Department of Epidemiology and Biostatistics, International Joint Research Center on Environment and Human Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China.
Int J Cancer. 2024 Mar 1;154(5):807-815. doi: 10.1002/ijc.34765. Epub 2023 Oct 17.
The proportion of lung cancer in never smokers is rising, especially among Asian women, but there is no effective early detection tool. Here, we developed a polygenic risk score (PRS), which may help to identify the population with higher risk of lung cancer in never-smoking women. We first performed a large GWAS meta-analysis (8595 cases and 8275 controls) to systematically identify the susceptibility loci for lung cancer in never-smoking Asian women and then generated a PRS using GWAS datasets. Furthermore, we evaluated the utility and effectiveness of PRS in an independent Chinese prospective cohort comprising 55 266 individuals. The GWAS meta-analysis identified eight known loci and a novel locus (5q11.2) at the genome-wide statistical significance level of P < 5 × 10 . Based on the summary statistics of GWAS, we derived a polygenic risk score including 21 variants (PRS-21) for lung cancer in never-smoking women. Furthermore, PRS-21 had a hazard ratio (HR) per SD of 1.29 (95% CI = 1.18-1.41) in the prospective cohort. Compared with participants who had a low genetic risk, those with an intermediate (HR = 1.32, 95% CI: 1.00-1.72) and high (HR = 2.09, 95% CI: 1.56-2.80) genetic risk had a significantly higher risk of incident lung cancer. The addition of PRS-21 to the conventional risk model yielded a modest significant improvement in AUC (0.697 to 0.711) and net reclassification improvement (24.2%). The GWAS-derived PRS-21 significantly improves the risk stratification and prediction accuracy for incident lung cancer in never-smoking Asian women, demonstrating the potential for identification of high-risk individuals and early screening.
不吸烟人群中的肺癌比例正在上升，尤其是在亚洲女性中，但目前尚无有效的早期检测工具。在这里，我们开发了一种多基因风险评分（PRS），它可能有助于识别不吸烟女性中肺癌风险较高的人群。我们首先对 8595 例病例和 8275 例对照进行了大规模 GWAS 荟萃分析，以系统地鉴定不吸烟亚洲女性肺癌的易感基因座，然后使用 GWAS 数据集生成 PRS。此外，我们在一个包含 55266 名个体的独立中国前瞻性队列中评估了 PRS 的实用性和有效性。GWAS 荟萃分析确定了八个已知的基因座和一个新的基因座（5q11.2），达到全基因组统计学意义水平 P < 5×10 -8 。基于 GWAS 的汇总统计数据，我们为不吸烟女性的肺癌衍生了一个包含 21 个变体的多基因风险评分（PRS-21）。此外，PRS-21 在前瞻性队列中的危险比（HR）为每 SD 增加 1.29（95%CI=1.18-1.41）。与遗传风险低的参与者相比，遗传风险中等（HR=1.32，95%CI：1.00-1.72）和高（HR=2.09，95%CI：1.56-2.80）的参与者患肺癌的风险显著更高。将 PRS-21 添加到常规风险模型中可使 AUC（0.697 至 0.711）和净重新分类改善（24.2%）适度显著提高。GWAS 衍生的 PRS-21 显著改善了不吸烟亚洲女性中肺癌的风险分层和预测准确性，表明有可能识别高危个体并进行早期筛查。
