Background: Genome‐wide association studies are widely used to map genomic regions contributing to lung cancer (LC) susceptibility, but they typically do not identify the precise disease‐causing genes/variants. To unveil the inherited genetic variants that cause LC, we performed focused exome‐sequencing analyses on genes located in 121 genome‐wide association study–identified loci previously implicated in the risk of LC, chronic obstructive pulmonary disease, pulmonary function level, and smoking behavior. Methods: Germline DNA from 260 case patients with LC and 318 controls were sequenced by utilizing VCRome 2.1 exome capture. Filtering was based on enrichment of rare and potential deleterious variants in cases (risk alleles) or controls (protective alleles). Allelic association analyses of single‐variant and gene‐based burden tests of multiple variants were performed. Promising candidates were tested in two independent validation studies with a total of 1773 case patients and 1123 controls. Results: We identified 48 rare variants with deleterious effects in the discovery analysis and validated 12 of the 43 candidates that were covered in the validation platforms. The top validated candidates included one well‐established truncating variant, namely, BRCA2, DNA repair associated gene (BRCA2) K3326X (OR = 2.36, 95% confidence interval [CI]: 1.38–3.99), and three newly identified variations, namely, lymphotoxin beta gene (LTB) p.Leu87Phe (OR = 7.52, 95% CI: 1.01–16.56), prolyl 3‐hydroxylase 2 gene (P3H2) p.Gln185His (OR = 5.39, 95% CI: 0.75–15.43), and dishevelled associated activator of morphogenesis 2 gene (DAAM2) p.Asp762Gly (OR = 0.25, 95% CI: 0.10–0.79). Burden tests revealed strong associations between zinc finger protein 93 gene (ZNF93), DAAM2, bromodomain containing 9 gene (BRD9), and the gene LTB and LC susceptibility. Conclusion: Our results extend the catalogue of regions associated with LC and highlight the importance of germline rare coding variants in LC susceptibility.

中文翻译：

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已知易感位点的罕见变异及其对肺癌风险的影响

背景：全基因组关联研究被广泛用于绘制导致肺癌 (LC) 易感性的基因组区域，但它们通常无法确定准确的致病基因/变异体。为了揭示导致 LC 的遗传变异，我们对位于 121 个全基因组关联研究中的基因进行了重点外显子组测序分析，这些基因位点先前与 LC、慢性阻塞性肺疾病、肺功能水平和吸烟行为的风险有关. 方法：利用 VCRome 2.1 外显子组捕获对 260 名 LC 患者和 318 名对照者的生殖系 DNA 进行测序。过滤是基于病例（风险等位基因）或对照（保护性等位基因）中罕见和潜在有害变异的富集。对多个变体的单变体和基于基因的负荷测试进行了等位基因关联分析。有希望的候选人在两项独立的验证研究中进行了测试，总共有 1773 名病例患者和 1123 名对照。结果：我们在发现分析中确定了 48 个具有有害影响的罕见变异，并验证了验证平台中涵盖的 43 个候选者中的 12 个。经验证最高的候选者包括一种成熟的截短变异，即 BRCA2、DNA 修复相关基因 (BRCA2) K3326X（OR = 2.36，95% 置信区间 [CI]：1.38–3.99）和三个新发现的变异，即，淋巴毒素 β 基因 (LTB) p.Leu87Phe (OR = 7.52, 95% CI: 1.01–16.56), 脯氨酰 3-羟化酶 2 基因 (P3H2) p.Gln185His (OR = 5.39, 95% CI: 0.75–15.43) 和蓬乱的形态发生 2 基因 (DAAM2) 相关激活剂 p.Asp762Gly (OR = 0.25, 95% CI: 0.10–0.79)。负荷试验揭示了锌指蛋白 93 基因 (ZNF93)、DAAM2、含溴结构域 9 基因 (BRD9) 与基因 LTB 和 LC 易感性之间的强关联。结论：我们的结果扩展了与 LC 相关的区域目录，并强调了种系稀有编码变异在 LC 易感性中的重要性。