O3-17-1 - Importance to clarify germline hMLH1 K618A missense mutation for clinical surveillance and genetic counseling

Abstract

Abstract Colorectal cancer (CRC) is the third common cancer and the fourth leading cause of cancer death worldwide. Subproportion CRC with defect function in one of the mismatch repair gene (MMR) are classed as inherited non-polyposis colorectal cancer (HNPCC) later called Lynch syndrome (LS). Disease causing germline mutations have so far been identified in five MMR genes. Among other MMR genes, germline mutations in hMLH1 account up to 50% LS patients and lead to increased risk of cancer development. hMLH1 K618A variant was first identified in our lab and was considered as a disease causing pathogenic alteration, our further investigation also support our previous findings. Although this variant has been investigated intensively during past decade, however the pathogenicity still remain unclear due to controversial data published up to date. In present study, hMLH1 K618A variant were genotyped in 2,743 individuals (1,087 sporadic CRC patients, 239 CRC patients with at least one affected close relative, 69 CRC cases with familial history and 1,348 controls) by TaqMan genotyping assay. Our results demonstrate that 30 individuals were heterozygous for the K618A variant; thirteen normal control had this variants and measurement of allele frequency was 0.96 % which is remarkably higher than previous published data, while eight were in sporadic CRC cases and allele frequency was 0.73 %, six were in CRC patients with at least one affected relative and allele frequency was 2.51 %, three were in CRC patients with familial history and allele frequency was 4.34 %. We conclude that hMLH1 K618A variant may not have effect in sporadic CRC development, in contrast that K618A may significantly increase CRC risk in CRC patients with strong familial history in Swedish population.