Aaltonen Lauri, Johns Louise, Järvinen Heikki, Mecklin Jukka-Pekka, Houlston Richard
Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Finland.
Clin Cancer Res. 2007 Jan 1;13(1):356-61. doi: 10.1158/1078-0432.CCR-06-1256.
There is a paucity of data quantifying the familial risk of colorectal cancer associated with 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.
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.
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.
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.
目前缺乏量化与错配修复（MMR）缺陷型和MMR稳定型肿瘤相关的结直肠癌家族风险的数据。为解决这一问题，我们分析了一系列基于人群的1042例经核实家族史的结直肠癌先证者。
系统筛查先证者的体质性DNA中的MYH变异，以及那些患有显示微卫星不稳定性（MSI）癌症的个体的种系MMR突变；根据临床表型和突变分析确定家族性腺瘤性息肉病和幼年性息肉病的诊断。根据年龄、性别和特定日历的人群发病率计算家族性结直肠癌风险。进行分离分析以得出结直肠癌残留家族聚集的模型。
在37例先证者中确定了结直肠癌的种系易感性[3.4%；95%置信区间（95%CI），2.4 - 4.6]：29例有MLH1/MSH2突变，2例有家族性腺瘤性息肉病，1例有幼年性息肉病，5例有双等位基因MYH变异。MSI和MMR稳定型癌症先证者的一级亲属患结直肠癌的风险分别增加了5.01倍（95%CI，3.73 - 6.59）和1.31倍（95%CI，1.07 - 1.59）。MSH2/MLH1突变占总体家族风险增加的50%，与MSI癌症相关风险的80%，但32%的家族风险无法用已知基因座解释。基于主要基因座的遗传模型对残留家族聚集的解释并不比简单的多基因模型更好。
我们分析得到的信息应有助于在临床实践中量化家族风险，并有助于设计研究以识别新的疾病等位基因。
