Lynch Syndrome: An Updated Review (original) (raw)
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Discussion Lynch Syndrome: An Updated Review
2014
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.
Prediction of Germline Mutations and Cancer Risk in the Lynch Syndrome
JAMA, 2006
HE LYNCH SYNDROME (IE, hereditary nonpolyposis colorectal cancer [HNPCC]) is the most common familial colorectal cancer (CRC). 1,2 It can be caused by germline deleterious mutations of DNA mismatch repair (MMR) genes, including MLH1, 3,4 MSH2, 5 MSH6, 6 and several others. 7 Screening for individuals likely to carry a deleterious mutation of these genes has traditionally relied on examination of family history, as per the Amsterdam Criteria, 8-10 and has recently moved toward multistep algorithms combining family history with molecular tumor characteristics such as micro-satellite instability (MSI), 11 as per the Bethesda Guidelines. 2,12 The latter were developed to help recognize those individuals who would potentially benefit from a more detailed molecular diagnostic workup, including MSI and subsequent germline testing. This approach is useful, but not without important limitations. First, MSI tests can only be performed on affected patients
Risks of Less Common Cancers in Proven Mutation Carriers With Lynch Syndrome
Journal of Clinical Oncology, 2012
Purpose Patients with Lynch syndrome are at high risk for colon and endometrial cancer, but also at an elevated risk for other less common cancers. The purpose of this retrospective cohort study was to provide risk estimates for these less common cancers in proven carriers of pathogenic mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6. Patients and Methods Data were pooled from the German and Dutch national Lynch syndrome registries. Seven different cancer types were analyzed: stomach, small bowel, urinary bladder, other urothelial, breast, ovarian, and prostate cancer. Age-, sex- and MMR gene–specific cumulative risks (CRs) were calculated using the Kaplan-Meier method. Sex-specific incidence rates were compared with general population incidence rates by calculating standardized incidence ratios (SIRs). Multivariate Cox regression analysis was used to estimate the impact of sex and mutated gene on cancer risk. Results The cohort comprised 2,118 MMR gene mutation ca...
Risks of Lynch Syndrome Cancers for MSH6 Mutation Carriers
JNCI Journal of the National Cancer Institute, 2010
Lynch syndrome, also known as hereditary nonpolyposis colon cancer syndrome (1), is a rare, autosomal, dominantly inherited syndrome caused by germline mutations in DNA mismatch repair genes, which confer substantial risks for cancers of the colorectum and endometrium and increased risks for cancers of the stomach, small intestine, hepatobiliary system, kidney, ureter, ovary, and sebaceous tumors (2,3). Mutations in the mismatch repair genes, MLH1 and MSH2, account for 70%-80% of all Lynch syndrome colorectal cancers (ie, colorectal cancers occurring in people with germline DNA mismatch repair gene mutations) (4-7).
The Application of Clinical Genetics, 2014
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 inactivation. Determining the underlying cause of tumor MMR deficiency in suspected Lynch syndrome cases is likely to reshape the current triaging schemes used to identify germline MMR gene mutations in cancer-affected individuals and their relatives.
British Journal of Cancer
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. Methods: Data from 1624 Lynch syndrome mutation carriers in the Danish hereditary non-polyposis colorectal cancer register were used to estimate the sex-and age-specific incidence rate ratios (IRRs) for 30 extra-colorectal malignancies with comparison to the general population. Results: Significantly increased IRRs were identified for 13 cancer types with differences related to gender, age and diseasepredisposing 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 multitumour syndrome. The variable incidences in relation to age, gender and gene suggest a need for individualised surveillance. Lynch syndrome is caused by mutations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2, and represents one of the most common hereditary cancer syndromes (de la Chapelle, 2005). The MMR deficiency genotype is associated with a 58-75% lifetime risk of cancer with frequent observations of synchronous/ metachronous tumour development (
Calculation of Risk of Colorectal and Endometrial Cancer Among Patients With Lynch Syndrome
Gastroenterology, 2009
Background & Aims-Lynch Syndrome is the most common hereditary colorectal cancer (CRC) syndrome. Previous estimates of lifetime risk for CRC and endometrial cancer (EC) did not control for ascertainment and were susceptible to bias towards overestimated risk. Methods-We studied 147 families with mismatch repair (MMR) gene mutations (55 MLH1, 81 MSH2, and 11 MSH6) identified at 2 U.S. cancer genetics clinics. Age-specific cumulative risks (penetrance) and hazard ratio (HR) estimates of CRC and EC risks were calculated and compared to the general population using modified segregation analysis. The likelihood for each pedigree was conditioned on the proband and first-degree relatives affected with CRC to reduce ascertainment bias and overestimation of penetrance. Results-We analyzed 628 cases of CRC, diagnosed at median ages of 42 and 47 years for men and women, respectively. Cumulative risk of CRC was 66.08% (95% confidence interval [CI 59.47%-76.17%) for men and 42.71% (95% CI 36.57%-52.83%) for women, with overall HRs of 148.4 and 51.1, respectively. CRC risk was highest for males with mutations in MLH1. There were 155 cases of EC, diagnosed at median age of 47.5 years. Cumulative risk of EC was 39.39% (95%