Mismatch repair genes founder mutations and cancer susceptibility in Lynch syndrome

Abstract

Founder mutations in specific populations are common in several Mendelian disorders. They are shared by apparently unrelated families that inherited them from a common ancestor that existed hundreds to thousands of years ago. They have been proven to impact in molecular diagnostics strategies in specific populations, where they can be assessed as the first screening step and, if positive, avoid further expensive gene scanning. In Lynch syndrome (LS), a dominantly inherited colorectal cancer disease, more than 50 founder pathogenic mutations have been described so far in the mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2). We here provide a comprehensive summary of the founder mutations found in the MMR genes and an overview of their main characteristics. At a time when high-throughput strategies are being introduced in the molecular diagnostics of cancer, genetic testing for founder mutations can complement next generation sequencing (NGS) technologies to most efficiently identify MMR gene mutations in any given population. Additionally, special attention is paid to MMR founder mutations with interesting anthropological significance.

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

“…Furthermore, the higher cancer penetrance and earlier onset associated with MLH1 and MSH2 mutations may have impacted reproductive fitness. Over 50 mutations showing founder effects have been described across the world and in some populations they have a large effect on the LS gene distribution24. In Finland, two MLH1 mutations cause >50% of all LS cases1925 and in the Netherlands26 and Sweden27, MSH6 mutations are unusually highly prevalent.…”

Recent progress in Lynch syndrome and other familial colorectal cancer syndromes

“…Although their population prevalence is not well understood, founder mutations in MSH2 (c.1906G>C, p.A636P) and MSH6 (c.3959_3962delCAAG and c.3984_3987dupGTCA) appear to account for the majority of Lynch syndrome cases in individuals of Ashkenazi Jewish ancestry . Additional data are identifying other candidate founder mutations in various populations with undefined prevalence, including Americans of German ancestry, African Americans, Latinos, Poles, and many other groups …”

“…42,43 Additional data are identifying other candidate founder mutations in various populations with undefined prevalence, including Americans of German ancestry, 44 African Americans, 45 Latinos, 46 Poles, 47 and many other groups. 48 Founder mutations may account for a sizeable fraction of individuals with BMMRD syndrome, which is caused by biallelic inheritance of pathogenic germline variants in the same MMR gene. 49 BMMRD is a rare and often devastating syndrome characterized by pediatric-onset brain tumors (including gliomas and medulloblastomas), small-bowel and large-bowel adenomas and adenocarcinomas, lymphomas, leukemias, ECs, and cafe-au-lait macules (which can lead to a misdiagnosis of neurofibromatosis type 1).…”

Characterization of a novel founder MSH6 mutation causing Lynch syndrome in the French Canadian population

“…Importantly, a number of founder mutations have been described in MMR genes (11) and, by testing them as a first step, it has been possible to lower the cost of molecular diagnosis in appropriate populations. Importantly, a number of founder mutations have been described in MMR genes (11) and, by testing them as a first step, it has been possible to lower the cost of molecular diagnosis in appropriate populations.…”