香烟烟雾,同时含有尼古丁和致癌物质,导致肺癌。然而,并非所有吸烟者都会患上肺癌,强调宿主易感性和环境暴露在肿瘤发生中相互作用的重要性。这里,我们的目的是描述烟草致癌物的代谢能力和吸烟强度在介导吸烟相关肺肿瘤发生的遗传易感性中的相互作用.使用汇总统计和个体水平的遗传数据分析了43个烟草致癌物代谢基因与肺癌的单变异和基于基因的关联,其次是孟德尔随机化的因果推断,调解分析,和结构方程建模。使用香烟烟雾暴露的细胞模型来检测与特定等位基因相关的基因表达模式。来自国际肺癌协会(29,266例和56,450例对照)和英国生物银行(2,155例和376,329例对照)的数据表明,CYP2A6内含子4中的遗传变异rs56113850C>T与吸烟者肺癌风险降低显着相关[优势比(OR)=0.88,95%置信区间=0.85-0.91,P=2.18×10-16]。可能与吸烟状态相互作用(P相互作用=0.028),并部分介导(ORindirect=0.987)。吸烟强度占CYP2A6活性对肺癌风险影响的82.3%,但完全介导rs56113850的遗传效应。机械上,rs56113850T等位基因挽救了香烟烟雾暴露引起的CYP2A6的下调,可能通过优先招募转录因子HLTF。一起,这项研究为吸烟相关肺肿瘤发生中宿主易感性和致癌物暴露之间的相互作用提供了更多的见解.
Cigarette smoke, containing both nicotine and carcinogens, causes lung cancer. However, not all smokers develop lung cancer, highlighting the importance of the interaction between host susceptibility and environmental exposure in tumorigenesis. Here, we aimed to delineate the interaction between metabolizing ability of tobacco carcinogens and smoking intensity in mediating genetic susceptibility to smoking-related lung tumorigenesis. Single-variant and gene-based associations of 43 tobacco carcinogen-metabolizing genes with lung cancer were analyzed using summary statistics and individual-level genetic data, followed by causal inference of Mendelian randomization, mediation analysis, and structural equation modeling. Cigarette smoke-exposed cell models were used to detect gene expression patterns in relation to specific alleles. Data from the International Lung Cancer Consortium (29,266 cases and 56,450 controls) and UK Biobank (2,155 cases and 376,329 controls) indicated that the genetic variant rs56113850 C>T located in intron 4 of CYP2A6 was significantly associated with decreased lung cancer risk among smokers (OR = 0.88, 95% confidence interval = 0.85-0.91, P = 2.18 × 10-16), which might interact (Pinteraction = 0.028) with and partially be mediated (ORindirect = 0.987) by smoking status. Smoking intensity accounted for 82.3% of the effect of CYP2A6 activity on lung cancer risk but entirely mediated the genetic effect of rs56113850. Mechanistically, the rs56113850 T allele rescued the downregulation of CYP2A6 caused by cigarette smoke exposure, potentially through preferential recruitment of transcription factor helicase-like transcription factor. Together, this study provides additional insights into the interplay between host susceptibility and carcinogen exposure in smoking-related lung tumorigenesis.
The causal pathway connecting CYP2A6 genetic variability and activity, cigarette consumption, and lung cancer susceptibility in smokers highlights the need for behavior modification interventions based on host susceptibility for cancer prevention.