RAD51 Genetic Variants and Oral Cancer Susceptibility: Gene-Environment Interactions with Smoking and Alcohol Consumption in a Taiwanese Population.

The demographic characteristics of the targeted Taiwan cohort. The demographic and clinical characteristics of the 958 patients with oral cancer and 958 healthy controls are summarized in Table I. The two groups were comparable with respect to age, with mean ages of 56.4±7.5 years for the oral cancer patients and 56.8±8.7 years for the controls ( p =0.3755). The gender distribution was well matched within the two groups, with males accounting for 76.0% and females for 24.0% in each group ( p =1.0000). In contrast, significant differences were observed in several established behavioral risk factors. The proportion of cigarette smokers was significantly higher among oral cancer patients than among controls (74.9% versus 69.7%, p =0.0107). Similarly, alcohol consumption was more prevalent among cases than controls (71.4% versus 67.0%, p =0.0377). The most pronounced difference was observed for betel quid chewing, which was reported in 80.7% of oral cancer patients compared with 53.0% of controls ( p <0.0001). Among the 958 oral cancer patients, the tongue was the most frequently affected primary tumor site (41.4%), followed by the buccal mucosa (37.2%) and the floor of the mouth (4.1%). Histologically, 892 patients (93.1%) had squamous cell carcinoma, whereas 66 (6.9%) had non-squamous cell carcinoma. Distribution of RAD51 genotypes and their association with oral cancer risk. Table II summarizes the distribution of RAD51 rs2619679, rs5030789, and rs1801320 genotypes among the 958 oral cancer patients and 958 cancer-free controls. All three polymorphisms were in Hardy-Weinberg equilibrium among the control subjects, with p values of 0.3244, 0.3077, and 0.1422 for rs2619679, rs5030789, and rs1801320, respectively, indicating that the control group was representative of the general population. For rs2619679, the TT genotype was observed in 55.2% of cases and 56.4% of controls, whereas the AT genotype occurred in 38.9% and 38.2%, respectively. The AA genotype frequencies were 5.9% among cases and 5.4% among controls. Compared with the TT genotype, neither the AT genotype (OR=1.04, 95% CI=0.86-1.25, p =0.7149) nor the AA genotype (OR=1.10, 95% CI=0.74-1.63, p =0.7130) was significantly associated with oral cancer risk. Consistently, neither the recessive model (OR=1.08, 95% CI=0.73-1.60, p =0.7663) nor the dominant model (OR=1.05, 95% CI=0.87-1.25, p =0.6455) showed a significant association. The Cochran-Armitage trend test also revealed no significant trend across rs2619679 genotypes ( p =0.5694, Table II). For rs5030789, the GG genotype was the most common genotype in both groups, occurring in 82.3% of cases and 84.4% of controls. The corresponding frequencies of the AG genotype were 16.0% and 14.7%, while those of the AA genotype were 1.7% and 0.9%, respectively. Neither AG (OR=1.11, 95% CI=0.87-1.43, p =0.4430) nor AA (OR=1.82, 95% CI=0.80-4.14, p =0.2125) was significantly associated with oral cancer compared with the GG genotype. Similarly, no significant associations were observed under the recessive model (OR=1.79, 95% CI=0.79-4.07, p =0.2271) or dominant model (OR=1.15, 95% CI=0.91-1.47, p =0.2696). The genotype-based trend analysis was also non-significant ( p =0.1538, Table II). Regarding rs1801320, the GG genotype frequencies were 71.8% in cases and 74.1% in controls, while CG and CC genotypes were present in 24.5% and 3.7% of cases, respectively, compared with 23.3% and 2.6% of controls. Relative to the GG genotype, neither the CG genotype (OR=1.09, 95% CI=0.88-1.34, p =0.4684) nor the CC genotype (OR=1.44, 95% CI=0.86-2.44, p =0.2107) showed a statistically significant association with oral cancer. No significant association was observed under either the recessive model (OR=1.42, 95% CI=0.84-2.38, p =0.2378) or dominant model (OR=1.12, 95% CI=0.92-1.37, p =0.2801). The trend analysis likewise did not demonstrate a significant genotype-dependent association ( p =0.1620, Table II). a Based on chi-square test with Yates’ correction. P trend , p -Value for Cochran-Armitage trend analysis. P HWE , p -Value for Hardy-Weinberg Equilibrium. n: Number. RAD51 allelic frequency distributions among Taiwanese subjects. Allelic frequency analysis was further conducted to validate the genotyping findings for three RAD51 polymorphisms, and the results are shown in Table III . First, for rs2619679, the T allele accounted for 75.5% of control alleles and 74.7% of case alleles, whereas the A allele frequencies were 24.5% and 25.3%, respectively. No significant association was observed between the A allele and oral cancer risk (OR=1.04, 95% CI=0.90-1.21, p =0.6011). Second, for rs5030789, the G allele frequencies were 91.7% in controls and 90.3% in cases, while the A allele frequencies were 8.3% and 9.7%, respectively. The A allele was not significantly associated with oral cancer susceptibility (OR=1.18, 95% CI=0.95-1.47, p =0.1577). Last, for rs1801320, the G allele was observed in 85.8% of controls and 84.1% of cases, whereas the C allele occurred at frequencies of 14.2% and 15.9%, respectively. The C allele did not demonstrate a statistically significant association with oral cancer risk (OR=1.14, 95% CI=0.95-1.36, p =0.1617, Table III). a Based on Chi-square test with Yates’ correction. n: Number. Stratified analysis according to sex. To determine whether the effects of RAD51 polymorphisms differed according to sex, genotype distributions were further evaluated separately in males and females after adjustment for age, smoking, alcohol drinking, and betel quid chewing ( Table IV ). For rs5030789, neither AG nor AA was significantly associated with oral cancer among males or females. Among males, the adjusted ORs were 1.21 (95% CI=0.91-1.63, p =0.2309) for AG and 1.70 (95% CI=0.72-3.89, p =0.2455) for AA. Corresponding estimates among females were 0.86 (95% CI=0.53-1.54, p =0.5986) and 2.38 (95% CI=0.31-21.15, p =0.3246), respectively. Likewise, no significant associations were identified between rs1801320 genotypes and oral cancer in either sex. Among males, the CG and CC genotypes yielded adjusted ORs of 1.12 (95% CI=0.86-1.36, p =0.3783) and 1.42 (95% CI=0.86-2.67, p =0.1489), respectively. Among females, the corresponding estimates were 1.03 (95% CI=0.71-1.54, p =0.9775) and 1.14 (95% CI=0.41-3.04, p =0.7918). a The aORs were estimated with multivariate logistic regression analysis after adjusted for age, smoking, alcohol drinking and areca chewing habits. n: Number; aOR: adjusted odds ratio; CI: confidence interval. Stratified analysis according to cigarette smoking. A distinct pattern emerged when the analysis was stratified by cigarette smoking status ( Table V ). Among smokers, the AG genotype of rs5030789 was significantly associated with an increased risk of oral cancer compared with the GG genotype (adjusted OR=1.43, 95% CI=1.08-1.94, p =0.0241). The AA genotype was also significantly associated with an increased risk of oral cancer among smokers (aOR=2.76, 95% CI=1.05-6.78, p =0.0424). For rs1801320, significant associations were observed among smokers for both the CG and CC genotypes. Compared with the GG genotype, smokers carrying the CG genotype had a significantly increased risk of oral cancer (aOR=1.50, 95% CI=1.17-1.94, p =0.0026), while those carrying the CC genotype also exhibited an increased risk (aOR=2.08, 95% CI=1.23-3.56, p =0.0112). In contrast, among nonsmokers, both the CG and CC genotypes were significantly associated with reduced oral cancer risk, with aORs of 0.43 (95% CI=0.28-0.68, p =0.0001) and 0.21 (95% CI=0.06-0.97, p =0.0358), respectively. a The aORs were estimated with multivariate logistic regression analysis after adjusted for age, gender, alcohol drinking and betel quid chewing habits. Statistically significant data are shown in bold. n: Number; aOR: adjusted odds ratio; CI: confidence interval. Stratified analysis according to alcohol drinking. The associations between RAD51 polymorphisms and oral cancer were further examined according to alcohol drinking status ( Table VI ). No significant association was observed between rs5030789 genotypes and oral cancer among either non-drinkers or alcohol drinkers. For rs1801320, the CC genotype was significantly associated with increased oral cancer susceptibility among alcohol drinkers compared with the GG genotype (aOR=2.01, 95% CI=1.06-3.58, p =0.0330). The CG genotype was also modestly but significantly associated with increased oral cancer risk among alcohol drinkers (aOR=1.31, 95% CI=1.03-1.64, p =0.0491). Among non-drinkers, neither CG nor CC was significantly associated with oral cancer. a The aORs were estimated with multivariate logistic regression analysis after adjusted for age, gender, smoking and betel quid chewing habits. Statistically significant data are shown in bold. n: Number; aOR: adjusted odds ratio; CI: confidence interval. Stratified analysis according to betel quid chewing. The potential associations of RAD51 variants with oral cancer were assessed according to betel quid chewing status ( Table VII ). No statistically significant associations were detected for rs5030789 or rs1801320 among either betel quid chewers or non-chewers (Table VII). a The aORs were estimated with multivariate logistic regression analysis after adjusted for age, gender, smoking and alcohol drinking habits. aOR: Adjusted odds ratio; CI: confidence interval.

Investigated Taiwanese cohort. A total of 958 patients with histologically verified oral cancer were recruited from the outpatient clinics of the Department of General Surgery at China Medical University Hospital, Taiwan. All participants were of Taiwanese ancestry, and the recruitment strategy has been described in detail in our previous reports ( 58 , 59 ). The clinical data were obtained and assessed by experienced surgical specialists. To further ensure diagnostic reliability, all tissue samples underwent independent pathological evaluation and grading by at least two certified pathologists. Patients were excluded if they had a prior malignancy, metastatic diseases, hereditary genetic disorders, or tumor-like lesions, including endometriosis, leiomyoma, and pterygium. A total of 958 cancer-free controls were recruited from individuals undergoing routine health examinations at China Medical University Hospital and were frequency-matched to the oral cancer cases by age and sex. Eligible controls had no history of malignancy at the time of enrollment. Information on cigarette smoking, alcohol consumption, and betel quid chewing was collected using a questionnaire and analyzed as categorical variables. Participants who reported engaging in the respective behavior more than twice per week were classified as exposed. Written informed consent was obtained from every participant before enrollment, including permission for the collection of peripheral blood specimens for subsequent genetic analyses. The study protocol received approval from the Institutional Review Board of China Medical University Hospital (DMR101-IRB1-306), and all study procedures complied with the ethical principles of the Declaration of Helsinki. The demographic and clinical characteristics of the enrolled population are presented in Table I . a Based on unpaired Student’s t -test. b Based on chi-square test without Yates’ correction. Significant p -values are shown in bold. SD: Standard deviation; SCC: squamous cell carcinoma. RAD51 genotyping procedures. Genomic DNA was extracted from peripheral blood leukocytes of both oral cancer patients and controls utilizing the QIAamp Blood Mini Kit (Blossom, Taipei, Taiwan) and processed following established methodologies ( 60 , 61 ). All three SNPs examined in the current study, rs2619679, rs5030789, and rs1801320 in RAD51 , were genotyped by means of a PCR-restriction fragment length polymorphism (PCR-RFLP). For promoter rs2619679 and rs5030789 polymorphisms, the same forward (5’-CCGTGCAGGCCTTATATGAT-3’) and reverse (5’-AGATAAACCTGGCCAACGTG-3’) primers were used. For 5’ UTR/exon 1 rs1801320, the sequences of the forward and reverse primers were 5’-CAGGATCAAGCTCTCGAGCT-3’ and 5’-GGTGTTGCCTATAAAGGCTC-3’, respectively. The PCR cycling conditions for RAD51 genotyping were all set as follows: an initial denaturation step at 94°C for 5 min, followed by 35 cycles of denaturation at 94°C for 30 s, annealing at 55°C for 30 s, and extension at 72°C for 30 s, with a final extension step at 72°C for 10 min. Subsequently, PCR products underwent digestion by the restriction enzymes, Hinf I, Hin1 II and PspG I (New England BioLabs, Ipswich, MA, USA). Genotypic analysis was conducted independently and blindly by laboratory personnel, with repeated data demonstrating 100% concordance. Statistical methodologies. The Hardy-Weinberg equilibrium among the control group was assessed using the chi-square goodness-of-fit test to confirm the representativeness of the genotype distribution. Differences in age between patients with oral cancer and control subjects were expressed as mean ± standard deviation (SD) and compared using the unpaired Student’s t -test. Trend analysis was conducted via Cochran-Armitage methodology. The distributions of RAD51 genotypes in the oral cancer and control groups were compared using Pearson’s chi-square test for 2×2 contingency tables without Yates’ continuity correction. The relationship between RAD51 genotypic variants and oral cancer susceptibility was quantified using odds ratios (ORs) with 95% confidence intervals (CIs), calculated under different stratification models. Multivariable logistic regression analyses were additionally performed with adjustment for confounding factors such as age, sex, and behavioral status to calculate adjusted odds ratios (aORs) and corresponding 95% CIs. Statistical significance was identified as a p -value below 0.05. All computations and analyses were performed using SPSS software, version 16.0 (SPSS, Inc., Chicago, IL, USA).

During the preparation of this manuscript, a large language model (ChatGPT, OpenAI) was used solely for language editing and stylistic improvements in select paragraphs. No sections involving the generation, analysis, or interpretation of research data were produced by generative AI. All scientific content was created and verified by the authors. Furthermore, no figures or visual data were generated or modified using generative AI or machine learning–based image enhancement tools.

Research design: Shih LC, Hsu CL and Tsai CW; patient and questionnaire summaries: Shih LC and Hsu CL; experimental work: He JL, Chen JC, Chang WS, Jeyabal N and Tsai CW; statistical analysis: He JL, Chen JC and Tsai CW; data clearance and validation: Shih LC, Chen JC, Tsai CW and Tung AC; article writing: Shih LC, Bau DT and Tsai CW; correction of manuscript: Shih LC, Tsai CW and Bau DT; review and revision: Shih LC, Tsai CW and Bau DT.

Accumulating evidence hints that RAD51 plays an important role in the development, progression, and treatment resistance of oral squamous cell carcinoma (OSCC). Indirect evidence was first provided by Tsai and his colleagues, demonstrating that high RAD51 protein expression predicted unfavorable survival in OSCC patients receiving adjuvant radiotherapy or chemotherapy and experimentally showed that RAD51 overexpression enhanced resistance to irradiation and multiple DNA-damaging agents, whereas RAD51 inhibition increased cisplatin cytotoxicity ( 62 ). Conversely, Zdĕblová Cermáková and his colleagues observed a non-significant trend toward improved survival among RAD51-positive patients treated exclusively with accelerated hyper-fractionated radiotherapy, highlighting the potential influence of treatment regimen and patient selection on the prognostic significance of RAD51 ( 63 ). Supporting a broader oncogenic role, Shi and his colleagues demonstrated that RAD51 mRNA and protein were upregulated in OSCC and that elevated expression was associated with adverse clinicopathological features, poor treatment response, tumor proliferation, invasion, and an immunosuppressive microenvironment ( 64 ). Moreover, RAD51 depletion further suppressed malignant phenotypes and increased cisplatin sensitivity ( 64 ). Most recently, Asiedu and his colleagues reported that RAD51 activity can be enhanced through an ANGPTL4/NRP1/ABL1-dependent phosphorylation pathway, thereby promoting HR repair capacity and cisplatin resistance, while inhibition of this signaling axis restored cisplatin sensitivity ( 65 ). To sum up, these findings support RAD51 as a functionally important determinant of OSCC progression and DNA-damage resistance and suggest that both RAD51 abundance and post-translational activation may serve as clinically relevant biomarkers and therapeutic targets. However, the role of RAD51 polymorphisms in oral carcinogenesis remains seldom elucidated. Several studies have investigated RAD51 polymorphisms, particularly rs1801320, rs1801321, and, less frequently, rs5030789 and rs12593359, in head and neck squamous cell carcinoma (HNSCC). In 2007, Lu and his colleagues reported that rs1801321 TT significantly reduced overall HNSCC risk and, importantly, was also protective against oral-cavity cancer, particularly among individuals carrying TP53 Arg72Arg and those with smoking or alcohol exposure, whereas rs1801320 showed no independent association ( 57 ). In contrast, Werbrouck and his colleagues found that the rs1801320 variant allele was associated with reduced HNSCC risk, especially among heavy smokers, while rs1801321 was not significantly related to susceptibility ( 56 ). A subsequent radio-genomic study by the same group found no significant association of either RAD51 polymorphism with severe radiation-induced oral mucositis, dermatitis, or dysphagia, with radiation dose and other DNA-repair genes providing stronger associations with toxicity ( 66 ). Sliwinski and his colleagues subsequently reported that the rs1801320 GC genotype markedly increased the risk of precancerous laryngeal lesions and HNSCC, with stronger effects in combination with XRCC3 variants and tobacco or alcohol exposure ( 55 ). Pratesi and his colleagues further demonstrated that rs1801320 GC/CC genotypes were associated with an approximately four-fold increased likelihood of clinically relevant dysphagia following radiotherapy or chemoradiotherapy for HNSCC ( 54 ). Gresner and his colleagues identified a protective association of the RAD51 promoter variant rs5030789 AA genotype and rs1801321 TT genotype with HNSCC, particularly among male smokers, while rs2619679 and rs1801320 both showed no significant effect ( 50 ). Kayani and his colleagues, using a cohort containing 90 oral-cavity cancer patients, reported that rs1801320 GC/CC and rs1801321 GT genotypes were associated with increased HNSCC susceptibility, with significant enrichment of these genotypes among oral-cavity tumors and additional modification by smoking status ( 53 ). In 2015, a meta-analysis further supported an increased HNSCC risk associated with the rs1801320 C allele, particularly among smokers and alcohol drinkers, whereas rs1801321 showed no overall association but a protective effect of TT among Caucasians ( 67 ). Santos and his colleagues found that RAD51 rs1801320 and rs1801321 interacted with smoking and alcohol exposure to influence susceptibility to oral and oropharyngeal carcinomas ( 51 ). More recently, Butkiewicz and his colleagues reported that RAD51 rs1801321 and rs12593359 may influence treatment outcomes or disease progression in HNSCC patients receiving radiotherapy or cisplatin-based chemoradiotherapy, although these associations did not remain significant after correction for multiple testing and therefore remain exploratory ( 68 ). Finally, Gudur and his colleagues found that rs1801320 CC was associated with advanced tumor stage and that rs1801321 TT was related to poorer tumor and nodal responses to radiotherapy in Indian HNSCC patients, although inconsistencies between summary analyses and genotype-specific regression results warrant cautious interpretation ( 52 ). The key characteristics, findings, and population-specific features of the studies discussed above are summarized in Table VIII . HNC: Head and neck cancer; SCCHN: squamous cell carcinoma of head and neck; WW: wild-wild genotype; WV: wild-variant genotype; VV: variant-variant genotype. These studies indicate that RAD51 polymorphisms may act as low-penetrance, context-dependent modifiers of HNSCC and oral cancer susceptibility and treatment response, with their effects varying according to ethnicity, tumor subsite, tobacco and alcohol exposure. Notably, the most directly relevant evidence for oral cancer comprises the enrichment of rs1801320 GC among Pakistani oral cavity cancer patients reported by Kayani and his colleagues (Table VIII). However, the sample size is relatively small and less representative. In the present study, none of the investigated RAD51 polymorphisms, including rs2619679, rs5030789, and rs1801320, was significantly associated with oral cancer susceptibility in the Taiwanese population (Table II and Table III). The sample size of the Taiwanese cohort is larger than those of previously published studies (Table I), and the percentages of rs5030789 homozygous variant AA genotype and rs1801320 homozygous variant CC genotype are 0.9% and 2.6% in our controls (Table II) without any gender difference (Table IV). Previous studies have reported considerable variation in the frequency of the homozygous variant CC genotype of RAD51 rs1801320 across different populations, ranging from 0.0% among Belgians ( 56 ) to 9.0% among Polish individuals ( 55 ). Specifically, the reported frequencies were 1.5% among Brazilians ( 51 ), 2.0% among Pakistanis ( 53 ), 2.3% and 9.0% among Polish populations ( 50 , 55 ), 0.0% among Belgians ( 56 ), and 0.1% among Americans ( 57 ) (Table VIII). The inconsistency between Gresner’s and Sliwinski’s reports, and lack of homozygous variant genotype in Werbrouck’s report can be explained by sampling bias and small size. Overall, the C-allele frequency was 14.2% in the present study (Table III), which was similar to the 15.0% frequency reported among 1,170 healthy individuals of East Asian ancestry in the NCBI database ( 69 ). We have compiled a summary of all the literature examining the association between RAD51 rs2619679, rs5030789, and rs1801320 genotypes and oral cancer and succinctly highlighted their key findings (Table VIII). Our study benefits from the largest sample size to date, but further validation in diverse populations with varying ethnic backgrounds is necessary. Importantly, our cohort represents the largest sample size to date, which provides sufficient statistical power to objectively evaluate interactions with environmental exposures. This allowed us to identify that although our study did not demonstrate a statistically significant association between RAD51 genotypes and altered oral cancer risk, the AG and AA genotypes of RAD51 rs5030789 may exert a combinational effect with cigarette smoking, contributing to an elevated risk of oral cancer (Table V), while no interaction with alcohol drinking (Table VI) or betel quid chewing behavior (Table VII). Similarly, the CG and CC genotypes of RAD51 rs1801320 may interact with cigarette smoking and alcohol consumption, respectively, to influence oral cancer susceptibility (Table V and Table VI). On the contrary, the CG and CC genotypes of RAD51 rs1801320 exhibited protective influence among non-smokers (Table V). In summary, our results provide evidence that RAD51 genetic variants alone are not reliable predictive biomarkers for oral cancer in Taiwanese, yet they may interact with smoking behavior to modulate individual susceptibility to oral cancer. Future investigations in ethnically diverse populations, along with mechanistic studies examining RAD51 expression in response to tobacco exposure, alcohol consumption, and betel quid chewing, are warranted to further clarify the functional implications of these polymorphisms and their contribution to oral carcinogenesis.

Oral cancer, characterized by a high propensity for metastasis and an overall unfavorable survival rate, represents the most prevalent malignant tumor affecting the head, neck, and maxillofacial region ( 1 ). Notably, Taiwan exhibits the highest incidence densities of oral cancer worldwide ( 2 - 4 ). Accumulating epidemiological evidence indicates that multiple environmental and lifestyle-related exposures contribute substantially to oral carcinogenesis. Established risk determinants include the consumption of alcohol, tobacco smoking, and betel quid chewing, together with inadequate oral hygiene practices, certain dental procedures, poor nutritional status, and viral infections ( 5 - 7 ). Beyond these external influences, insights from molecular epidemiology increasingly suggest that inherited genetic factors may also modulate individual susceptibility to oral cancer. Several investigations have reported associations between specific genetic variants and the risk of developing this malignancy, supporting the notion that host genetic background contributes to inter-individual susceptibility ( 8 - 11 ). To sum up, an integrative analytical framework incorporating genomic predisposition, environmental exposures, and individual behavioral characteristics may provide a more comprehensive understanding of oral cancer etiology. Such multidimensional approaches are expected to facilitate the development of more precise risk stratification strategies and advance personalized therapeutic interventions for patients with oral cancer. Cellular DNA repair systems are essential for maintaining genomic stability following damage induced by endogenous metabolic processes or exogenous genotoxic exposures. Inefficient or inaccurate repair can promote genomic instability and the progressive accumulation of somatic mutations, thereby facilitating malignant transformation ( 12 , 13 ). Among the various forms of DNA damage, DNA double-strand breaks (DSBs) are particularly detrimental because unrepaired or incorrectly repaired lesions may lead to chromosomal abnormalities and loss of genetic integrity. Mammalian cells primarily resolve DSBs through non-homologous end joining (NHEJ) and homologous recombination (HR) ( 14 , 15 ). Whereas NHEJ directly rejoins broken DNA ends and is therefore relatively error-prone, HR uses a homologous DNA template to achieve high-fidelity repair ( 16 , 17 ). RAD51 is a key recombinase in the HR pathway and plays a central role in the recognition and repair of DSBs. The human RAD51 gene is located at chromosome 15q15.1 and encodes a 339-amino-acid protein that is indispensable for homologous recombination and the preservation of genome integrity ( 18 , 19 ). Elevated RAD51 expression has been reported in several cancer types ( 20 - 31 ), as well as head and neck cancer (HNC) ( 32 ). Beyond alterations in RAD51 expression, germline variation within RAD51 has also been investigated as a potential determinant of individual cancer susceptibility. Among the most extensively studied variants is rs1801320, which has been examined in relation to multiple malignancies ( 33 ). Previous studies have evaluated the association of rs1801320 with breast ( 34 , 35 ), lung ( 36 ), laryngeal ( 37 ), colorectal ( 38 , 39 ), prostate ( 33 ), ovarian ( 40 , 41 ), cervical ( 42 ), endometrial cancer ( 43 , 44 ), pterygium ( 45 ), and glioblastoma ( 46 ) susceptibility. Other RAD51 promoter polymorphisms have received comparatively less attention. In particular, rs2619679 has been evaluated in HNC, prostate, breast, and lung cancers ( 47 - 50 ), whereas rs5030789 has been investigated in HNC, prostate, and breast cancers ( 47 , 48 , 50 ). To date, only one study has specifically examined the association between RAD51 genetic polymorphisms and oral cancer susceptibility ( 51 ). In contrast, a broader body of evidence has evaluated the potential contribution of RAD51 variants to the risk of HNC ( 50 , 52 - 57 ). Nevertheless, the effects of these variants appear to vary across ethnic populations and may be further modified by exposure to established environmental carcinogens. Accordingly, the present study investigated the associations of three RAD51 polymorphisms, rs2619679, rs5030789, and rs1801320 ( Figure 1 ), with oral cancer susceptibility in a Taiwanese case-control cohort comprising 958 patients with oral cancer and 958 cancer-free control individuals. In addition to assessing the independent effects of these genetic variants, we examined whether their associations with oral cancer were modified by major lifestyle-related exposures, with particular emphasis on cigarette smoking, alcohol consumption, and betel quid chewing. Furthermore, to contextualize our findings across populations, previously published studies addressing these RAD51 polymorphisms in oral cancer and HNC were comparatively reviewed with consideration of ethnic background and exposure-related differences. Physical map of RAD51 rs2619679, rs5030789, and rs1801320 polymorphic sites. The rs2619679 and rs5030789 are located at the promoter region (shown in blue), whereas rs1801320 is located at the 5’ UTR/exon 1 of RAD51 (shown in orange).

The Authors declare no conflicts of interest with any company or person.

The Authors are grateful to the Tissue Bank of China Medical University Hospital and doctors/nurses for their excellent sample collection and technical assistance. We sincerely thank Yi-Chen Ke and Yun-Chi Wang for their valuable technical assistance. This study was supported by China Medical University Hospital and Asia University (ASIA-114-CMUH-03).