Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Clin Transl Gastroenterol. 2019 Dec;10(12):e00106. doi: 10.14309/ctg.0000000000000106.
Family history (FH) is associated with increased risk of colorectal cancer (CRC). We aimed to examine the potential for CRC risk stratification by known common genetic variants beyond FH in a large population-based case-control study from Germany.
Four thousand four hundred forty-seven cases and 3,480 controls recruited in 2003-2016 were included for whom comprehensive interview, medical, and genomic data were available. Associations with CRC risk were estimated from multiple logistic regression models for FH and a genetic risk score (GRS) based on 90 previously identified risk variants.
CRC in a first-degree relative was associated with a 1.71-fold (95% confidence interval 1.47-2.00) increase in CRC risk. A higher risk increase (odds ratio 2.06, 95% confidence interval 1.78-2.39) was estimated for the GRS when it was dichotomized at a cutoff yielding the same positivity rate as FH among controls. Furthermore, the GRS provides substantial additional risk stratification in both people with and especially without FH. Equal or even slightly higher risks were observed for participants without FH with a GRS in the upper 20% compared with participants with FH with a GRS below median. The observed patterns were confirmed in a replication study.
In contrast to common perception, known genetic variants do not primarily reflect some minor share of the familial excess risk of CRC, but rather reflect a substantial share of risk independent of FH.
家族史（FH）与结直肠癌（CRC）的风险增加相关。我们旨在通过德国一项大型基于人群的病例对照研究，在已知常见遗传变异之外，检查通过 FH 对 CRC 风险进行分层的可能性。
纳入了 2003 年至 2016 年期间招募的 4447 例病例和 3480 例对照者，他们有全面的访谈、医疗和基因组数据。使用多因素逻辑回归模型估计 FH 和基于 90 个先前确定的风险变异的遗传风险评分（GRS）与 CRC 风险的关联。
一级亲属的 CRC 与 CRC 风险增加 1.71 倍（95%置信区间 1.47-2.00）相关。当 GRS 分为截断值时，风险增加更大（优势比 2.06，95%置信区间 1.78-2.39），该截断值在对照组中与 FH 具有相同的阳性率。此外，GRS 可在具有和特别是不具有 FH 的人群中进行实质性的额外风险分层。与 FH 患者中 GRS 中位数以下的患者相比，无 FH 的患者中 GRS 在前 20%的患者风险相等或甚至略高。在一项复制研究中证实了观察到的模式。
与普遍看法相反，已知的遗传变异并非主要反映 CRC 家族性超额风险的一小部分，而是反映了独立于 FH 的相当大的风险份额。
