Common genetic variants associated with lung cancer have been well studied in the past decade. However, only 12.3% heritability has been explained by these variants. In this study, we investigate the contribution of rare variants (RVs) (minor allele frequency <0.01) to lung cancer through two large whole exome sequencing case-control studies. We first performed gene-based association tests using a novel Bayes Factor statistic in the International Lung Cancer Consortium, the discovery study (European, 1042 cases vs. 881 controls). The top genes identified are further assessed in the UK Biobank (European, 630 cases vs. 172 864 controls), the replication study. After controlling for the false discovery rate, we found two genes, CTSL and APOE, significantly associated with lung cancer in both studies. Single variant tests in UK Biobank identified 4 RVs (3 missense variants) in CTSL and 2 RVs (1 missense variant) in APOE stongly associated with lung cancer (OR between 2.0 and 139.0). The role of these genetic variants in the regulation of CTSL or APOE expression remains unclear. If such a role is established, this could have important therapeutic implications for lung cancer patients.

中文翻译：

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大规模全外显子组测序研究确定了与肺癌相关的两个基因：CTSL 和 APOE。

过去十年中，与肺癌相关的常见遗传变异已得到深入研究。然而，这些变异仅解释了 12.3% 的遗传力。在本研究中，我们通过两项大型全外显子组测序病例对照研究研究了罕见变异 (RV)（次要等位基因频率 <0.01）对肺癌的影响。我们首先使用国际肺癌联盟发现研究（欧洲，1042 例病例与 881 例对照）中的新型贝叶斯因子统计数据进行基于基因的关联测试。确定的主要基因在英国生物库（欧洲，630 个病例与 172 864 个对照）和复制研究中得到进一步评估。在控制了错误发现率后，我们在两项研究中发现了两个基因，CTSL 和 APOE，与肺癌显着相关。英国生物银行的单变异测试发现 CTSL 中的 4 个 RV（3 个错义变异）和 APOE 中的 2 个 RV（1 个错义变异）与肺癌密切相关（OR 在 2.0 和 139.0 之间）。这些遗传变异在 CTSL 或 APOE 表达调节中的作用仍不清楚。如果这种作用得到证实，这可能对肺癌患者产生重要的治疗意义。