Department of Medical Genetics, Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
Cancer Epidemiol Biomarkers Prev. 2010 Jun;19(6):1478-83. doi: 10.1158/1055-9965.EPI-09-1320. Epub 2010 May 25.
Genomewide association studies have identified 10 low-penetrance loci that confer modestly increased risk for colorectal cancer (CRC). Although they underlie a significant proportion of CRC in the general population, their impact on the familial risk for CRC has yet to be formally enumerated. The aim of this study was to examine the combined contribution of the 10 variants, rs6983267, rs4779584, rs4939827, rs16892766, rs10795668, rs3802842, rs4444235, rs9929218, rs10411210, and rs961253, on familial CRC.
The population-based series of CRC samples included in this study consisted of 97 familial cases and 691 sporadic cases. Genotypes in the 10 loci and clinical data, including family history of cancer verified from the Finnish Cancer Registry, were available. The overall number of risk alleles (0-20) was determined, and its association with familial CRC was analyzed. Excess familial risk was estimated using cancer incidence data from the first-degree relatives of the cases.
A linear association between the number of risk alleles and familial CRC was observed (P = 0.006). With each risk-allele addition, the odds of having an affected first-degree relative increased by 1.16 (95% confidence interval, 1.04-1.30). The 10 low-penetrance loci collectively explain approximately 9% of the variance in familial risk for CRC.
This study provides evidence to support the previous indirect estimations that these low-penetrance variants account for a relatively small proportion of the familial aggregation of CRC.
Our results emphasize the need to characterize the remaining molecular basis of familial CRC, which should eventually yield in individualized targeting of preventive interventions.
全基因组关联研究已经确定了 10 个低外显率基因座，这些基因座使结直肠癌（CRC）的风险略有增加。尽管它们是普通人群中 CRC 的重要组成部分，但它们对 CRC 的家族风险的影响尚未正式确定。本研究的目的是检查 rs6983267、rs4779584、rs4939827、rs16892766、rs10795668、rs3802842、rs4444235、rs9929218、rs10411210 和 rs961253 这 10 个变体在家族性 CRC 中的综合贡献。
本研究中包含的基于人群的 CRC 样本系列包括 97 个家族性病例和 691 个散发性病例。这些位点的基因型和临床数据（包括从芬兰癌症登记处验证的癌症家族史）均可用。确定了风险等位基因的总数（0-20），并分析了其与家族性 CRC 的关系。使用病例一级亲属的癌症发病率数据来估计过度家族性风险。
观察到风险等位基因数量与家族性 CRC 之间存在线性关联（P=0.006）。每增加一个风险等位基因，一级亲属患病的几率增加 1.16（95%置信区间，1.04-1.30）。这 10 个低外显率基因座共同解释了结直肠癌家族风险变异的约 9%。
本研究提供了证据支持先前的间接估计，即这些低外显率变体仅占 CRC 家族聚集的相对较小比例。
我们的结果强调了需要阐明家族性 CRC 的其余分子基础，这最终应该会导致针对预防性干预的个体化靶向。
