Abstract
BackgroundGermline defects of mismatch repair (MMR) genes underlie Lynch Syndrome (LS). We aimed to gain comprehensive genetic and epigenetic profiles of LS families in Singapore, which will facilitate efficient molecular diagnosis of LS in Singapore and the region.MethodsFifty nine unrelated families were studied. Mutations in exons, splice-site junctions and promoters of five MMR genes were scanned by high resolution melting assay followed by DNA sequencing, large fragment deletions/duplications and promoter methylation in MLH1, MSH2, MSH6 and PMS2 were evaluated by multiplex ligation-dependent probe amplification. Tumor microsatellite instability (MSI) was assessed with five mononucleotide markers and immunohistochemical staining (IHC) was also performed.ResultsPathogenic defects, all confined to MLH1 and MSH2, were identified in 17 out of 59 (28.8%) families. The mutational spectrum was highly heterogeneous and 28 novel variants were identified. One recurrent mutation in MLH1 (c.793C>T) was also observed. 92.9% sensitivity for indication of germline mutations conferred by IHC surpassed 64.3% sensitivity by MSI. Furthermore, 15.6% patients with MSS tumors harbored pathogenic mutations.ConclusionsAmong major ethnic groups in Singapore, all pathogenic germline defects were confined to MLH1 and MSH2. Caution should be applied when the Amsterdam criteria and consensus microsatellite marker panel recommended in the revised Bethesda guidelines are applied to the local context. We recommend a screening strategy for the local LS by starting with tumor IHC and the hotspot mutation testing at MLH1 c.793C>T followed by comprehensive mutation scanning in MLH1 and MSH2 prior to proceeding to other MMR genes.
Highlights
Lynch Syndrome (LS), is an autosomal, dominantly inherited syndrome associated with substantial risks for colorectal cancers (CRC)
Mutations are most commonly identified in MLH1 (50%) and MSH2 (40%). 7% of the mutations are found in MSH6 and 3% in PMS2 [2]
Constitutional epimutation resulting in transcriptional silencing of MMR genes have been attributed as the cause of disabled mismatch repair functions in some LS cases [9,10]
Summary
Lynch Syndrome (LS), (previously referred to as hereditary nonpolyposis colorectal cancer, HNPCC), is an autosomal, dominantly inherited syndrome associated with substantial risks for colorectal cancers (CRC). Inactivating mutations in at least four mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2) have been identified [2] and account for 50–60% of cases that fulfill clinical criteria [3,4,5]. Over 600 causative mutations have been reported scattered throughout MMR genes with no obvious mutation hotspots (Atlas of Genetics and Cytogenetics in Oncology and Haematology, http:// AtlasGeneticsOncology.org). The majority of these descriptions arise from Western populations. We aimed to gain comprehensive genetic and epigenetic profiles of LS families in Singapore, which will facilitate efficient molecular diagnosis of LS in Singapore and the region
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