Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China.
Department of Bioinformatics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
Int J Cancer. 2018 Aug 15;143(4):878-885. doi: 10.1002/ijc.31351. Epub 2018 Mar 15.
Emerging evidence indicates that germline variations may interact with somatic events in carcinogenesis. However, the germline-somatic interaction in lung cancer remains largely unknown. We investigated whether lung cancer driver genes (CDGs) were more likely to locate within cancer susceptibility regions. Pathway analysis was performed to identify common pathways underlying CDGs and cancer susceptibility genes (CSGs). Next, we analyzed the associations between lung cancer risk SNPs and somatic alterations, including mutations and copy number alterations, in the level of genes, pathways, and overall burden of alterations. Enrichment analysis showed that lung CDGs are more likely to locate within cancer susceptibility regions (p = 8.40 × 10 ). Both of lung CSGs and CDGs showed significant enrichment in pathways such as cell cycle and p53 signaling pathway. Gene-based analysis showed that rs36600 (22q12.2) was associated with somatic mutations within ARID1A (OR = 2.45, 95%CI: 1.47-4.08, p = 5.78 × 10 ). Pathway-based analysis of somatic truncation mutations identified rs2395185 and rs3817963 at 6p22.1 was associated with cell cycle pathway (OR = 1.56, p = 3.61 × 10 for rs2395185; OR = 1.58, p = 4.15 × 10 for rs3817963), and rs3817963 was also associated with MAPK signaling pathway (OR = 1.54, p = 8.58 × 10 ). Further analysis associated rs2395185 at 6p22.1 (HLA class II genes) with increased APOBEC3A expression (p = 9.50 × 10 ) and elevated APOBEC mutagenesis (p = 3.58 × 10 ). These results indicate germline-somatic interactions in lung tumorigenesis, and help to uncover the molecular mechanisms underlying lung cancer risk SNPs.
新兴证据表明，种系变异可能与致癌作用中的体细胞事件相互作用。然而，肺癌中的种系-体细胞相互作用在很大程度上仍然未知。我们研究了肺癌驱动基因 (CDG) 是否更有可能位于癌症易感性区域内。进行了途径分析以确定 CDG 和癌症易感基因 (CSG) 的常见途径。接下来，我们分析了肺癌风险 SNPs 与基因、途径和整体改变负担水平的体细胞改变之间的关联。富集分析表明，肺癌 CDG 更有可能位于癌症易感性区域内 (p=8.40×10-8)。肺癌 CSG 和 CDG 均在细胞周期和 p53 信号通路等途径中表现出显著富集。基于基因的分析表明，rs36600(22q12.2) 与 ARID1A 中的体细胞突变(rs36600) 相关 (OR=2.45,95%CI:1.47-4.08,p=5.78×10-8)。体细胞截断突变的基于途径的分析确定 rs2395185 和 rs3817963 位于 6p22.1 与细胞周期途径相关 (rs2395185 的 OR=1.56,p=3.61×10-8;rs3817963 的 OR=1.58,p=4.15×10-8)，rs3817963 还与 MAPK 信号通路相关 (OR=1.54,p=8.58×10-8)。进一步的分析将 6p22.1 上的 rs2395185(HLA 类 II 基因)与 APOBEC3A 表达增加相关联 (p=9.50×10-8)，并与 APOBEC 诱变升高相关联 (p=3.58×10-8)。这些结果表明肺癌发生中的种系-体细胞相互作用，并有助于揭示肺癌风险 SNPs 的分子机制。
