Carcinogenesis Advance Access published online on April 30, 2009
Carcinogenesis, 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, P. R.. China
2 National Food Institute, Technical University of Denmark, Mørkhøj Bygade 18, DK-2860, Søborg, Denmark
3 Department of Thoracic Surgery, Liaoning Cancer Hospital, Shenyang (110042), Liaoning Province, P. R. China
4 Department of Epidemiology, Shenyang Medical College, Shenyang (110034), Liaoning Province, P.R. China
5 Department of Cell Biology and Medical Genetics, Shenyang Medical College, Shenyang (110034), Liaoning Province, P.R. China
6 To whom correspondence should be addressed: Jiaoyang Yin, Key Laboratory of Environment and Population Health of University in Liaoning Province, Shenyang Medical College, Shenyang (110034), Liaoning Province, P. R. China, Tel: 0086-24-62215664, Fax: 0086-24-62215656, Email: yinjyf{at}yahoo.com.cn
DNA repair genes have been proposed as candidate cancer-susceptibility genes. The ERCC2 (excision repair cross-complementing rodent repair deficiency, complementation group 2)/XPD(xeroderma pigmentosum complementary group D) protein is considered to be a key enzyme in NER (Nucleotide excision repair) 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 SNPs (htSNPs)(rs238403, rs50871, rs3916840, rs238415, rs3916874, 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 [OR(95%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 also confirmed that considerable linkage disequilibrium exists between the pairs of the six htSNPs within ERCC2. These results suggested that the risk sub-haplotypes co-segregate with one or more biologically functional polymorphism. Our results provide evidence to support a role for ERCC2 in lung cancer development in a Chinese population.
Key Words: ERCC2/XPD • HapMap database • htSNP • lung cancer suscptibility • Chinese population
Received March 17, 2009; revised April 22, 2009; accepted April 25, 2009.