Du, Mulong 
ORCID: 0000-0002-2733-6490, Xin, Junyi ORCID: 0000-0001-6677-3936, Zheng, Rui ORCID: 0000-0001-7020-3354, Yuan, Qianyu ORCID: 0000-0003-0878-3030, Wang, Zhihui ORCID: 0009-0000-4306-2373, Liu, Hongliang ORCID: 0000-0001-7639-0904, Liu, Hanting ORCID: 0009-0005-2801-2729, Cai, Guoshuai ORCID: 0000-0002-5331-1297, Albanes, Demetrius ORCID: 0000-0001-8330-4293, Lam, Stephen ORCID: 0000-0002-3964-1492 et al (show 35 more authors)
(2024)
CYP2A6 Activity and Cigarette Consumption Interact in Smoking-Related Lung Cancer Susceptibility.
Cancer research, 84 (4).
pp. 616-625.
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Du et al A causal pathway of CYP2A6 activity and cigarette consumption involved in smoking-related lung cancer susceptibility.pdf - Author Accepted Manuscript Available under License Creative Commons Attribution. Download (3MB) | Preview |
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.<h4>Significance</h4>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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Humans, Lung Neoplasms, Transcription Factors, Carcinogens, Smoking, Tobacco Products, Carcinogenesis, Cytochrome P-450 CYP2A6 |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 07 Feb 2024 09:26 |
| Last Modified: | 21 Mar 2024 18:11 |
| DOI: | 10.1158/0008-5472.can-23-0900 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3178515 |
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