A comprehensive analysis of phase I and phase II metabolism gene polymorphisms and risk of non-small cell lung cancer in smokers.
Lung cancer is a leading cause of cancer mortality worldwide with smoking and occupational exposure to carcinogenic compounds as the major risk factors. Susceptibility to lung cancer is affected by existence of polymorphic genes controlling the levels of metabolic activation and detoxification of carcinogens. We have investigated 105 single nucleotide polymorphisms (SNPs) in 31 genes from the phase I and phase II metabolism genes and antioxidant defense genes for association with the risk of non-small cell lung cancer (NSCLC) in a Norwegian population-based study. Our results indicate that several SNPs in the phase I genes, CYP1B1, CYP2D6, CYP2E1 and CYP3A4, are associated with the risk of NSCLC. Moreover, significant associations with multiple SNPs in the phase II genes ALDH2, COMT, EPHX1, SOD2, NAT1, NAT2, GSTM3, GSTP1, GSTT2 and MPO were also found. We prioritized our findings by use of two different recently developed Bayesian statistical tools, employing conservative prior probabilities of association. When we corrected for multiple testing using these statistical tools, three novel associations of NSCLC risk with SNPs in the CYP1B1 (Arg48Gly), COMT (Val158Met) and GSTT2 (Met139Ile) genes were found noteworthy. However, only four of the previously reported associations with polymorphisms in the GSTP1 (Ala14Val), SOD2 (Val16Ala), EPHX1 (His139Arg) genes and the NAT1 fast acetylator phenotype remained significantly associated with lung cancer.
Zienolddiny
Shanbeh
S
Section of Toxicology, Department of Biological and Chemical Work Environment, National Institute of Occupational Health N-0033, Oslo, Norway. shan.zienolddiny@stami.no
Campa
Daniele
D
Lind
Helge
H
Ryberg
David
D
Skaug
Vidar
V
Stangeland
Lodve B
LB
Canzian
Federico
F
Haugen
Aage
A
D000123:Acetyltransferases / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008780:Methyltransferases / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects; D015262:Xenobiotics / Q000378:metabolism
D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D008780:Methyltransferases; D000123:Acetyltransferases; D005982:Glutathione Transferase