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.

Lymphovascular invasion (LVI) is a biological manifestation of aggressive behavior in colorectal cancer. This study sought to identify and examine the association between genetic and pathologic alterations implicated in this invasive tumor progression. We consecutively recruited 81 and 79 colorectal cancer patients with and without LVI, respectively. Biological changes were evaluated by clinicopathological parameters together with CEA and E-cadherin expressions using immune staining. Allelic loss or MSI was examined using 10 microsatellite markers on chromosomes 10, 16, 18, and TGFbetaRII, possibly associated with colorectal cancer. The germline mutation of BMPR1A and SMAD4 was also sought. Tumor stage and lymph node metastasis were significantly greater in patients with LVI tumor than without it (P < 0.001). Decreased CEA expression was closely correlated with allelic loss or MSI at D16S421, D18S46, and D18S474 (P = 0.004-0.047). Allelic loss at D10S14 was specific to LVI tumors (P = 0.007). Using multivariate analysis, allelic loss at D18S46 significantly correlated with histological differentiation (P = 0.02). In addition, allelic loss and MSI at D18S474, histological differentiation, and expression of CEA and E-cadherin were closely associated with the progression of LVI (P = 0.005-0.049). However, no germline mutation in BMPR1A or SMAD4 was detected in all patients regardless of LVI status. In summary, in a subset of colorectal cancers, histological differentiation and expression of CEA or E-cadherin appear to determine aggressive behavior such as LVI. These changes are closely associated with chromosomal alterations at 10q22-23, 16q22 and 18q21, which carry several tumor suppressor genes.