The XRCC1 399Gln Polymorphism and the Frequency of p53 Mutations in Taiwanese Oral Squamous Cell Carcinomas 1 Ling-Ling Hsieh, 2 Huei-Tzu Chien, I-How Chen, Chun-Ta Liao, Hung-Ming Wang, Shih-Ming Jung, Pei-Feng Wang, Joseph Tung-Chieh Chang, Min-Chi Chen, and Ann-Joy Cheng Departments of Public Health [L-L. H., H-T. C., P-F. W., M-C. C.] and Otolaryngology Oncology, Head and Neck Surgery [I-H. C., C-T. L.], Division of Hematology/Oncology Department of Internal Medicine [H-M. W.], and Department of Medical Technology [A-J. C.], Chang Gung University, Tao- Yuan 333, Taiwan; Departments of Pathology [S-M. J.], and Radiation Oncology [J. T-C. C.], Chang Gung Memorial Hospital, Tao-Yuan 333, Taiwan; and Taipei Chang Gung Memorial Hospital Head and Neck Oncology Group, Tao-Yuan, 333 Taiwan [L-L. H., I-H. C., C-T. L., H-M. W., S-M. J., J. T-C. C., M-C. C., A-J. C.]. Abstract DNA repair gene polymorphisms have been implicated as susceptibility factors in cancer development. It is possible that DNA repair polymorphisms may also influence the risk of gene mutation. The 399Gln polymorphism in the DNA repair gene XRCC1 has been indicated to have a contributive role in DNA adduct formation, sister chromatid exchange, and an increased risk of cancer development. Two hundred thirty-seven male oral squamous cell carcinomas (OSCCs) were included in a study to investigate the role of the XRCC1 194Trp, 280His, and 399Gln polymorphisms on p53 gene mutation. PCR-single-strand conformation polymorphism and DNA sequencing were used to analyze the conserved regions of the p53 gene (exons 5–9). The XRCC1 genotype was determined by PCR-RFLP. Nineteen (8.02%) of the 237 OSCCs had a Gln/Gln genotype. One hundred six (43.88%) of the 237 OSCCs showed p53 gene mutations at exons 5–9. The OSCC patients with a Gln/Gln genotype exhibited a significantly higher frequency of p53 mutation than those with an Arg/Gln and an Arg/Arg genotype. After adjustment for age, cigarette smoking, areca quid chewing, and alcohol drinking, the Gln/Gln genotype still showed an independent association with the frequency of p53 mutation (odd ratio, 4.50; 95% confidence interval, 1.52–13.36). The findings support the hypothesis that XRCC1 Arg399Gln amino acid change may alter the phenotype of the XRCC1 protein, resulting in a DNA repair deficiency. This study also suggests an important role for the XRCC1 399Gln polymorphism in p53 gene mutation in Taiwanese OSCCs. Introduction Tobacco and alcohol are well-established risk factors for oral cancer. A dose relationship between the consumption of to- bacco or alcohol or both and oral cancer has been demonstrated in the Western countries. On the basis of epidemiological studies in India, a working group of the IARC concluded that there was adequate evidence for an association between chew- ing AQ 3 together with tobacco use (chewing or smoking) and oral cancer (1). In Taiwan, 80% of all oral cancer patients are associated with the AQ chewing habit (2). In addition, most Taiwanese AQ chewers are also smokers and alcohol drinkers. AQ is a combination of areca nut, lime, betle leaf, and tobacco. The composition of the AQ varies in different geo- graphical locations. In Taiwan, tobacco is not included in the preparation of AQ. As an alternative, Piper betle, which is not used elsewhere except Papua New Guinea, inflorescence is added to AQ, and it contains a high concentration of safrole (3). Safrole-DNA adducts have been detected in 77% (23 of 30) of the OSCC tissues in a study of Taiwanese oral cancer patients with an AQ chewing history (4). Tobacco smoke contains an array of potent carcinogens including polycyclic aromatic hy- drocarbons, aromatic amines, and tobacco-specific nitro- samines. These carcinogens can be metabolized in vivo and form adducts with DNA. Previous studies have shown that certain carcinogens may induce a “fingerprint”-like pattern of mutations at the p53 gene, in terms of both mutation type and codon specificity (5). The most striking example is the p53 mutational spectrum found in hepatocellular carcinoma from either Qidong, People’s Repub- lic of China (6, 7) or Southern Africa (8, 9). A G:C to T:A transversion at the third base position of codon 249 of the p53 gene is strongly associated with dietary aflatoxin intake and hepatitis B virus infection. This type of mutation is consistent with mutations caused in vitro by aflatoxin B1 (10, 11). Hence, the mutation spectrum associated with a human cancer can provide clues as to the nature of the incriminating carcinogens and the mutagenic mechanisms responsible for the genetic lesions that drive human carcinogenesis. Recently, we reported an important contributive role for tobacco carcinogens in p53 mutation for a series of Taiwanese patients with OSCCs (12). In addition, alcohol significantly increased the frequency of p53 mutations (OR, 2.24; 95% CI, 1.21– 4.15) after adjustment for Received 5/28/02; revised 1/16/03; accepted 1/31/03. 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 Grants NSC 89-2314-B182-096 and NSC 90-2320-B182-055 from the National Science Council and by Grants DOH88-HR-802, NHRI-GT- EX89P802P, NHRI-EX90-8802PP, and NHRI-CN-IN-9005P from the National Health Research Institute, Department of Health, The Executive Yuan, Republic of China. 2 To whom requests for reprints should be addressed, at Department of Public Health, Chang Gung University, 259 Wen-Hwa 1 Road, Kwei-San, Tao-Yuan 33332, Taiwan, Republic of China. 3 The abbreviations used are: AQ, areca quid; OSCC, oral squamous cell carci- noma; OR, odds ratio; CI, confidence interval; NNK, 4-(methylnitrosamino)-1- (3-pyridyl)-1-butanone; PARP, poly(ADP-ribose) polymerase; AFB1-DNA, af- latoxin B1-DNA; SSCP, single-stranded conformation polymorphism; BRCT, BRCA1 C-terminal. 439 Vol. 12, 439 – 443, May 2003 Cancer Epidemiology, Biomarkers & Prevention Research. on November 26, 2021. © 2003 American Association for Cancer cebp.aacrjournals.org Downloaded from