Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer
Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer
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DOI：
10.1158/1055-9965.epi-16-0693
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发表时间：
2017-03-01
影响因子：
3.8
通讯作者：
Maclnnis, Robert J.
中科院分区：
文献类型：
--
作者：
Win, Aung Ko;Jenkins, Mark A.;Maclnnis, Robert J.
背景：虽然已确定的主要易感基因(DNA错配修复基因和MUTYH)的高危突变导致了结直肠癌的一些家族聚集性，但其人群流行率和剩余家族聚集性的原因尚不清楚。方法：我们研究了从美国、加拿大和澳大利亚的人群癌症登记中招募的5744例结直肠癌患者(先证者)的家庭，并筛查先证者的错配修复基因和MUTYH突变。我们根据先证者确诊时的年龄，利用一级亲属的癌症病史进行了改良的分离分析。结果：我们估计279人中有1人携带错配修复基因突变(MLH1=1,946，MSH2=1,841，MSH6=1,758，PMS2=714)，1/45携带MUTYH基因突变，1/504携带与结直肠癌风险平均增加31倍相关的未识别主基因突变。在考虑了未知主效基因后，估计的多基因方差减少了30%至50%，在年龄=70岁时，估计的多基因方差从3.3降低(相当于同胞相对危险度分别为5.1至1.3)。结论：未知主效基因可能解释了结直肠癌缺失遗传性的三分之一至一半。(C)2016年AACR。
Background: Although high-risk mutations in identified major susceptibility genes (DNA mismatch repair genes and MUTYH) account for some familial aggregation of colorectal cancer, their population prevalence and the causes of the remaining familial aggregation are not known.Methods: We studied the families of 5,744 colorectal cancer cases (probands) recruited from population cancer registries in the United States, Canada, and Australia and screened probands for mutations in mismatch repair genes and MUTYH. We conducted modified segregation analyses using the cancer history of first-degree relatives, conditional on the proband's age at diagnosis. We estimated the prevalence of mutations in the identified genes, the prevalence of HR for unidentified major gene mutations, and the variance of the residual polygenic component.Results: We estimated that 1 in 279 of the population carry mutations in mismatch repair genes (MLH1 = 1 in 1,946, MSH2 = 1 in 2,841, MSH6 = 1 in 758, PMS2 = 1 in 714), 1 in 45 carry mutations in MUTYH, and 1 in 504 carry mutations associated with an average 31-fold increased risk of colorectal cancer in unidentified major genes. The estimated polygenic variance was reduced by 30% to 50% after allowing for unidentified major genes and decreased from 3.3 for age = 70 years (equivalent to sibling relative risks of 5.1 to 1.3, respectively).Conclusions: Unidentified major genes might explain one third to one half of the missing heritability of colorectal cancer.Impact: Our findings could aid gene discovery and development of better colorectal cancer risk prediction models. (C)2016 AACR.