Characterization of new Ashkenazi Jewish founder mutations in MSH6 causing Lynch syndrome.

Abstract

1514 Background: Founder mutations are an important cause of Lynch syndrome and facilitate genetic testing in specific ethnic populations. Two recently described mutations in MSH6 are putative founder mutations, warranting careful clinical and genetic analysis. Methods: MSH6 exon 9 insertion and deletion mutations were analyzed in 2,660 colorectal cancer (CRC) cases and 3,270 healthy controls of Ashkenazi Jewish (AJ) descent from population-based and hospital-based case-control studies in Israel, Canada and the USA. Microsatellite markers and single nucleotide polymorphisms were analyzed in carriers from case-control studies and clinical series. Age of the mutation was estimated using a Bayesian MCMC linkage disequilibrium mapping approach (DMLE+ software). Results: We characterized two recently described mutations in MSH6 exon 9, c.3984_3987dupGTCA (MSH6 dup) and c.3959_3962delCAAG (MSH6 del). MSH6 dup was found in 8 of 2,660 cases and 1 of 3,270 controls, consistent with a very high risk of CRC (odds ratio [OR] = 9.8, 95% confidence interval [CI] = 1.2-78.7, Fisher's exact p = 0.0136). Of note, the only control carrying MSH6 dup had a remote history of endometrial cancer (age 61) and developed cecal cancer at age 76, several years after being ascertained as a control without CRC. The MSH6 del was less common, identified in 3 of 2660 cases and no controls. Survival analysis indicates a trend of better overall survival among CRC patients with MSH6 dup or del (hazard ratio [HR] = 0.7, 95% CI = 0.5-1.1) compared to CRC patients without MMR mutations. Haplotype analysis demonstrated separate conserved haplotypes for each mutation. Four recombination events in MSH6 dup carriers allowed estimation of the age of the mutation, which arose ∼650 years ago in the fourteenth century. No carriers of either mutation were identified in 450 Sephardi Jewish cases or 490 Sephardi Jewish controls. Conclusions: MSH6 truncating mutations c.3984_3987dupGTCA and c.3959_3962delCAAG are founder mutations in Ashkenazi Jews that cause Lynch syndrome. Although less common than other Jewish founder mutations, these mutations substantially contribute to CRC in this ethnic group and are relevant for the diagnosis and management of AJ Lynch syndrome patients. No significant financial relationships to disclose.