Trendowski Matthew R, Lusk Christine M, Wenzlaff Angela S, Neslund-Dudas Christine, Purrington Kristen S, Beebe-Dimmer Jennifer L, Schwartz Ann G
Karmanos Cancer Institute and Department of Oncology, Wayne State University School of Medicine, Detroit, MI.
Department of Public Health Sciences, Henry Ford Health, Detroit, MI.
JCO Precis Oncol. 2025 Jan;9:e2400558. doi: 10.1200/PO-24-00558. Epub 2025 Jan 24.
Although lung cancer is one of the most common malignancies, the underlying genetics regarding susceptibility remain poorly understood. We characterized the spectrum of pathogenic/likely pathogenic (P/LP) germline variants within DNA damage response (DDR) genes among lung cancer cases and controls in non-Hispanic Whites (NHWs) and African Americans (AAs).
Rare, germline variants in 67 DDR genes with evidence of pathogenicity were identified using the ClinVar database. These P/LP variants were genotyped in a sample of 3,040 lung cancer cases and controls from the Inflammation, Health, Ancestry, and Lung Epidemiology study (NHW: n = 1,915; AA: n = 1,125) and were tested for their association with lung cancer using multivariate logistic regression adjusting for age, sex, pack-years, and race.
We identified 49 unique rare P/LP variants in 21 genes among 156 carriers. Approximately 5.9% of lung cancer cases and 4.2% of controls carried at least one P/LP variant. P/LP variants in DDR genes were more common in lung cancer cases, particularly those diagnosed with adenocarcinoma (odds ratio [OR], 1.46 [95% CI, 1.00 to 2.14]). variants were associated with lung cancer overall (OR, 1.82 [95% CI, 1.10 to 3.12]), with the strongest associations among never smokers (OR, 3.37 [95% CI, 1.08 to 10.26]), and in individuals who do not meet current USPSTF screening criteria (OR, 2.85 [95% CI, 1.20 to 7.53]).
Germline variants in DDR genes appear to be associated with lung cancer, particularly when examined by gene subtype and morphologic subtype. , a gene historically associated with colorectal and other GI malignancies, emerged as a candidate gene that should be examined in individuals who do not have a significant smoking history.
尽管肺癌是最常见的恶性肿瘤之一，但关于易感性的潜在遗传学仍知之甚少。我们对非西班牙裔白人（NHW）和非裔美国人（AA）的肺癌病例和对照中DNA损伤反应（DDR）基因内的致病/可能致病（P/LP）种系变异谱进行了特征分析。
使用ClinVar数据库鉴定了67个具有致病性证据的DDR基因中的罕见种系变异。在来自炎症、健康、血统和肺癌流行病学研究的3040例肺癌病例和对照样本（NHW：n = 1915；AA：n = 1125）中对这些P/LP变异进行基因分型，并使用多变量逻辑回归分析调整年龄、性别、吸烟包年数和种族后，测试它们与肺癌的关联。
我们在156名携带者中的21个基因中鉴定出49个独特的罕见P/LP变异。约5.9%的肺癌病例和4.2%的对照携带至少一个P/LP变异。DDR基因中的P/LP变异在肺癌病例中更常见，尤其是那些被诊断为腺癌的病例（优势比[OR]，1.46[95%置信区间，1.00至2.14]）。这些变异总体上与肺癌相关（OR，1.82[95%置信区间，1.10至3.12]），在从不吸烟者中关联最强（OR，3.37[95%置信区间，1.08至10.26]），在不符合当前美国预防服务工作组筛查标准的个体中也是如此（OR，2.85[95%置信区间，1.20至7.53]）。
DDR基因中的种系变异似乎与肺癌相关，特别是在按基因亚型和形态学亚型进行检查时。 ，一个历史上与结直肠癌和其他胃肠道恶性肿瘤相关的基因，成为一个候选基因，应在没有显著吸烟史的个体中进行检查。
