Dataset Information

Novel Association of Genetic Markers Affecting CYP2A6 Activity and Lung Cancer Risk.

ABSTRACT: Metabolism of nicotine by cytochrome P450 2A6 (CYP2A6) is a suspected determinant of smoking dose and, consequently, lung cancer risk. We conducted a genome-wide association study (GWAS) of CYP2A6 activity, as measured by the urinary ratio of trans-3'-hydroxycotinine and its glucuronide conjugate over cotinine (total 3HCOT/COT), among 2,239 smokers in the Multiethnic Cohort (MEC) study. We identified 248 CYP2A6 variants associated with CYP2A6 activity (P < 5 × 10-8). CYP2A6 activity was correlated (r = 0.32; P < 0.0001) with total nicotine equivalents (a measure of nicotine uptake). When we examined the effect of these variants on lung cancer risk in the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium GWAS dataset (13,479 cases and 43,218 controls), we found that the vast majority of these individual effects were directionally consistent and associated with an increased lung cancer risk. Two hundred and twenty-six of the 248 variants associated with CYP2A6 activity in the MEC were available in TRICL. Of them, 81% had directionally consistent risk estimates, and six were globally significantly associated with lung cancer. When conditioning on nine known functional variants and two deletions, the top two SNPs (rs56113850 in MEC and rs35755165 in TRICL) remained significantly associated with CYP2A6 activity in MEC and lung cancer in TRICL. The present data support the hypothesis that a greater CYP2A6 activity causes smokers to smoke more extensively and be exposed to higher levels of carcinogens, resulting in an increased risk for lung cancer. Although the variants identified in these studies may be used as risk prediction markers, the exact causal variants remain to be identified. Cancer Res; 76(19); 5768-76. ©2016 AACR.

SUBMITTER: Patel YM

PROVIDER: S-EPMC5050097 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Novel Association of Genetic Markers Affecting CYP2A6 Activity and Lung Cancer Risk.

Patel Yesha M YM Park Sunghim L SL Han Younghun Y Wilkens Lynne R LR Bickeböller Heike H Rosenberger Albert A Caporaso Neil N Landi Maria Teresa MT Brüske Irene I Risch Angela A Wei Yongyue Y Christiani David C DC Brennan Paul P Houlston Richard R McKay James J McLaughlin John J Hung Rayjean R Murphy Sharon S Stram Daniel O DO Amos Christopher C Le Marchand Loïc L

Cancer research 20160803 19

Metabolism of nicotine by cytochrome P450 2A6 (CYP2A6) is a suspected determinant of smoking dose and, consequently, lung cancer risk. We conducted a genome-wide association study (GWAS) of CYP2A6 activity, as measured by the urinary ratio of trans-3'-hydroxycotinine and its glucuronide conjugate over cotinine (total 3HCOT/COT), among 2,239 smokers in the Multiethnic Cohort (MEC) study. We identified 248 CYP2A6 variants associated with CYP2A6 activity (P < 5 × 10<sup>-8</sup>). CYP2A6 activity w ...[more]

PMID: 27488534

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Project description:While smoking is the primary cause of lung cancer, only 11-24% of smokers develop the malignancy over their lifetime. The primary addictive agent in tobacco smoke is nicotine and variation in nicotine metabolism may influence the smoking levels of an individual. Therefore, inter-individual variation in lung cancer risk among smokers may be due in part to differences in the activity of enzymes involved in nicotine metabolism. In most smokers, cytochrome P450 2A6 (CYP2A6)-catalyzed C-oxidation accounts for >75% of nicotine metabolism, and the activity of this enzyme has been shown to correlate with the amount of nicotine and carcinogens drawn from cigarettes. We prospectively evaluated the association of urinary biomarkers of nicotine uptake (total nicotine equivalents [TNE]) and CYP2A6 activity (ratio of urinary total trans-3'-hydroxycotinine to cotinine) with lung cancer risk among 2,309 Multiethnic Cohort Study participants who were current smokers at time of urine collection; 92 cases were diagnosed during a mean follow-up of 9.5 years. We found that higher CYP2A6 activity and TNE was associated with increased lung cancer risk after adjusting for age, sex, race/ethnicity, body mass index, smoking duration, and urinary creatinine (p's = 0.002). The association for CYP2A6 activity remained even after adjusting for self-reported cigarettes per day (CPD) (Hazard Ratio [HR] per unit increase in log-CYP2A6 activity = 1.52; p = 0.005) and after adjusting for TNE (HR = 1.46; p = 0.01). In contrast, the association between TNE and lung cancer risk was of borderline statistical significance when adjusted for CPD (HR = 1.53; p = 0.06) and not statistically significant when further adjusted for CYP2A6 activity (HR = 1.30; p = 0.22). These findings suggest that CYP2A6 activity provides information on lung cancer risk that is not captured by smoking history or a (short-term) biomarker of dose. CYP2A6 activity should be further studied as a risk biomarker for smoking-related lung cancer.

Project description: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.SignificanceThe 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.

Dataset Information

Novel Association of Genetic Markers Affecting CYP2A6 Activity and Lung Cancer Risk.

Publications

Novel Association of Genetic Markers Affecting CYP2A6 Activity and Lung Cancer Risk.

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