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Patel, Y.M.* ; Park, S.L.* ; Han, Y.* ; Wilkens, L.R.* ; Bickeböller, H.* ; Rosenberger, A.* ; Caporaso, N.* ; Landi, M.T.* ; Brüske, I. ; Risch, A.* ; Wei, Y.* ; Christiani, D.C.* ; Brennan, P.* ; Houlston, R.S.* ; Mckay, J.* ; McLaughlin, J.* ; Hung, R.J.* ; Murphy, S.E.* ; Stram, D.O.* ; Amos, C.I.* ; Le Marchand, L.*

Novel association of genetic markers affecting CYP2A6 activity and lung cancer risk.

Cancer Res. 76, 5768-5776 (2016)
Publ. Version/Full Text Research data DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
Metabolism of nicotine by cytochrome 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<5x10-8). 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, 43,218 controls), we found that the vast majority of these individual effects were directionally consistent and associated with an increased lung cancer risk. 226 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Genome-wide Association; Nicotine Metabolism; Susceptibility Locus; Ethnic/racial Groups; Smoking-behavior; Complex Traits; Metaanalysis; Variants; Genotype; Glucuronidation
ISSN (print) / ISBN 0008-5472
e-ISSN 1538-7445
Journal Cancer Research
Quellenangaben Volume: 76, Issue: 19, Pages: 5768-5776 Article Number: , Supplement: ,
Publisher American Association for Cancer Research (AACR)
Publishing Place Philadelphia, Pa.
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology (EPI)