Assessing Lung Cancer Absolute Risk Trajectory Based on a Polygenic Risk Model.
Assessing Lung Cancer Absolute Risk Trajectory Based on a Polygenic Risk Model.
复制标题
DOI：
10.1158/0008-5472.can-20-1237
复制
发表时间：
2021-03-15
期刊：
影响因子：
11.2
通讯作者：
Amos CI
中科院分区：
文献类型：
--
作者：
Hung RJ;Warkentin MT;Brhane Y;Chatterjee N;Christiani DC;Landi MT;Caporaso NE;Liu G;Johansson M;Albanes D;Marchand LL;Tardon A;Rennert G;Bojesen SE;Chen C;Field JK;Kiemeney LA;Lazarus P;Zienolddiny S;Lam S;Andrew AS;Arnold SM;Aldrich MC;Bickeböller H;Risch A;Schabath MB;McKay JD;Brennan P;Amos CI
肺癌是全球癌症死亡的主要原因。改进的风险分层策略可以提高低剂量计算机断层扫描 (LDCT) 筛查的效率。在此，我们评估了个体的遗传背景在 LDCT 筛查中是否具有临床实用性。基于国际肺癌联盟中 13,119 名肺癌患者和 10,008 名具有欧洲血统的对照，我们通过 10 倍交叉验证和正则化惩罚回归构建了多基因风险评分 (PRS)。使用英国生物样本库数据（N=335,931）评估了整合 PRS 的风险模型的性能，包括校准和区分能力。绝对风险是根据特定年龄的肺癌发病率和全因死亡率作为竞争风险来估计的。为了评估其潜在的临床实用性，在国家肺部筛查试验（N = 50,772 名参与者）中模拟了 PRS 分布。在验证集中，PRS 分布顶部十分之一个体与底部 10% 个体的肺癌比值比 (OR) 为 2.39 (95%CI=1.92–3.00，P=1.80×10−14)（趋势 p 值为 5.26 × 10−20）。验证集中总体肺癌风险的 PRS 增加的标准差 OR 为 1.26 (95%CI=1.20–1.32, P=9.69×10−23)。当考虑绝对风险时，不同 PRS 十分位的个体表现出不同的 5 年和累积绝对风险轨迹。达到 LDCT 筛查建议阈值的年龄可能会有 4 至 8 岁的差异，具体取决于个人的遗传背景、吸烟状况和家族史。总的来说，这些结果表明个体的遗传背景可能会影响最佳的肺癌 LDCT 筛查策略。
Lung cancer is the leading cause of cancer death globally. An improved risk stratification strategy can increase efficiency of low-dose computed tomography (LDCT) screening. Here we assessed whether individual’s genetic background has clinical utility for risk stratification in the context of LDCT screening. Based on 13,119 lung cancer patients and 10,008 controls with European ancestry in the International Lung Cancer Consortium, we constructed a polygenic risk score (PRS) via 10-fold cross-validation with regularized penalized regression. The performance of risk model integrating PRS, including calibration and ability to discriminate, was assessed using UK biobank data (N=335,931). Absolute risk was estimated based on age-specific lung cancer incidence and all-cause mortality as competing risk. To evaluate its potential clinical utility, the PRS distribution was simulated in the National Lung Screening Trial (N=50,772 participants). The lung cancer odds ratio (ORs) for individuals at the top decile of the PRS distribution versus those at bottom 10% was 2.39 (95%CI=1.92–3.00, P=1.80×10−14) in the validation set (trend p-value of 5.26 × 10−20). The OR per standard deviation of PRS increase was 1.26 (95%CI=1.20–1.32, P=9.69×10−23) for overall lung cancer risk in the validation set. When considering absolute risks, individuals at different PRS deciles showed differential trajectories of 5-year and cumulative absolute risk. The age reaching the LDCT screening recommendation threshold can vary by 4 to 8 years, depending on the individual’s genetic background, smoking status and family history. Collectively, these results suggest that individual’s genetic background may inform the optimal lung cancer LDCT screening strategy.
影响因子：
4.6
作者：
Puddu PE;Piras P;Kromhout D;Tolonen H;Kafatos A;Menotti A
通讯作者：
Menotti A