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Woods MO, Younghusband HB, Parfrey PS, et al. The genetic basis of colorectal cancer in a population-based incident cohort with a high rate of familial disease. Gut. 2010;59(10):1369-77. This is a systematic clinical and genetic classification of a large consecutive series of colorectal cancers from the Newfoundland Colorectal Cancer Registry, a region with a high prevalence of familial colorectal cancer.
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This paper describes the colorectal, endometrial, and ovarian cancer risks in a large (537) number of families with Lynch Syndrome and confirms variations in both risk and age of onset by Lynch genotype
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Bonadona V, Bonaïti B, Olschwang S, et al. French Cancer Genetics Network. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011;305(22):2304-10. This paper describes the colorectal, endometrial, and ovarian cancer risks in a large (537) number of families with Lynch Syndrome and confirms variations in both risk and age of onset by Lynch genotype.
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Hampel H, Frankel WL, Martin E, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med. 2005;352(18):1851-60. This older paper is important because it illustrates the low level of recognition of Lynch Syndrome in clinical practice in the United States.
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Ligtenberg MJ, Kuiper RP, Chan TL, et al. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1. Nat Genet. 2009;41:112-7. This is the initial report of EPCAM deletions causing Lynch syndrome due to methylation of MSH2.
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This collaborative effort reported that of 58 CRCs with MSH2 loss without identifiable mutation, 11 (19%) had EPCAM deletions leading to MSH2 hypermethylation, 1 had MSH2 hypermethylation without EPCAM deletion, and the cause of the others remains to be discovered
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Rumilla K, Schowalter KV, Lindor NM, et al. Frequency of deletions of EPCAM (TACSTD1) in MSH2-associated Lynch syndrome cases. J Mol Diagn. 2011;13(1):93-9. This collaborative effort reported that of 58 CRCs with MSH2 loss without identifiable mutation, 11 (19%) had EPCAM deletions leading to MSH2 hypermethylation, 1 had MSH2 hypermethylation without EPCAM deletion, and the cause of the others remains to be discovered.
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This study evaluated cancer prevalence in 194 EPCAM deletion carriers with 16 different deletions and found that endometrial cancer risk was substantially lower in this group than in MMR mutation carriers. In EPCAM deletion carriers, the endometrial cancer risk seemed to be confined to those with deletions that were close to or extended into the MSH2 promoter
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Kempers MJ, Kuiper RP, Ockeloen CW, et al. Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: A cohort study. Lancet Oncol. 2011;12(1):49-55. This study evaluated cancer prevalence in 194 EPCAM deletion carriers with 16 different deletions and found that endometrial cancer risk was substantially lower in this group than in MMR mutation carriers. In EPCAM deletion carriers, the endometrial cancer risk seemed to be confined to those with deletions that were close to or extended into the MSH2 promoter.
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Kastrinos F, Steyerberg EW, Mercado R, et al. The PREMM (1,2,6) model predicts risk of MLH1, MSH2, and MSH6 germline mutations based on cancer history. Gastroenterology. 2011;140 (1):73-81. This paper describes and validates a predictive model that adds prediction of MSH6 mutation risk to the previous PREMM 1,2 model.
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This group developed a Markov model to estimate the relative costeffectiveness of a variety of molecular and clinical predictive models for identification of Lynch syndrome and concluded that universal molecular testing of CRCs with immunohistochemistry (IHC) followed by BRAF mutation analysis of those with MLH1 loss was, overall, the most cost-effective approach, although predictive modeling with MMR Pro followed by IHC was estimated to be almost as effective at less cost
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Ladabaum U, Wang G, Terdiman J, et al. Strategies to identify the Lynch syndrome among patients with colorectal cancer: A costeffectiveness analysis. Ann Intern Med. 2011;155(2):69-79. This group developed a Markov model to estimate the relative costeffectiveness of a variety of molecular and clinical predictive models for identification of Lynch syndrome and concluded that universal molecular testing of CRCs with immunohistochemistry (IHC) followed by BRAF mutation analysis of those with MLH1 loss was, overall, the most cost-effective approach, although predictive modeling with MMR Pro followed by IHC was estimated to be almost as effective at less cost.
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This longer term follow-up of a controlled trial of aspirin in Lynch gene carriers raised the possibility of a decrease in CRC risk in those who had been randomized to aspirin. This is the first suggestion of the possibility of effective chemoprevention in this syndrome
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Burn J, Gerdes AM, Macrae F, et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: An analysis from the CAPP2 randomised controlled trial. Lancet. 2011;378(9809):2081-7. This longer term follow-up of a controlled trial of aspirin in Lynch gene carriers raised the possibility of a decrease in CRC risk in those who had been randomized to aspirin. This is the first suggestion of the possibility of effective chemoprevention in this syndrome.
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