Carcinogenesis Advance Access originally published online on April 30, 2009
Carcinogenesis 2009 30(7):1181-1185; doi:10.1093/carcin/bgp107
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HapMap-based study of the DNA repair gene ERCC2 and lung cancer susceptibility in a Chinese population
1 Key Laboratory of Environment and Population Health of University in Liaoning Province, Shenyang Medical College, Shenyang 110034, Liaoning Province, People’s Republic of China
2 Department of Cell Biology and Genetics, Shenyang Medical College, Shenyang 110034, Liaoning Province, People's Republic of China
3 Department of Toxicology and Risk Assessment, National Food Institute, Technical University of Denmark, Mørkhøj Bygade 18, DK-2860, Søborg, Denmark
4 Department of Thoracic Surgery, Liaoning Cancer Hospital, Shenyang 110042, Liaoning Province, People’s Republic of China
5 Department of Epidemiology, Shenyang Medical College, Shenyang 110034, Liaoning Province, People's Republic of China
* To whom correspondence should be addressed. Email: yinjyf{at}yahoo.com.cn
DNA repair genes have been proposed as candidate cancer susceptibility genes. The excision repair cross-complementing rodent repair deficiency, complementation group 2 (ERCC2)/xeroderma pigmentosum complementary group D (XPD) protein is considered to be a key enzyme in nucleotide excision repair (NER) pathway. To elucidate whether common ERCC2 variants are associated with lung cancer susceptibility, we conducted a case–control study consisting of 339 cases with primary lung cancer and 358 controls matched on age, gender and ethnicity in a Chinese population. Six haplotype tagging single-nucleotide polymorphisms (htSNPs) (rs238403, rs50871, rs3916840, rs238415, rs3916874 and rs1799787) from HapMap database were analyzed, which provide an almost complete coverage of the genetic variations in the ERCC2 gene. Although none of the six htSNPs was individually associated with lung cancer risk, we found that two ERCC2 haplotypes were associated with risk of lung cancer. Haplotype 4 defined by rs238403T-rs50871T-rs3916840C-rs238415C-rs3916874G-rs1799787C and haplotype 7 defined by rs238403C-rs50871G-rs3916840C-rs238415C-rs3916874G-rs1799787C were strongly associated with an increased risk of lung cancer [odds ratio, OR (95% confidence interval, CI) = 2.62 (1.53–4.50), P = 0.0003 for hap4; OR (95% CI) = 3.01 (1.36–6.63), P = 0.004 for hap7]. Furthermore, diplotype analyses also strengthened the significant associations of risk haplotype 4 [OR (95% CI) = 3.56 (2.12–5.87), P < 0.001] or risk haplotype 7 [OR (95% CI) = 3.38 (1.75–6.55), P < 0.001] and lung cancer. Analysis of linkage disequilibrium (LD) also confirmed that considerable LD exists between the pairs of the six htSNPs within ERCC2. These results suggested that the risk subhaplotypes cosegregate with one or more biologically functional polymorphisms. Our results provide evidence to support a role for ERCC2 in lung cancer development in a Chinese population.
Abbreviations: CI, confidence interval; ERCC1, excision repair cross-complementing rodent repair deficiency, complementation group 1; ERCC2, excision repair cross-complementing rodent repair deficiency, complementation group 2; htSNP, haplotype tagging single-nucleotide polymorphism; LD, linkage disequilibrium; NER, nucleotide excision repair; OR, odds ratio; PCR, polymerase chain reaction; SNP, single-nucleotide polymorphism; TAMRA, 6-carboxytetramethylrhodamine; XPD, xeroderma pigmentosum complementary group D
Received March 17, 2009; revised April 22, 2009; accepted April 25, 2009.