Nasopharyngeal Carcinoma and Genetic Polymorphisms of DNA Repair Enzymes XRCC1 and hOGG1 1 En-Yu Cho, Allan Hildesheim, Chien-Jen Chen, Mow-Ming Hsu, I-How Chen, Beth F. Mittl, Paul H. Levine, Mei-Ying Liu, Jen-Yang Chen, Louise A. Brinton, Yu-Juen Cheng, 2 Czau-Siung Yang Graduate Institute of Epidemiology, College of Public Health [E-Y. C., Y-J. C., C-J. C.], Department of Otorhinolaryngology [M-M. H.], and Graduate Institute of Microbiology, College of Medicine [M-Y. L., J-Y. C., C-S. Y.], National Taiwan University, Taipei 10018, Taiwan; Department of Otorhinolaryngology, MacKay Memorial Hospital, Taipei, Taiwan [I-H. C.]; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, 20892 [A. H., L. A. B.]; Westat, Inc., Rockville, Maryland, [B. F. M.]; School of Public Health and Health Sciences, George Washington University, Washington, DC [P. H. L.] Abstract Nitrosamine consumption and polymorphisms in CYP2E1, the product of which is involved in the activation of nitrosamines into reactive intermediates, have been shown to be associated with nasopharyngeal carcinoma (NPC) risk. Given that reactive intermediates created during nitrosamine metabolism are capable of DNA damage, we further hypothesized that differences between individuals in their ability to repair DNA damage might be important in NPC pathogenesis. To evaluate this hypothesis, this study focused on effects of genetic polymorphisms of DNA repair genes hOGG1 and XRCC1 on the development of NPC. We conducted a case-control study to investigate the genotypes of 334 patients with NPC and 283 healthy community controls matched by sex, age, and residence. The PCR-based RFLP assay was used to identify genetic polymorphisms. After adjustment for sex, age, and ethnicity, the odds ratio (OR) of developing NPC for hOGG1 codon 326 genotypes of Ser/Cys and Cys/Cys compared with the Ser/ Ser genotype was 1.6 (95% CI, 1.0 –2.6). For XRCC1 codon 280 genotypes of Arg/His and His/His compared with the Arg/Arg genotype, the OR was 0.64 (95% CI, 0.43– 0.96). Among subjects with putative high-risk genotypes for both hOGG1 and XRCC1, the OR was 3.0 (95% CI, 1.0 – 8.8). Furthermore, subjects with putative high-risk genotypes for hOGG1, XRCC1, and CYP2E1 had an OR of disease of 25 (95% CI, 3.5–177). Polymorphisms of the DNA repair genes hOGG1 (codon 326) and XRCC1 (codon 280) are associated with an altered risk of NPC. Carriers of multiple putative high- risk genotypes have the highest risk of developing NPC. Introduction NPC 3 has a striking geographic and ethnic distribution, with particularly high rates observed among southeast Chinese and other individuals of Chinese descent (1, 2). NPC is linked to EBV infection (3–7). In addition to EBV, numerous other environmental and host factors have been shown to be associ- ated with the development of NPC (8 –15). In particular, long- term cigarette smoking, consumption of salted fish and foods containing nitrosamine or nitrosamine precursors at an early age, and occupational exposure to wood dust have been shown to be consistently associated with this disease. Host factors previously shown to be associated with NPC development include HLA class I and II alleles (likely involved via their regulation of the immunological response to EBV infection) and CYP2E1 gene polymorphisms (likely involved via its mod- ulation of the activation of environmental procarcinogens, in- cluding nitrosamines, into reactive intermediates capable of DNA damage; Refs. 2, 16). Various cellular metabolic processes result in the forma- tion of hydroxyl radicals that can cause oxidative damage to DNA (17). This damage often results in single base changes that can be reversed by BER mechanisms (18, 19). hOGG1 and XRCC1 are two of the enzymes participating in the BER path- way, the DNA repair system involved in the repair of damage resultant from oxidative stress. hOGG1 can recognize and ex- cise oh8Gua, the major form of oxidative DNA damage in- duced by reactive free radicals (20, 21). XRCC1 complexes with DNA polymerase  via the NH 2 terminus domain and with DNA ligase III via a blue ribbon commission on transportation (BRCT) domain to repair nicks or gaps left in the BER pathway (22, 23). XRCC1 has also been shown to be involved in the detection of single strand breaks between incision and ligation, an effect that likely occurs via poly(ADP-ribose) polymerase- dependent and poly(ADP-ribose) polymerase-independent mechanisms (24 –26). Genetic polymorphisms of DNA repair genes have been reported to determine susceptibility to several cancers, includ- ing lung, esophageal, bladder, and nonmelanoma skin cancers (19, 27–31). No studies, to date, have examined the association between genetic polymorphisms in DNA repair genes and NPC. In this study, we describe results from a case-control study (334 NPC cases; 283 community controls) conducted in Taiwan in which polymorphisms in the hOGG1 (codon 326) and XRCC1 (codons 280 and 399) genes are investigated. We were moti- Received 1/27/03; revised 6/13/03; accepted 6/23/03. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported by the National Science Council Grant NSC89-2314-B-002-427. 2 To whom requests for reprints should be addressed, at Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Room 1552, 1 Jen-Ai Road Section 1, Taipei 10018, Taiwan. E-mail: chengtwu@ ha.mc.ntu.edu.tw. 3 The abbreviations used are: NPC, nasopharyngeal carcinoma; hOGG1, human 8-oxoguanine DNA glycosylase 1; XRCC1, X-ray repair cross-complementing 1; BER, base excision repair; oh8Gua, 8-hydroxyguanine; OR, odds ratio; CI, confidence interval. 1100 Vol. 12, 1100 –1104, October 2003 Cancer Epidemiology, Biomarkers & Prevention Research. on November 27, 2021. © 2003 American Association for Cancer cebp.aacrjournals.org Downloaded from