XRCC1 Rs25487 Research Articles

Genomic Profiling Reveals Novel Predictive Biomarkers for Chemo-Radiotherapy Toxicity and Efficacy in Non-Small-Cell Lung Cancer

<h3>Purpose/Objective(s)</h3> Chemo-radiotherapy (CRT) remains the main treatment modality for non-small-cell lung cancer (NSCLC). However, its clinical efficacy is largely limited by individual variations in radio-sensitivity and risk of radiation-induced thoracic toxicity (RITT). There is an urgent need to identify genetic determinants that can explain patients' likelihood to develop recurrence and RITT following CRT. <h3>Materials/Methods</h3> We performed comprehensive genomic profiling, using a 474-cancer and radiotherapy-related gene panel, on pretreatment biopsy samples from patients with unresectable stage III NSCLCs who underwent definitive CRT. Patients' clinical and genomic features were correlated with progression-free survival (PFS), overall survival (OS), and high-grade RITT development, after CRT. <h3>Results</h3> A total of 122 patients were enrolled (median age, 62 years; 87% males). Of these, the majority (n = 84, 69%) had squamous cell carcinoma (SCC) and the remaining 38 (31%) were adenocarcinoma (ADC). Median PFS and OS of the cohort were 11.4 and 34.6 months, respectively. No clear survival difference was seen between the histological subtypes or other clinical features, other than an association between smoking history and an unfavorable outcome (PFS HR = 1.89 [95% CI, 1.11-3.21], <i>P</i> = 0.02; OS HR = 1.59 [0.80-3.16], <i>P</i> = 0.19). Genetic association analysis identified alterations in NOTCH2, KEAP1, FGFR1/3 alterations as potential risk factors of CRT resistance, with reduced PFS and OS compared with patients carrying the respective wild-type genes. The rates of grade 2 or higher (high-grade) radiation-induced pneumonitis and esophagitis were 32% and 13%, respectively. Polymorphisms in the DNA repair-associated XRCC5 (rs3835) and XRCC1 (rs25487) were associated with an increased risk of high-grade esophagitis and pneumonitis, respectively. Moreover, XRCC5 (rs3835) was also associated with an earlier occurrence of high-grade esophagitis. MTHFR (rs1801133) and NQO1 (rs1800566) were additional risk alleles associated with an increased susceptibility to RITT overall. <h3>Conclusion</h3> Our results provide a set of clinically usable predictive biomarkers for chemo-radiotherapy toxicity and efficacy. These findings suggest that pre-treatment testing for a combination of genetic variants, which likely act together to confer resistance or toxicity after CRT, might be clinically useful.

Genetic variants of APEX1 p.Asp148Glu and XRCC1 p.Gln399Arg with the susceptibility of hepatocellular carcinoma.

The DNA repair genes have a crucial function in the base excision repair (BER) mechanism among different cancerous disorders, particularly hepatocellular carcinoma (HCC). The foremost objective of this study is to explore the association of genetic variants of the APEX1 p.Asp148Glu and the XRCC1 p.Gln399Arg with the susceptibility of HCC and to identify the computational bioinformatics frameworks of these missense variants. A total of 250 participants were enrolled in this study, including 150 HCC patients and 100 cancer-free controls. The genomic DNA was characterized and genotyped by applying the PCR-CTPP method. The frequency of the APEX1 (rs1130409*Glu) allele was statistically significant with increased risk of HCC (OR = 1.66, 95% CI = 1.12-2.45), while the XRCC1 (rs25487*Gln) allele conferred a protection against the progression of HCC (OR = 0.64, 95% CI = 0.42-0.96). Furthermore, HCC patients carrying the APEX1 p.Asp148Glu and the XRCC1 p.Gln399Arg variants indicated no significant difference with the clinical, and laboratory parameters (p > .05). Our findings confirmed that the APEX1 p.Asp148Glu variant was associated with increased risk of HCC, while the XRCC1 p.Gln399Arg variant revealed protection against the development of HCC.

Association of RAD51 and XRCC2 Gene Polymorphisms with Cervical Cancer Risk in the Bangladeshi Women

Objective:Alterations in common DNA repair genes (RAD51 and XRCC2) may lead to cervical cancer (CC) development. In the present study, we analyzed the association between RAD51 rs1801320 and XRCC2 rs3218536 polymorphisms and CC. Methods:Variants were selected based on their associations with some cancers in several ethnicities and the risk allele frequency (>0.05) in different populations. The variants were detected using the PCR-RFLP method. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were determined by logistic regression models. Result:Significantly increased risk (p<0.05) were detected for both SNPs with CC (rs1801320- GC vs. GG: aOR=2.21, 95% CI=1.43-3.42; CC vs. GG: aOR=4.48, 95% CI=1.76-11.42; dominant model: aOR=2.49, 95% CI=1.65-3.76; recessive model: aOR=3.52, 95% CI=1.40-8.88; allele model: OR=2.30, 95% CI=1.63-3.26, and rs3218536- GA vs. GG: aOR=2.77, 95% CI=1.85-4.17; AA vs. GG: aOR=5.86, 95% CI=2.08-16.50; dominant model: aOR=2.97, 95% CI=1.99-4.42; recessive model: aOR=3.56, 95% CI=1.30-9.73; and allele model: aOR=2.21, 95% CI=1.62-3.00). Besides, older patients (>60 years) with rs1801320 showed significantly reduced risk (OR=0.53, 95% CI=0.29-0.96, p=0.04) but with rs3218536 depicted significantly increased risk (aOR=2.44, 95% CI=1.20-4.96, p=0.01) for CC. Conclusion:This study indicates an association of rs1801320 and rs3218536 polymorphisms with CC and confirms that patients older than 60 years are more likely to develop CC for rs3218536 polymorphism.

Pharmacogenetic study in gastric cancer patients treated with adjuvant fluorouracil/leucovorin or epirubicin/cisplatin/fluorouracil before and after chemoradiation on CALGB 80101 (Alliance).

There is a lack of pharmacogenetic predictors of outcome in gastric cancer patients. The aim of this study was to assess previously identified candidate genes associated with 5-fluorouracil (5-FU), cisplatin, or epirubicin toxicity or response in a cohort of resected gastric cancer patients treated on CALGB (Alliance) 80101. Gastric or gastroesophageal cancer patients randomized to adjuvant 5-FU/leucovorin or epirubicin/cisplatin/5-FU before and after 5-FU chemoradiation were genotyped for single nucleotide polymorphisms (SNPs) in GSTP1 (rs1695), ERCC1 (rs11615 and rs3212986), XRCC1 (rs25487), UGT2B7 (rs7439366) and the 28 base-pair tandem repeats in TYMS (rs34743033). Logistic regression and log rank tests were used to assess the association between each SNP and incidence of grade 3/4 neutropenia and leukopenia, overall (OS) and progression-free survival (PFS), respectively. Toxicity endpoint analyses were adjusted for the treatment arm, while OS and PFS were also adjusted for performance status, sex, age, lymph node involvement, and primary tumor site and size. Of 281 subjects with successful genotyping results and available clinical (toxicity and efficacy) data, 166 self-reported non-Hispanic White patients were included in the final analysis. There was a lack of evidence of an association among any SNPs tested with grade 3/4 neutropenia and leukopenia or OS and PFS. Age, lymph node involvement, and primary tumor size were significantly associated with OS and PFS. This study failed to confirm results of previous gastric cancer pharmacogenetic studies.

Role of XRCC1, XPC, NBN gene polymorphisms in spermatogenesis

The damaging effect of chemical, physical and biological factors on germ cells has an important role in the pathogenesis of male infertility. Maintaining integrity and stability of the genetic information of male germ cells is carried out by the DNA repair system. Data on the association of DNA repair system gene polymorphisms with pathospermia are few and contradictory. The study of the DNA repair system gene polymorphisms among men with various types of pathospermia can provide essential information for the formation of groups with an increased risk of disturbances in the process of spermatogenesis. The aim of this work is investigating the role of polymorphisms of genes of the DNA repair system as factors of predisposition to male infertility, as well as to study their intergenic interaction. In this study the frequency of repair system gene polymorphisms (XRCC1 rs25487, rs25489; NBN rs1805794 and XPC rs2228001) was tested in reproductive-age men of the population of Rostov region. The samples were classified into four groups according to semen analyses: normozoospermia, oligozoospermia, asthenozoospermia and the combined group with pathospermia. As a result, we found that the Arg280His (839G>A) (rs25489) polymorphism of the XRCC1 gene may be associated with an impairment of the human spermatogenesis process. In men with genotype Arg/His comparing with genotype Arg/Arg it was more often found reducing the spermatozoa concentration (OR 4.26; 95% CI 1.02–17.75; p < 0.05). Variant His/His also may be associated with an increased risk of oligozoospermia (OR 4.77; 95% CI 0.19–120.47; p < 0.05). The data obtained in this work are a step towards proving that polymorphic variants of the DNA repair system genes XRCC1, XPC and NBN contribute to the risk of pathospermia.

Male and female breast cancer: the two faces of the same genetic susceptibility coin

Background Breast cancer (BC) is the most common cancer in women. In contrast, male BC is about 100 times less common than in women, being considered a rare disease. Male BC may be a distinctive subtype of BC and available data seems to indicate that male BC has a higher dependence on genetic variants than female BC. Nevertheless, the same prognostic and predictive markers are used to determine optimal management strategies for both male and female BC. Several studies have assessed the role of genetic polymorphisms (SNPs) in DNA repair genes in female BC susceptibility. However, data on male BC is scarce. Thus, the current study aimed to assess the role of SNPs in XRCC1, MUTYH and TP53 genes in a male cohort of BC, and, in addition, compare the male data with matched results previously genotyped in female BC patients.Methods The male BC cohort was genotyped through Real-Time PCR using TaqMan Assays for several SNPs previously analysed in Portuguese female BC patients.ResultsThe results obtained indicate significant differences in BC susceptibility between males and females for the XRCC1 rs1799782, MUTYH rs3219489 and TP53 rs1042522 and rs8064946 variants.ConclusionsIn males, XRCC1 and TP53 variants, when in heterozygosity, seem to be related with lower susceptibility for BC, contrasting with higher susceptibility for a MUTYH variant in females. These findings may help to explain the difference in incidence of BC between the two sexes.

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.

Relationship of the XRCC1 rs25487 polymorphism with demographic, behavioral, clinical, and histological parameters in oral potentially malignant disorders and oral squamous cell carcinoma in a Colombian population

ObjectivesTo evaluate the salivary detection of XRCC1 rs25487 single-nucleotide polymorphism (SNP), its relationship with clinicopathological characteristics, and the interactions with demographic/behavioral variables in the etiopathogenesis of oral potentially malignant disorders (OPMD) and oral squamous cell carcinoma (OSCC) in a Colombian population. MethodsDemographic/behavioral data and saliva samples were obtained from patients with oral leukoplakia (OL, n = 17) and oral lichenoid lesions with epithelial dysplasia (OLL-ED, n = 10), or OSCC (n = 45), along with healthy controls (n = 40). Tissue biopsies were obtained for histological assessment and genetic analysis was performed using polymerase chain reaction-restriction fragment length polymorphism. Descriptive analyses were used to compare the distribution of genotypes/alleles between study groups alongside an analysis of the interaction between genetic findings and demographic/behavioral variables. ResultsNo association was observed between the genotype and allele frequencies in OPMD or OSCC. The AG genotype was significantly more frequent in OL with high-grade dysplasia, acanthotic epithelial lining, moderate-to-severe mitotic count, and negative-to-mild apoptotic count; and in OSCC cases with stage III/IV, poorly differentiated, perineural/lymphovascular invasion, severe cellular atypia, moderate-to-severe mitotic count, and negative-to-mild apoptotic counts. Significant interaction effects were detected in the AG genotype with regard to ageing, smoking habits, and alcohol consumption in both OL and OSCC. ConclusionAlthough rs25487 SNP appeared to not modulate the risk of OPMD/OSCC independently, its significant association with clinicopathological characteristics in OL and OSCC, and the synergistic interaction between ageing and smoking/alcohol consumption, might play a role in these two diseases.

A PRISMA-compliant meta-analysis on association between X-ray repair cross complementing (XRCC1, XRCC2, and XRCC3) polymorphisms and oral cancer susceptibility.

Oral Cancer (OC) is one of the leading causes of death and the disease mainly occurs over 50years of age. Herein, a meta-analysis aimed to assess the association between X-ray repair cross complementing (XRCC) polymorphisms and OC risk. Four databases were searched extensively until June 5, 2020. Subgroup analysis, meta-regression, and funnel plots, as well as the quality assessment were estimated. Fifteen studies were entered to the analysis. With regards to allele, homozygote, heterozygote, recessive, and dominant models, the pooled ORs for XRCC1 rs1799782 polymorphism were 1.51 (P=0.01), 1.45 (P=0.11), 1.45 (P=0.0003), 1.44 (P=0.0002), and 1.29 (P=0.26); for XRCC1 rs1799782 polymorphism were 1.65 (P=0.11), 1.50 (P=0.33), 1.06 (P=0.83), 1.57 (P=0.12), and 1.32 (P=0.45); for XRCC1 rs25489 polymorphism were 0.01 (P=0.19), 1.44 (P=0.48), 1.21 (P=0.72), 1.17 (P=0.19), and 1.38 (P=0.54); for XRCC2 rs2040639 polymorphism were 0.68 (P=0.0002), 0.63 (P=0.02), 0.95 (P=0.92), 0.79 (P=0.49), and 0.61 (P=0.005); and for XRCC3 rs861539 polymorphism were 1.24 (P=0.20), 1.28 (P=0.48), 0.99 (P=0.95), 1.15 (P=0.46), and 1.52 (P=0.15), respectively. The T allele and CT genotype of XRCC1 rs1799782 polymorphism had an elevated risk, whereas the G allele and GG genotype of XRCC2 rs2040639 polymorphism had a protective role in OC.

Association of XRCC3 rs1799794 polymorphism with survival of glioblastoma multiforme patients treated with combined radio-chemotherapy.

This study reports the results of a monocentric prospective analysis conducted with the aim of evaluating the impact of XRCC1 rs25487, XRCC3 rs861539, XRCC3 rs1799794, RAD51 rs1801320 and GSTP-1 rs1695 single nucleotide polymorphisms (SNP) on patients with high-grade glioma treated with concomitant radio-chemotherapy. From October 2010 to August 2019, a total of 75 patients aged ≥18years, with histological diagnosis of high-grade glioma, isocitrate dehydrogenase (IDH) 1/2 wild type and treated with radio-chemotherapy and sequential chemotherapy with temozolomide (TMZ) were prospectively recruited. The local ethic committee approved this study (Comitato Etico di Area Vasta Nord Ovest [CEAVNO]; protocol 3304/2011). After a median follow up of 25months (range: 7-98months), median progression-free survival (PFS) and overall survival (OS) were 11months (CI95%: 8-14months) and 18months (CI95%: 15-21months), respectively. In univariate and multivariate Cox regression analysis, a statistically significant association with PFS and OS was found with XRCC3 rs1799794 SNP. The study suggests that XRCC3 rs1799794 SNP can be associated with different PFS and OS in glioblastoma patients treated with radio-chemotherapy.

Influence of single nucleotide polymorphisms among cigarette smoking and non-smoking patients with coronary artery disease, urinary bladder cancer and lung cancer.

IntroductionCigarette smoke is suggested to be a risk factor for coronary artery disease (CAD), urinary bladder cancer (UBCa) or lung cancer (LCa). However, not all heavy smokers develop these diseases and elevated cancer risk among first-degree relatives suggests an important role of genetic factor.MethodsThree hundred and ten healthy blood donors (controls), 98 CAD, 74 UBCa and 38 LCa patients were included in this pilot study. The influence of 92 single nucleotide polymorphisms (SNPs) and impact of cigarette smoking were analysed.ResultsOut of 92 SNPs tested, differences in distribution of 14 SNPs were detected between controls and patient groups. Only CTLA4 rs3087243 showed difference in both CAD and UBCa patient group compared to control group. Stratified by smoking status, the impact of smoking was associated to frequencies of 8, 3 and 4 SNPs in CAD, UBCa, LCa patients, respectively. None of these 92 SNPs showed a statistically significant difference to more than one type of disease among smoking patients. In non-smoking patients, 7, 3 and 6 SNPs were associated to CAD, UBCa, LCa, respectively. Out of these 92 SNPs, CTLA4 rs3087243 was associated to both non-smoking CAD and UBCa. The XRCC1 rs25487 was associated to both non-smoking UBCa and LCa.ConclusionSNPs might be important risk factors for CAD, UBCa and LCa. Distribution of the SNPs was specific for each patient group, not a random event. Impact of cigarette smoking on the disease was associated to the specific SNP sequences. Thus, smoking individuals with SNPs associated to risk of these serious diseases is an important target group for smoking cessation programs.

Molecular genetic markers of sensitivity to industrial environment factors at miners

Background. Active ribosomal genes and DNA repair genes play an important role in restoring genome integrity. Therefore we were studied relationship of active ribosomal genes dose and DNA repair genes polymorphisms with high level of chromosomal disorders in miners.&#x0D; Materials and methods. The DNA damage level was assessed using chromosomal aberrations (CA) at 288 coal miners and 676 men in the control group. The dose of active ribosomal gene (AcRG) has been analyzed using Ag-NORS staining regions of chromosomes and cytogenetic semi-quantitative evaluation method. Real-time PCR and allele-specific PCR techniques were used to analyze polymorphic variants of the XPG (rs17655), XPD (rs13181), XRCC2 (rs3218536), and XRCC3 (rs861539) genes.&#x0D; Results. A statistically significant (p = 0.0001) increase of the СА level at miners was found in comparison with the control group. The association XPD 2251TG locus with increasing CA level is revealed of in recessive inheritance model (padj = 0.0001). The association XPG 3310GC locus with increasing СА level is revealed at the smoking workers (padj = 0.017). An average dose of AcRG was registered a statistically significant increase in the frequency of single fragments (p = 0.016) at the miners.&#x0D; Conclusion. The obtained data on associations of chromosomal aberrations with different variants of DNA repair genes and the dose of active ribosomal genes are useful for the formation of high-risk groups.

Effect of DPYD, MTHFR, ABCB1, XRCC1, ERCC1 and GSTP1 on chemotherapy related toxicity in colorectal carcinoma

ABCB1, DPYD, MHTFR, XRCC1, ERCC1, GSTP1 and UGT1A1 genetic variants affect proteins related to CRC chemotherapy toxicity.A retrospective cohort study was conducted in 194 CRC patients.In first line treatment, DPYD rs17376848 AG genotype was associated with hematological toxicity (OR = 4.85; p = 0.03); GSTP1 G-allele (OR = 3.01; p = 0.005) and MTHFR rs1801133 T allele (OR = 2.51; p = 0.03) with respiratory toxicity; GSTP1 G-allele with cardiovascular toxicity (OR = 4.05; p = 0.01); ERCC1 rs11615 GG genotype with neurological toxicity (OR = 3.98; p = 0.01) and with asthenia (OR = 2.91; p = 0.08); XRCC1 rs1799782 T allele (OR = 0.31; p = 0.03) and GSTP1 G-allele (OR = 1.81; p = 0.01) with cutaneous toxicity. In second line treatment, XRCC1 rs1799782 T-allele was associated with asthenia (OR = 0.17; p = 0.03) and XRCC1 rs25487 T-allele with gastrointestinal toxicity (OR = 3.03; p = 0.005). After stratifying by treatment, in the 5-Fluorouracil group, the DPYD rs17376848 AG genotype was associated with hematological toxicity (OR = 2.76; p = 0.003), ABCB1 rs1045642 T-allele with the need of treatment adjustment due to toxicity (OR = 3.06; p = 0.01), and rs1045642 CC genotype with gastrointestinal toxicity (OR = 5.80; p = 0.03). In the capecitabine group, the MTHFR rs1801131 CC genotype was associated with asthenia (OR = 3.48; p = 0.009). In the oxaliplatin group, rs1045642 TT genotype was associated with the need to adjust treatment (OR = 0.32; p = 0.02), ERCC1 rs11615 GG genotype with asthenia (OR = 3.01; p = 0.01) and rs1615 GSTP1 GG genotype with respiratory toxicity (OR = 5.07; p = 0.009).ABCB1 rs1045642 T-allele reduces the need for treatment modification with both 5FU and oxaliplatin. Although several biomarkers predicted different toxic effects, they cannot be considered as risk factors for severe toxicity.

Radiation-induced lymphopenia during chemoradiation therapy for non-small cell lung cancer is linked with age, lung V5, and XRCC1 rs25487 genotypes in lymphocytes

Background & PurposeWe investigated clinical and genetic factors associated with severe radiation-induced lymphopenia (RIL) in a randomized clinical trial of photon vs. proton radiation, with chemotherapy, for non-small cell lung cancer. MethodsXRCC1 rs25487 was genotyped in lymphocytes from serial peripheral blood samples. Severe RIL was defined as absolute lymphocyte count (ALC) < 0.3 × 109 cells/L. Univariate and multivariate analyses were used to identify independent risk factors, which were then used to group patients for risk of severe RIL. ResultsUnivariate analysis of the 178 patients in this analysis showed that older age, larger tumors, higher lung V5 and mean lung dose, and higher heart V5 and mean heart dose were associated with severe RIL during treatment (P < 0.05). The XRCC1 rs25487 AA genotype was also associated with increased risk of severe RIL during treatment (AA vs. others: hazard ratio [HR] = 1.665, 95% confidence interval [CI] 1.089–2.500, P = 0.018). Multivariate analyses showed that older age (HR = 1.031, 95% CI 1.009–1.054, P = 0.005), lung V5 (HR = 1.039, 95% CI 1.023–1.055, P < 0.0001), and AA genotype (AA vs. others, HR = 1.768, 95% CI 1.165–2.684, P = 0.007) were independently associated with higher incidence of severe RIL. These three risk factors (age ≥ 56 years, lung V5 ≥ 51% and XRCC1 rs25487 AA) distinguished patients at different risk of developing severe RIL (P < 0.0001). ConclusionsAge, lung V5 and XRCC1 rs25487 AA were all linked with risk of severe RIL. Our predictive risk model may be helpful for identifying patients at high risk of severe RIL so that treatment can be modified.

Genetic polymorphisms of GSTP1, XRCC1, XPC and ERCC1: prediction of clinical outcome of platinum-based chemotherapy in advanced non-small cell lung cancer patients of Bangladesh.

Inter-individual genetic makeup can trigger variability in platinum-based chemotherapeutic responses and corresponding adverse drug reactions and toxicities. Exploring the genetic causes behind these inter-individual variabilities in platinum-based chemotherapeutic responses by investigating the effects of GSTP1 (rs1695), XRCC1 (rs25487), XPC (rs2228001) and ERCC1 (rs11615) genetic polymorphisms on toxicity and therapeutic response of this treatment among Bangladeshi advanced non-small cell lung cancer (NSCLC) patients was the aim of this study. 285 Clinically proven either stage IIIB or IV (advanced) NSCLC patients aging not less than 18years old and receiving platinum-based chemotherapy were recruited to assess the influence of these four single nucleotide polymorphisms (SNPs) on peripheral leukocytes. Toxicity and response were evaluated by multivariate regression analyses using SPSS statistical software (version 17.0). XRCC1 (rs25487) polymorphism was found to act as a predictive factor for not only grade 3 and 4 anemia (p = 0.008), neutropenia (p = 0.010), thrombocytopenia (p = 0.025) and gastrointestinal toxicity (p = 0.002) but also for therapeutic response (p = 0.012) in platinum-based chemotherapy. Although GSTP1 (rs1695) polymorphism might serve as prognostic factor regarding grade 3 or 4 neutropenia, a significant (p = 0.044) improvement in response to platinum-based chemotherapy was observed. However, XPC (rs2228001) and ERCC1 (rs11615) polymorphisms could not establish any significant relation with toxicity or therapeutic response. XRCC1 (rs2228001) and GSTP1 (rs1695) polymorphisms might explain platinum-induced clinical outcomes in terms of both toxicity and therapeutic response variations among Bangladeshi advanced NSCLC patients.

Impact of single nucleotide polymorphisms in the OGG1 and XRCC1 genes on modulation of DNA damage in pesticide-exposed agricultural workers in Punjab, North-West India

Pesticide-induced DNA damage is primarily repaired by base excision repair (BER) pathway. However, polymorphism in DNA repair genes may modulate individual’s DNA repair capacity (DRC) leading to increased genotoxicity and adverse health effects. Our first study in North-West Indian population aimed to evaluate the impact of OGG1 rs1052133 (Ser326Cys; C1245G), XRCC1 rs1799782 (Arg194Trp; C26304T) and XRCC1 rs25487 (Arg399Gln; G28152A) polymorphisms on the modulation of pesticide-induced DNA damage in a total of 450 subjects (225 pesticide-exposed agricultural workers and 225 age- and sex-matched controls). DNA damage was estimated by alkaline comet assay using silver-staining method. Genotyping was carried out by PCR-RFLP using site-specific restriction enzymes. Mann-Whitney U-test revealed elevation in DNA damage parameters (p < 0.01) in pesticide-exposed agricultural workers than controls. Chi-square test showed significant (p < 0.05) differences in the XRCC1 Arg194Trp (C26304T) and Arg399Gln (G28152A) genotypes among two groups. Multivariate logistic-regression analysis revealed that heterozygous genotypes of OGG1 rs1052133 (326Ser/Cys; 1245CA), XRCC1 rs1799782 (194Arg/Trp; 26304CT) and XRCC1 rs25487 (399Arg/Gln; 2815GA) were positively associated (p < 0.05) with elevated DNA damage parameters in pesticide-exposed agricultural workers. Our results strongly indicate significant positive association of variant OGG1 and XRCC1 genotypes with reduced DRC and higher pesticide-induced DNA damage in North-West Indian agricultural workers.

Predictive value of genetic variants XRCC1 rs1799782, APEX1 rs1760944, and MUTYH rs3219489 for adjuvant concurrent chemoradiotherapy outcomes in oral squamous cell carcinoma patients.

Genetic variations in DNA base excision repair (BER) genes may affect tumor sensitivity to chemotherapy and radiotherapy. Thus, we investigated the effects of single-nucleotide polymorphisms (SNPs) in key BER pathway genes on clinical outcomes in male patients who received concurrent chemoradiotherapy (CCRT). Seven SNPs from XRCC1, OGG1, APEX1, and MUTYH were genotyped using the Sequenom iPLEX MassARRAY system in samples from 319 men with advanced oral squamous cell carcinoma. The disease-free survival (DFS) rates of the MUTYH rs3219489 genotypes and those of the other genotypes differed significantly (log-rank test p = 0.027). Multivariate Cox proportional hazard analysis showed that the MUTYH rs3219489 GG genotype was associated with poor DFS (recessive model: hazard ratio [HR] = 2.01, 95% confidence interval [CI] = 1.31-3.10; p = 0.002). The CT + TT genotypes of XRCC1 rs1799782 (dominant model: HR = 0.65, 95% CI = 0.43-0.99; p = 0.044) and GG genotype of APEX1 rs1760944 (recessive model: HR = 1.64, 95% CI = 1.00-2.70; p = 0.050) were associated with overall survival (OS). Carrying the two risk genotypes, CC and GG of XRCC1 rs1799782 and APEX1 rs1760944, respectively, (HR = 2.95, 95% CI = 1.47-5.88; p = 0.002) increased mortality risk. Our findings showed that carrying the two risk genotypes of XRCC1 rs1799782 and APEX1 rs1760944 was associated with poor OS, while the GG genotype of MUTYH rs3219489 was associated with poor DFS. Patients carrying the risk genotypes may not benefit from CCRT; therefore, they will need alternative treatments.

Efficacy and toxicity of adjuvant chemotherapy on colorectal cancer patients: how much influence from the genetics?

We studied the predictive value for response and toxicity of functional polymorphisms in genes involved in the oxaliplatin/fluorouracil pathway in colorectal cancer patients. One hundred and twenty-seven (127) patients were treated with curative intended surgery followed by adjuvant chemotherapy with FOLFOX (fluorouracil, leucovorin and oxaliplatin) regimen. The median age was 65.53 (27–80) years (66.9% male, 59.1% rectum). The median follow-up was 8.5 years (IQR, 4.1–9.4). At the end of follow-up, 59 patients (46.5%) had relapsed or died in the whole study population. We did find that XRCC1GG genotype is associated with a higher risk of developing haematologic toxicity. Furthermore, we report a significant association of the TS 3′UTR 6 bp/6 bp polymorphism and the XRCC1 rs25487 with a higher risk of developing anaemia and diarrhoea, respectively. On the other hand, none of the studied polymorphisms showed clinically relevant association with disease-free survival and overall survival or early failure to adjuvant FOLFOX therapy.

Genetic Variations of RAD51 and XRCC2 Genes Increase the Risk of Colorectal Cancer in Bangladeshi Population.

Objectives:In case of Bangladeshi population, no report is observed till now showing the genetic variations of RAD51 (rs1801320) and XRCC2 (rs3218536) genes polymorphism having association with colorectal cancer risk. For this reason the aim of this study is to ascertain their interrelation with colorectal cancer occurrence in Bangladeshi population. Materials and Methods:A case control study was conducted where 200 colorectal cancer patients and 200 healthy volunteers were figured for this research using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). Results:Here, in case of RAD51 (rs1801320), G/C heterozygous genotype was found significant (p=0.037; OR=1.64; 95% CI=1.03 to 2.6). On the other hand, G/G genotype was not found statistically significant (p=0.423; OR=1.61; 95% CI=0.49 to 5.22) and significance was observed for GC+GG (p=0.030; OR=1.63; 95% CI=1.05 to 2.55). In case of XRCC2 (rs3218536), C/T heterozygous genotype was remarked statistically significant (p=0.033; OR=1.60; 95% CI=1.04 to 2.46). The T/T genotype was not recorded statistically significant (p=0.237; OR=1.65; 95% CI=0.72 to 3.76) but significance found for CT+TT (p=0.027; OR=1.61; 95% CI=1.05 to 2.45). Moreover, it is found that the risk factor of developing CRC is observed in G/C, C/T heterozygote and GC+GG, CT+TT (heterozygote+ mutant) in RAD51 (rs1801320) and XRCC2 (rs3218536) respectively although no significance is observed in case of G/G and T/T mutant. Conclusions:So, the association of RAD51 (rs1801320) and XRCC2 (rs3218536) genes polymorphism with colorectal cancer risk is observed in Bangladeshi population.

MTHFR, XRCC1 and OGG1 genetic polymorphisms in breast cancer: a case-control study in a population from North Sardinia

BackgroundDespite conflicting results, considerable evidence suggests the association between single nucleotide polymorphisms in MTHFR, XRCC1 and OGG1 genes and, risk of developing breast cancer. Here a case-control study is reported, including 135 breat cancer patients and 112 healthy women, all representative of Northern Sardinian population.MethodsPolymerase chain reaction/restriction fragment length polymorphism method was used to determine the genotypes of five polymorphisms: MTHFR C677T (rs1801133) and A1298C (rs1801131), XRCC1 Arg194Trp (rs1799782) and Arg399Gln (rs25487) and OGG1 Ser326Cys (rs1052133). Allelic, genotypic and haplotype association analyses with disease risk and clinicopathological parameters were performed.ResultsA nominally significant association with breast cancer risk was observed for MTHFR C677T polymorphism heterozygous genotype in the codominant model (OR: 0.57, 95% CI: 0.32–1.00, p = 0.049) and for Cys/Cys genotype of the OGG1 Ser326Cys polymorphism in the recessive model (OR: 0.23, 95% CI: 0.05–1.11, p = 0.0465). No significant differences were found at genotype-level for A1298C polymorphism of the MTHFR gene and Arg194Trp and Arg399Gln of the XRCC1 gene. Furthermore, the OGG1 and XRCC1 rs25487 polymorphisms were nominally associated with PgR, Her2 status and with sporadic breast cancer, respectively.ConclusionsBased on genetic characteristics of individuals included in this study, results suggest that MTHFR CT and OGG1 Cys/Cys genotypes have a protective effect that may have an influence on breast cancer risk in a representative Northern Sardinian population.