figshare
Browse
can-23-0900_supplementary_materials_suppsd.docx (6.63 MB)

Supplementary Materials from CYP2A6 Activity and Cigarette Consumption Interact in Smoking-Related Lung Cancer Susceptibility

Download (6.63 MB)
journal contribution
posted on 2024-02-15, 08:20 authored by Mulong Du, Junyi Xin, Rui Zheng, Qianyu Yuan, Zhihui Wang, Hongliang Liu, Hanting Liu, Guoshuai Cai, Demetrius Albanes, Stephen Lam, Adonina Tardon, Chu Chen, Stig E. Bojesen, Maria Teresa Landi, Mattias Johansson, Angela Risch, Heike Bickeböller, H-Erich Wichmann, Gad Rennert, Susanne Arnold, Paul Brennan, John K. Field, Sanjay S. Shete, Loïc Le Marchand, Geoffrey Liu, Angeline S. Andrew, Lambertus A. Kiemeney, Shan Zienolddiny, Kjell Grankvist, Mikael Johansson, Neil E. Caporaso, Angela Cox, Yun-Chul Hong, Jian-Min Yuan, Matthew B. Schabath, Melinda C. Aldrich, Meilin Wang, Hongbing Shen, Feng Chen, Zhengdong Zhang, Rayjean J. Hung, Christopher I. Amos, Qingyi Wei, Philip Lazarus, David C. Christiani

Supplementary Methods and Figures

Funding

National Institute of Environmental Health Sciences (NIEHS)

United States Department of Health and Human Services

Find out more...

National Cancer Institute (NCI)

United States Department of Health and Human Services

Find out more...

History

ARTICLE ABSTRACT

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.

Usage metrics

    Cancer Research

    Categories

    Keywords

    BiomarkersGenetic biomarkersGenetics of Cancer Risk & OutcomeCarcinogen metabolism polymorphismsLung Cancer

    Licence

    CC BY

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC