XRCC1 Arg399Gln Polymorphisms Research Articles

Abstract B034: Polymorphisms in XRCC1 Arg399Gln and XRCC3 Thr241Met DNA repair genes elevate cervical cancer risk among Bangladeshi female population

Abstract Introduction and Objective: Cervical cancer is the second most common cancer in women worldwide and is both a preventable and a curable disease especially if identified at an early stage. Sequence variations in DNA repair genes can cause aberration in cellular functions leading to cancer. Genetic polymorphisms in XRCC1 (Arg399Gln) and XRCC3 (Thr241Met) genes result in individual variation in their DNA repair capacity. The aim of this study was to identify the association between XRCC1 Arg399Gln and XRCC3 Thr241Met single nucleotide polymorphisms (SNPs) and susceptibility to cervical cancer in Bangladeshi populations. Methods: The case-control study comprised 124 cervical cancer patients and 148 healthy controls. Genomic DNAs were isolated from peripheral blood and genotyped for candidate SNPs using polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) method. Results: For XRCC1, heterozygous Arg/Gln and combined heterozygous plus variant homozygous Gln/Gln genotypes showed 1.78-fold (95% CI 1.0037 to 2.8771, p=0.0484) and 1.8627-fold (95% CI 1.1470 to 3.0250, p = 0.0119) increased risk of cervical cancer, respectively, when compared with normal homozygous Arg/Arg genotype. The variant Gln allele was positively associated with cervical cancer by 1.68-fold increase (95% CI 1.1732 to 2.3980, p = 0.0046). Similarly, for XRCC3, Thr/Met heterozygous and combined Thr/Met + Met/Met genotypes were found to be associated with 1.6993-fold (95% CI 1.0398 to 3.0166, p=0.0354) and 1.8312-fold (95% CI 1.0890 to 3.0791, p = 0.0225) higher risk, respectively, when compared with normal homozygous Thr/Thr genotypes. The variant Met allele showed significant association with 1.71-fold increased risk. Conclusion: XRCC1 (Arg399Gln) and XRCC3 (Thr241Met) polymorphisms may be associated with increased cervical cancer risk in Bangladeshi females. Citation Format: Md. Mustafizur Rahman, Laboni Das, Sadia Rahman, Amir Hossain, Razia Sultana. Polymorphisms in XRCC1 Arg399Gln and XRCC3 Thr241Met DNA repair genes elevate cervical cancer risk among Bangladeshi female population [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr B034.

Association between single nucleotide polymorphisms in DNA repair genes and the efficacy of radiotherapy in nasopharyngeal carcinoma patients.

Single nucleotide polymorphisms (SNPs) in DNA repair genes are mainly correlated with the response to radiotherapy in nasopharyngeal cancer (NPC). In NPC patients, previous research has studied the association between X-ray repair cross-complementing group 1 and 3 (XRCC1 and XRCC3) polymorphisms and radio-therapeutic response. The objective of our study was to test the association between XRCC1 Arg399Gln and XRCC3 Thr241Met polymorphisms and the response to radiotherapy in the NPC Moroccan population. A total of 100 patients with NPC were genotyped for polymorphisms in XRCC1 and XRCC3 genes. The results revealed that the genotypes and alleles of both SNPs did not show any significant association with clinical stages (for XRCC1 Arg399Gln: p [genotype] = 0.559; p [allele] = 0.440) and (for XRCC3 Thr241Met: p [genotype] = 0.638; p [allele] = 0.567). Moreover, in the study of the association between the polymorphisms and radiotherapy, the response to radiation therapy between genotypes and alleles was not statistically significant (for XRCC1 Arg399Gln p [genotype] = 0.583; p [allele] = 0.459) and (for XRCC3 Thr241Met p [genotype] = 0.660; p [allele] = 0.590). The present study suggests that XRCC1 Arg399Gln polymorphism does not have any impact on the radio-therapeutic response in Moroccan NPC patients whereas XRCC3 Thr241Met polymorphism may act as a prognostic indicator for NPC patients treated with radiotherapy. However, studies with a larger sample are needed to confirm our results.

Gene polymorphisms and prognosis of head and neck squamous cell carcinoma: a systematic review.

Head and neck squamous cell carcinomas (HNSCCs) are associated with variable prognosis even with similar clinical characteristics and treatments. Gene polymorphisms have been suggested as prognostic factors for HNSCC which can justified this variable prognosis. So, the aim was to review literatures on gene polymorphisms and prognosis of HNSCCs. A systematic search was conducted using PubMed, Web of science, SCOPUS, Google Scholar and Cochrane library databases to find all related articles published up to December 2021 in the field of gene polymorphisms and HNSCC prognosis. Of 1029 initial searched articles, 71 articles were selected for inclusion in this systematic review. About 93 genes and 204 polymorphisms have been discussed in these articles. Among the most studied polymorphisms, the XRCC1 Arg399Gln and Arg194Trp polymorphisms were not associated with survival in most studies; the ERCC1 C19007T polymorphism had no significant association in any of the studies. Different gene polymorphisms of glutathione s-transferase family, including GSTM1 deletion, GSTT1 deletion and GSTP1 A313G, were not associated with survival in included studies. There are conflicting results regarding the association between polymorphisms such as ERCC2 A35931C, Asp312Asn, ERCC5 rs1047768 and rs17655 with HNSCC prognosis. Less studied polymorphisms, such as hOGG1 rs1052133 or the VEGF rs699947, were generally not associated with HNSCC prognosis. Reviewed articles reported varied and contradictory results regarding the association of gene polymorphisms and HNSCC prognosis, which necessitates further studies along with meta-analysis on the results of such studies.

Genetic polymorphisms in DNA repair genes and their association with risk of cervical cancer: A systematic review and meta-analysis.

There have been a large number of epidemiologic studies regarding the association between genetic polymorphisms in DNA repair genes and onset of cervical cancer. However, results are inconsistent. Articles published before June 2021 and regarding genetic polymorphisms in DNA repair genes and cervical cancer were searched in following databases: PubMed, Web of Science, Google Scholar, and CNKI. With at least three articles for each polymorphism, we made meta-analysis to compute multivariate odds ratios (ORs) and their 95% confidence intervals (CIs). The present study showed significant associations between XRCC1 Arg399Gln polymorphisms and risk of cervical cancer in Asian, whereas no significant association between them were showed in Caucasian (Asian: GA vs. GG: OR = 1.27, 95%CI 1.06-1.52; AA vs. GG: OR = 1.91, 95%CI 1.29-2.83; GA + AA vs. GG: OR = 1.36, 95%CI 1.12-1.65; AA vs. GG + GA: OR = 1.66, 95%CI 1.17-2.37; Caucasian: GA vs. GG: OR = 1.08, 95%CI 0.83-1.41; AA vs. GG: OR = 2.18, 95%CI 0.75-6.31; GA + AA vs. GG: OR = 1.23, 95%CI 0.85-1.78; AA vs. GG + GA: OR = 1.70, 95%CI 0.69-4.18). In addition, there were significant associations between ERCC2 rs13181 polymorphisms and risk of cervical cancer in Asian (AC vs AA: OR = 0.53, 95%CI 0.37-0.75, I2 = 0.0%, p value of Q test = 0.847; AC + CC vs AA: OR = 0.50, 95%CI 0.36-0.70, I2 = 0.0%, p value of Q test = 0.856). The meta-analysis showed that there were significant associations between XRCC1 Arg399Gln and ERCC2 rs13181 polymorphisms and risk of cervical cancer.

Association Between X-Ray Repair Cross-Complementing Group 1 Arg399Gln Polymorphism and Risk of Oral Leukoplakia: A Meta-analysis.

Aims: Previous studies have have reported inconsistent results regarding the association of the XRCC1 polymorphism Arg399Gln with oral leukoplakia (OLK) risk. This study was designed to assess the existing evidence of this association using a meta-analytic approach. Materials and Methods: The literature was searched using multiple databases, including PubMed, EMBASE, and China National Knowledge Infrastructure (CNKI), through October 22, 2020. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of any associations. Results: A total of 671 Indian cases and 1009 Indian controls from seven case-control studies were included in the meta-analysis. The overall analysis revealed that the AA genotype was associated with a significantly increased OLK risk compared with the GG+GA genotypes (OR = 1.51, 95% CI = 1.10-2.06). In the subgroup analysis stratified by tobacco use, a significant association was found in the mixed group (OR = 1.51, 95% CI = 1.12-2.56), but not in the tobacco-using group or the no tobacco use group. In the OLK subtype subgroup analysis, a significantly increased risk was found in the hyperplastic subgroup (OR = 5.01, 95% CI = 1.39-18.11), whereas no associations were found in the dysplastic or mixed subgroups. Conclusions: The results of this meta-analysis suggest that the XRCC1 Arg399Gln polymorphism may significantly contribute to susceptibility to OLK in the Indian population.

Cytokinesis-block micronucleus cytome (CBMN-CYT) assay and its relationship with genetic polymorphisms in welders

Fumes generated in the welding process are composed of micrometric and nanometric particles that form when metal fumes condense. The International Agency for Research on Cancer established that many compounds derived from the welding process are carcinogenic to humans. Still, there are few studies related to the role of genetic polymorphisms. This work aimed to analyze the influence of OGG1 Ser326Cys, XRCC1 Arg280His, XRCC1 Arg194Thr, XRCC1 Arg399Gln, XRCC3 Thr241Met, GSTM1, and GSTT1 gene polymorphisms on DNA damage of 98 subjects occupationally exposed to welding fumes and 100 non exposed individuals. The results showed that individuals exposed to welding fumes with XRCC3 Thr241Thr, XRCC3 Thr241Met, and GSTM1 null genotypes demonstrated a significantly higher micronucleus frequency in lymphocytes. In contrast, individuals with XRCC1 Arg399Gln and XRCC1 Gln399Gln genotypes had significant levels of NPBs. OGG1 326 Ser/Cys, OGG1 326 Cys/Cys, XRCC1 194Arg/Thr, XRCC1 194Thr/Thr, and GSTT1 null genotypes exhibited significantly higher apoptotic values. Also, XRCC1 194Arg/Trp, XRCC1 194Thr/Thr, and GSTM1 null genotype carriers had higher necrotic levels compared to XRCC1 194Arg/Arg and GSTM1 nonnull carriers. Compositional analysis revealed the presence of iron, manganese, silicon as well as particles smaller than 2 μm that adhere to each other and form agglomerates. These results may be associated with a mixture of components, such as nitrogen dioxide, carbon monoxide, and metallic fumes, leading to significant DNA damage and cell death processes. These findings demonstrated the importance of the association between individual susceptibility and DNA damage levels due to occupational exposure to welding fumes; and constitute one of the first studies carried out in exposed workers from Colombia.

Impact of ERCC2 Lys751Gln (rs13181), ERCC2 Asp312Asn (rs1799793) and XRCC1 Arg399Gln (rs25487) polymorphisms on the risk of prostate cancer among cases from the central region of Saudi Arabia

This study was undertaken to investigate an association between genetic variants of ERCC2 (Lys751Gln), ERCC2 (Asp312Asn) or XRCC1 (Arg399Gln) polymorphisms with the risk of prostate cancer (PC) in Saudi population. This is a case-control study conducted on 124 PC patients and 425 healthy human controls. Blood samples were used for DNA extraction and gene polymorphisms for ERCC2 (Lys751Gln), ERCC2 (Asp312Asn) and XRCC1 (Arg399Gln). The risk of the associations was calculated by odds ratio (OR) and 95% confidence interval (CI). The data demonstrated no significant associations between ERCC2 (Lys751Gln) polymorphism and PC risk, whereas ERCC2 (Asp312Asn) and XRCC1 (Arg399Gln) polymorphisms were found to be significantly associated with PC risk (OR of 2.2, 95% CI, 1.1–4.1; p = 0.02) and (OR of 2.4, 95% CI, 1.3–4.5; p = 0.005), respectively. Likewise, recessive genotype models also showed significant association of ERCC2 (Asp312Asn) and XRCC1 (Arg399Gln) polymorphisms with PC risk (p = 0.009). Interestingly, these genetic associations were more pronounced in aged populations (p = 0.003) as well as in smokers (p < 0.0001). Combination of ERCC2 (Asp312Asn) and XRCC1 (Arg399Gln) genotypes showed strong association with the risk of PC onset (p < 0.001). These novel findings indicate that ERCC2 (Lys751Gln) polymorphism was not associated with risk of PC, whereas ERCC2 (Asp312Asn) and XRCC1 (Arg399Gln) polymorphisms showed strongly associated with the increased risk of PC. Combination of ERCC2 (Asp312Asn) and XRCC1 (Arg399 Gln) genotypes also showed strong association with increased risk of PC. In addition, more risk of PC onset was noticed in aged population and for those who were reported to have smoking history.

A Meta-Analysis for Association of XRCC1, XRCC2 and XRCC3 Polymorphisms with Susceptibility to Thyroid Cancer.

Background:We conducted a comprehensive meta-analysis to explore the association of polymorphisms at XRCC1, XRCC2 and XRCC3 genes with susceptibility to thyroid cancer (TC). Methods:We searched PubMed, EMBASE, Web of Science, and CNKI for relevant available studies. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of the associations. Results:A total of 67 studies including 17 studies with 6,806 cases and 5,229 controls on XRCC1 Arg399Gln, 13 studies with 3,234 cases and 4,807 controls on XRCC1 Arg280His, 13 studies with 2,956 cases and 3,860 controls on XRCC1 Arg194Trp, five studies with 1,287 cases and 1,422 controls on XRCC2 Arg188His, 13 studies with 2,488 cases and 3,586 controls on XRCC3 Thr241Met, and six studies with 1,828 cases and 2,060 controls on XRCC3 IVS5-14 polymorphism were selected. Polled data revealed that the XRCC1 Arg399Gln, Arg280His, Arg194Trp, XRCC2 Arg188His and XRCC3 Thr241Met and IVS5-14 polymorphisms were not significantly associated with an increased risk of TC. Stratified analyses by ethnicity showed that the XRCC1 Arg399Gln polymorphism was associated with TC risk in Caucasians, but not in Asians. Conclusions:Our meta-analysis indicated that the XRCC1 Arg399Gln, Arg280His, Arg194Trp, XRCC2 Arg188His, XRCC3 Thr241Met and IVS5-14 polymorphisms were not associated with risk of TC in the global population. Further well-designed investigations with large sample sizes are required to confirm our results.

Genetic polymorphisms of base excision repair gene XRCC1 and susceptibility to benzene among employees of chemical industries

Benzene is the most dangerous combination of volatile organic compounds (VOCs) due to its carcinogenicity and toxic effects on the blood system. Benzene toxicity is rooted in its metabolism. This material can break the DNA and cause some changes in the base sequence. The XRCC1 gene plays an important role in repairing the damaged base since the polymorphisms of gene XRCC1 (rs1799782) and (rs25487), which lead to an increased risk of various cancers, are common. In this study, the association between the mentioned polymorphisms and the risk of individuals' vulnerability to benzene was investigated in a group of people exposed to benzene in an Iranian context. One hundred thirty-eight subjects suffering from blood disorders (case group) and 168 subjects without any blood disorder (control group) were evaluated. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used for XRCC1 Arg194Trp and XRCC1 Arg399Gln polymorphism detection. The results showed that XRCC1 Arg194Trp and Arg399Gln polymorphisms had no significant association with susceptibility to benzene. Similarly, Arg399Gln and Arg194Trp genotypes did not have any significant relationship with hematological parameters. The obtained results indicated that the distribution of genotypes was in Hardy-Weinberg equilibrium in both groups. Different geographic locations, population size, and different genetic backgrounds might probably have affected the results.

Association of X-ray repair cross-complementing group 1 Arg399gln polymorphisms with the susceptibility to develop oral squamous cell carcinoma in tamol chewer's population in Assam, India

Background: Various environmental factors have been reported to play key role in the development of oral squamous cell carcinoma (OSCC). A lesser known risk factor of oral cancer in India is the uncontrolled use of areca nut chewing. In North-East India, Areca nut, locally called as “Tamol” in Assam, is raw betel nut, lime and betel leaf without tobacco, which are more effective as compared to dried which can be the important contributing factor for OSCC. Objectives: The aim of the study was to detect the association between XRCC1 polymorphisms and increased risk of OSCC in tamol chewers population in Assam, India. Methods: 50 OSCC patients, 50 tamol chewers and 50 controls were enrolled in the study. XRCC1 Arg399Gln polymorphisms were determined by using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Results: There was a significant association for XRCC1 codon 399 (Arg/Gln+Gln/Gln) (p<0.05; OR=1.909, CI= 0.8622- 4.227) with the wild type in cancer sample as compared with control sample. Similarly, the positive association for 399G/G (p<0.05; OR =2.842, CI = 0.919-8.79) genotypes with oral carcinoma and control sample. In case of tamol chewers, the AA genotype was found to be associated with 2-fold (OR- 2.25, CI= 0.709-7.14) increase risk of developing oral cancer while GA+AA genotype was associated with one and half fold (OR-1.62, CI=0.7354- 3.568) risk of developing oral cancer. Conclusions: Based on these results, the XRCC1399G>A genotype could be used as a useful molecular biomarker to predict genetic susceptibility in tamol chewers population and its susceptibility to develop OSCC.

Gene XRCC1Arg399Gln polymorphism and its genotype variations: clinical associations in Egyptian systemic lupus erythematosus patients

BackgroundImpaired deoxyribonucleic acid (DNA) repair may induce an autoimmune response in susceptible individuals. The association between DNA repair gene XRCC1 Arg399Gln gene polymorphism and susceptibility of systemic lupus erythematosus (SLE) is controversial. This study aimed to detect the association of XRCC1 Arg399Gln gene polymorphism with SLE and its clinical manifestations in the Egyptian population.ResultsA significant association was found between weight loss and genotype GG (P = 0.048); however, genotype AG was significantly associated with high serum creatinine and low C3 level (P = 0.039, P = 0.009, respectively). On the other hand, there was no significant difference between patients and controls regarding genotype and allele frequency.ConclusionsAn association was found between weight loss, high serum creatinine, and low C3 level and genotypes of XRCC1 Arg 399 Gln gene polymorphism.

The impacts of prominent gene polymorphisms in DNA repair enzymes on Parkinson’s disease

Parkinson’s Disease (PD), a chronic and progressive neurodegenerative disease of the brain, is associated with the loss of dopaminergic neurons. Its pathogenesis remains unclear; however, oxidative DNA damage due to reactive oxygen species (ROS) is believed to play a major role in the etiology of PD. DNA repair systems can mitigate oxidative DNA damage and help to maintain genomic stability and thus prevent neuronal death. However, gene polymorphisms on DNA repair enzymes may alter the functions of enzymes and increase the risk of PD. The present study aims to investigate a possible link between the OGG1, XRCC1, and MTH1 gene polymorphisms and PD risk in 97 patients with PD and 102 controls in the Turkish population. Our genotyping study utilizing polymerase chain reaction-restriction fragment length polymorphism revealed no relationship between two gene polymorphisms (OGG1Ser326Cys and MTH1Val83Met) and PD risk. Participants with the XRCC1 variant genotypes had a two to three and a half fold higher risk of PD than controls (p = 0.046, OR = 1.910, 95 % CI= [1.013–3.603] and p = 0.006, OR = 3.742, 95 % CI= [1.470–9.525], respectively). Our results suggested that XRCC1 Arg399Gln polymorphism is a risk factor for PD.

Clinicopathological Association of DNA Repair Gene Polymorphisms in Colorectal Cancer Patients

Several polymorphisms in DNA repair genes, especially ERCC1 C118T, ERCC2 Lys751Gln and XRCC1 Arg399Gln have been found to affect treatment efficacy and prognosis in patients with colorectal cancer (CRC). However, scarce reports available on the association of these polymorphisms with clinicopathological parameters. As clinicopathological factors provide important information to determine prognosis in CRC, present study evaluated association of DNA repair gene polymorphisms with clinicopathological parameters. ERCC1 C118T, ERCC2 Lys751Gln and XRCC1 Arg399Gln polymorphisms were studied by PCRRFLP in 143 primary CRC patients. For ERCC1 C118T polymorphism, predominance of heterozygous C/T (56%) was noted compared to wild type C/C (29%) and variant T/T (15%) genotypes. ERCC2 Lys751Gln polymorphism showed 44% of wild type A/A, 40% of heterozygous A/C, and 16% of variant C/C genotypes. XRCC1 Arg399Gln polymorphism displayed wild type G/G (48%), heterozygous G/A (42%), and variant A/A (10%). In relation to clinicopathological parameters, ERCC1 C118T polymorphism was significantly associated with tumor site (P=0.021); tumor location (P=0.039); and tumor differentiation (P=0.041). Moreover, a significant correlation of ERCC2 Lys751Gln polymorphism was noted with lymphocytic stromal response (P=0.026) and necrosis (P=0.041). However, XRCC1 Arg399Gln polymorphism was not significantly associated with clinicopathological factors. Further, a significant positive correlation was observed between ERCC2 and XRCC1 polymorphism (P=0.002). To conclude, higher frequency of ERCC1 118 variant C/T and T/T genotypes was noted in patients with colon cancer and right side located tumors. Variant C allele of ERCC2 751 polymorphism was associated with less aggressive colorectal tumors. Moreover, significant association between ERCC2 and XRCC1 polymorphisms proposes interlink of genes of different DNA repair pathways in CRC.

ERCC1 C8092A polymorphism predicts fair survival outcome in Japanese patients with pharyngo-laryngeal squamous cell carcinoma.

To evaluate the prognostic significance of DNA excision repair gene polymorphisms, excision repair cross-complementation group 1 (ERCC1) and X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1) polymorphisms were investigated in Japanese patients with head and neck squamous cell carcinoma (HNSCC). A total of 225 consecutive patients with HNSCC who underwent surgery or chemoradiotherapy/radiotherapy (CRT/RT) with curative intent as primary treatment from 2006 to 2017 were recruited. ERCC1 C8092A and XRCC1 Arg399Gln polymorphisms in DNA extracted from individual blood samples were determined by the polymerase chain reaction-restriction fragment length polymorphism method. Cumulative survival was estimated by Kaplan-Meier analysis with a log-rank test and Cox proportional hazards model stratified by treatment arm, adjusting for clinical prognostic factors. Multivariate analysis showed that carriers with the ERCC1 8092 (C/A+A/A) genotype (hazard ratio, 3.56; 95% confidence interval, 1.22-7.39; p = 0.02) had significantly worse survival than those with ERCC1 8092 C/C who received CRT/RT. Conversely, the XRCC1 Arg399Gln polymorphism did not influence survival in patients who received CRT/RT as well as surgery. The ERCC1 C8092A polymorphism might be an independent predictor of response to CRT and survival outcome in patients with HNSCC. This is the first report to investigate the role of DNA excision repair gene polymorphisms in patients with head and neck cancer in a Japanese population.

Abstract 1617: Genetic polymorphisms in DNA repair genes XRCC1 and 3 are associated with increased risk of breast cancer in Bangladeshi population

Abstract Background: Breast cancer is the most commonly occurring cancer in women worldwide and its prevalence vary among different ethnic groups. Genetic polymorphisms in DNA repair genes may affect individual variation in DNA repair capacity which may contribute to individual susceptibility for developing various cancers. This study aimed to investigate the contribution of polymorphisms in two DNA repair genes, namely XRCC1 (Arg399Gln, rs25487) and XRCC3 (Thr241Met, rs861539) to breast cancer risk in Bangladeshi females and their role as susceptibility markers. Methods: A case-control study comprising 121 breast cancer patients and 133 healthy volunteers was conducted taking the age, breast feeding status, menopausal status, education etc into account. Genomic DNA isolated from peripheral blood was used to genotype the target polymorphisms using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Risk-stratified subgroup analyses were conducted to find out the association between the genotypes and age-, menopause-, lactating status-related characteristics of breast cancer patients. Results: A significant positive association was found between XRCC1 (Arg399Gln,) and XRCC3 (Thr241Met) polymorphisms and breast cancer risk in the studied population. In case of XRCC1 Arg399Gln polymorphism, the heterozygous Arg/Gln (G/A) and homozygous Gln/Gln (A/A) genotypes showed 1.78-fold (OR=1.78, 1.0084 to 3.1442, p=0.0467) and 2.41-fold (OR=2.41, 95% CI= 1.0354 to 5.5914, p=0.0413) increased risk of breast cancer, respectively when compared with homozygous Arg/Arg genotype. The presence of any XRCC1 Gln (Arg/Gln or Gln/Gln) was associated with 1.93-fold increased risk (OR=1.93, 95% CI= 1.1574 to 3.2290, p=0.0118). The variant Gln (A) allele also was associated with increased risk of breast cancer (OR=1.78, 95% CI= 1.1885 to 2.6805, p=0.0052). The Gln/Gln genotype was more prevalent in breast cancer cases at ages 55 or above and in menopausal state. In case of XRCC3 (Thr241Met) polymorphism, Thr/Met (C/T) heterozygote, and combined Thr/Met+Met /Met (C/T+T/T) genotypes were significantly associated with 1.85- and 1.89- fold higher risk of breast cancer, respectively (OR=1.85, 95% CI=1.0815 to3.1834, p=0.0248; OR=1.89, 95% CI=1.1199 to 3.1908, p=0.0171, respectively). The variant Met (T) allele showed significant association with increased susceptibility (1.70-fold) to breast cancer (OR=1.70, 95% CI=1.0849 to 2.6172, p= 0.0206). Among breast cancer cases significant differences in genotype frequency were evident in patients with age 55 years or above and with menopause. Conclusion: Our results suggest that XRCC1 (Arg399Gln) and XRCC3 (Thr241Met) polymorphisms are associated with increased risk of breast cancer in Bangladeshi females. In addition, this association was significantly related to age and lactating status. Citation Format: Md. Mustafizur Rahman, Nupur Rani Hawlader, Md. Mostafizur Rahman, Md. Amir Hossain. Genetic polymorphisms in DNA repair genes XRCC1 and 3 are associated with increased risk of breast cancer in Bangladeshi population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1617.

Association of Polymorphisms in the DNA Repair Genes XRCC1 and XRCC3 with Systemic Lupus Erythematosus

Background: Evidence suggests that DNA damage is implicated in the development of Systemic Lupus Erythematosus (SLE). Objective: Investigate the possible association of polymorphisms in the DNA repair genes XRCC1 and XRCC3 with SLE and its clinical and laboratory features. Methods: This is a case-control study comparing the polymorphisms in the DNA repair genes XRCC1 and XRCC3 in SLE patients and control individuals. Genotyping for DNA repair genes was performed by polymerase chain reaction-restriction fragment length polymorphism in 76 patients and 82 healthy control individuals. Results: Our data indicated that the genotype frequencies in patients with the XRCC1 Arg399Gln and XRCC3 Thr241Met polymorphisms were similar to those observed in the control group (p &gt; 0.05). However, the frequencies of the 399Gln allele (p = 0.023, OR = 0.58, 95% CI = 0.36–0.93) and 241Met allele (p = 0.0039, OR = 0.59, 95% CI = 0.36–0.98) were significantly lower in the patients than those in the control subjects. Conclusion: We demonstrated that 399Gln and 241Met alleles may play a protective role in SLE susceptibility.

XRCC1 variants do not represent a risk for dermatomyositis and systemic lupus erythematosus in Bulgarian patients

Systemic lupus erythematosus (SLE) and dermatomyositis (DM) share a similar pathogenesis, and genetic, hormonal, and environmental factors are known to trigger the autoimmune process. The X-ray repair cross-complementing genes (XRCC1 and XRCC3) are known to play a central role in mammalian DNA repair processes. Evidence suggests that impaired DNA repair efficiency is implicated in the development of autoimmune diseases. This case-control study investigates the association between the XRCC1 Arg194Trp (C>T) and Arg399Gln (G>A) polymorphisms and the susceptibility to DM and SLE in Bulgarian patients. Altogether 88 patients, 55 with SLE and 33 with DM, and 94 unrelated healthy controls were included in this study. None of the polymorphisms showed an association with SLE, DM, or their clinical parameters. The allele and genotype frequency of the two single nucleotide polymorphisms was similar to those found in other healthy Caucasian populations. Our results indicate that the XRCC1 rs1799782 Arg194Trp and rs25487 Arg399Gln polymorphisms do not play a role in the susceptibility to SLE and DM.

The frequency of the DNA repair gene XRCC1 Arg399Gln polymorphism in Saudi Arabian and other ethnic groups and the risk of leukemias

The frequency of the DNA repair gene XRCC1 Arg399Gln polymorphism in Saudi Arabian and other ethnic groups and the risk of leukemias

Arg399Gln substitution in XRCC1 as a prognostic and predictive biomarker for prostate cancer: Evidence from 8662 subjects and a structural analysis.

The Arg399Gln polymorphism in the X-ray repair cross-complementing group 1 gene (XRCC1) may alter the risk of prostate cancer (PCa). The present study aimed to investigate the association of the XRCC1-Arg399Gln polymorphism with PCa risk in an Iranian population, as followed by a meta-analysis and an in silico analysis. In a case-control study, 360 subjects were included (180 men with PCa and 180 healthy controls). XRCC1-Arg399Gln genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism method. In the meta-analysis, 14 eligible studies were included to which our case-control data were added to estimate the pooled odds ratios. Some bioinformatics tools were employed to evaluate the effects of Arg399Gln substitution on molecular aspects of the XRCC1 protein. Our case-control study revealed a significant association between the XRCC1-Arg399Gln polymorphism and PCa risk. The data from overall meta-analysis showed significant associations between the mentioned polymorphism and PCa risk in allelic and recessive genetic models. In addition, we observed statistically significant associations in stratified analyses by ethnicity, sample size and source of controls. Our in silico analysis showed that Arg399Gln substitution could be damaging with respect to the function and structure of the XRCC1 protein. Based on these results, the XRCC1-Arg399Gln polymorphism might be a risk factor for PCa and it could be considered as a prognostic and predictive biomarker for susceptible men.

Impact of polymorphism in DNA repair genes OGG1 and XRCC1 on seminal parameters and human male infertility

The DNA repair capacity in the mature spermatozoa is highly compromised due to the base-excision repair (BER) route being truncated. In the mature spermatozoa, only the first enzyme of the route (OGG1) is present. Consequently, reduced activity of the enzymes of the BER route both during spermatogenesis and in the mature spermatozoa may be detrimental for fertility. The objective of our study was to investigate the correlation between two representative SNPs of those enzymes, SNPs OGG1 Ser326Cys (rs1052133) and XRCC1 Arg399Gln (rs25487) and male infertility. A total of 313 seminal samples from infertile patients and 80 from donors with proven fertility were included in the study. All samples were subjected to a regular sperm analysis and genotyped using the PCR-RFLP system. We found significant differences in the genotype frequencies between patients and donors for the XRCC1 Arg399Gln polymorphism (χ2(2)=8.7, p=0.013), with the Gln allele showing a protective role and for the OGG1 Ser326Cys polymorphism between normozoospermic and non-normozoospermic patients (χ2(2)=12.67, p=0.002) with the Cys allele showing a detrimental effect over concentration. In conclusion, our study shows that polymorphisms in the genes coding for the DNA damage repair enzymes may be associated with poor sperm parameters and male infertility.