title: 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.
authors.affiliation: Department of Preventive Medicine and Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Yesha M
authors.initials: YM
authors.lastname: Patel
authors.affiliation: Department of Preventive Medicine and Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Sunghim L
authors.initials: SL
authors.lastname: Park
authors.affiliation: Department of Biomedical Data Science, Dartmouth College, Hanover, New Hampshire.
authors.forename: Younghun
authors.initials: Y
authors.lastname: Han
authors.affiliation: Epidemiology Program, University of Hawai'i Cancer Center, Honolulu, Hawaii.
authors.forename: Lynne R
authors.initials: LR
authors.lastname: Wilkens
authors.affiliation: Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen, Göttingen, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Bickeböller
authors.affiliation: Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen, Göttingen, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Rosenberger
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Neil
authors.initials: N
authors.lastname: Caporaso
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Landi
authors.affiliation: Helmholtz Centre Munich, German Research Centre for Environmental Health, Institute of Epidemiology I, Neuherberg, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Brüske
authors.affiliation: Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
authors.forename: Angela
authors.initials: A
authors.lastname: Risch
authors.affiliation: Nanjing Medical University School of Public Health, Nanjing, China.
authors.forename: Yongyue
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts. Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: David C
authors.initials: DC
authors.lastname: Christiani
authors.affiliation: Genetic Epidemiology Group, International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Houlston
authors.affiliation: Genetic Epidemiology Group, International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: James
authors.initials: J
authors.lastname: McKay
authors.affiliation: Public Health Ontario, Toronto, Ontario, Canada.
authors.forename: John
authors.initials: J
authors.lastname: McLaughlin
authors.affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Rayjean
authors.initials: R
authors.lastname: Hung
authors.affiliation: Department of Biochemistry Molecular Biology and Biophysics and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Sharon
authors.initials: S
authors.lastname: Murphy
authors.affiliation: Department of Preventive Medicine and Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Stram
authors.affiliation: Department of Biomedical Data Science, Dartmouth College, Hanover, New Hampshire.
authors.forename: Christopher
authors.initials: C
authors.lastname: Amos
authors.affiliation: Epidemiology Program, University of Hawai'i Cancer Center, Honolulu, Hawaii. loic@cc.hawaii.edu.
authors.forename: Loïc
authors.initials: L
authors.lastname: Le Marchand
mesh_terms: D000368:Aged; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005819:Genetic Markers; D055106:Genome-Wide Association Study; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D012907:Smoking / Q000009:adverse effects*
chemical_list: D005819:Genetic Markers; D065637:Cytochrome P-450 CYP2A6