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

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 Bickeboller; 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

doi:10.1158/0008-5472.CAN-23-0900

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

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 Bickeboller
, 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

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

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 X 10^-16), which might interact (P_interaction = 0.028) with and partially be mediated (OR_indirect = 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.

Original language	English
Pages (from-to)	616-625
Number of pages	10
Journal	Cancer Research
Volume	84
Issue number	4
DOIs	https://doi.org/10.1158/0008-5472.CAN-23-0900
State	Published - 2024

Bibliographical note

Publisher Copyright:
© 2023 American Association for Cancer Research.

Funding

A. Risch reports grants from Deutsche Krebshilfe and NIH during the conduct of the study. J.K. Field reports grants from Roy Castle Lung Cancer Foundation during the conduct of the study. J.-M. Yuan reports grants from NIH during the conduct of the study. M.C. Aldrich reports grants from NIH/NCI and personal fees from Guardant Health outside the submitted work. No disclosures were reported by the other authors. This work was partially supported by R01 ES025460-01 from National Institute of Environmental Health Sciences (PI: P. Lazarus) and U01 CA209414 from NCI (PI: D. C. Christiani). CARET is funded by the NCI, NIH through grants U01-CA063673, UM1-CA167462, and U01-CA167462 (PI: C. Chen).

Funders	Funder number
National Institutes of Health (NIH)	U01-CA167462, U01-CA063673
National Institutes of Health (NIH)
National Childhood Cancer Registry – National Cancer Institute
National Institutes of Health/National Institute of Environmental Health Sciences	U01 CA209414
National Institutes of Health/National Institute of Environmental Health Sciences
Roy Castle Lung Cancer Foundation
Deutsche Krebshilfe

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1158/0008-5472.CAN-23-0900

Cite this

Du, M., Xin, J., Zheng, R., Yuan, Q., Wang, Z., Liu, H., Liu, H., Cai, G., Albanes, D., Lam, S., Tardon, A., Chen, C., Bojesen, S. E., Landi, M. T., Johansson, M., Risch, A., Bickeboller, H., Wichmann, H. E., Rennert, G., ... Christiani, D. C. (2024). CYP2A6 Activity and Cigarette Consumption Interact in Smoking-Related Lung Cancer Susceptibility. Cancer Research, 84(4), 616-625. https://doi.org/10.1158/0008-5472.CAN-23-0900

@article{a353c6c9be024dd3bd06c96ba805e9f9,

title = "CYP2A6 Activity and Cigarette Consumption Interact in Smoking-Related Lung Cancer Susceptibility",

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 X 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.",

author = "Mulong Du and Junyi Xin and Rui Zheng and Qianyu Yuan and Zhihui Wang and Hongliang Liu and Hanting Liu and Guoshuai Cai and Demetrius Albanes and Stephen Lam and Adonina Tardon and Chu Chen and Bojesen, \{Stig E.\} and Landi, \{Maria Teresa\} and Mattias Johansson and Angela Risch and Heike Bickeboller and Wichmann, \{H. Erich\} and Gad Rennert and Susanne Arnold and Paul Brennan and Field, \{John K.\} and Shete, \{Sanjay S.\} and \{Le Marchand\}, Lo{\"i}c and Geoffrey Liu and Andrew, \{Angeline S.\} and Kiemeney, \{Lambertus A.\} and Shan Zienolddiny and Kjell Grankvist and Mikael Johansson and Caporaso, \{Neil E.\} and Angela Cox and Hong, \{Yun Chul\} and Yuan, \{Jian Min\} and Schabath, \{Matthew B.\} and Aldrich, \{Melinda C.\} and Meilin Wang and Hongbing Shen and Feng Chen and Zhengdong Zhang and Hung, \{Rayjean J.\} and Amos, \{Christopher I.\} and Qingyi Wei and Philip Lazarus and Christiani, \{David C.\}",

note = "Publisher Copyright: {\textcopyright} 2023 American Association for Cancer Research.",

year = "2024",

doi = "10.1158/0008-5472.CAN-23-0900",

language = "English",

volume = "84",

pages = "616--625",

number = "4",

}

Du, M, Xin, J, Zheng, R, Yuan, Q, Wang, Z, Liu, H, Liu, H, Cai, G, Albanes, D, Lam, S, Tardon, A, Chen, C, Bojesen, SE, Landi, MT, Johansson, M, Risch, A, Bickeboller, H, Wichmann, HE, Rennert, G, Arnold, S, Brennan, P, Field, JK, Shete, SS, Le Marchand, L, Liu, G, Andrew, AS, Kiemeney, LA, Zienolddiny, S, Grankvist, K, Johansson, M, Caporaso, NE, Cox, A, Hong, YC, Yuan, JM, Schabath, MB, Aldrich, MC, Wang, M, Shen, H, Chen, F, Zhang, Z, Hung, RJ, Amos, CI, Wei, Q, Lazarus, P & Christiani, DC 2024, 'CYP2A6 Activity and Cigarette Consumption Interact in Smoking-Related Lung Cancer Susceptibility', Cancer Research, vol. 84, no. 4, pp. 616-625. https://doi.org/10.1158/0008-5472.CAN-23-0900

TY - JOUR

T1 - CYP2A6 Activity and Cigarette Consumption Interact in Smoking-Related Lung Cancer Susceptibility

AU - Du, Mulong

AU - Xin, Junyi

AU - Zheng, Rui

AU - Yuan, Qianyu

AU - Wang, Zhihui

AU - Liu, Hongliang

AU - Liu, Hanting

AU - Cai, Guoshuai

AU - Albanes, Demetrius

AU - Lam, Stephen

AU - Tardon, Adonina

AU - Chen, Chu

AU - Bojesen, Stig E.

AU - Landi, Maria Teresa

AU - Johansson, Mattias

AU - Risch, Angela

AU - Bickeboller, Heike

AU - Wichmann, H. Erich

AU - Rennert, Gad

AU - Arnold, Susanne

AU - Brennan, Paul

AU - Field, John K.

AU - Shete, Sanjay S.

AU - Le Marchand, Loïc

AU - Liu, Geoffrey

AU - Andrew, Angeline S.

AU - Kiemeney, Lambertus A.

AU - Zienolddiny, Shan

AU - Grankvist, Kjell

AU - Johansson, Mikael

AU - Caporaso, Neil E.

AU - Cox, Angela

AU - Hong, Yun Chul

AU - Yuan, Jian Min

AU - Schabath, Matthew B.

AU - Aldrich, Melinda C.

AU - Wang, Meilin

AU - Shen, Hongbing

AU - Chen, Feng

AU - Zhang, Zhengdong

AU - Hung, Rayjean J.

AU - Amos, Christopher I.

AU - Wei, Qingyi

AU - Lazarus, Philip

AU - Christiani, David C.

PY - 2024

Y1 - 2024

N2 - 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 X 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.

AB - 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 X 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.

UR - https://www.scopus.com/pages/publications/85185218849

UR - https://www.scopus.com/pages/publications/85185218849#tab=citedBy

U2 - 10.1158/0008-5472.CAN-23-0900

DO - 10.1158/0008-5472.CAN-23-0900

M3 - Article

C2 - 38117513

AN - SCOPUS:85185218849

SN - 0008-5472

VL - 84

SP - 616

EP - 625

JO - Cancer Research

JF - Cancer Research

IS - 4

ER -

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

Abstract

Bibliographical note

Funding

UN SDGs

ASJC Scopus subject areas

Access to Document

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