potentially reinforcing longer term colonoscopy adherence. PMID:23414081

  9. Cell cycle-related genes as modifiers of age of onset of colorectal cancer in Lynch syndrome: a large-scale study in non-Hispanic white patients.

    Science.gov (United States)

    Chen, Jinyun; Pande, Mala; Huang, Yu-Jing; Wei, Chongjuan; Amos, Christopher I; Talseth-Palmer, Bente A; Meldrum, Cliff J; Chen, Wei V; Gorlov, Ivan P; Lynch, Patrick M; Scott, Rodney J; Frazier, Marsha L

    2013-02-01

    Heterogeneity in age of onset of colorectal cancer in individuals with mutations in DNA mismatch repair genes (Lynch syndrome) suggests the influence of other lifestyle and genetic modifiers. We hypothesized that genes regulating the cell cycle influence the observed heterogeneity as cell cycle-related genes respond to DNA damage by arresting the cell cycle to provide time for repair and induce transcription of genes that facilitate repair. We examined the association of 1456 single nucleotide polymorphisms (SNPs) in 128 cell cycle-related genes and 31 DNA repair-related genes in 485 non-Hispanic white participants with Lynch syndrome to determine whether there are SNPs associated with age of onset of colorectal cancer. Genotyping was performed on an Illumina GoldenGate platform, and data were analyzed using Kaplan-Meier survival analysis, Cox regression analysis and classification and regression tree (CART) methods. Ten SNPs were independently significant in a multivariable Cox proportional hazards regression model after correcting for multiple comparisons (P Lynch syndrome.

  10. Surface-water and ground-water quality in the Powell Creek and Armstrong Creek Watersheds, Dauphin County, Pennsylvania, July-September 2001

    Science.gov (United States)

    Galeone, Daniel G.; Low, Dennis J.

    2003-01-01

    Powell Creek and Armstrong Creek Watersheds are in Dauphin County, north of Harrisburg, Pa. The completion of the Dauphin Bypass Transportation Project in 2001 helped to alleviate traffic congestion from these watersheds to Harrisburg. However, increased development in Powell Creek and Armstrong Creek Watersheds is expected. The purpose of this study was to establish a baseline for future projects in the watersheds so that the effects of land-use changes on water quality can be documented. The Pennsylvania Department of Environmental Protection (PADEP) (2002) indicates that surface water generally is good in the 71 perennial stream miles in the watersheds. PADEP lists 11.1 stream miles within the Armstrong Creek and 3.2 stream miles within the Powell Creek Watersheds as impaired or not meeting water-quality standards. Siltation from agricultural sources and removal of vegetation along stream channels are cited by PADEP as likely factors causing this impairment.

  11. Streamflow characteristics and trends along Soldier Creek, Northeast Kansas

    Science.gov (United States)

    Juracek, Kyle E.

    2017-08-16

    Historical data for six selected U.S. Geological Survey streamgages along Soldier Creek in northeast Kansas were used in an assessment of streamflow characteristics and trends. This information is required by the Prairie Band Potawatomi Nation for the effective management of tribal water resources, including drought contingency planning. Streamflow data for the period of record at each streamgage were used to assess annual mean streamflow, annual mean base flow, mean monthly flow, annual peak flow, and annual minimum flow.Annual mean streamflows along Soldier Creek were characterized by substantial year-to-year variability with no pronounced long-term trends. On average, annual mean base flow accounted for about 20 percent of annual mean streamflow. Mean monthly flows followed a general seasonal pattern that included peak values in spring and low values in winter. Annual peak flows, which were characterized by considerable year-to-year variability, were most likely to occur in May and June and least likely to occur during November through February. With the exception of a weak yet statistically significant increasing trend at the Soldier Creek near Topeka, Kansas, streamgage, there were no pronounced long-term trends in annual peak flows. Annual 1-day, 30-day, and 90-day mean minimum flows were characterized by considerable year-to-year variability with no pronounced long-term trend. During an extreme drought, as was the case in the mid-1950s, there may be zero flow in Soldier Creek continuously for a period of one to several months.

  12. Large woody debris budgets in the Caspar Creek Experimental Watersheds

    Science.gov (United States)

    Sue Hilton

    2012-01-01

    Monitoring of large woody debris (LWD) in the two mainstem channels of the Caspar Creek Experimental Watersheds since 1998, combined with older data from other work in the watersheds, gives estimates of channel wood input rates, survival, and outputs in intermediate-sized channels in coastal redwood forests. Input rates from standing trees for the two reaches over a 15...

  13. Preliminary investigations on the Ichthyodiversity of Kilifi Creek, Kenya

    African Journals Online (AJOL)

    (Smith, 1939) off the Kenyan coast at Malindi only. 50 km north of ... communities, river fed creek, upstream and the bay proper, in Gazi ... habitat degradation: pollution, overfishing, ..... exploitable fishes from a marine park and its effect on the ...

  14. 78 FR 67084 - Drawbridge Operation Regulation; Broad Creek, Laurel, DE

    Science.gov (United States)

    2013-11-08

    ...-AA09 Drawbridge Operation Regulation; Broad Creek, Laurel, DE AGENCY: Coast Guard, DHS. ACTION: Notice....25, both at Laurel, DE. The proposed new rule would change the current regulation by requiring a..., mile 8.2, all at Laurel, shall open on signal if at least 48 hours notice is given. Previous regulation...

  15. Short notes and reviews The fossil fauna of Mazon Creek

    NARCIS (Netherlands)

    Schultze, Hans-Peter

    1998-01-01

    Review of: Richardson’s Guide to the Fossil Fauna of Mazon Creek, edited by Charles W. Shabica & Andrew A. Hay. Northeastern Illinois University, Chicago, Illinois, 1997: XVIII + 308 pp., 385 figs., 4 tables, 1 faunal list; $75.00 (hard cover) ISBN 0-925065-21-8. Since the last century, the area

  16. Forest Creeks Research Natural Area: guidebook supplement 39

    Science.gov (United States)

    Reid Schuller; Ron Halvorson

    2010-01-01

    This guidebook describes Forest Creeks Research Natural Area, a 164-ha (405-ac) area comprising two geographically distinct canyons and associated drainages. The two units have been established as examples of first- to third-order streams originating within a ponderosa pine (Pinus ponderosa) zone. The two riparian areas also represent examples of...

  17. Copepod composition, abundance and diversity in Makupa Creek ...

    African Journals Online (AJOL)

    Evenness (J) was, however, relatively constant (0.67 to 0.84) during the entire sampling period. These results point to suppressed copepod diversity and abundance in Makupa Creek, and possible reasons for this, which may include environmental degradation caused by pollution, are presented. Western Indian Ocean ...

  18. Cherry Creek Research Natural Area: guidebook supplement 41

    Science.gov (United States)

    Reid Schuller; Jennie Sperling; Tim Rodenkirk

    2011-01-01

    This guidebook describes Cherry Creek Research Natural Area, a 239-ha (590-ac) area that supports old-growth Douglas-fir-western hemlock (Pseudotsuga menziesii- Tsuga heterophylla) forest occurring on sedimentary materials in the southern Oregon Coast Range. Major plant associations present within the area include the western hemlock/Oregon oxalis...

  19. Fish Creek Rim Research Natural Area: guidebook supplement 50

    Science.gov (United States)

    Reid Schuller; Ian Grinter

    2016-01-01

    This guidebook describes major biological and physical attributes of the 3531-ha (8,725-ac) Fish Creek Rim Research Natural Area located within the Northern Basin and Range ecoregion and managed by the Bureau of Land Management, Lakeview District (USDI BLM 2003).

  20. WARM SPRINGS CREEK GEOTHERMAL STUDY, BLAIN COUNTY IDAHO, 1987

    Science.gov (United States)

    In the Warm Springs Creek drainage near Ketchum, Idaho (17040219), a leaking pipeline coveys geothermal water through the valley to heat nearby homes as well as to supply a resorts swimming pool. Several domestic wells in close proximity to this line have exhibited increasing fl...

  1. Tillman Creek Mitigation Site As-Build Report.

    Energy Technology Data Exchange (ETDEWEB)

    Gresham, Doug [Otak, Inc.

    2009-05-29

    This as-built report describes site conditions at the Tillman Creek mitigation site in South Cle Elum, Washington. This mitigation site was constructed in 2006-2007 to compensate for wetland impacts from the Yakama Nation hatchery. This as-built report provides information on the construction sequence, as-built survey, and establishment of baseline monitoring stations.

  2. 78 FR 47427 - AUC, LLC Reno Creek, In Situ

    Science.gov (United States)

    2013-08-05

    ... NUCLEAR REGULATORY COMMISSION [Docket No. 040-09092; NRC-2013-0164] AUC, LLC Reno Creek, In Situ... October 3, 2012, AUC submitted a license application to the U.S. Nuclear Regulatory Commission (NRC... provided the first time that a document is referenced. The AUC License Application request and additional...

  3. 75 FR 43915 - Basin Electric Power Cooperative: Deer Creek Station

    Science.gov (United States)

    2010-07-27

    ... factors that could be affected by the proposed Project were evaluated in detail in the EIS. These issues... DEPARTMENT OF AGRICULTURE Rural Utilities Service Basin Electric Power Cooperative: Deer Creek... Energy Facility project (Project) in Brookings and Deuel Counties, South Dakota. The Administrator of RUS...

  4. EAARL topography-Potato Creek watershed, Georgia, 2010

    Science.gov (United States)

    Bonisteel-Cormier, J.M.; Nayegandhi, Amar; Fredericks, Xan; Jones, J.W.; Wright, C.W.; Brock, J.C.; Nagle, D.B.

    2011-01-01

    This DVD contains lidar-derived first-surface (FS) and bare-earth (BE) topography GIS datasets of a portion of the Potato Creek watershed in the Apalachicola-Chattahoochee-Flint River basin, Georgia. These datasets were acquired on February 27, 2010.

  5. A baseline and watershed assessment in the Lynx Creek, Brenot Creek, and Portage Creek watersheds near Hudson's Hope, BC : summary report

    International Nuclear Information System (INIS)

    Matscha, G.; Sutherland, D.

    2005-06-01

    This report summarized a baseline monitoring program for the Lynx Creek, Brenot Creek, and Portage Creek watersheds located near Hudson's Hope, British Columbia (BC). The monitoring program was designed to more accurately determine the effects of potential coalbed gas developments in the region, as well as to assess levels of agricultural and forest harvesting, and the impacts of current land use activities on water quantity and quality. Water quality was sampled at 18 sites during 5 different flow regimes, including summer and fall low flows; ice cover; spring run-off; and high flows after a heavy summer rain event. Sample sites were located up and downstream of both forest and agricultural activities. The water samples were analyzed for 70 contaminants including ions, nutrients, metals, hydrocarbons, and hydrocarbon fractions. Results showed that while many analyzed parameters met current BC water quality guidelines, total organic carbon, manganese, cadmium, E. coli, fecal coliforms, and fecal streptococci often exceeded recommended guidelines. Aluminum and cobalt values exceeded drinking water guidelines. The samples also had a slightly alkaline pH and showed high conductance. A multiple barrier approach was recommended to reduce potential risks of contamination from the watersheds. It was concluded that a more refined bacteria source tracking method is needed to determine whether fecal pollution has emanated from human, livestock or wildlife sources. 1 tab., 9 figs

  6. 78 FR 2990 - Bear Creek Storage Company, L.L.C.; Notice of Request Under Blanket Authorization

    Science.gov (United States)

    2013-01-15

    ... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. CP13-34-000] Bear Creek..., 2012, Bear Creek Storage Company, L.L.C. (Bear Creek), 569 Brookwood Village, Suite 749, Birmingham....208, 157.213 and 157.216 of the Commission's Regulations under the Natural Gas Act, and Bear Creek's...

  7. Pine Creek Ranch, FY 2001 annual report; ANNUAL

    International Nuclear Information System (INIS)

    Berry, Mark E.

    2001-01-01

    Pine Creek Ranch was purchased in 1999 by the Confederated Tribes of Warm Springs using Bonneville Power Administration Fish and Wildlife Habitat Mitigation funds. The 25,000 acre property will be managed in perpetuity for the benefit of fish and wildlife habitat. Major issues include: (1) Restoring quality spawning and rearing habitat for stealhead. Streams are incised and fish passage barriers exist from culverts and possibly beaver dams. In addition to stealhead habitat, the Tribes are interested in overall riparian recovery in the John Day River system for wildlife habitat, watershed values and other values such as recreation. (2) Future grazing for specific management purposes. Past grazing practices undoubtedly contributed to current unacceptable conditions. The main stem of Pine Creek has already been enrolled in the CREP program administered by the USDA, Natural Resource Conservation Service in part because of the cost-share for vegetation restoration in a buffer portion of old fields and in part because of rental fees that will help the Tribes to pay the property taxes. Grazing is not allowed in the riparian buffer for the term of the contract. (3) Noxious weeds are a major concern. (4) Encroachment by western juniper throughout the watershed is a potential concern for the hydrology of the creek. Mark Berry, Habitat Manager, for the Pine Creek Ranch requested the Team to address the following objectives: (1) Introduce some of the field staff and others to Proper Functioning Condition (PFC) assessments and concepts. (2) Do a PFC assessment on approximately 10 miles of Pine Creek. (3) Offer management recommendations. (4) Provide guidelines for monitoring

  8. Identification and verification of a pathogenic MLH1 mutation c.1145dupA in a Lynch syndrome family

    Directory of Open Access Journals (Sweden)

    Huang Feifei

    2017-06-01

    Full Text Available Lynch syndrome (LS, an autosomal-dominant disorder with an increased risk of predominantly colorectal and endometrial cancers, is caused by germ-line mutations in mismatch repair genes. The identification of germ-line mutations that predispose to cancer is important to further our understanding of tumorigenesis, guide patient management and inform the best practice for healthcare. A 45-year-old woman with atypical endometrial hyperplasia who suffered colon cancer at the age of 30 years underwent hysterectomy and genetic counseling. Pedigree analysis revealed her family fulfilling the Amsterdam I criteria. Next-generation sequencing was offered to the patient. A mutation in the MLH1 gene, c.1145dupA, was identified and verified by Sanger sequencing. In addition, her nine family members were tested for the mutation. Two were affected (colon cancer at the age of 43 years and 45 years and one healthy relative carried the same mutation in the MLH1 gene. The mutation resulted in a frame-shift (p.Met383Aspfs*12 located in exon12, as well as a polypeptide truncation of 393 amino acids by the formation of a premature stop codon. An immunohistochemistry analysis of endometrial hyperplasia tissues revealed defects in MLH1 and PMS2 protein expression in the patient. Based on the 2015 American College of Medical Genetics and Genomics (ACMG guideline, we report this MLH1 c.1145dupA variation to be a pathogenic mutation that contributes to a strongly increased cancer risk in this LS family. Proper screening suggestions were offered to the three affected patients and the healthy carrier. To the best of our knowledge, this germ-line mutation of MLH1 was previously submitted to the Leiden Open Variation Database (LOVD database, but no comprehensive evidence or supporting observations were reported previously in the literature. The present report found a single nucleotide insertion in exon12 of the MLH1 gene, which can be considered causative of Lynch phenotype

  9. Linchamientos y conflicto político en Los Andes Lynchings and Political conflict in The Andes

    Directory of Open Access Journals (Sweden)

    Carlos M. Vilas

    2007-06-01

    Full Text Available En 2004, los alcaldes de dos municipalidades de la región aimara de los Andes fueron linchados en la aparente culminación de agudos conflictos políticos internos y entre las respectivas comunidades y el Estado central. En este artículo se discuten ambos casos con el fin de ilustrar las transformaciones experimentadas en años recientes en la organización y la dinámica interna de las comunidades andinas, y de la articulación conflictiva de la política local en los procesos e instituciones de más amplio alcance. Precariedad social e incapacidad o renuencia del Estado para responder con eficacia a demandas básicas de determinados grupos de población configuran enmarcamientos socioeconómicos e institucionales de los linchamientos. En contraste con enfoques que enfatizan en factores culturales tradicionales o en un supuesto nacionalismo indígena, en el artículo se destaca la gravitación de fenómenos y procesos político- institucionales recientes en la transformación cultural y política de las comunidades, en el modo en que éstas procesan sus conflictos internos y con el Estado central.In 2004, two municipalitys mayors form the aimara Andes of Peru and Bolivia were subjected to mass lynchings as a result of the apparent culmination of violent political confrontations. This paper deals with these events as dramatic illustrations of the transformations the Andean communities experienced during recent decades in their internal dynamics, as well as in the articulation of local politics to processes and institutions beyond the communal limits. Structural precariousness combined with the state's inability or reluctance to come to terms with social or political demands from relevant segments of the people in the communities set the socioeconomic and institutional stage for lynchings. In contrast with approaches relating these events to an alleged indigenous cultural identity, the analysis points to the impact of the communities' political

  10. Assessment of hydrology, water quality, and trace elements in selected placer-mined creeks in the birch creek watershed near central, Alaska, 2001-05

    Science.gov (United States)

    Kennedy, Ben W.; Langley, Dustin E.

    2007-01-01

    Executive Summary The U.S. Geological Survey, in cooperation with the Bureau of Land Management, completed an assessment of hydrology, water quality, and trace-element concentrations in streambed sediment of the upper Birch Creek watershed near Central, Alaska. The assessment covered one site on upper Birch Creek and paired sites, upstream and downstream from mined areas, on Frying Pan Creek and Harrison Creek. Stream-discharge and suspended-sediment concentration data collected at other selected mined and unmined sites helped characterize conditions in the upper Birch Creek watershed. The purpose of the project was to provide the Bureau of Land Management with baseline information to evaluate watershed water quality and plan reclamation efforts. Data collection began in September 2001 and ended in September 2005. There were substantial geomorphic disturbances in the stream channel and flood plain along several miles of Harrison Creek. Placer mining has physically altered the natural stream channel morphology and removed streamside vegetation. There has been little or no effort to re-contour waste rock piles. During high-flow events, the abandoned placer-mine areas on Harrison Creek will likely contribute large quantities of sediment downstream unless the mined areas are reclaimed. During 2004 and 2005, no substantial changes in nutrient or major-ion concentrations were detected in water samples collected upstream from mined areas compared with water samples collected downstream from mined areas on Frying Pan Creek and Harrison Creek that could not be attributed to natural variation. This also was true for dissolved oxygen, pH, and specific conductance-a measure of total dissolved solids. Sample sites downstream from mined areas on Harrison Creek and Frying Pan Creek had higher median suspended-sediment concentrations, by a few milligrams per liter, than respective upstream sites. However, it is difficult to attach much importance to the small downstream increase

  11. Geophysical Characterization of the Hilton Creek Fault System

    Science.gov (United States)

    Lacy, A. K.; Macy, K. P.; De Cristofaro, J. L.; Polet, J.

    2016-12-01

    The Long Valley Caldera straddles the eastern edge of the Sierra Nevada Batholith and the western edge of the Basin and Range Province, and represents one of the largest caldera complexes on Earth. The caldera is intersected by numerous fault systems, including the Hartley Springs Fault System, the Round Valley Fault System, the Long Valley Ring Fault System, and the Hilton Creek Fault System, which is our main region of interest. The Hilton Creek Fault System appears as a single NW-striking fault, dipping to the NE, from Davis Lake in the south to the southern rim of the Long Valley Caldera. Inside the caldera, it splays into numerous parallel faults that extend toward the resurgent dome. Seismicity in the area increased significantly in May 1980, following a series of large earthquakes in the vicinity of the caldera and a subsequent large earthquake swarm which has been suggested to be the result of magma migration. A large portion of the earthquake swarms in the Long Valley Caldera occurs on or around the Hilton Creek Fault splays. We are conducting an interdisciplinary geophysical study of the Hilton Creek Fault System from just south of the onset of splay faulting, to its extension into the dome of the caldera. Our investigation includes ground-based magnetic field measurements, high-resolution total station elevation profiles, Structure-From-Motion derived topography and an analysis of earthquake focal mechanisms and statistics. Preliminary analysis of topographic profiles, of approximately 1 km in length, reveals the presence of at least three distinct fault splays within the caldera with vertical offsets of 0.5 to 1.0 meters. More detailed topographic mapping is expected to highlight smaller structures. We are also generating maps of the variation in b-value along different portions of the Hilton Creek system to determine whether we can detect any transition to more swarm-like behavior towards the North. We will show maps of magnetic anomalies, topography

  12. Simulation of water quality for Salt Creek in northeastern Illinois

    Science.gov (United States)

    Melching, Charles S.; Chang, T.J.

    1996-01-01

    Water-quality processes in the Salt Creek watershed in northeastern Illinois were simulated with a computer model. Selected waste-load scenarios for 7-day, 10-year low-flow conditions were simulated in the stream system. The model development involved the calibration of the U.S. Environmental Protection Agency QUAL2E model to water-quality constituent concentration data collected by the Illinois Environmental Protection Agency (IEPA) for a diel survey on August 29-30, 1995, and the verification of this model with water-quality constituent concentration data collected by the IEPA for a diel survey on June 27-28, 1995. In-stream measurements of sediment oxygen demand rates and carbonaceous biochemical oxygen demand (CBOD) decay rates by the IEPA and traveltime and reaeration-rate coefficients by the U.S. Geological Survey facilitated the development of a model for simulation of water quality in the Salt Creek watershed. In general, the verification of the calibrated model increased confidence in the utility of the model for water-quality planning in the Salt Creek watershed. However, the model was adjusted to better simulate constituent concentrations measured during the June 27-28, 1995, diel survey. Two versions of the QUAL2E model were utilized to simulate dissolved oxygen (DO) concentrations in the Salt Creek watershed for selected effluent discharge and concentration scenarios for water-quality planning: (1) the QUAL2E model calibrated to the August 29-30, 1995, diel survey, and (2) the QUAL2E model adjusted to the June 27-28, 1995, diel survey. The results of these simulations indicated that the QUAL2E model adjusted to the June 27-28, 1995, diel survey simulates reliable information for water-quality planning. The results of these simulations also indicated that to maintain DO concentrations greater than 5 milligrams per liter (mg/L) throughout most of Salt Creek for 7-day, 10-year low-flow conditions, the sewage-treatment plants (STP's) must discharge

  13. Development and validation of an instrument to measure the impact of genetic testing on self-concept in Lynch syndrome.

    Science.gov (United States)

    Esplen, M J; Stuckless, N; Gallinger, S; Aronson, M; Rothenmund, H; Semotiuk, K; Stokes, J; Way, C; Green, J; Butler, K; Petersen, H V; Wong, J

    2011-11-01

    A positive genetic test result may impact on a person's self-concept and affect quality of life. The purpose of the study was to develop a self-concept scale to measure such impact for individuals carrying mutations for a heritable colorectal cancer Lynch syndrome (LS). Two distinct phases were involved: Phase 1 generated specific colorectal self-concept candidate scale items from interviews with eight LS carriers and five genetic counselors, which were added to a previously developed self-concept scale for BRCA1/2 mutation carriers, Phase II had 115 LS carriers complete the candidate scale and a battery of validating measures. A 20-item scale was developed with two dimensions identified through factor analysis: stigma/vulnerability and bowel symptom-related anxiety. The scale showed excellent reliability (Cronbach's α = 0.93), good convergent validity by a high correlation with impact of event scale (r(102) = 0.55, p Rosenberg self-esteem scale (r(108) = -0.59, p scale's performance was stable across participant characteristics. This new scale for measuring self-concept has potential to be used as a clinical tool and as a measure for future studies. © 2011 John Wiley & Sons A/S.

  14. A case of early onset rectal cancer of Lynch syndrome with a novel deleterious PMS2 mutation.

    Science.gov (United States)

    Nomura, Sachio; Fujimoto, Yoshiya; Yamamoto, Noriko; Sato, Yuri; Ashihara, Yuumi; Kita, Mizuho; Yamaguchi, Junya; Ishikawa, Yuichi; Ueno, Masashi; Arai, Masami

    2015-10-01

    Heterozygous deleterious mutation of the PMS2 gene is a cause of Lynch syndrome, an autosomal dominant cancer disease. However, the frequency of PMS2 mutation is rare compared with that of the other causative genes; MSH2, MLH1 and MSH6. PMS2 mutation has so far only been reported once from a Japanese facility. Detection of PMS2 mutation is relatively complicated due to the existence of 15 highly homologous pseudogenes, and its gene conversion event with the pseudogene PMS2CL. Therefore, for PMS2 mutation analysis, it is crucial to clearly distinguish PMS2 from its pseudogenes. We report here a novel deleterious 11 bp deletion mutation of exon 11 of PMS2 distinguished from PMS2CL in a 34-year-old Japanese female with rectal cancer. PMS2 mutated at c.1492del11 results in a truncated 500 amino acid protein rather than the wild-type protein of 862 amino acids. This is supported by the fact that, although there is usually concordance between MLH1 and PMS2 expression, cells were immunohistochemically positive for MLH1, whereas PMS2 could not be immunohistochemically stained using an anti-C-terminal PMS2 antibody, or effective PMS2 mRNA degradation with NMD caused by the frameshift mutation. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  15. Identification of Lynch syndrome mutations in the MLH1-PMS2 interface that disturb dimerization and mismatch repair.

    Science.gov (United States)

    Kosinski, Jan; Hinrichsen, Inga; Bujnicki, Janusz M; Friedhoff, Peter; Plotz, Guido

    2010-08-01

    Missense alterations of the mismatch repair gene MLH1 have been identified in a significant proportion of individuals suspected of having Lynch syndrome, a hereditary syndrome that predisposes for cancer of colon and endometrium. The pathogenicity of many of these alterations, however, is unclear. A number of MLH1 alterations are located in the C-terminal domain (CTD) of MLH1, which is responsible for constitutive dimerization with PMS2. We analyzed which alterations may result in pathogenic effects due to interference with dimerization. We used a structural model of CTD of MLH1-PMS2 heterodimer to select 19 MLH1 alterations located inside and outside two candidate dimerization interfaces in the MLH1-CTD. Three alterations (p.Gln542Leu, p.Leu749Pro, p.Tyr750X) caused decreased coexpression of PMS2, which is unstable in the absence of interaction with MLH1, suggesting that these alterations interfere with dimerization. All three alterations are located within the dimerization interface suggested by our model. They also compromised mismatch repair, suggesting that defects in dimerization abrogate repair and confirming that all three alterations are pathogenic. Additionally, we provided biochemical evidence that four alterations with uncertain pathogenicity (p.Ala586Pro, p.Leu636Pro, p.Thr662Pro, and p.Arg755Trp) are deleterious because of poor expression or poor repair efficiency, and confirm the deleterious effect of eight further alterations.

  16. Frameshift mutational target gene analysis identifies similarities and differences in constitutional mismatch repair-deficiency and Lynch syndrome.

    Science.gov (United States)

    Maletzki, Claudia; Huehns, Maja; Bauer, Ingrid; Ripperger, Tim; Mork, Maureen M; Vilar, Eduardo; Klöcking, Sabine; Zettl, Heike; Prall, Friedrich; Linnebacher, Michael

    2017-07-01

    Mismatch-repair deficient (MMR-D) malignancies include Lynch Syndrome (LS), which is secondary to germline mutations in one of the MMR genes, and the rare childhood-form of constitutional mismatch repair-deficiency (CMMR-D); caused by bi-allelic MMR gene mutations. A hallmark of LS-associated cancers is microsatellite instability (MSI), characterized by coding frameshift mutations (cFSM) in target genes. By contrast, tumors arising in CMMR-D patients are thought to display a somatic mutation pattern differing from LS. This study has the main goal to identify cFSM in MSI target genes relevant in CMMR-D and to compare the spectrum of common somatic mutations, including alterations in DNA polymerases POLE and D1 between LS and CMMR-D. CMMR-D-associated tumors harbored more somatic mutations compared to LS cases, especially in the TP53 gene and in POLE and POLD1, where novel mutations were additionally identified. Strikingly, MSI in classical mononucleotide markers BAT40 and CAT25 was frequent in CMMR-D cases. MSI-target gene analysis revealed mutations in CMMR-D-associated tumors, some of them known to be frequently hit in LS, such as RNaseT2, HT001, and TGFβR2. Our results imply a general role for these cFSM as potential new drivers of MMR-D tumorigenesis. © 2017 Wiley Periodicals, Inc.

  17. Diversity of genetic events associated with MLH1 promoter methylation in Lynch syndrome families with heritable constitutional epimutation.

    Science.gov (United States)

    Leclerc, Julie; Flament, Cathy; Lovecchio, Tonio; Delattre, Lucie; Ait Yahya, Emilie; Baert-Desurmont, Stéphanie; Burnichon, Nelly; Bronner, Myriam; Cabaret, Odile; Lejeune, Sophie; Guimbaud, Rosine; Morin, Gilles; Mauillon, Jacques; Jonveaux, Philippe; Laurent-Puig, Pierre; Frébourg, Thierry; Porchet, Nicole; Buisine, Marie-Pierre

    2018-04-12

    PurposeConstitutional epimutations are an alternative to genetic mutations in the etiology of genetic diseases. Some of these epimutations, termed secondary, correspond to the epigenetic effects of cis-acting genetic defects transmitted to the offspring following a Mendelian inheritance pattern. In Lynch syndrome, a few families with such apparently heritable MLH1 epimutations have been reported so far.MethodsWe designed a long-range polymerase chain reaction next-generation sequencing strategy to screen MLH1 entire gene and applied it to 4 French families with heritable epimutations and 10 additional patients with no proven transmission of their epimutations.ResultsThis strategy successfully detected the insertion of an Alu element in MLH1 coding sequence in one family. Two previously unreported MLH1 variants were also identified in other epimutation carriers: a nucleotide substitution within intron 1 and a single-nucleotide deletion in the 5'-UTR. Detection of a partial MLH1 duplication in another family required multiplex ligation-dependent probe amplification technology. We demonstrated the segregation of these variants with MLH1 methylation and studied the functional consequences of these defects on transcription.ConclusionThis is the largest cohort of patients with MLH1 secondary epimutations associated with a broad spectrum of genetic defects. This study provides further insight into the complexity of molecular mechanisms leading to secondary epimutations.GENETICS in MEDICINE advance online publication, 12 April 2018; doi:10.1038/gim.2018.47.

  18. First description of mutational analysis of MLH1, MSH2 and MSH6 in Algerian families with suspected Lynch syndrome.

    Science.gov (United States)

    Ziada-Bouchaar, H; Sifi, K; Filali, T; Hammada, T; Satta, D; Abadi, N

    2017-01-01

    Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disorder characterized by the early onset of colorectal cancer (CRC) linked to germline defects in Mismatch Repair (MMR) genes. We present here, the first molecular study of the correlation between CRC and mutations occurring in these genes performed in twenty-one unrelated Algerian families. The presence of germline mutations in MMR genes, MLH1, MSH2 and MSH6 genes was tested by sequencing all exons plus adjacent intronic sequences and Multiplex ligand-dependent probe amplification (MLPA) for testing large genomic rearrangements. Pathogenic mutations were identified in 20 % of families with clinical suspicion on HNPCC. Two novel variants described for the first time in Algerian families were identified in MLH1, c.881_884delTCAGinsCATTCCT and a large deletion in MSH6 gene from a young onset of CRC. Moreover, the variants of MSH2 gene: c.942+3A>T, c.1030C>T, the most described ones, were also detected in Algerian families. Furthermore, the families HNPCC caused by MSH6 germline mutation may show an age of onset that is comparable to this of patients with MLH1 and MSH2 mutations. In this study, we confirmed that MSH2, MLH1, and MSH6 contribute to CRC susceptibility. This work represents the implementation of a diagnostic algorithm for the identification of Lynch syndrome patients in Algerian families.

  19. Stakeholder perspectives on implementing a universal Lynch syndrome screening program: a qualitative study of early barriers and facilitators.

    Science.gov (United States)

    Schneider, Jennifer L; Davis, James; Kauffman, Tia L; Reiss, Jacob A; McGinley, Cheryl; Arnold, Kathleen; Zepp, Jamilyn; Gilmore, Marian; Muessig, Kristin R; Syngal, Sapna; Acheson, Louise; Wiesner, Georgia L; Peterson, Susan K; Goddard, Katrina A B

    2016-02-01

    Evidence-based guidelines recommend that all newly diagnosed colon cancer be screened for Lynch syndrome (LS), but best practices for implementing universal tumor screening have not been extensively studied. We interviewed a range of stakeholders in an integrated health-care system to identify initial factors that might promote or hinder the successful implementation of a universal LS screening program. We conducted interviews with health-plan leaders, managers, and staff. Interviews were audio-recorded and transcribed. Thematic analysis began with a grounded approach and was also guided by the Practical Robust Implementation and Sustainability Model (PRISM). We completed 14 interviews with leaders/managers and staff representing involved clinical and health-plan departments. Although stakeholders supported the concept of universal screening, they identified several internal (organizational) and external (environment) factors that promote or hinder implementation. Facilitating factors included perceived benefits of screening for patients and organization, collaboration between departments, and availability of organizational resources. Barriers were also identified, including: lack of awareness of guidelines, lack of guideline clarity, staffing and program "ownership" concerns, and cost uncertainties. Analysis also revealed nine important infrastructure-type considerations for successful implementation. We found that clinical, laboratory, and administrative departments supported universal tumor screening for LS. Requirements for successful implementation may include interdepartmental collaboration and communication, patient and provider/staff education, and significant infrastructure and resource support related to laboratory processing and systems for electronic ordering and tracking.

  20. In Silico Systems Biology Analysis of Variants of Uncertain Significance in Lynch Syndrome Supports the Prioritization of Functional Molecular Validation.

    Science.gov (United States)

    Borras, Ester; Chang, Kyle; Pande, Mala; Cuddy, Amanda; Bosch, Jennifer L; Bannon, Sarah A; Mork, Maureen E; Rodriguez-Bigas, Miguel A; Taggart, Melissa W; Lynch, Patrick M; You, Y Nancy; Vilar, Eduardo

    2017-10-01

    Lynch syndrome (LS) is a genetic condition secondary to germline alterations in the DNA mismatch repair (MMR) genes with 30% of changes being variants of uncertain significance (VUS). Our aim was to perform an in silico reclassification of VUS from a large single institutional cohort that will help prioritizing functional validation. A total of 54 VUS were detected with 33 (61%) novel variants. We integrated family history, pathology, and genetic information along with supporting evidence from eight different in silico tools at the RNA and protein level. Our assessment allowed us to reclassify 54% (29/54) of the VUS as probably damaging, 13% (7/54) as possibly damaging, and 28% (15/54) as probably neutral. There are more than 1,000 VUS reported in MMR genes and our approach facilitates the prioritization of further functional efforts to assess the pathogenicity to those classified as probably damaging. Cancer Prev Res; 10(10); 580-7. ©2017 AACR . ©2017 American Association for Cancer Research.

  1. White Oak Creek embayment sediment retention structure design and construction

    International Nuclear Information System (INIS)

    Van Hoesen, S.D.; Kimmell, B.L.; Page, D.G.; Wilkerson, R.B.; Hudson, G.R.; Kauschinger, J.L.; Zocolla, M.

    1994-01-01

    White Oak Creek is the major surface water drainage throughout the Department of Energy (DOE) Oak Ridge National Laboratory (ORNL). Samples taken from the lower portion of the creek revealed high levels of Cesium 137 and lower level of Cobalt 60 in near surface sediment. Other contaminants present in the sediment included: lead, mercury, chromium, and PCBs. In October 1990, DOE, US Environmental Protection Agency (EPA), and Tennessee Department of Environment and Conservation (TDEC) agreed to initiate a time critical removal action in accordance with the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) to prevent the transport of the contaminated sediments into the Clinch River system. This paper discusses the environmental, regulatory, design, and construction issues that were encountered in conducting the remediation work

  2. Hydrologic data for North Creek, Trinity River basin, Texas, 1976

    Science.gov (United States)

    Kidwell, C.C.

    1978-01-01

    This report contains rainfall and runoff data collected during the 1976 water year for a 21.6-square mile area above the stream-gaging station on North Creek near Jacksboro, Texas. A continuous water-stage recording gage was installed at one representative floodwater-retarding structure (site 28-A) on Oct. 5, 1972. The data are used to compute the contents, surface area, inflow, and outflow at this site. The stream-gaging station on North Creek near Jacksboro continuously records the water level which, with measurements of streamflow, is used to compute the runoff from the study area. Streamflow records at this gage began on Aug. 8, 1956. Detailed rainfall-runoff computations, including hydrographs and mass curves, are included for two storm periods during the 1976 water year at the stream-gaging station. (Woodard-USGS)

  3. Hydrologic data for North Creek, Trinity River basin, Texas, 1979

    Science.gov (United States)

    Kidwell, C.C.

    1981-01-01

    This report contains rainfall and runoff data collected during the 1979 water year for the 21.6-square mile area above the stream-gaging station North Creek near Jacksboro, Texas. A continuous water-stage recording gage was installed at one representative floodwater-retarding structure (site 28-A) on Oct. 5, 1972. The data are collected to compute the contents, surface area, inflow, and outflow at this site. The stream-gaging station on North Creek near Jacksboro continuously records the water level which, with measurements of streamflow, is used to compute the runoff from the study area. Streamflow records at this gage began on Aug. 8, 1956. Detailed rainfall-runoff computations are included for one storm during the 1979 water year at the stream-gaging station. (USGS)

  4. Retran simulation of Oyster Creek generator trip startup test

    International Nuclear Information System (INIS)

    Alammar, M.A.

    1987-01-01

    RETRAN simulation of Oyster Creek generator trip startup test was carried out as part of Oyster Creek RETRAN model qualification program for reload licensing applications. The objective of the simulation was to qualify the turbine model and its interface with the control valve and bypass systems under severe transients. The test was carried out by opening the main breakers at rated power. The turbine speed governor closed the control valves and the pressure regulator opened the bypass valves within 0.5 sec. The stop valves closed by a no-load turbine trip, before the 10 percent overspeed trip was reached and the reactor scrammed on high APRM neutron flux. The simulation resulted in qualifying a normalized hydraulic torque for the turbine model and a 0.3 sec, delay block for the bypass model to account for the different delays in the hydraulic linkages present in the system. One-dimensional kinetics was used in this simulation

  5. Water quality monitoring report for the White Oak Creek Embayment

    International Nuclear Information System (INIS)

    Ford, C.J.; Wefer, M.T.

    1993-01-01

    Water quality monitoring activities that focused on the detection of resuspended sediments in the Clinch River were conducted in conjunction with the White Oak Creek Embayment (WOCE) time-critical Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) removal action to construct a sediment-retention structure at the mouth of White Oak Creek (WOC). Samples were collected by use of a 24-h composite sampler and through real-time water grab sampling of sediment plumes generated by the construction activities. Sampling stations were established both at the WOC mouth, immediately adjacent to the construction site, and at K-1513, the Oak Ridge K-25 Site drinking water intake approximately 9.6 km downstream in the Clinch River. Results are described

  6. Numerical simulation of flow in Brush Creek Valley, Colorado

    International Nuclear Information System (INIS)

    Leone, J.M. Jr.; Lee, R.L.

    1987-06-01

    In this paper, we present some results from our three-dimensional, non-hydrostatic, finite element model applied to simulations of flow in Brush Creek Valley. These simulations are not intended to reproduce any particular experiment, but rather are to evaluate the qualitative performance of the model, to explore the major difficulties involved, and to begin sensitivity studies of the flows of interest. 2 refs., 11 figs

  7. Canyon Creek: A late Pleistocene vertebrate locality in interior Alaska

    Science.gov (United States)

    Weber, Florence R.; Hamilton, Thomas D.; Hopkins, David M.; Repenning, Charles A.; Haas, Herbert

    1981-09-01

    The Canyon Creek vertebrate-fossil locality is an extensive road cut near Fairbanks that exposes sediments that range in age from early Wisconsin to late Holocene. Tanana River gravel at the base of the section evidently formed during the Delta Glaciation of the north-central Alaska Range. Younger layers and lenses of fluvial sand are interbedded with arkosic gravel from Canyon Creek that contains tephra as well as fossil bones of an interstadial fauna about 40,000 years old. Solifluction deposits containing ventifacts, wedge casts, and rodent burrows formed during a subsequent period of periglacial activity that took place during the maximum phase of Donnelly Glaciation about 25,000-17,000 years ago. Overlying sheets of eolian sand are separated by a 9500-year-old paleosol that may correlate with a phase of early Holocene spruce expansion through central Alaska. The Pleistocene fauna from Canyon Creek consists of rodents (indicated by burrows), Mammuthus primigenius (woolly mammoth), Equus lambei (Yukon wild ass), Camelops hesternus (western camel), Bison sp. cf. B. crassicornis (large-horned bison), Ovis sp. cf. O. dalli (mountain sheep), Canis sp. cf. C. lupus (wolf), Lepus sp. cf. L. othus or L. arcticus (tundra hare), and Rangifer sp. (caribou). This assemblage suggests an open landscape in which trees and tall shrubs were either absent or confined to sheltered and moist sites. Camelops evidently was present in eastern Beringia during the middle Wisconsin interstadial interval but may have disappeared during the following glacial episode. The stratigraphic section at Canyon Creek appears to demonstrate that the Delta Glaciation of the north-central Alaska Range is at least in part of early Wisconsin age and was separated from the succeeding Donnelly Glaciation by an interstadial rather than interglacial episode.

  8. NITRATE REDUCTION PROGRAM AT THE LINE CREEK OPERATION

    OpenAIRE

    Jeff W Hawley

    2015-01-01

    Blasting activities at the Line Creek operation are releasing oxides of nitrogen and arecontributing to chemical changes in the surrounding watersheds. Through analysis of themechanisms of nitrogen release, history of explosive usage, historical nitrate release, changingregulatory requirements, strategy analysis and social impacts associated with the release ofnitrates a nitrate reduction plan will be established.The paper develops the framework for engineering groups, operations groups andma...

  9. Screening of the DNA mismatch repair genes MLH1, MSH2 and MSH6 in a Greek cohort of Lynch syndrome suspected families

    International Nuclear Information System (INIS)

    Thodi, Georgia; Fountzilas, George; Yannoukakos, Drakoulis; Fostira, Florentia; Sandaltzopoulos, Raphael; Nasioulas, George; Grivas, Anastasios; Boukovinas, Ioannis; Mylonaki, Maria; Panopoulos, Christos; Magic, Mirjana Brankovic

    2010-01-01

    Germline mutations in the DNA mismatch repair genes predispose to Lynch syndrome, thus conferring a high relative risk of colorectal and endometrial cancer. The MLH1, MSH2 and MSH6 mutational spectrum reported so far involves minor alterations scattered throughout their coding regions as well as large genomic rearrangements. Therefore, a combination of complete sequencing and a specialized technique for the detection of genomic rearrangements should be conducted during a proper DNA-testing procedure. Our main goal was to successfully identify Lynch syndrome families and determine the spectrum of MLH1, MSH2 and MSH6 mutations in Greek Lynch families in order to develop an efficient screening protocol for the Greek colorectal cancer patients' cohort. Forty-two samples from twenty-four families, out of which twenty two of Greek, one of Cypriot and one of Serbian origin, were screened for the presence of germline mutations in the major mismatch repair genes through direct sequencing and MLPA. Families were selected upon Amsterdam criteria or revised Bethesda guidelines. Ten deleterious alterations were detected in twelve out of the twenty-four families subjected to genetic testing, thus our detection rate is 50%. Four of the pathogenic point mutations, namely two nonsense, one missense and one splice site change, are novel, whereas the detected genomic deletion encompassing exon 6 of the MLH1 gene has been described repeatedly in the LOVD database. The average age of onset for the development of both colorectal and endometrial cancer among mutation positive families is 43.2 years. The mutational spectrum of the MMR genes investigated as it has been shaped by our analysis is quite heterogeneous without any strong indication for the presence of a founder effect

  10. Stability of a sand spit due to dredging in an adjacent creek

    Digital Repository Service at National Institute of Oceanography (India)

    Patgaonkar, R.S.; Ilangovan, D.; Vethamony, P.; Babu, M.T.; Jayakumar, S.; Rajagopal, M.D.

    , safety factor 1. Introduction The Jatadharmohan creek (hereinafter referred to as JMC) is a tidal creek oriented in the NE-SW direction (Fig. 1) and lies to the south of Paradip, along the east coast of India. This creek runs almost parallel... cor = 15 + (Nobs -15)/2, for Nobs > 15 b) Overburden correction: Ncor = Nobs x 350/ (? + 70) where, ? = overburden pressure The critical circular failure surface is the one for which factor of safety is the least. This is arrived...

  11. Restoration Potential of a Mining-Impacted Urban Stream: Horseshoe Branch of Lion Creek, Oakland, CA

    OpenAIRE

    Hackenjos, Bethany; Woelfle-Erskine, Cleo; Wood, Jacob

    2010-01-01

    Horseshoe Creek, located in the Oakland Hills of California, flows through a remnant oak and redwood forests in Horseshoe Canyon. From the 1880s through the 1930s, nearby Leona sulfur mine deposited massive tailings piles in the valleys east of Horseshoe Creek. During that time, clear-cut logging of redwoods denuded and destabilized the surrounding hillsides. Today, most of Horseshoe Creekʼs upper and middle reaches are either culverted or transformed into an engineered channel, and Merritt C...

  12. Feasibility Report and Environmental Statement for Water Resources Development, Cache Creek Basin, California

    Science.gov (United States)

    1979-02-01

    classified as Porno , Lake Miwok, and Patwin. Recent surveys within the Clear Lake-Cache Creek Basin have located 28 archeological sites, some of which...additional 8,400 acre-feet annually to the Lakeport area. Porno Reservoir on Kelsey Creek, being studied by Lake County, also would supplement M&l water...project on Scotts Creek could provide 9,100 acre- feet annually of irrigation water. Also, as previously discussed, Porno Reservoir would furnish

  13. Estimates of Nutrient Loading by Ground-Water Discharge into the Lynch Cove Area of Hood Canal, Washington

    Science.gov (United States)

    Simonds, F. William; Swarzenski, Peter W.; Rosenberry, Donald O.; Reich, Christopher D.; Paulson, Anthony J.

    2008-01-01

    field investigations show that ground-water discharge into the Lynch Cove area of Hood Canal is highly dynamic and strongly affected by the large tidal range. In areas with a steep shoreline and steep hydraulic gradient, ground-water discharge is spatially concentrated in or near the intertidal zone, with increased discharge during low tide. Topographically flat areas with weak hydraulic gradients had more spatial variability, including larger areas of seawater recirculation and more widely dispersed discharge. Measured total-dissolved-nitrogen concentrations in ground water ranged from below detection limits to 2.29 milligrams per liter and the total load entering Lynch Cove was estimated to be approximately 98 ? 10.3 metric tons per year (MT/yr). This estimate is based on net freshwater seepage rates from Lee-type seepage meter measurements and can be compared to estimates derived from geochemical tracer mass balance estimates (radon and radium) of 231 to 749 MT/yr, and previous water-mass-balance estimates (14 to 47 MT/ yr). Uncertainty in these loading estimates is introduced by complex biogeochemical cycles of relevant nutrient species, the representativeness of measurement sites, and by energetic dynamics at the coastal aquifer-seawater interface caused by tidal forcing.

  14. Systematic study on genetic and epimutational profile of a cohort of Amsterdam criteria-defined Lynch Syndrome in Singapore.

    Directory of Open Access Journals (Sweden)

    Yanqun Liu

    Full Text Available BACKGROUND: Germline defects of mismatch repair (MMR genes underlie Lynch Syndrome (LS. We aimed to gain comprehensive genetic and epigenetic profiles of LS families in Singapore, which will facilitate efficient molecular diagnosis of LS in Singapore and the region. METHODS: Fifty nine unrelated families were studied. Mutations in exons, splice-site junctions and promoters of five MMR genes were scanned by high resolution melting assay followed by DNA sequencing, large fragment deletions/duplications and promoter methylation in MLH1, MSH2, MSH6 and PMS2 were evaluated by multiplex ligation-dependent probe amplification. Tumor microsatellite instability (MSI was assessed with five mononucleotide markers and immunohistochemical staining (IHC was also performed. RESULTS: Pathogenic defects, all confined to MLH1 and MSH2, were identified in 17 out of 59 (28.8% families. The mutational spectrum was highly heterogeneous and 28 novel variants were identified. One recurrent mutation in MLH1 (c.793C>T was also observed. 92.9% sensitivity for indication of germline mutations conferred by IHC surpassed 64.3% sensitivity by MSI. Furthermore, 15.6% patients with MSS tumors harbored pathogenic mutations. CONCLUSIONS: Among major ethnic groups in Singapore, all pathogenic germline defects were confined to MLH1 and MSH2. Caution should be applied when the Amsterdam criteria and consensus microsatellite marker panel recommended in the revised Bethesda guidelines are applied to the local context. We recommend a screening strategy for the local LS by starting with tumor IHC and the hotspot mutation testing at MLH1 c.793C>T followed by comprehensive mutation scanning in MLH1 and MSH2 prior to proceeding to other MMR genes.

  15. MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer.

    Science.gov (United States)

    Roberts, Maegan E; Jackson, Sarah A; Susswein, Lisa R; Zeinomar, Nur; Ma, Xinran; Marshall, Megan L; Stettner, Amy R; Milewski, Becky; Xu, Zhixiong; Solomon, Benjamin D; Terry, Mary Beth; Hruska, Kathleen S; Klein, Rachel T; Chung, Wendy K

    2018-01-18

    PurposeAn association of Lynch syndrome (LS) with breast cancer has been long suspected; however, there have been insufficient data to address this question for each of the LS genes individually.MethodsWe conducted a retrospective review of personal and family history in 423 women with pathogenic or likely pathogenic germ-line variants in MLH1 (N = 65), MSH2 (N = 94), MSH6 (N = 140), or PMS2 (N = 124) identified via clinical multigene hereditary cancer testing. Standard incidence ratios (SIRs) of breast cancer were calculated by comparing breast cancer frequencies in our study population with those in the general population (Surveillance, Epidemiology, and End Results 18 data).ResultsWhen evaluating by gene, the age-standardized breast cancer risks for MSH6 (SIR = 2.11; 95% confidence interval (CI), 1.56-2.86) and PMS2 (SIR = 2.92; 95% CI, 2.17-3.92) were associated with a statistically significant risk for breast cancer whereas no association was observed for MLH1 (SIR = 0.87; 95% CI, 0.42-1.83) or MSH2 (SIR = 1.22; 95% CI, 0.72-2.06).ConclusionOur data demonstrate that two LS genes, MSH6 and PMS2, are associated with an increased risk for breast cancer and should be considered when ordering genetic testing for individuals who have a personal and/or family history of breast cancer.GENETICS in MEDICINE advance online publication, 18 January 2018; doi:10.1038/gim.2017.254.

  16. Evaluation of current prediction models for Lynch syndrome: updating the PREMM5 model to identify PMS2 mutation carriers.

    Science.gov (United States)

    Goverde, A; Spaander, M C W; Nieboer, D; van den Ouweland, A M W; Dinjens, W N M; Dubbink, H J; Tops, C J; Ten Broeke, S W; Bruno, M J; Hofstra, R M W; Steyerberg, E W; Wagner, A

    2018-07-01

    Until recently, no prediction models for Lynch syndrome (LS) had been validated for PMS2 mutation carriers. We aimed to evaluate MMRpredict and PREMM5 in a clinical cohort and for PMS2 mutation carriers specifically. In a retrospective, clinic-based cohort we calculated predictions for LS according to MMRpredict and PREMM5. The area under the operator receiving characteristic curve (AUC) was compared between MMRpredict and PREMM5 for LS patients in general and for different LS genes specifically. Of 734 index patients, 83 (11%) were diagnosed with LS; 23 MLH1, 17 MSH2, 31 MSH6 and 12 PMS2 mutation carriers. Both prediction models performed well for MLH1 and MSH2 (AUC 0.80 and 0.83 for PREMM5 and 0.79 for MMRpredict) and fair for MSH6 mutation carriers (0.69 for PREMM5 and 0.66 for MMRpredict). MMRpredict performed fair for PMS2 mutation carriers (AUC 0.72), while PREMM5 failed to discriminate PMS2 mutation carriers from non-mutation carriers (AUC 0.51). The only statistically significant difference between PMS2 mutation carriers and non-mutation carriers was proximal location of colorectal cancer (77 vs. 28%, p PMS2 mutation carriers (AUC 0.77) and overall (AUC 0.81 vs. 0.72). We validated these results in an external cohort of 376 colorectal cancer patients, including 158 LS patients. MMRpredict and PREMM5 cannot adequately identify PMS2 mutation carriers. Adding location of colorectal cancer to PREMM5 may improve the performance of this model, which should be validated in larger cohorts.

  17. Refining the role of PMS2 in Lynch syndrome: germline mutational analysis improved by comprehensive assessment of variants.

    Science.gov (United States)

    Borràs, Ester; Pineda, Marta; Cadiñanos, Juan; Del Valle, Jesús; Brieger, Angela; Hinrichsen, Inga; Cabanillas, Ruben; Navarro, Matilde; Brunet, Joan; Sanjuan, Xavier; Musulen, Eva; van der Klift, Helen; Lázaro, Conxi; Plotz, Guido; Blanco, Ignacio; Capellá, Gabriel

    2013-08-01

    The majority of mismatch repair (MMR) gene mutations causing Lynch syndrome (LS) occur either in MLH1 or MSH2. However, the relative contribution of PMS2 is less well defined. The aim of this study was to evaluate the role of PMS2 in LS by assessing the pathogenicity of variants of unknown significance (VUS) detected in the mutational analysis of PMS2 in a series of Spanish patients. From a cohort of 202 LS suspected patients, 13 patients showing loss of PMS2 expression in tumours were screened for germline mutations in PMS2, using a long range PCR based strategy and multiplex ligation dependent probe amplification (MLPA). Pathogenicity assessment of PMS2 VUS was performed evaluating clinicopathological data, frequency in control population and in silico and in vitro analyses at the RNA and protein level. Overall 25 different PMS2 DNA variants were detected. Fourteen were classified as polymorphisms. Nine variants were classified as pathogenic: seven alterations based on their molecular nature and two after demonstrating a functional defect (c.538-3C>G affected mRNA processing and c.137G>T impaired MMR activity). The c.1569C>G variant was classified as likely neutral while the c.384G>A remained as a VUS. We have also shown that the polymorphic variant c.59G>A is MMR proficient. Pathogenic PMS2 mutations were detected in 69% of patients harbouring LS associated tumours with loss of PMS2 expression. In all, PMS2 mutations account for 6% of the LS cases identified. The comprehensive functional analysis shown here has been useful in the classification of PMS2 VUS and contributes to refining the role of PMS2 in LS.

  18. Psychological distress in newly diagnosed colorectal cancer patients following microsatellite instability testing for Lynch syndrome on the pathologist's initiative.

    Science.gov (United States)

    Landsbergen, K M; Prins, J B; Brunner, H G; van Duijvendijk, P; Nagengast, F M; van Krieken, J H; Ligtenberg, M; Hoogerbrugge, N

    2012-06-01

    According to the Dutch Guideline on Hereditary Colorectal Cancer published in 2008, patients with recently diagnosed colorectal cancer (CRC) should undergo microsatellite instability (MSI) testing by a pathologist immediately after tumour resection if they are younger than 50 years, or if a second CRC has been diagnosed before the age of 70 years, owing to the high risk of Lynch syndrome (MIPA). The aim of the present MIPAPS study was to investigate general distress and cancer-specific distress following MSI testing. From March 2007 to September 2009, 400 patients who had been tested for MSI after newly diagnosed CRC were recruited from 30 Dutch hospitals. Levels of general distress (SCL-90) and cancer-specific distress (IES) were assessed immediately after MSI result disclosure (T1) and 6 months later (T2). Response rates were 23/77 (30%) in the MSI-positive patients and 58/323 (18%) in the MSI-negative patients. Levels of general distress and cancer-specific distress were moderate. In the MSI-positive group, 27% of the patients had high general distress at T1 versus 18% at T2 (p = 0.5), whereas in the MSI-negative group, these percentage were 14 and 18% (p = 0.6), respectively. At T1 and T2, cancer-specific distress rates in the MSI-positive group and MSI-negative group were 39 versus 27% (p = 0.3) and 38 versus 36% (p = 1.0), respectively. High levels of general distress were correlated with female gender, low social support and high perceived cancer risk. Moderate levels of distress were observed after MSI testing, similar to those found in other patients diagnosed with CRC. Immediately after result disclosure, high cancer-specific distress was observed in 40% of the MSI-positive patients.

  19. Performance of Lynch syndrome predictive models in quantifying the likelihood of germline mutations in patients with abnormal MLH1 immunoexpression.

    Science.gov (United States)

    Cabreira, Verónica; Pinto, Carla; Pinheiro, Manuela; Lopes, Paula; Peixoto, Ana; Santos, Catarina; Veiga, Isabel; Rocha, Patrícia; Pinto, Pedro; Henrique, Rui; Teixeira, Manuel R

    2017-01-01

    Lynch syndrome (LS) accounts for up to 4 % of all colorectal cancers (CRC). Detection of a pathogenic germline mutation in one of the mismatch repair genes is the definitive criterion for LS diagnosis, but it is time-consuming and expensive. Immunohistochemistry is the most sensitive prescreening test and its predictive value is very high for loss of expression of MSH2, MSH6, and (isolated) PMS2, but not for MLH1. We evaluated if LS predictive models have a role to improve the molecular testing algorithm in this specific setting by studying 38 individuals referred for molecular testing and who were subsequently shown to have loss of MLH1 immunoexpression in their tumors. For each proband we calculated a risk score, which represents the probability that the patient with CRC carries a pathogenic MLH1 germline mutation, using the PREMM 1,2,6 and MMRpro predictive models. Of the 38 individuals, 18.4 % had a pathogenic MLH1 germline mutation. MMRpro performed better for the purpose of this study, presenting a AUC of 0.83 (95 % CI 0.67-0.9; P < 0.001) compared with a AUC of 0.68 (95 % CI 0.51-0.82, P = 0.09) for PREMM 1,2,6 . Considering a threshold of 5 %, MMRpro would eliminate unnecessary germline mutation analysis in a significant proportion of cases while keeping very high sensitivity. We conclude that MMRpro is useful to correctly predict who should be screened for a germline MLH1 gene mutation and propose an algorithm to improve the cost-effectiveness of LS diagnosis.

  20. Lynch syndrome-associated extracolonic tumors are rare in two extended families with the same EPCAM deletion.

    Science.gov (United States)

    Lynch, Henry T; Riegert-Johnson, Douglas L; Snyder, Carrie; Lynch, Jane F; Hagenkord, Jill; Boland, C Richard; Rhees, Jennifer; Thibodeau, Stephen N; Boardman, Lisa A; Davies, Janine; Kuiper, Roland P; Hoogerbrugge, Nicoline; Ligtenberg, Marjolijn J L

    2011-10-01

    The Lynch syndrome (LS) is an inherited cancer syndrome showing a preponderance of colorectal cancer (CRC) in context with endometrial cancer and several other extracolonic cancers, which is due to pathogenic mutations in the mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2. Some families were found to show a LS phenotype without an identified MMR mutation, although there was microsatellite instability and absence of MSH2 expression by immunohistochemistry. Studies of a subset of these families found a deletion at the 3' end of the epithelial cell adhesion molecule (EPCAM) gene, causing transcription read-through resulting in silencing of MSH2 through hypermethylation of its promoter. The tumor spectrum of such families appears to differ from classical LS. Our study of two large families (USA Family R and Dutch Family A) with an EPCAM deletion was carried out using each institution's standard family study protocol. DNA was extracted from peripheral blood and EPCAM deletion analysis was performed. Both families were found to harbor the same deletion at the 3' end of EPCAM. Analysis showed that the deletion originated from a common ancestor. Family R and Family A members showed segregation of CRC with the presence of this EPCAM mutation. Compared with classic LS, there were almost no extracolonic cancers. Members of Family R and Family A, all with the same EPCAM deletion, predominantly presented with CRC but no LS-associated endometrial cancer, confirming findings seen in other, smaller, LS families with EPCAM mutations. In these EPCAM mutation carriers, cancer surveillance should be focused on CRC.