Microsatellite instability in Hereditary and Sporadic Colorectal Cancer – Genetic and Epigenetic Mechanisms

Abstract

Inactivation of the DNA mismatch repair (MMR) system would lead to an increased mutation rate and predispose to the development of colorectal cancer (CRC) with the microsatellite instability (MSI) phenotype. The two DNA MMR genes most commonly affected are the MSH2 and MLH1 genes, and biallelic inactivation of either gene is needed for CRC development. These can be achieved through a combination of germline/somatic mutations in patients with the Hereditary NonPolyposis Colorectal Cancer (HNPCC) Syndromes, or bi-allelic inactivation by aberrant promoter methylation in 15% of sporadic CRCs. Screening for MSI in CRCs constitutes a useful initial test to suggest HNPCC and the need for follow up genetic diagnosis. The distinction between germline versus somatic causes of MSI CRCs has profound implication for patient management and prophylactic screening of their family. We have identified a unique germline MSH2 c.1452-1455delAATG founder mutation, which accounts for a significant proportion of early-onset and familial CRCs in Hong Kong Chinese, and may contribute to the observed high incidence of early-onset CRC locally. Recently, we have discovered a novel mechanism for HNPCC, due to a stably inherited germline methylation of the MSH2 gene promoter, but with highly mosaic tissue-specific distribution of the methylated alleles (Nat Genet 2006;38:1178-83). Along with recent reports by other groups of germline methylation of MLH1 in some putative HNPCC patients, epigenetic silencing is increasingly recognized to cause not only sporadic, but also hereditary cancers in humans. Germline methylation of MLH1 and MSH2 exhibit interesting differences in terms of the propensity for transmission to offspring and the degree of mosaicism of the methylated alleles, which have revealed for the first time the diversity and complexity of epigenetic changes as a cause of hereditary disease in humans. Recognition of these new mechanisms for genetic disease is important as the disease manifestation may deviate from Mendelian inheritance and the mosaic distribution of the methylated alleles may create problem in genetic diagnosis. Specifically, presence of methylated MLH1 promoter in CRCs are easily misinterpreted as somatic event whereas detection of methylation in corresponding normal tissue may easily be dismissed as age-related non-specific changes.