Germline mutation and protein expression analysis of mismatch repair genes MSH6 and PMS2 in Malaysian Lynch syndrome patients

Abstract

Dear Editor: Hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome is the most common hereditary form of colorectal cancer (CRC). The diagnosis of HNPCC or Lynch syndrome represents a major challenge because of its genotype and phenotype heterogeneity. Although Amsterdam criteria and Bethesda criteria might be useful for the diagnosis assessment of HNPCC family, there will be clinical situations involving families that may be wholly uninformative for the application of these criteria. The genetic basis of Lynch syndrome has been associated with potentially pathogenic mutations in a group of DNA MMR genes (MLH1 , MSH2 , MSH6 , PMS1 , and PMS2). Germline mutation analysis of DNA MMR genes is the most crucial process for the confirmation of the clinical diagnosis of Lynch syndrome cases. The mutation spectrum of DNA MMR genes appear to be diverse in both distribution and nature of mutations. Although mutation data is available from different parts of the world in varying frequencies, reports on Malaysian patients are scarce. This study was undertaken to unravel the spectrum of germline mutation in DNA MMR genes in Malaysian Lynch syndrome patients. Due to the minor role of germline MSH6 and PMS2 mutations, we adapted the Lynch syndrome detection strategy for the Malaysian population of CRC patients, whereby germline mutations were first sought for MLH1 and MSH2 genes, to be followed byMSH6 and PMS2 genes. The choice about which gene should be tested first was guided by immunohistochemical (IHC) analysis of protein expression of MMR genes. Earlier, we did germlinemutation analysis ofMLH1 and MSH2 genes in 50 Lynch syndrome patients, out of which the data for 34 Lynch syndrome patients has already been reported [1]. In addition to and continuation of the previous report, this report specifically focus on the protein expression profile and germline mutations of MSH6 and PMS2 genes in 50 Malaysian Lynch syndrome suspected patients.