Cortactin is a prognostic marker for oral squamous cell carcinoma and its overexpression is involved in oral carcinogenesis.

EMS1 (chromosome eleven, band q13, mammary tumor and squamous cell carcinoma-associated gene 1) gene amplification and the concomitant cortactin overexpression have been reported to associate with poor prognosis and tumor metastasis. In this study, we examined cortactin expression by immunohistochemistry in human oral tumors and murine tongue tumors which were induced by the carcinogen 4-nitroquinoline 1-oxide (4-NQO). The immunostaining results show over- to moderate expression of cortactin in 85% (104/122) of oral squamous cell carcinoma (OSCC) tissues and in all 15 leukoplakia tissues examined. Further, statistical analysis indicates that cortactin overexpression appears to be a predictor for shorter survival and poorer prognosis in OSCC patients. In an animal model, cortactin is shown to upregulate in infiltrating squamous cell carcinoma, papilloma, and epithelia with squamous hyperplasia, indicating that cortactin induction is an early event during oral carcinogenesis. It is suggested that cortactin expression is mediated in the progression of pre-malignancy to papilloma, based on earlier cortactin induction in pre-malignancy preceding cyclin D1 in papilloma. In conclusion, cortactin overexpression is frequently observed in human OSCC and mouse tongue tumors. Thus, cortactin may have an important role in the development of oral tumors in human and mice. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 799-812, 2017.

The joint effect of smoking and hOGG1 genotype on oral cancer in Taiwan.

This study aimed at evaluating the association and interaction among human 8-oxoguanine DNA N-glycosylase 1 (hOGG1) genotypic polymorphism, smoking status and oral cancer risk in Taiwan. For this purpose, the well-known polymorphic variants of hOGG1, codon 326, was analyzed for its association with oral cancer susceptibility, and its joint effect with individual smoking habits on oral cancer susceptibility. In total, 620 patients with oral cancer and 620 healthy controls were recruited from the China Medical Hospital and genotyped. The results showed that the hOGG1 codon 326 genotypes were differently distributed between the oral cancer and control groups (p=0.0266), with the C allele of hOGG1 codon 326 being significantly (p=0.0046) more frequently found in cancer patients than in controls. We further analyzed the genetic-smoking joint effects on oral cancer risk and found an interaction between hOGG1 codon 326 genotypes and smoking status. The hOGG1 codon 326 CC genotype was associated with oral cancer risk only in the smoker group (p=0.0198), but not in the non-chewer group (p=0.8357). Our results provide evidence that the C allele of hOGG1 codon 326 may have a joint effect with smoking on the development of oral cancer.

The joint effect of hOGG1 single nucleotide polymorphism and betel quid chewing on oral cancer in Taiwan.

AIM: To evaluate the association and interaction among hOGG1 genotypic polymorphism, betel quid chewing status and oral cancer risk in Taiwan. MATERIALS AND METHODS: The well-known polymorphic variants of hOGG1, codon 326, were analyzed in association with oral cancer susceptibility, and discussed regarding its joint effect with individual habits on oral cancer susceptibility. In total, 620 patients with oral cancer and 620 healthy controls recruited from the China Medical Hospital were analyzed by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). RESULTS: The hOGG1 codon 326 genotypes were differently distributed between the oral cancer and control groups (p=0.0266) and the C allele of hOGG1 codon 326 was significantly (p=0.0046) more frequently found in cancer patients than in controls. We further analyzed the joint effects of gene variants and habits on oral cancer risk and found an interaction between hOGG1 codon 326 genotype and betel quid chewing status. The association of the C allele for hOGG1 codon 326 with oral cancer risk was found to be significant only in the betel quid chewer group (p=0.0149), not in the non-chewer group (p=0.8028). CONCLUSION: Our results provide evidence that the C allele of hOGG1 codon 326 may have a joint effect with betel quid chewing on the development of oral cancer.

Comparison of pharyngeal stenosis between hypopharyngeal patients undergoing primary versus salvage laryngopharyngectomy.

OBJECTIVE: To survey the risk factors of pharyngeal stenosis after laryngopharyngectomy in patients with advanced hypopharyngeal cancers. STUDY DESIGN: Case series with chart review. SETTING: Tertiary medical center. SUBJECTS AND METHODS: Pharyngeal stenosis rates and risk factors were compared between two groups of laryngopharyngectomy patients: a group that underwent concurrent chemoradiation therapy followed by surgical salvage, and a surgery initiated group with adjuvant chemoradiation. RESULTS: Of 160 patients, 25 developed pharyngeal stenosis, which was diagnosed by barium esophagography with a pooling of barium contrast above the neopharyngeal inlet. These patients required nasogastric tube feeding or gastrostomy feeding because an oral liquid diet could not meet their nutritional needs. Primary closure and old age were risk factors for pharyngeal stenosis. Pharyngeal stenosis did not affect survival in patients with advanced hypopharyngeal cancer who underwent laryngopharyngectomy. CONCLUSION: Primary closure reconstruction is discouraged in patients over the age of 65 years.

Risk factors affect the survival outcome of hard palatal and maxillary alveolus squamous cell carcinoma: 10-year review in a tertiary referral center.

OBJECTIVE: Hard palatal cancer is relatively rare in the head and neck region. Treatment outcome, risk factors that lead to poor survival outcome, and treatment strategy are still controversial. STUDY DESIGN: Retrospective study in a tertiary medical center. RESULTS: Surgery is a better treatment strategy than concurrent chemoradiation therapy (CCRT) for achieving positive survival outcomes. We also found a higher surgical salvage rate in patients with hard palatal cancer who had local recurrence or neck relapse. Soft palate or infratemporal fossa involvement had poor outcomes. Ulcerative tumor features, tumor volumes larger than 10 mL, and local recurrent tumors that could not undergo salvage surgery also had poorer survival outcomes in our study. CONCLUSION: Surgical management is still the first choice for patients with hard palate or alveolus squamous cell carcinomas even when patients had local or neck regional recurrence.

Comparison of pharyngocutaneous fistula between patients followed by primary laryngopharyngectomy and salvage laryngopharyngectomy for advanced hypopharyngeal cancer.

BACKGROUND: We analyzed the incidence rate, possible etiology, and management of pharyngocutaneous fistula after laryngopharyngectomy between hypopharyngeal cancer patients who received surgery first and subsequently concurrent chemoradiation therapy (CCRT) and those who received CCRT first followed by surgical salvage. METHODS: This is a case cohort, retrospective study collected in a tertiary medical center from January 1996 to July 2007. RESULTS: From the total of 160 patients, 52 patients (32.5%) developed pharyngocutaneous fistula. There is a significant difference between the pharyngocutaneous fistula rate of those with initial CCRT and the initial surgery groups. By univariate analysis and multiple logistic regression, tests revealed that preoperative radiation and hypo-albuminemia are risk factors for pharyngocutaneous fistula. A prolonged hospital course was noted among patients in the fistula group, especially when they received surgical repair, had hypo-albuminemia (albumin, <2.5 g/dL), or received preoperative radiation therapy (pre-OPRT). CONCLUSIONS: Preoperative radiation therapy and hypo-albuminemia increase the fistula rate significantly. A prolonged hospital course was noted among all fistula patients.

Co-treating with arecoline and 4-nitroquinoline 1-oxide to establish a mouse model mimicking oral tumorigenesis.

The aim of this study was to establish an effective mouse model of oral cancer and to use this model to identify potential markers of oral tumor progression. C57BL/6JNarl mice were treated with arecoline, 4-nitroquinoline 1-oxide (4-NQO), or both arecoline and 4-NQO in high and low doses for 8 weeks to induce oral tumor. The induced oral lesions were observed for 20 weeks to assess the efficiency of cancer induction and survival rate of the mice. In addition, two target proteins that are frequently overexpressed during tongue cancer tumorigenesis, alphaB-crystallin and Hsp27, were examined by immunohistochemical analysis. In mice exposed to 4-NQO (200 microg/mL) and arecoline (500 microg/mL), the tongue lesions showed evidence of hyperplasia, papilloma, dysplasia, and carcinoma, and the lesions were pathologically similar to those lesions in human oral cancer. The tongue tumor incidence rate was 100% in mice exposed to concomitant 4-NQO (200 microg/mL) and arecoline (500 microg/mL) treatment, 57% in mice exposed to 4-NQO only, and 0% in mice exposed to arecoline only. Immunohistochemical analysis demonstrated that, consistent with human studies, alphaB-crystallin and Hsp27 were upregulated in murine oral tumors. In conclusion, we have established a powerful animal model that enables the study of the promoting effects of arecoline on tongue tumorigenesis. Data subsequently attained from this mouse model support a role for alphaB-crystallin and Hsp27 as clinical markers for tumor progression.

Interaction of Exo1 genotypes and smoking habit in oral cancer in Taiwan.

Exonuclease 1 (Exo1) is an important nuclease involved in the mismatch repair system that helps to maintain genomic stability, to modulate DNA recombination, and to mediate cell cycle arrest. Potential polymorphisms in Exo1 may alter cancer risks by influencing the repair activity of Exo1. Therefore, we hypothesized that single-nucleotide polymorphisms in Exo1 were associated with the risk of oral cancer. In this hospital-based study, the associations of Exo1 A-1419G (rs3754093), C-908G (rs10802996), A238G (rs1776177), C498T (rs1635517), K589E (rs1047840), G670E (rs1776148), C723R (rs1635498), L757P (rs9350) and C3114T (rs851797) polymorphisms with oral cancer risk in a central Taiwan population were investigated. In total, 680 patients with oral cancer and 680 age- and gender-matched healthy controls recruited from the China Medical University Hospital were genotyped. A significantly different distribution is found in the frequency of the Exo1 K589E genotype, but not the other genotypes, between the oral cancer and control groups. The A allele Exo1 K589E conferred a significant (P=6.18E-8) increased risk of oral cancer. Gene-environment interactions with smoking were significant for Exo1 K589E polymorphism (OR=2.509, 95% CI=1.914-3.287). Our results provide evidence that the A allele of the Exo1 K589E may be associated with the development of oral cancer.

Lung cancer susceptibility and genetic polymorphisms of Exo1 gene in Taiwan.

AIM: To evaluate the association between the polymorphisms of the Exo1 gene and the risk of lung cancer in central Taiwan. PATIENTS AND METHODS: In this hospital-based study, the association of Exol A-1419G (rs3754093), C-908G (rs10802996), A238G (rs1776177), C498T (rs1635517), K589E (rs1047840), G670E (rs1776148), C723R (rs1635498), L757P (rs9350) and C3114T (rs851797) polymorphisms with lung cancer risk in a central Taiwanese population was investigated. In total, 358 patients with lung cancer and 358 age- and gender-matched healthy controls recruited from the China Medical Hospital in central Taiwan were genotyped. RESULTS: A significantly different distribution was found in the frequency of the Exo1 K589E genotype, but not the other genotypes, between the lung cancer and control groups. The A allele Exo1 K589E conferred a significantly (p = 0.0097) increased risk of lung cancer. As for the rest of the polymorphisms, there was no difference in distribution between the lung cancer and control groups. Gene environment interactions with smoking were significant for Exo1 K589E polymorphism. The Exo1 K589E AG and AA genotype in association with smoking conferred an increased risk of 1.7208 (95% confidence interval = 1.2188-2.4295) for lung cancer. CONCLUSION: Our results provide the first evidence that the A allele of Exo1 K589E may be associated with the development of lung cancer and may be a novel useful marker for primary prevention and anticancer intervention.

Functional genomic analysis identified epidermal growth factor receptor activation as the most common genetic event in oral squamous cell carcinoma.

A 250K single-nucleotide polymorphism array was used to study subchromosomal alterations in oral squamous cell carcinoma (OSCC). The most frequent amplification was found at 7p11.2 in 9 of 29 (31%) oral cancer patients. Minimal genomic mapping verified a unique amplicon spanning from 54.6 to 55.3 Mb on chromosome 7, which contains SEC61G and epidermal growth factor receptor (EGFR). Results from fluorescence in situ hybridization, transcriptome, and immunohistochemistry analyses indicated that the expression level of EGFR, but not of SEC61G, was up-regulated and tightly correlated with DNA copy number in 7p11.2 amplified tumors. Among the members of the erbB family, EGFR (HER1) was found to be the most frequently amplified and highly expressed gene in both human and mouse oral tumors (P < 0.01). Genes for downstream effectors of EGFR, including KRAS, mitogen-activated protein kinase 1, and CCND1, were also found amplified or mutated, which resulted in activation of EGFR signaling in 55% of OSCC patients. Head and neck squamous cancer cells with different EGFR expression levels showed differential sensitivity to antitumor effects of AG1478, a potent EGFR inhibitor. AG1478-induced EGFR inactivation significantly suppressed tumor development and progression in a mouse oral cancer model. Our data suggest that EGFR signaling is important in oral cancer development and that anti-EGFR therapy would benefit patients who carry the 7p11.2 amplicon in their tumors.

Association between DNA double strand break gene Ku80 polymorphisms and oral cancer susceptibility.

The DNA double strand break repair gene Ku80 is thought to play a major role in the caretaking of the overall genome stability. It is very possible that defective in double strand break repair capacity can lead to human carcinogenesis. Thus, the polymorphic variants of Ku80 were firstly investigated regarding their association with oral cancer susceptibility. In this hospital-based case-control study, the association of Ku80 promoter G-1401T (rs828907), promoter C-319T (rs11685387), and intron19 (rs9288518) polymorphisms with oral cancer risk in a Taiwanese population was investigated. 600 patients with oral cancer and 600 age- and gender-matched healthy controls recruited were genotyped and analyzed by PCR-RFLP method. There were significant differences between oral cancer and control groups in the distributions of their genotypes (P=0.0038) and allelic frequencies (P=0.0044) in the Ku80 promoter G-1401T polymorphism. In the other two polymorphisms, there was no difference between both groups in the distribution of either genotype or allelic frequency. There is a synergistic gene-environmental interaction between Ku80 and areca chewing. Compared with G/G genotype in Ku80 promoter G-1401T, the G/T plus T/T significantly enhanced the risk only in the areca chewers (odds ratio=1.603; 95% confidence interval=1.053-2.011), not in the non-areca chewers. In conclusion, the Ku80 promoter G-1401T is correlated with oral cancer susceptibility and this polymorphism may be a useful marker for oral cancer prevention and early detection.

Association of XRCC4 codon 247 polymorphism with oral cancer susceptibility in Taiwan.

BACKGROUND: The DNA repair gene XRCC4, an important caretaker of overall genome stability, is thought to play a major role in the development of human carcinogenesis. However, the association of the polymorphic variants of XRCC4 with oral cancer susceptibility has never been reported. MATERIALS AND METHODS: In this hospital-based case-control study, the association of XRCC4 codon 247 (rs3734091), G-1394T (rs6869366), intron 7 (rs28360317) and intron 7 (rs1805377) polymorphisms with oral cancer risk in a Central Taiwanese population was investigated. In total, 318 patients with oral cancer and 318 age- and gender-matched healthy controls recruited from the China Medical Hospital in Central Taiwan were genotyped. RESULTS: A significantly different distribution was found in the frequency of the XRCC4 codon 247 genotype, but not the XRCC4 G-1394T or intron 7 genotypes, between the oral cancer and control groups. A/C heterozygosity at XRCC4 codon 247 conferred a significant (2.04-fold) increased risk of oral cancer. As for XRCC4 G-1394T and intron 7 polymorphisms, there was no difference in distribution between the oral cancer and control groups. Gene-environment interactions with smoking, but not with betel quid chewing or alcohol consumption, were significant for XRCC4 codon 247 polymorphism. The XRCC4 codon 247 A/C genotype in association with smoking conferred an increased risk of 3.44 (95% confidence interval = 1.24-9.60) for oral cancer. CONCLUSION: Our results provide the first evidence that the heterozygous A allele of the XRCC4 codon 247 may be associated with the development of oral cancer and may be a novel useful marker for primary prevention and anticancer intervention.

Oral cancer and genetic polymorphism of DNA double strand break gene Ku70 in Taiwan.

The DNA repair gene Ku70, an important caretaker of the overall genome stability, is thought to play a major role in the DNA double strand break repair system. It is known that defects in double strand break repair capacity can lead to irreversible genomic instability. However, the polymorphic variants of Ku70 and their association with oral cancer susceptibility has never been reported on. In this hospital-based case-control study, the association of Ku70 promoter T-991C (rs5751129), promoter G-57C (rs2267437), promoter A-31G (rs132770), and intron3 (rs132774) polymorphisms with oral cancer risk in a Taiwanese population was investigated. In total, 318 patients with oral cancer and 318 age- and gender-matched healthy controls recruited from the China Medical Hospital in Taiwan were genotyped. The results showed that there were significant differences between the oral cancer and control groups in the distribution of their genotypes (P=0.0031) and allelic frequency (P=0.0009) in the Ku70 promoter T-991C polymorphism. Individuals who carried at least one C allele (T/C or C/C) had a 2.15-fold increased risk of developing oral cancer compared to those who carried the T/T wild-type genotype (95% CI: 1.37-3.36). In the other three polymorphisms, there was no difference between both groups in the distribution of either genotype or allelic frequency. In conclusion, the Ku70 promoter T-991C, but not the Ku70 promoter C-57G, promoter A-31G or intron3, is connected to oral cancer susceptibility. This polymorphism may be a novel useful marker for primary prevention and anticancer intervention.

A novel single nucleotide polymorphism in XRCC4 gene is associated with oral cancer susceptibility in Taiwanese patients.

The DNA double strand break repair gene XRCC4, an important caretaker of genome stability, is suggested to play a role in the development of human carcinogenesis. However, no evidence has been provided showing that XRCC4 was associated with oral oncology. In this hospital-based case-control study, the association of XRCC4 G-1394T (rs6869366), intron 3 (rs28360071), intron 7 (rs28360317), and intron 7 (rs1805377) polymorphisms with oral cancer risk in a Taiwanese population was first investigated. In total, 318 patients with oral cancer and 318 age- and gender-matched healthy controls were genotyped. We found a significant different distribution in the frequency of the XRCC4 intron 3 genotype, but not the XRCC4 G-1394T or intron 7 genotypes, between the oral cancer and control groups. Those who had heterozygous del/ins at XRCC4 intron 3 showed a 1.57-fold (95% confidence interval=1.12-2.21) increased risk of oral cancer compared to those with ins/ins. As for XRCC4 G-1394T or intron 7 polymorphisms, there was no difference in the distribution between the oral cancer and control groups. There were significant gene-environment interactions between XRCC4 intron 3 genotype with smoking and with betel quid chewing, but not with alcoholism. In smoker and betel quid chewer groups, the XRCC4 intron 3 del variants exhibited 2.57- and 3.03-fold higher risks than the ins genotype, respectively. Our results firstly suggest that the XRCC4 intron 3 del genotype may be associated with oral oncology and may be a novel useful marker for primary prevention and anticancer intervention.

A novel single nucleotide polymorphism in ERCC6 gene is associated with oral cancer susceptibility in Taiwanese patients.

The DNA repair gene ERCC6, an important caretaker of the overall genome stability, is thought to play a role in the development of human malignancy. However, the polymorphic variants of ERCC6, has never been reported about their association with oral cancer susceptibility. In this hospital-based case-control study, the association of ERCC6 codon 399, 1097 and 1413 polymorphisms with oral cancer risk in a Central Taiwanese population was first investigated. In total, 292 patients with oral cancer and 290 age- and gender-matched healthy controls recruited from the China Medical Hospital in Central Taiwan were genotyped. We found a significant different distribution in the frequency of the ERCC6 codon 399 genotypes, but not the ERCC6 codon 1097 or 1413 genotypes, between the oral cancer and control groups. Those who had homozygous A/A or heterozygous A/G at ERCC6 codon 399 showed a 1.82- and 1.22-fold (95% confidence interval=1.19-2.79 and 0.83-1.78, respectively) increased risk of oral cancer compared to those with G/G. As for ERCC6 codon 1097 or 1413, there was no difference in distribution between the oral cancer and control groups. Gene-environment interactions with smoking and betel quid chewing, but not alcohol drinking, were significant for ERCC6 polymorphisms. ERCC6 codon 399, G/A+A/A ever user groups exhibited an increased risk of 2.36 (95% CI=1.36-4.10) for smoking and 2.72 (95% CI=1.31-5.63) for betel quid chewing. Our results firstly suggest that the heterozygous and homozygous A allele of the ERCC6 codon 399 may be associated with the development of oral cancer and may be a novel useful marker for primary prevention and anticancer intervention.

Significant association of XRCC4 single nucleotide polymorphisms with prostate cancer susceptibility in Taiwanese males.

The DNA repair gene X-ray cross-complementing group 4 (XRCC4), a member of the non-homologous end-joining (NHEJ) repair system, plays a major role in the repair of the double-strand breaks of the DNA sequence. This gene is critical to the maintenance of overall genome stability, and is also thought to play a key role in human carcinogenesis. In this case-control study, several novel polymorphic variants of XRCC4, including C-1622T (rs7727691), G-1394T (rs6869366), C-571T (rs2075686) and intron3 DIP (rs28360071), were investigated, and the correlation of these variants to prostate cancer susceptibility in a Taiwanese population was observed. A total of 134 prostate cancer patients were recruited along with 134 age-matched healthy controls, and the association of their selected genotypes with susceptibility to prostate cancer was determined. The G-1394T variant of XRCC4 proved, after analysis of the frequencies of each variant in the prostate cancer and control groups, to be a significant single nucleotide polymorphism (SNP) in prostate carcinogenesis. Our data clearly indicate that the heterogeneous G of G-1394T increases the risk of suceptibility to prostate cancer (P=0.0106), while no difference in distribution of XRCC4 C-1622T (rs7727691), C-571T (rs2075686) or intron3 DIP (rs28360071) between the prostate cancer and control groups was found. In conclusion, our findings suggest that the G allele of XRCC4 G-1394T may be responsible for prostate carcinogenesis, and could be useful in the early detection and prevention of the disease.

Survival outcome by early chemoradiation therapy salvage or early surgical salvage for the treatment of hypopharyngeal cancer.

OBJECTIVE: To compare survival data between patients who had surgery followed by concomitant chemoradiation therapy (CCRT) versus CCRT followed by early surgical salvage. STUDY DESIGN: Retrospective study. METHODS: We retrospectively analyzed 202 patients with hypopharyngeal carcinoma (HPC) who were treated with different treatment strategy according to the choice of the patients by surgery first or CCRT first. In 72 (35.6%) cases, the primary treatment was surgery. Postoperative radiation therapy was given to 47 patients. Radiation therapy was the primary treatment in 130 (64.4%) patients; among them, 69 (34.2%) patients received salvage surgery within 2 months after CCRT course if there was a residual tumor visible on post-CCRT CT image or clinically residual tumor. RESULTS AND CONCLUSION: The 5-year disease-specific survival rate was 80% for stage I-II, 44.8% for stage III, and 14.3% for stage IV disease. Surgery plus concomitant chemoradiotherapy led to a better survival rate than CCRT plus salvage surgery in patients with stage III-IV HPC.

Survival study and treatment strategy for second primary malignancies in patients with head and neck squamous cell carcinoma and nasopharyngeal carcinoma.

CONCLUSION: Patients at risk of developing second primary malignancies (SPMs) comprise those with primary hypopharyngeal, laryngeal, and oral cavity index cancers, patients with well-differentiated squamous cell carcinomas, those aged >70 years, patients who are heavy smokers, alcohol drinkers, or betel quid chewers, and those with a family history of SPM. OBJECTIVE: SPMs are commonly found after successful treatment of index cancers in the head and neck region; however, treatment guidelines for SPMs have not been established. We compared the differences in the clinical characteristics, treatment outcomes, and 10-year survival rate between patients with SPMs who had been treated for head and neck squamous cell carcinoma (HNSCC) and those who had been treated for nasopharyngeal carcinoma (NPC) in order to establish an effective treatment strategy. PATIENTS AND METHODS: This was a 10-year retrospective study of 125 patients who had developed SPMs after being treated for either HNSCC or NPC during the period from January 1995 to July 2005. The average follow-up time was 34.9 months, and the setting for the study was a tertiary referral center. RESULTS: The survival rate of patients with SPMs is not significantly poor. The survival is worse if the SPM is associated with a primary advanced stage index cancer or it is synchronous; if the SPM occurs in an area other than the head and neck region; or if SPM patients undergo palliative treatment.

Relationship between polymorphisms of nucleotide excision repair genes and oral cancer risk in Taiwan: evidence for modification of smoking habit.

Inherited polymorphisms in DNA repair genes may be associated with differences in the repair capacity and contribute to individual's susceptibility to smoking-related cancers. Both XPA and XPD encode proteins that are part of the nucleotide excision repair (NER) pathway. In a hospital-based case-control study, we have investigated the influence of XPA A-23G and XPD Lys751Gln polymorphisms on oral cancer risk in a Taiwanese population. In total, 154 patients with oral cancer, and 105 age-matched controls recruited from the Chinese Medical Hospital in Central Taiwan were genotyped. No significant association was found between the heterozygous variant allele (AG), the homozygous variant allele (AA) at XPA A-23G, the heterozygous variant allele (AC), the homozygous variant allele (CC) at XPD Lys751Gln, and oral cancer risk. There was no significant joint effect of XPA A-23G and XPD Lys751Gln on oral cancer risk either. Since XPA and XPD are both NER genes, which are very important in removing tobacco-induced DNA adducts, further stratified analyses of both genotype and smoking habit were performed. We found a synergistic effect of variant genotypes of both XPA and XPD, and smoking status on oral cancer risk. Our results suggest that the genetic polymorphisms are modified by environmental carcinogen exposure status, and combined analyses of both genotype and personal habit record are a better access to know the development of oral cancer and useful for primary prevention and early intervention.