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Potentially Functional Single Nucleotide Polymorphisms in the Core Nucleotide Excision Repair Genes and Risk of Squamous Cell Carcinoma of the Head and Neck

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Potentially Functional Single Nucleotide Polymorphisms in the Core Nucleotide Excision Repair Genes and Risk of Squamous Cell Carcinoma of the Head and Neck 1633 Potentially Functional Single Nucleotide Polymorphisms in the Core Nucleotide Excision Repair Genes and Risk of Squamous Cell Carcinoma of the Head and Neck Jiaze An,1 Zhensheng Liu,1 Zhibin Hu,1 Guojun Li,1 Li-E Wang,1 Erich M. Sturgis,1,2 AdelK. El-Naggar, 2,3 Margaret R. Spitz,1 and Qingyi Wei1 Departments of 1Epidemiology, 2Head and Neck Surgery, and 3Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas Abstract Susceptibility to cancer has been associated with DNA SCCHN risk (adjusted odds ratio, 1.65; 95% confidence repair capacity, a global reflection of all functional variants, interval, 1.16-2.36). In analysis of the joint effects, the most of which are relatively rare. Among the 1,098 single number of observed risk genotypes was associated with nucleotide polymorphisms (SNP) identified in the eight SCCHN risk in a dose-response manner (P for trend = 0.017) core nucleotide excision repair genes, only a few are and those who carried four or more risk genotypes exhibited common nonsynonymous or regulatory SNPs that are a borderline significant 1.23-fold increased SCCHN risk potentially functional. We tested the hypothesis that seven (adjusted odds ratio, 1.23; 95% confidence interval, 0.99-1.53). selected common nonsynonymous and regulatory variants In the stratified analysis, the dichotomized combined effect in the nucleotide excision repair core genes are associated of the seven SNPs was slightly more evident among older with risk of squamous cell carcinoma of the head and neck subjects, women, and laryngeal cancer. These findings (SCCHN) in a hospital-based, case-control study of 829 suggest that these potentially functional SNPs may collec- SCCHN cases and 854 cancer-free controls. Assuming a tively contribute to susceptibility to SCCHN. These findings recessive genetic model, we found that only carriers of the need to be validated in larger, independent studies. (Cancer XPC 499Val/Val genotype had a significantly increased Epidemiol Biomarkers Prev2007;16(8):1633–8) Introduction Squamous cell carcinoma of the head and neck (SCCHN; localization of repair complexes or to assure the correct three- including cancers of the oral cavity, pharynx, and larynx) is dimensional assembly (9). Subsequently, the open DNA com- relatively common worldwide (1). Although smoking and plex creates the substrate for cleavage by two structure-specific alcohol use play major roles in the etiology of SCCHN (2, 3), endonucleases ERCC1-XPF (at 5¶ of the lesion) and XPG (at 3¶ only a small fraction of cigarette smokers/alcohol users of the lesion; refs. 10, 11). develops SCCHN, which suggests a differential susceptibility Germ-line mutations in the core NER repair genes (i.e., XPA, to the disease in the general population. Tobacco smoke XPB, XPC, XPD, XPE, XPF, and XPG) that severely alter their contains many kinds of carcinogens that can cause DNA protein functions cause the xeroderma pigmentosum (XP) damage, and variations in repair of tobacco carcinogen– syndrome. XP fits a recessive genetic model, in which only induced DNA damage may contribute to the variation in mutant homozygotes manifest the disease phenotype (12). susceptibility to cancer (4). Nucleotide excision repair (NER) is The defective DNA repair capacity (DRC) phenotype in XP one of the major repair pathways for removing DNA damage represents the extreme low end of the repair spectrum that caused by tobacco carcinogens as well as other helix-distorting is associated with a >1,000-fold increased risk of sunlight- lesions that interfere with base pairing and obstruct replication induced skin cancer (13). Moreover, there is an f5-fold and transcription (5, 6). variation in DRC in the general population (14, 15) that may Several critical genes participate in the NER process and result from the effects of genetic variants in the NER genes have functions central to the ability of the cell to cope with (16, 17). Previously, we reported that an intronic poly (AT) different types of DNA damage and to maintain genomic variant in XPC was associated with both the DRC phenotype integrity (5). In NER, the XPC-HR23B complex detects a (17) and SCCHN risk (18). We also reported a nonsignificantly damage site in DNA and then recruits the transcription factor increased SCCHN risk associated with the ERCC1 C8092A and IIH (TFIIH, including two helicases: XPD and XPB) to open the XPD Asp312Asn and Lys751Gln polymorphisms in two small DNA strands around the site of the lesion (7, 8). XPA, in case-control studies (19, 20). It is known that cancer etiology is conjunction with the single-strand DNA-binding protein repli- polygenic, and a single genetic variant is usually insufficient to cation protein A, constitutes a regulatory factor that monitors predict risk of cancer that has a complex disease phenotype. DNA binding and unwinding to verify the damage-specific In an early pilot study, we showed that reduced DRC seemed to contribute to an individual’s susceptibility to SCCHN (21). However, if the DRC phenotype is genetically Received 3/21/07; revised 5/3/07; accepted 5/15/07. determined, as shown in XP patients, it should reflect the Grant support: NIH grants ES 11740 (Q. Wei), CA100264 (Q. Wei), and CA 16672 genetic effects of all possible functional variants, most of which (M. D. Anderson Cancer Center). may be relatively rare. Indeed, among the 1,098 single nucleo- The costs of publication of this article were defrayed in part by the payment of page charges. tide polymorphisms (SNP) identified to date in the eight This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. ERCC1, XPA, XPB, XPC, XPD, XPE, XPF Section 1734 solely to indicate this fact. core genes (i.e., , and 4 Requests for reprints: Qingyi Wei, Department of Epidemiology, The University of Texas XPG) of the NER pathway (Table 1), there are a total of M. D. Anderson Cancer Center, Unit 1365, 1155 Pressler, Houston, TX 77030. Phone: 713-792-3020; Fax: 713-563-0999. E-mail: [email protected] Copyright D 2007 American Association for Cancer Research. doi:10.1158/1055-9965.EPI-07-0252 4 http://egp.gs.washington.edu/directory.html Cancer Epidemiol Biomarkers Prev 2007;16(8). August2007 Downloaded from cebp.aacrjournals.org on September 25, 2021. © 2007 American Association for Cancer Research. 1634 NER Functional SNPs and Risk of Head and Neck Cancer Table 1. Known SNPs in the eight NER core genes available in the National Institute of Environmental Health Science resequencing database NER core Nucleotides/ Location Function No. SNPs SNP density No. nsSNPs No. nsSNPs with genes protein (per kb) MAF > 0.05 ERCC1 14 kb/297 aa 19q13.2-q13.3 Endonuclease 73 5.2 1 — XPA 22 kb/273 aa 9q22.3 Damage detection 140 6.4 2 — XPB/ERCC3 37 kb/782 aa 2q21 Helicase 136 3.7 2 — XPC 33 kb/940 aa 3p25 Damage detection 145 4.4 12 rs2228000 (A499V) rs2228001 (K939Q) XPD/ERCC2 19 kb/760 aa 19q13.3 Helicase 136 7.2 2 rs1799793 (D312N) rs13181 (K751Q) XPE/DDB2 24 kb/427 aa 11p12-p11 Damaged DNA binding 77 3.2 2 — XPF/ERCC4 28 kb/916 aa 16p13.3-p13.11 Endonuclease 214 7.6 7 — XPG/ERCC5 30 kb/1,186 aa 13q22 Endonuclease 177 5.9 12 rs17655 (D1104H) Total 1,098 40 5* Abbreviations: aa, amino acids; MAF, minor allele frequency. *The total number of nsSNPs with MAF > 0.05 in non-Hispanic whites. 40 nonsynonymous SNPs (nsSNP) but only 5 are confirmed alcohol use. Those who had smoked <100 cigarettes in their as common (i.e., minor allele frequency > 0.05) nsSNPs lifetime were considered ‘‘never smokers’’; all others were [i.e., XPC Ala499Val (rs2228000) and Lys939Gln (rs2228001), considered ‘‘ever smokers.’’ Among ever smokers, those who XPD Asp312Asn (rs1799793) and Lys751Gln (rs13181), and XPG had quit and had not smoked for >1 year were considered His1104Asp (rs17655)] in non-Hispanic whites. Other than these ‘‘former smokers’’ and the others were considered ‘‘current nsSNPs, two common regulatory SNPs located at the 3¶- smokers.’’ Similarly, subjects who had drunk alcoholic untranslated region of ERCC1 (C8092A, rs3212986) and beverages at least once weekly for >1 year were considered 5¶-untranslated region of XPA (G23A, rs1800975) were well ‘‘ever drinkers’’ and all others were considered ‘‘nondrinkers.’’ documented and suggested a correlation with the DRC Among ever drinkers, those who had quit drinking and phenotype (22). Compared with other SNPs, these common, had not had an alcoholic drink for >1 year were consi- potentially functional SNPs are likely to collectively have an dered ‘‘former drinkers’’ and the others were considered effect on the DRC phenotype in the general population. To ‘‘current drinkers.’’ Each subject provided 30 mL of blood assess the role of these seven common potentially functional for biomarker tests. The research protocol was approved by the SNPs in the etiology of SCCHN, we expanded our previous M. D. Anderson Cancer Center institutional review board. work to a large SCCHN study of 829 SCCHN cases and Genotyping. The primers, PCR annealing time, and 854 cancer-free controls to further test the hypothesis that restriction enzyme (New England Biolabs) conditions for common, potentially functional SNPs in the NER core genes XPA G23A (24), XPC Ala499Val and Lys939Gln (25), XPD are associated with risk of SCCHN. Asp312Asn (19) and Lys751Gln (20), and XPG His1104Asp (26) have been described previously. For the ERCC1 C8092A variant (rs3212986), the primers were newly designed: forward, 5¶- Materials and Methods TACACAGGCTGCTGCTGCAGCT-3¶ (22 bp; 16,307-16,328) ¶ Study Subjects. The recruitment of subjects for the ongoing and reverse, 5 -GCCAGAGACAGTGCCCCAAGAG-3 (22 bp; SCCHN study has been described previously (23).
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