Phenotypic Heterogeneity by Germline Mismatch Repair Gene Defect in Lynch Syndrome Patients.

Abstract

Lynch syndrome is the most common form of hereditary colorectal cancer, being also responsible for endometrial andother types of cancers. It is associated with germline mutations in DNA mismatch repair genes and microsatellite instability. MLH1 andMSH2 mutations have a "classical" Lynch syndrome phenotype, with MSH2 having a higher association with extracolonic cancer. MSH6and PMS2 mutations have an atypical phenotype. Clinical expression is heterogeneous, with correlation between mismatch repairmutated gene and phenotypic patterns. We retrospectively analyzed data from patients fulfilling Amsterdam criteria or having mismatch repair genemutations, between September 2012 and October 2015. We identified 28 patients. Seventeen had colorectal cancer with right colon predominance. Five developed endometrialcancer (median age of diagnosis - 53), with no MSH6 mutations. Five developed other cancers. All mutated mismatch repair casesstudied had microsatellite instability. Most cases had MSH2 mutations despite MLH1 being described in the literature as the most frequently mutated.Interestingly, colorectal cancer patients showed no tendency for high inflammatory infiltrate. Despite the high incidence of synchronousand metachronous tumours, most patients underwent a partial colectomy. Prophylactic hysterectomy and adnexectomy was performedin menopausal/perimenopausal patients. A standardized registration of patient's data may lead to better management and knowledge about Lynch syndrome.Use of Bethesda Guidelines might identify new cases non-identified by Amsterdam criteria. Microsatellite instability analysis must beperformed in a much larger scale. The genotypic/phenotypic correlation described in the literature was not verified in our study withstatistical significance, perhaps due to small data sample and insufficient clinical registration.