INTRODUCTION Lung cancer is the leading cause of cancer deaths in the world, and adenocarcinoma (LUAD) is its most prevalent subtype. Symptoms often appear in advanced disease when treatment options are limited. Identifying genetic risk factors will enable better identification of high-risk individuals. METHODS To identify LUAD risk genes, we performed a case-control association study for gene-level burden of rare, deleterious variants (RDVs) in germline whole-exome sequencing (WES) data of 1,083 LUAD patients and 7,650 controls, split into discovery and validation cohorts. Of these, we performed WES on 97 patients and acquired the rest from multiple public databases. We annotated all rare variants for pathogenicity conservatively, using ACMG guidelines and ClinVar curation, and investigated gene-level RDV burden using penalized logistic regression. All statistical tests were two-sided. RESULTS We discovered and replicated the finding that the burden of germline ATM RDVs was significantly higher in LUAD patients versus controls (ORcombined=4.6; p=1.7e-04; 95% CI=2.2-9.5; 1.21% of cases; 0.24% of controls). Germline ATM RDVs were also enriched in an independent clinical cohort of 1,594 patients from the MSK-IMPACT study (0.63%). Additionally, we observed that an Ashkenazi Jewish (AJ) founder ATM variant, rs56009889, was statistically significantly more frequent in AJ cases versus AJ controls in our cohort (ORcombined, AJ=2.7, p=6.9e-03, 95% CI=1.3-5.3). CONCLUSIONS Our results indicate that ATM is a moderate-penetrance LUAD risk gene, and that LUAD may be part of the ATM-related cancer syndrome spectrum. Individuals with ATM RDVs are at elevated LUAD risk and can benefit from increased surveillance (particularly CT scanning), early detection and chemoprevention programs, improving prognosis.

中文翻译：

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ATM中遗传的罕见有害变异增加肺腺癌风险

引言 肺癌是全球癌症死亡的主要原因，而腺癌 (LUAD) 是其最普遍的亚型。当治疗选择有限时，症状通常出现在晚期疾病中。识别遗传风险因素将有助于更好地识别高风险个体。方法 为了识别 LUAD 风险基因，我们对 1,083 名 LUAD 患者和 7,650 名对照的生殖系全外显子组测序 (WES) 数据中罕见有害变异 (RDV) 的基因水平负担进行了病例对照关联研究，分为发现和验证队列。其中，我们对 97 名患者进行了 WES，并从多个公共数据库中获取了其余患者。我们使用 ACMG 指南和 ClinVar 管理保守地注释了所有罕见变异的致病性，并使用惩罚逻辑回归研究了基因水平的 RDV 负担。所有统计测试都是双向的。结果 我们发现并重复了这一发现，即 LUA​​D 患者的种系 ATM RDV 负担显着高于对照组（ORcombined=4.6；p=1.7e-04；95% CI=2.2-9.5；1.21% 的病例；0.24%控制）。来自 MSK-IMPACT 研究的 1,594 名患者的独立临床队列（0.63%）也丰富了 Germline ATM RDV。此外，我们观察到德系犹太人 (AJ) 创始人 ATM 变体 rs56009889 在 AJ 病例中的频率显着高于我们队列中的 AJ 对照（ORcombined, AJ=2.7, p=6.9e-03, 95% CI=1.3 -5.3)。结论 我们的结果表明，ATM 是一种中等外显率的 LUAD 风险基因，并且 LUAD 可能是 ATM 相关癌症综合征谱的一部分。