Department of Epidemiology, International Joint Research Center on Environment and Human Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.
Cancer Epidemiol Biomarkers Prev. 2020 Jul;29(7):1423-1429. doi: 10.1158/1055-9965.EPI-19-1085. Epub 2020 Apr 10.
A substantial proportion of cancer driver genes (CDG) are also cancer predisposition genes. However, the associations between genetic variants in lung CDGs and the susceptibility to lung cancer have rarely been investigated.
We selected expression-related single-nucleotide polymorphisms (eSNP) and nonsynonymous variants of lung CDGs, and tested their associations with lung cancer risk in two large-scale genome-wide association studies (20,871 cases and 15,971 controls of European descent). Conditional and joint association analysis was performed to identify independent risk variants. The associations of independent risk variants with somatic alterations in lung CDGs or recurrently altered pathways were investigated using data from The Cancer Genome Atlas (TCGA) project.
We identified seven independent SNPs in five lung CDGs that were consistently associated with lung cancer risk in discovery ( < 0.001) and validation ( < 0.05) stages. Among these loci, rs78062588 in (1q21.3) was a new lung cancer susceptibility locus (OR = 0.86, = 1.65 × 10). Subgroup analysis by histologic types further identified nine lung CDGs. Analysis of somatic alterations found that in lung adenocarcinomas, rs78062588[C] allele ( in 1q21.3) was associated with elevated somatic copy number of (OR = 1.16, = 0.02). In lung adenocarcinomas, rs1611182 ( in 6p22.1) was associated with truncation mutations of the transcriptional misregulation in cancer pathway (OR = 0.66, = 1.76 × 10).
Genetic variants can regulate functions of lung CDGs and influence lung cancer susceptibility.
Our findings might help unravel biological mechanisms underlying lung cancer susceptibility.
很大一部分癌症驱动基因（CDG）也是癌症易感性基因。然而，肺 CDG 中的遗传变异与肺癌易感性之间的关联很少被研究过。
我们选择了与肺 CDG 表达相关的单核苷酸多态性（eSNP）和非同义变体，并在两项大规模全基因组关联研究（20871 例欧洲裔病例和 15971 例对照）中测试了它们与肺癌风险的关联。进行条件和联合关联分析以确定独立的风险变异。使用癌症基因组图谱（TCGA）项目的数据研究了独立风险变异与肺 CDG 中的体细胞改变或反复改变的途径之间的关联。
我们在发现阶段（ < 0.001）和验证阶段（ < 0.05）一致鉴定了五个肺 CDG 中的七个独立 SNPs 与肺癌风险相关。在这些位点中，1q21.3 中的 rs78062588 是一个新的肺癌易感性位点（OR = 0.86， = 1.65 × 10）。组织学类型的亚组分析进一步鉴定了九个肺 CDG。体细胞改变分析发现，在肺腺癌中，rs78062588[C]等位基因（在 1q21.3 中）与 （OR = 1.16， = 0.02）的体细胞拷贝数升高相关。在肺腺癌中，rs1611182（在 6p22.1 中）与癌症转录失调途径的截断突变相关（OR = 0.66， = 1.76 × 10）。
遗传变异可以调节肺 CDG 的功能并影响肺癌易感性。
我们的研究结果可能有助于揭示肺癌易感性的生物学机制。
