Explaining the familial colorectal cancer risk associated with mismatch repair (MMR)-deficient and MMR-stable tumors
Explaining the familial colorectal cancer risk associated with mismatch repair (MMR)-deficient and MMR-stable tumors
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DOI：
10.1158/1078-0432.ccr-06-1256
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发表时间：
2007-01-01
影响因子：
11.5
通讯作者：
Houlston, Richard
中科院分区：
文献类型：
--
作者：
Aaltonen, Lauri;Johns, Louise;Houlston, Richard
用途：目前缺乏与错配修复（MMR）缺陷和MMR稳定肿瘤相关的结直肠癌家族风险的量化数据。为了解决这个问题，我们分析了一个基于人群的系列1,042结直肠癌先证者与验证的家族histors.Experimental设计：宪法DNA先证者进行了系统的筛选MYH变异和那些与癌症显示微卫星不稳定性（MSI）的生殖系MMR突变;诊断家族性腺瘤性息肉病和青少年息肉病的基础上建立的临床表型和突变分析。家族性结直肠癌的风险是根据年龄、性别和特定人群的发病率来计算的。分离分析，以获得一个模型的残留家族聚集性结直肠cancer.Results：生殖系易感性结直肠癌被确定在37个先证者[3.4%，95%置信区间（95%CI），2.4-4.6]：29 MLH 1/MSH 2突变，2与家族性腺瘤性息肉病，1与青少年息肉病，5与双等位基因MYH变异。MSI和MMR稳定癌症先证者的一级亲属患结直肠癌的风险分别增加5.01倍（95%CI，3.73-6.59）和1.31倍（95%CI，1.07-1.59）。MSH 2/MLH 1突变导致了50%的总体过度家族风险和80%的与MSI癌症相关的风险，但32%的家族风险未被已知基因座所解释。基于主要基因位点的遗传模型没有提供一个更好的解释比一个简单的多基因model.Conclusions：从我们的分析信息应该是有用的，在量化的家庭风险在临床实践中，并在设计的研究，以确定新的疾病等位基因的残留的家族聚集。
Purpose: There is a paucity of data quantifying the familial risk of colorectal cancer associatedwith mismatch repair (MMR)-deficient and MMR-stable tumors. To address this, we analyzed a population-based series of 1,042 colorectal cancer probands with verified family histories.Experimental Design: Constitutional DNA from probands was systematically screened for MYH variants and those with cancers displaying microsatellite instability (MSI) for germ-line MMR mutations; diagnoses of familial adenomatous polyposis and juvenile polyposis were established based on clinical phenotype and mutational analysis. Familial colorectal cancer risks were enumerated from age-, sex-, and calendar-specific population incidence rates. Segregation analysis was conducted to derive a model of the residual familial aggregation of colorectal cancer.Results: Germ-line predisposition to colorectal cancer was identified in 37 probands [3.4%; 95% confidence interval (95% CI), 2.4-4.6]: 29 with MLH1/MSH2 mutations, 2 with familial adenomatous polyposis, 1 with juvenile polyposis, and 5 with biallelic MYH variants. The risk of colorectal cancer in first-degree relatives of probands with MSI and MMR-stable cancers was increased 5.01-fold (95% CI, 3.73-6.59) and 1.31-fold (95% CI, 1.07-1.59), respectively. MSH2/MLH1 mutations were responsible for 50% of the overall excess familial risk and 80% of the risk associated with MSI cancers but 32% of the familial risk was unaccounted for by known loci. Genetic models based on major gene loci did not provide a better explanation of the residual familial aggregation than a simple polygenic model.Conclusions: The information from our analyses should be useful in quantifying familial risks in clinical practice and in the design of studies to identify novel disease alleles.