Risk stratification for lung cancer (LC) screening is so far mostly based on smoking history. This study aimed to assess if and to what extent such risk stratification could be enhanced by additional consideration of genetic risk scores (GRSs) and epigenetic risk scores defined by DNA methylation. We conducted a nested case-control study of 143 incident LC cases and 1460 LC-free controls within a prospective cohort of 9949 participants aged 50–75 years with 14-year follow-up. Lifetime smoking history was obtained in detail at recruitment. We built a GRS based on 31 previously identified LC-associated single-nucleotide polymorphisms (SNPs) and a DNA methylation score (MRS) based on methylation of 151 previously identified smoking-associated cytosine-phosphate-guanine (CpG) loci. We evaluated associations of GRS and MRS with LC incidence by logistic regression models, controlling for age, sex, smoking status, and pack-years. We compared the predictive performance of models based on pack-years alone with models additionally including GRS and/or MRS using the area under the receiver operating characteristic curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI). GRS and MRS showed moderate and strong associations with LC risk even after comprehensive adjustment for smoking history (adjusted odds ratio [95% CI] comparing highest with lowest quartile 1.93 [1.05–3.71] and 5.64 [2.13–17.03], respectively). Similar associations were also observed within the risk groups of ever and heavy smokers. Addition of GRS and MRS furthermore strongly enhanced LC prediction beyond prediction by pack-years (increase of optimism-corrected AUC among heavy smokers from 0.605 to 0.654, NRI 26.7%, p = 0.0106, IDI 3.35%, p = 0.0036), the increase being mostly attributable to the inclusion of MRS. Consideration of MRS, by itself or in combination with GRS, may strongly enhance LC risk stratification.

中文翻译：

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遗传和甲基化风险评分对增强肺癌风险分层的个人和联合贡献：来自德国基于人群的队列的数据。

迄今为止，肺癌 (LC) 筛查的风险分层主要基于吸烟史。本研究旨在评估通过额外考虑遗传风险评分 (GRS) 和由 DNA 甲基化定义的表观遗传风险评分是否可以以及在多大程度上增强这种风险分层。我们对 9949 名 50-75 岁参与者的前瞻性队列中的 143 例 LC 病例和 1460 例无 LC 对照进行了巢式病例对照研究，并进行了 14 年的随访。在招募时详细获得终生吸烟史。我们基于 31 个先前确定的 LC 相关单核苷酸多态性 (SNP) 和基于 151 个先前确定的吸烟相关胞嘧啶-磷酸-鸟嘌呤 (CpG) 位点甲基化的 DNA 甲基化评分 (MRS) 构建了 GRS。我们通过逻辑回归模型评估了 GRS 和 MRS 与 LC 发病率的关联，控制了年龄、性别、吸烟状况和包年。我们使用接收者操作特征曲线 (AUC)、净重分类改进 (NRI) 和综合鉴别改进 (IDI) 下的面积，比较了仅基于包装年的模型与另外包括 GRS 和/或 MRS 的模型的预测性能。即使在对吸烟史进行全面调整后，GRS 和 MRS 仍显示出与 LC 风险的中度和强相关性（调整后的优势比 [95% CI] 分别与最低四分位数 1.93 [1.05-3.71] 和 5.64 [2.13-17.03] 相比）。在曾经和重度吸烟者的风险组中也观察到类似的关联。GRS 和 MRS 的加入进一步增强了超过包年预测的 LC 预测（重度吸烟者的乐观校正 AUC 从 0.605 增加到 0.654，NRI 26.7%，p = 0.0106，IDI 3.35%，p = 0.0036），增加主要归因于包含 MRS。考虑 MRS 本身或与 GRS 结合，可能会大大增强 LC 风险分层。