Genotyping Possible Polymorphic Variants of Human Mismatch Repair Genes in Healthy Korean Individuals and Sporadic Colorectal Cancer Patients

Abstract

The genotypic consequences of numerous single-nucleotide variants in human mismatch repair genes are mostly undetermined. We examined 27 reported single-nucleotide variants, rarely or ambiguously verified in a population-based study, to identify single-nucleotide polymorphisms (SNPs), haplotypes, and the genotype-phenotype association in Korean populations of 330 healthy individuals, 107 sporadic colorectal cancer patients, and 107 of their first-degree relatives. Real-time PCR 5'-nuclease assays (TaqMan) MGB assay) were used to determine 24 single-nucleotide variants, and restriction fragment length polymorphism (RFLP) assays were used to determine 3 variants. Of these 27 variants, 4 (hMSH2 gIVS12-6, hMLH1 655, hMLH1 1151, and hMSH2 1168, in descending order) were identified as SNPs occurring in 4.5 to 53.1% of healthy individuals, with polymorphism levels of 0.023-0.3 (mean, 0.092). East Asian populations had an ethnic predilection for the hMLH1 1151 SNP. The genotype distribution for all four SNPs showed no association with sporadic colorectal cancer. Twenty-three variants were not identified in the Korean population, suggesting that fifteen of these variants are colorectal cancer-related mutations and eight are SNPs. Two haplotype patterns existed exclusively, but with rare frequency, in sporadic colorectal cancer patients. The hMLH1 655 allele was closely correlated with hMLH1 protein expression (P = 0.02), but none of the four SNPs was associated with clinicopathologic variables. Among the 27 single nucleotide variants of mismatch repair genes, 12 were suggestive of nonfunctional SNPs and 15 may be colorectal cancer-related mutations. Further verification in other ethnic groups may provide the genotypic and phenotypic significance of single nucleotide variants found in mismatch repair genes.

MLH1 and XRCC1 polymorphisms in Mexican patients with colorectal cancer

“…Actually, the 655G allele appears to confer a 2-fold increased risk to develop CRC in Mexican patients, a finding similar to that observed in 140 Spanish patients with sporadic CRC (Nejda et al, 2009). According to immunohistochemical analysis, it has been suggested that this polymorphism correlates with protein expression (Kim et al, 2004). In vitro mismatch repair assays led to classification of the 655A>G polymorphism as MMR+ (mismatch repair activity >60%) and a normal protein function was revealed by SIFT analysis (Takahashi et al, 2007).…”

RAD51 gene polymorphisms and sporadic colorectal cancer risk in Poland

“…We found in the literature that the studies performed in Chinese and Korean populations did not find any association between variants in DNA mismatch repair genes (MMR) and sporadic CRC [25,26]. The Asp132His variant was present but not associated with sporadic CRC in the Chinese population [25].…”

The genotype of MLH1 identifies a subgroup of follicular lymphoma patients who do not benefit from doxorubicin: FIL-FOLL study

“…In other disease models, the MLH1 rs1799977 polymorphism associates with reduced MLH1 protein expression in tumor cells. 16,32,33 Alternatively, the MLH1 rs1799977 polymorphism might be in linkage disequilibrium with other functionally relevant SNP of the MLH1 gene, 34 suggesting that multiple variants within the MLH1 locus may contribute to the risk of treatment failure in FL.…”