The association between genetic variants in hMLH1 and hMSH2 and the development of sporadic colorectal cancer in the Danish population.
The association between genetic variants in hMLH1 and hMSH2 and the development of sporadic colorectal cancer in the Danish population.
复制标题
HMLH1和HMSH2中的遗传变异与丹麦种群中零星大结直肠癌的发展之间的关联。
DOI：
10.1186/1471-2350-9-52
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发表时间：
2008-06-11
影响因子：
--
通讯作者：
Orntoft, Torben F.
中科院分区：
文献类型：
--
作者：
Christensen, Lise Lotte;Madsen, Bo E.;Wikman, Friedrik P.;Wiuf, Carsten;Koed, Karen;Tjonneland, Anne;Olsen, Anja;Syvanen, Ann-Christine;Andersen, Claus L.;Orntoft, Torben F.
错配修复基因hMLH1和hMSH2的突变易患遗传性非息肉病性结直肠癌（HNPCC）。对350多名丹麦结直肠癌（CRC）患者进行的基因筛查发现了hMLH1和hMSH2中的几种新的遗传变异（例如错义、沉默和非编码）。本研究的目的是调查丹麦散发性结直肠癌患者和健康背景人群中hMLH1和hMSH2这些变异的频率。其目的是揭示是否有任何常见变异导致结直肠癌易感性增加。使用病例队列设计评估hMLH1和hMSH2遗传变异与散发性结直肠癌之间的关联。对380例散发性结直肠癌患者和770例亚组人群的血液中分离的DNA进行基因分型。使用单碱基延伸（SBE）标签阵列分析DNA样品。使用Bonferroni校正的Fisher精确检验来检验每个变体的基因型与结直肠癌之间的关联。使用HaploView（v3.31）研究连锁不平衡（LD）。在35个分析的变体中的13个中检测到杂合和纯合变化。两个变异与结直肠癌有临界关联，而其余变异则没有关联。此外，在丹麦人群中，覆盖hMLH1和hMSH2的基因组区域显示出高度的连锁不平衡。在散发性结直肠癌病例和子队列中均未检测到22种变异。这些罕见变异中的一些已被分类为致病性突变或其他人群中的中性变异，有些是未分类的丹麦变异。本研究中分析的hMLH 1和hMSH 2变体均与丹麦人群的结直肠癌高度相关。覆盖hMLH1和hMSH2的基因组区域的高度连锁不平衡表明，这两个基因中的常见遗传变异通常不参与散发性结直肠癌的发展。然而，hMLH1和hMSH2中的一些罕见的未分类的变体可能参与了它们最初被鉴定的家族中的结直肠癌的发展。
Mutations in the mismatch repair genes hMLH1 and hMSH2 predispose to hereditary non-polyposis colorectal cancer (HNPCC). Genetic screening of more than 350 Danish patients with colorectal cancer (CRC) has led to the identification of several new genetic variants (e.g. missense, silent and non-coding) in hMLH1 and hMSH2. The aim of the present study was to investigate the frequency of these variants in hMLH1 and hMSH2 in Danish patients with sporadic colorectal cancer and in the healthy background population. The purpose was to reveal if any of the common variants lead to increased susceptibility to colorectal cancer. Associations between genetic variants in hMLH1 and hMSH2 and sporadic colorectal cancer were evaluated using a case-cohort design. The genotyping was performed on DNA isolated from blood from the 380 cases with sporadic colorectal cancer and a sub-cohort of 770 individuals. The DNA samples were analyzed using Single Base Extension (SBE) Tag-arrays. A Bonferroni corrected Fisher exact test was used to test for association between the genotypes of each variant and colorectal cancer. Linkage disequilibrium (LD) was investigated using HaploView (v3.31). Heterozygous and homozygous changes were detected in 13 of 35 analyzed variants. Two variants showed a borderline association with colorectal cancer, whereas the remaining variants demonstrated no association. Furthermore, the genomic regions covering hMLH1 and hMSH2 displayed high linkage disequilibrium in the Danish population. Twenty-two variants were neither detected in the cases with sporadic colorectal cancer nor in the sub-cohort. Some of these rare variants have been classified either as pathogenic mutations or as neutral variants in other populations and some are unclassified Danish variants. None of the variants in hMLH1 and hMSH2 analyzed in the present study were highly associated with colorectal cancer in the Danish population. High linkage disequilibrium in the genomic regions covering hMLH1 and hMSH2, indicate that common genetic variants in the two genes in general are not involved in the development of sporadic colorectal cancer. Nevertheless, some of the rare unclassified variants in hMLH1 and hMSH2 might be involved in the development of colorectal cancer in the families where they were originally identified.
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3.9
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通讯作者：
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