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Novel Association of Genetic Markers Affecting CYP2A6 Activity and Lung Cancer Risk
Cancer research (Chicago, Ill.), 2016-10, Vol.76 (19), p.5768-5776
Patel, Yesha M
Park, Sunghim L
Han, Younghun
Wilkens, Lynne R
Bickeböller, Heike
Rosenberger, Albert
Caporaso, Neil
Landi, Maria Teresa
Brüske, Irene
Risch, Angela
Wei, Yongyue
Christiani, David C
Brennan, Paul
Houlston, Richard
McKay, James
McLaughlin, John
Hung, Rayjean
Murphy, Sharon
Stram, Daniel O
Amos, Christopher
Le Marchand, Loïc
2016
Details
Autor(en) / Beteiligte
Patel, Yesha M
Park, Sunghim L
Han, Younghun
Wilkens, Lynne R
Bickeböller, Heike
Rosenberger, Albert
Caporaso, Neil
Landi, Maria Teresa
Brüske, Irene
Risch, Angela
Wei, Yongyue
Christiani, David C
Brennan, Paul
Houlston, Richard
McKay, James
McLaughlin, John
Hung, Rayjean
Murphy, Sharon
Stram, Daniel O
Amos, Christopher
Le Marchand, Loïc
Titel
Novel Association of Genetic Markers Affecting CYP2A6 Activity and Lung Cancer Risk
Ist Teil von
Cancer research (Chicago, Ill.), 2016-10, Vol.76 (19), p.5768-5776
Ort / Verlag
United States
Erscheinungsjahr
2016
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
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 ). 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.
Sprache
Englisch
Identifikatoren
ISSN: 0008-5472
eISSN: 1538-7445
DOI: 10.1158/0008-5472.can-16-0446
Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5050097
Format
–
Schlagworte
Aged
,
Cytochrome P-450 CYP2A6 - genetics
,
Cytochrome P-450 CYP2A6 - metabolism
,
Female
,
Genetic Markers
,
Genome-Wide Association Study
,
Humans
,
Lung Neoplasms - etiology
,
Lung Neoplasms - genetics
,
Male
,
Middle Aged
,
Polymorphism, Single Nucleotide
,
Risk
,
Smoking - adverse effects
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