Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, Ontario, Canada.
Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
PLoS Genet. 2023 Sep 22;19(9):e1010902. doi: 10.1371/journal.pgen.1010902. eCollection 2023 Sep.
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.
在过去的十年中，人们对与肺癌相关的常见遗传变异进行了深入研究。然而，这些变异只能解释 12.3%的遗传率。在这项研究中，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（RVs）（次要等位基因频率<0.01）对肺癌的贡献。我们首先在国际肺癌联合会的发现研究（欧洲，1042 例病例与 881 例对照）中使用一种新的贝叶斯因子统计量进行了基于基因的关联测试。在英国生物库（欧洲，630 例病例与 172864 例对照）的复制研究中，进一步评估了鉴定出的顶级基因。在控制了错误发现率后，我们发现 CTSL 和 APOE 这两个基因在两项研究中均与肺癌显著相关。在英国生物库中的单变体测试鉴定出 CTSL 中 4 个 RVs（3 个错义变体）和 APOE 中 2 个 RVs（1 个错义变体）与肺癌强烈相关（OR 介于 2.0 和 139.0 之间）。这些遗传变异在 CTSL 或 APOE 表达调控中的作用尚不清楚。如果这种作用得到证实，这可能对肺癌患者具有重要的治疗意义。
