Dependence of colorectal cancer risk on the parent-of-origin of mutations in DNA mismatch repair genes.
Dependence of colorectal cancer risk on the parent-of-origin of mutations in DNA mismatch repair genes.
复制标题
结直肠癌风险对 DNA 错配修复基因突变的亲本来源的依赖性。
DOI：
10.1002/humu.21408
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发表时间：
2011
期刊：
影响因子：
3.9
通讯作者：
Hopper,JohnL
中科院分区：
文献类型：
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作者：
vanVliet,ChristineM;Dowty,JamesG;vanVliet,JaneL;Smith,Letitia;Mead,LeeanneJ;Macrae,FinlayA;StJohn,DJamesB;Giles,GrahamG;Southey,MelissaC;Jenkins,MarkA;Velan,GaryM;Hopper,JohnL
与微卫星DNA中的动态突变相关的遗传疾病通常显示出起源效应（POE），其中疾病的风险取决于疾病等位基因遗传的父母的性别。错配修复（MMR）基因的生殖系突变携带者具有高风险的结直肠癌（CRC）。我们研究了这些风险是否取决于突变的起源。我们研究了422名受试者，包括89名MMR基因突变携带者，来自17个基于人群的家庭，每个家庭都通过45岁之前诊断的CRC病例招募，并发现携带MMR基因突变。POE风险比（HRPOE），定义为母源性突变携带者的CRC发病率除以相应的父源性发病率，使用改良分离分析的新应用进行估计。男性HRPOE（95%置信区间）估计为3.2（1.1 - 9.8）（P = 0.03），女性HRPOE（95%置信区间）估计为0.8（0.2 - 2.8）（P = 0.5），80岁时的相应累积风险为88%（54%-100%），男性携带者为母源性突变，所有其他携带者为38 - 48%。如果通过更大规模的研究证实，这些结果将对CRC的病因学和MMR基因突变携带者的临床管理具有重要意义。© 2011 Wiley利斯公司
Genetic diseases associated with dynamic mutations in microsatellite DNA often display parent‐of‐origin effects (POEs) in which the risk of disease depends on the sex of the parent from whom the disease allele was inherited. Carriers of germline mutations in mismatch repair (MMR) genes have high risks of colorectal carcinoma (CRC). We investigated whether these risks depend on the parent‐of‐origin of the mutation. We studied 422 subjects, including 89 MMR gene mutation carriers, from 17 population‐based families who were each recruited via a CRC case diagnosed before age 45 years and found to carry a MMR gene mutation. The POE hazard ratio (HRPOE), defined to be the CRC incidence for carriers with maternally derived mutations divided by the corresponding paternal incidence, was estimated using a novel application of modified segregation analysis. HRPOE(95% confidence interval) was estimated to be 3.2 (1.1–9.8) for males (P= 0.03) and 0.8 (0.2–2.8) for females (P= 0.5) and the corresponding cumulative risks to age 80 years were 88% (54%–100%) for male carriers with maternally derived mutations and 38–48% for all other carriers. If confirmed by larger studies, these results will have important implications for the etiology of CRC and for the clinical management of MMR gene mutation carriers.Hum Mutat 32: 1‐6, 2011. © 2011 Wiley‐Liss, Inc.