Abstract
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 smaller.
Highlights
Lynch syndrome (LS) is an autosomal dominant inherited syndrome that increases the risk of cancer, primarily in the colon, the rectum and the endometrial lining of the uterus, and to a lesser degree in the stomach, the ovary, the hepatobiliary tract, the urinary tract, the small bowel and the brain [1,2]
Genetic anticipation is a phenomenon where symptoms of a hereditary disease appear at an earlier age and/or are more severe in successive generations
Several studies have investigated anticipation in Lynch syndrome, the most common hereditary colorectal cancer syndrome, yet there is a debate concerning whether anticipation occurs and what underlying mechanism there is
Summary
Lynch syndrome (LS) is an autosomal dominant inherited syndrome that increases the risk of cancer, primarily in the colon, the rectum and the endometrial lining of the uterus, and to a lesser degree in the stomach, the ovary, the hepatobiliary tract, the urinary tract, the small bowel and the brain [1,2]. LS is one of the most common heritable cancer syndromes, accounting for up to 4% of the total colorectal cancer burden in Europe, where patients have up to 70% lifetime risk of developing colorectal or endometrial cancer at an early age [1]. LS was formerly known as hereditary non-polyposis colorectal cancer (HNPCC), but when clinical criteria evolved to take into account colorectal cancer to identify families with LS [3,4] the name Lynch Syndrome became generally accepted [5]. Today the diagnosis LS is restricted to families with a known pathogenic germline mutation in one of the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 irrespective of family history [6,7]. In human the recognition of nucleotide mismatches is mediated by the protein heterodimers MSH2/MSH6 or MSH2/MSH3, while the removal and resynthesis of nucleotides is mediated by MLH1/PMS2 [9]
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