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

Home , Base excision repair, ERCC1, XPA

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

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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). Briefly, all 16,402-16,423). These primers generated a PCR product of patients had newly diagnosed, untreated SCCHN that was histopathologically confirmed at The University of Texas M. D. Anderson Cancer Center between May 1995 and March 2005. Table 2. Distribution of selected variables between SCCHN Patients with second SCCHN primary tumors, primary tumors cases and cancer-free controls of the nasopharynx or sinonasal tract, primary tumors outside the upper aerodigestive tract, cervical metastases of unknown Cases (n = 829), Controls (n = 854), P* origin, or any histopathologic diagnosis other than SCCHN n (%) n (%) were excluded. Because genotype frequencies can vary Age (y) 0.126 between ethnic groups and few minority patients were <45 111 (13.4) 147 (17.2) recruited, we included only non-Hispanic whites in this 45-55 252 (30.4) 266 (31.1) analysis. Of the eligible cases we approached for participation, 56-65 271 (32.7) 255 (29.9) theresponseratewasf93%. Consequently, this study >65 195 (23.5) 186 (21.8) included 829 non-Hispanic white subjects with primary Sex 0.361 n n Male 625 (75.4) 660 (77.3) tumors of the oral cavity ( = 253; 30.5%), pharynx ( = 424; Female 204 (24.6) 194 (22.7) 51.2%, including 386 oropharynx and 38 hypopharynx), or Smoking status <0.001 larynx (n = 152; 18.3%). Never 213 (25.7) 402 (47.1) Cancer-free control subjects were recruited from hospital Former 329 (39.7) 317 (37.1) visitors, genetically unrelated to the enrolled case subjects or Current 287 (34.6) 135 (15.8) Drinking status <0.001 each other, who accompanied patients to the clinics but were Never 193 (23.3) 344 (40.3) not seeking medical care. We first surveyed potential control Former 214 (25.8) 165 (19.3) subjects at the clinics by using a short questionnaire to deter- Current 422 (50.9) 345 (40.4) mine their willingness to participate in research studies and to Cancer sites obtain demographic information for frequency matching to Oral cavity 253 (30.5) the cases by age (F5 years) and sex. Of the eligible controls, the Pharynx 386 (46.6) f Hypopharynx 38 (4.6) response rate was 85%. Having obtained informed consent, Larynx 152 (18.3) we interviewed each eligible subject to collect additional information about risk factors, such as tobacco smoking and *m2 test for differences in the distributions between the cases and controls.

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Table 3. Genotype frequencies of the NER core gene polymorphisms among SCCHN cases and control subjects and their associations with risk of SCCHN

Variables Cases (n = 829), n (%) Controls (n = 854), n (%) OR (95% CI)

Crude Adjusted* ERCC1 C8092A CC 455 (54.9) 485 (56.8) 1.00 1.00 AC 326 (39.3) 315 (36.9) 1.10 (0.90-1.35) 1.10 (0.89-1.36) AA 48 (5.8) 54 (6.3) 0.95 (0.63-1.43) 0.93 (0.61-1.42) CC and AC 781 (94.2) 800 (93.7) 1.00 1.00 AA 48 (5.8) 54 (6.3) 0.91 (0.61-1.36) 0.89 (0.59-1.35) XPA G23A GG 359 (43.3) 380 (44.5) 1.00 1.00 AG 360 (43.4) 346 (40.5) 1.10 (0.90-1.35) 1.09 (0.88-1.35) AA 110 (13.3) 128 (15.0) 0.91 (0.68-1.22) 0.90 (0.67-1.23) GG and AG vs 719 (86.7) 726 (85.0) 1.00 1.00 AA c 110 (13.3) 128 (15.0) 0.87 (0.66-1.14) 0.87 (0.65-1.16) XPC Ala499Val Ala/Ala 445 (53.7) 454 (53.2) 1.00 1.00 Ala/Val 293 (35.3) 342 (40.0) 0.87 (0.71-1.07) 0.89 (0.72-1.10) Val/Val 91 (11.0) 58 (6.8) 1.60 (1.12-2.28) 1.57 (1.09-2.27) Ala/Ala and Ala/Val vs 738 (89.0) 796 (93.2) 1.00 1.00 Val/Val 91 (11.0) 58 (6.8) 1.69 (1.20-2.39) 1.65 (1.16-2.36) XPC Lys939Gln Lys/Lys 312 (37.7) 315 (36.9) 1.00 1.00 Lys/Gln 399 (48.1) 425 (49.8) 0.95 (0.77-1.17) 1.00 (0.81-1.24) Gln/Gln 118 (14.2) 114 (13.3) 1.05 (0.77-1.41) 1.08 (0.79-1.47) Lys/Lys and Lys/Gln vs 711 (85.8) 740 (86.7) 1.00 1.00 Gln/Gln 118 (13.4) 114 (13.3) 1.08 (0.82-1.42) 1.08 (0.81-1.43) XPD Asp312Asn Asp/Asp 330 (39.8) 370 (43.3) 1.00 1.00 Asp/Asn 395 (47.6) 386 (45.2) 1.15 (0.94-1.41) 1.07 (0.86-1.32) Asn/Asn 104 (12.6) 98 (11.5) 1.19 (0.87-1.63) 1.20 (0.86-1.66) Asp/Asp and Asp/Asn vs 725 (87.5) 756 (88.5) 1.00 1.00 Asn/Asn 104 (12.5) 98 (11.5) 1.11 (0.83-1.49) 1.15 (0.85-1.57) XPD Lys751Gln Lys/Lys 330 (39.8) 358 (41.9) 1.00 1.00 Lys/Gln 394 (47.5) 386 (45.2) 1.11 (0.90-1.36) 1.08 (0.87-1.33) Gln/Gln 105 (12.7) 110 (12.9) 1.04 (0.76-1.41) 1.10 (0.80-1.52) Lys/Lys and Gln/Gln vs 724 (87.3) 744 (87.1) 1.00 1.00 Gln/Gln 105 (12.7) 110 (12.9) 0.98 (0.74-1.31) 1.06 (0.79-1.43) XPG His1104Asp His/His 507 (61.2) 519 (60.8) 1.00 1.00 His/Asp 286 (34.5) 289 (33.8) 1.01 (0.83-1.24) 1.00 (0.81-1.23) Asp/Asp 36 (4.3) 46 (5.4) 0.80 (0.51-1.26) 0.80 (0.50-1.28) His/His and His/Asp vs 793 (95.7) 808 (94.6) 1.00 1.00 Asp/Asp 36 (4.3) 46 (5.4) 0.80 (0.51-1.25) 0.80 (0.51-1.28)

*Adjusted by age, sex, smoking status, and drinking status. cm2 test: P = 0.005 for the difference in genotype distribution between the cases and controls.

117 bp and digested by PvuII (New England Biolabs) into established at P < 0.05 with a two-side test. All data were 97 and 20 bp for CC; 117, 97, and 20 bp for CA; and the uncut analyzed by using Statistical Analysis System software 117 bp for AA. The genotyping assays for 10% of the samples (version 9.1.3; SAS Institute). were repeated, and the results were 100% concordant. StatisticalAnalysis. Differences in the selected demographic Results variables and smoking and drinking status between the cases and controls were evaluated by using the m2 test. The All case patients and control subjects were non-Hispanic associations between genotypes of the selected polymor- whites adequately matched by age and sex; however, phisms and SCCHN risk were estimated by computing the compared with the controls, cases had more smokers (current odds ratios (OR) and 95% confidence intervals (95% CI) from smokers: 34.6% versus 15.8%) and more drinkers (current both univariate and multivariate unconditional logistic regres- drinkers: 50.9% versus 40.4%; P < 0.001 for both smoking sion analyses with adjustment for age, sex, smoking status, status and drinking status; Table 2). To control for possible and drinking status. To assess the joint or interactive effects confounding effects of these variables, they were further of two potentially interactive variables, a new indicator adjusted in later multivariate logistic regression analyses of variable combining the two was created and used in the main effects of the genotypes. tabulation and logistical regression modeling. A more-than- Table 3 shows the genotype distributions of the selected Â multiplicative interaction was suggested when OR11 >OR01 polymorphisms for cases and controls and their associations OR10, in which OR11 = the OR when both factors were with risk of SCCHN. The genotype distribution of each nsSNP present, OR01 = the OR when only factor 1 was present, and in the control subjects was consistent with those expected from OR10 = the OR when only factor 2 was present. To assess the the Hardy-Weinberg equilibrium (data not shown). We further combined effect of all genotypes, the number of ‘‘at-risk’’ tested the hypothesis that variant homozygous genotypes are genotypes was added, assuming the risk associated with each associated with risk of SCCHN, assuming a recessive genetic of these genotypes was simply additive. The significance was model for the effect of a variant allele (i.e., only considering the

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Table 4. Joint effects of NER core genotypes on SCCHN risk

No. risk genotypes Cases (n = 829), n (%) Controls (n = 854), n (%) OR (95% CI)* 1 7 (0.9) 10 (1.2) 2 107 (12.9) 130 (15.2) 1.00 3 453 (54.6) 477 (55.9) 1.18 (0.88-1.57) 4 194 (23.4) 177 (20.7) 1.38 (0.99-1.93) 5 53 (6.4) 55 (6.4) 1.23 (0.77-1.97) 6 15 (1.8) 5 (0.6) 4.10 (1.41-11.98) P for trend 0.017 Dichotomized groups 1-3 risk genotypes 567 (68.4) 617 (72.2) 1.00 (reference) 4-6 risk genotypes 262 (31.6) 237 (27.8) 1.23 (0.99-1.53)

*Adjusted by age, sex, smoking status, and drinking status. variant homozygous genotype as the risk genotype). As shown OR, 1.49; 95% CI, 1.01-2.21; Table 5). Furthermore, there was no in Table 3, only the XPC 499Val/Val genotype was associated evidence of any interaction between the risk genotypes and with a significantly greater risk of SCCHN (adjusted OR, 1.65; these variables on risk of SCCHN (data not shown). 95% CI, 1.16-2.36) in the single locus analysis (i.e., Val/Val versus Ala/Ala + Ala/Val) with adjustment for age, sex, smoking, and alcohol use. Discussion In the analyses of combined genotypes, we categorized all putative risk (ORs > 1.0) genotypes (assuming a recessive The present study investigated the associations between seven genetic model) from each SNP into a new variable according potentially functional SNPs of the five core NER genes to the number of risk genotypes (for the protective genotype, (ERCC1, XPA, XPC, XPD, and XPG) and SCCHN risk. When we reversed the reference group). As shown in Table 4, the we evaluated each polymorphism separately, a significant number of observed risk genotypes was associated with increased risk of SCCHN was only found to be associated SCCHN risk in a dose-response manner (adjusted OR, 1.18; with the XPC 499Val allele in a recessive model. In the 95% CI, 0.88-1.57 for three risk genotypes; adjusted OR, 1.38; combined analysis, the number of observed risk genotypes 95% CI, 0.99-1.93 for four risk genotypes; adjusted OR, 1.23; 95% (assuming a recessive model) was associated with SCCHN CI, 0.77-1.97 for five risk genotypes; and adjusted OR, 4.10; risk in a dose-response manner and the dichotomized 95% CI, 1.41-11.98 for six risk genotypes; P for trend = 0.017). combined effect of these SNPs was borderline significantly When we dichotomized these combined effects, subjects associated with SCCHN risk. To the best of our knowledge, carrying four to six risk genotypes exhibited a 1.23-fold this is the largest case-control study of the association increased risk for SCCHN (95% CI, 0.99-1.53). Further between these seven potentially functional NER SNPs and stratification analysis showed that this risk was slightly more the risk of SCCHN. evident among older subjects (adjusted OR, 1.42; 95% CI, 1.04- It has been shown that the XPC-HR23B complex can interact 1.94), women (adjusted OR, 1.54; 95% CI, 0.97-2.44), former with the transcription factor IIH (TFIIH) both in vivo and smokers (adjusted OR, 1.45; 1.02-2.05), and current drinkers in vitro, and this interaction is essential for basal transcription (adjusted OR, 1.49; 1.06-2.10) and laryngeal cancer (adjusted and initiation of NER (8). All of the four nsSNPs in XPC and

Table 5. Stratified analysis on the combined effects of NER core genotypes on SCCHN risk

Dichotomized groups

Cases (n = 829) Controls (n = 854) Adjusted OR (95% CI)*

1-3 risk genotypes, 4-6 risk genotypes, 1-3 risk genotypes, 4-6 risk genotypes, 1-3 risk genotypes 4-6 risk genotypes n (%) n (%) n (%) n (%) Age (y) V56 285 (69.7) 124 (30.3) 299 (71.0) 122 (29.0) 1.00 1.08 (0.79-1.47) >56 282 (67.1) 138 (32.9) 318 (73.4) 115 (26.6) 1.00 1.42 (1.04-1.94) Sex Male 430 (68.8) 195 (31.2) 471 (71.4) 189 (28.6) 1.00 1.17 (0.91-1.50) Female 137 (67.2) 67 (32.8) 146 (75.3) 48 (24.7) 1.00 1.54 (0.97-2.44) Smoking status Ever smokers 417 (67.7) 199 (32.3) 325 (71.9) 127 (28.1) 1.00 1.30 (0.99-1.71) Current 196 (68.3) 91 (31.7) 92 (68.2) 43 (31.8) 1.00 1.03 (0.65-1.63) Former 221 (67.2) 108 (32.8) 233 (73.5) 84 (26.5) 1.00 1.45 (1.02-2.05) Never smokers 150 (70.4) 63 (29.6) 292 (72.6) 110 (27.4) 1.00 1.13 (0.78-1.64) Drinking status Ever drinkers 440 (69.2) 196 (30.8) 382 (74.9) 128 (25.1) 1.00 1.29 (0.99-1.69) Current 300 (71.1) 122 (28.9) 272 (78.8) 73 (21.2) 1.00 1.49 (1.06-2.10) Former 140 (65.4) 74 (34.6) 110 (66.7) 55 (33.3) 1.00 0.99 (0.64-1.55) Never drinkers 127 (65.8) 66 (34.2) 235 (68.3) 109 (31.7) 1.00 1.14 (0.78-1.67) Cancer sites Oral cavityc 173 (68.4) 80 (31.6) 1.00 1.25 (0.91-1.72) Pharynx 294 (69.3) 130 (30.7) 617 (72.2) 237 (27.8) 1.00 1.18 (0.90-1.53) Larynx 100 (65.8) 52 (34.2) 1.00 1.49 (1.01-2.21)

*Adjusted by age, sex, smoking status, and drinking status. cIncluded oropharynx.

XPD have been well characterized in both functional and rigorous epidemiologic design in selecting the study subjects, epidemiologic studies. In the analysis of correlation with the and used further statistical adjustments to minimize potential DNA repair phenotype, we have shown that the XPD 312Asn, biases. Because we had missing data on pack-years smoked 751Gln variant alleles were associated with a suboptimal DRC from a substantial portion of the controls, we did not do phenotype (16, 17), but the XPC Lys939Gln variant does not rigorous analyses of gene-environment interactions. Although influence the DRC phenotype, as detected by using an allele- the low penetrance of these common nsSNPs in SCCHN specific complementation assay (27), although when post-UV susceptibility needs further validation with larger, population- host cell reactivation was used, it altered base excision repair based studies with additional SNPs representing a much activity in radiation-specific DNA repair (28). greater coverage of the genetic variation in the eight core NER Several case-control studies have been reported in which genes, the findings in this study suggest that these SNPs may the associations between the XPC Ala499Val polymorphism be biomarkers of susceptibility to SCCHN. The use of these and risk of cancers were assessed (25, 29–31). In a study of biomarkers may be further validated by collaborative data the XPC Ala499Val polymorphism in 320 patients with lung pooling efforts, such as the International Head and Neck cancer and 322 cancer-free controls in a Chinese population, Cancer Epidemiology Consortium (INHANCE). the 499Val variant allele was found to be associated with an increased risk of lung cancer (25), but this was not confirmed Acknowledgments in a Korean study of 432 patients with lung cancer and 432 XPC 499 We thank Margaret Lung, Kathryn Patterson, and Leanel Fairly for healthy controls (29). Others found that the Ala Val their assistance in recruiting the subjects; Yawei Qiao for technical variant had little effect on bladder cancer susceptibility (30) assistance; Jianzhong He and Kejin Xu for their laboratory assistance; but contributed only to risk of advanced colorectal adenoma Joanne Sider for manuscript preparation; and Susan Eastwood for by modifying the effects of smoking (31). However, associa- scientific editing. tion studies have suggested that the XPC 939Gln allele is associated with risk of bladder cancer (32), breast cancer (33), melanoma (34), and colorectal adenoma (31). Such conflicting References results have also been reported by others for lung cancer 1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA (25, 29), bladder cancer (30, 35), and melanoma (36). Cancer J Clin 2005;55:74 – 108. Several case-control studies with different ethnic popula- 2. Blot WJ, McLaughlin JK, Winn DM, et al. Smoking and drinking in relation XPD to oral and pharyngeal cancer. Cancer Res 1988;48:3282 – 7. tions have also investigated the associations between 3. Kabat GC, Chang CJ, Wynder EL. The role of tobacco, alcohol use, and polymorphisms and cancer risk, particularly lung cancer; body mass index in oral and pharyngeal cancer. 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Cancer Epidemiol Biomarkers Prev 2007;16(8). August2007 Downloaded from cebp.aacrjournals.org on September 25, 2021. © 2007 American Association for Cancer Research. 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, Zhensheng Liu, Zhibin Hu, et al.

Cancer Epidemiol Biomarkers Prev 2007;16:1633-1638.

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