Kim Jin C, Roh Seon A, Koo Kum H, Ka In H, Kim Hee C, Yu Chang S, Lee Kang H, Kim Jung S, Lee Han I, Bodmer Walter F
Department of Surgery, University of Ulsan College of Medicine, and Laboratory of Cancer Biology & Genetics, Asan Institute for Life Sciences, 388-1 Poongnap-2-Dong Songpa-Ku, Seoul 138-736, Korea.
Fam Cancer. 2004;3(2):129-37. doi: 10.1023/B:FAME.0000039919.66461.8f.
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.
人类错配修复基因中众多单核苷酸变异的基因型后果大多尚未确定。我们检测了27个已报道的单核苷酸变异，这些变异在基于人群的研究中很少被验证或验证结果不明确，以确定330名健康个体、107名散发性结直肠癌患者及其107名一级亲属的韩国人群中的单核苷酸多态性（SNP）、单倍型以及基因型与表型的关联。采用实时荧光定量PCR 5'-核酸酶分析（TaqMan MGB分析）来确定24个单核苷酸变异，采用限制性片段长度多态性（RFLP）分析来确定3个变异。在这27个变异中，4个（按降序排列分别为hMSH2 gIVS12-6、hMLH1 655、hMLH1 1151和hMSH2 1168）被鉴定为SNP，在4.5%至53.1%的健康个体中出现，多态性水平为0.023 - 0.3（平均0.092）。东亚人群对hMLH1 1151 SNP有种族偏好。所有四个SNP的基因型分布与散发性结直肠癌均无关联。在韩国人群中未鉴定出23个变异，提示其中15个变异是与结直肠癌相关的突变，8个是SNP。在散发性结直肠癌患者中仅存在两种单倍型模式，但频率很低。hMLH1 655等位基因与hMLH1蛋白表达密切相关（P = 0.02），但这四个SNP均与临床病理变量无关。在错配修复基因的27个单核苷酸变异中，12个提示为无功能的SNP，15个可能是与结直肠癌相关的突变。在其他种族群体中进行进一步验证可能会揭示错配修复基因中发现的单核苷酸变异的基因型和表型意义。
