Polymorphisms In DNA Repair Genes Research Articles

X-ray Repair Cross Complementing 1 (XRCC1) Gene Polymorphism in Hepatocellular Carcinoma (HCC)

Abstract Background Several risk factors for hepatocellular carcinoma (HCC) have been identified, including chronic infection of hepatitis B virus (HBV) and hepatitis C virus (HCV). Nevertheless, only a fraction of infected patients develops HCC during their lifetime suggesting that genetic factors might modulate HCC development. The human X-ray repair cross- complementing protein 1 (XRCC1) gene encodes for one of the major repair factors involved in base excision repair (BER), which is reported to be associated with the risk of several cancers. A few studies have explored the association between risk of hepatocellular carcinoma (HCC) and single-nucleotide polymorphisms (SNPs) in different DNA repair genes. Aim of the Work to investigate the possible association between XRCC1-G28152A (rs25487) single nucleotide polymorphism (SNP) and hepatocellular carcinoma (HCC) in chronic hepatitis C patients. Patients and Methods The study included 35 patients who had HCC and 15 patients who had liver cirrhosis. XRCC1 gene polymorphism was done to all participants by RT-PCR After collection of relevant clinical data and basic laboratory tests. Results A statistically higher frequency of XRCC1 (GG, GA) genotypes and increased (G) allele frequency in patients with HCC was found in comparison to cirrhotic HCV patients as well as control group but Our results revealed that the genotypic and allelic frequencies of XRCC1 gene polymorphism rs25487 didn’t show statistically significant difference between HCC patients group and liver cirrhosis control group. Conclusion The present study had demonstrated that there was no significant association between XRCC1 gene polymorphism (rs25487) and HCC in the sample of Egyptian population included in our study. Also, non-significant differences among the XRCC1 genotypes and alleles were found regarding age, sex, BMI and laboratory data including CBC, AFP, coagulation profile (PT, INR), liver function test ( total protein, albumin, AST, total bilirubin and direct bilirubin), BCLC and Milan criteria. While a statistically significant difference was observed as regards PTT and ALT between genotypes.

Ethnic Differences, Lung Cancer Risk, and Association of NRF2 Gene Polymorphism with Gemcitabine-Based Chemotherapy.

The cancer burden is rising every year. Lung cancer is one of themost common cancers and non-small cell lung cancer is the most common type. Chemotherapy based on platinum drugs and third-generation nucleoside anti-metabolites such as gemcitabine are used widely. Gemcitabine has a complex metabolic pathway, with many mechanisms contributing to its cytotoxicity. Derangements in the metabolic pathway genes contribute to drug resistance and toxicity with this drug. Association studies including these genetic polymorphisms in the metabolic pathway, clinical outcomes, and cancer risk reported inter-individual differences. Thus, the aim of this study was to ascertain the role of these genetic variants in South Indian cancer patients treated with gemcitabine-based therapy. The study was done with 184 healthy volunteers for frequency establishment and 123 cancer patients were treated with gemcitabine-based chemotherapy for response and toxicity assessment. The participants were aged 18-65 years and resided in the southern states of India. DNA extraction was done from the leukocyte fraction of the blood by phenol-chloroform extraction procedures and genotyping was done by reverse transcription-polymerase chain reaction (RT-PCR) techniques to identify DNA repair gene polymorphisms. Tumor response was determined using Response evaluation criteria in solid tumors (RECIST) guidelines and toxicity using Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. The patients were followed up for survival analysis. The minor allele frequency of the single nucleotide polymorphism (SNP) NRF2-617 C>A (rs6721961) in the healthy population was 12.8%. SNPs were in Hardy-Weinberg equilibrium (p>0.05). Gender-based differences were not observed with the studied SNP in the healthy population and the lung cancer patients. These frequencies of NRF2 were found to be similar when compared to EUR (European) and all the South Asian subpopulations. They are significantly divergent compared to AFR (African), AMR (American), and EAS (East Asian) populations. The minor allele frequency in cancer patients was found to be 14.2% and the lung cancer risk with the SNP studied could not be detected. There was no association found with the response, toxicity, and survival among lung cancer patients. NRF2, being a multifaced molecule, did not showa significant association with lung cancer risk, response, and toxicity in patients with gemcitabine-based chemotherapy.

Influence of genetic polymorphisms of Hg metabolism and DNA repair on the frequencies of micronuclei, nucleoplasmic bridges, and nuclear buds in communities living in gold mining areas

Fishing communities living near gold mining areas are at increased risk of mercury (Hg) exposure via bioaccumulation of methylmercury (MeHg) in fish. This exposure has been linked to health effects that may be triggered by genotoxic events. Genetic polymorphisms play a role in the risk associated with Hg exposure. This study evaluated the effect of single nucleotide polymorphisms (SNPs) in metabolic and DNA repair genes on genetic instability and total hair Hg (T-Hg) levels in 78 individuals from "La Mojana" in northern Colombia and 34 individuals from a reference area. Genetic instability was assessed by the frequency of micronuclei (MNBN), nuclear buds (NBUDS), and nucleoplasmic bridges (NPB). We used a Poisson regression to assess the influence of SNPs on T-Hg levels and genetic instability, and a Bayesian regression to examine the interaction between Hg detoxification and DNA repair. Among exposed individuals, carriers of XRCC1Arg399Gln had a significantly higher frequency of MNBN. Conversely, the XRCC1Arg194Trp and OGG1Ser326Cys polymorphisms were associated with lower frequencies of MNBN. XRCC1Arg399Gln, XRCC1Arg280His, and GSTM1Null carriers showed lower NPB frequencies. Our results also indicated that individuals with the GSTM1Nulland GSTT1null polymorphisms had a 1.6-fold risk for higher T-Hg levels. The Bayesian model showed increased MNBN frequencies in carriers of the GSTM1Null polymorphism in combination with XRCC1Arg399Gln and increased NBUDS frequencies in the GSTM1Null carriers with the XRCC3Thr241Met and OGG1Ser326Cys alleles. The GSTM1+ variant was found to be a protective factor in individuals carrying OGG1Ser326Cys (MNBN) and XRCC1Arg280His (NPB); the GSTT1+ polymorphism combined with XRCCArg194Trp also modulated lower MNBN frequencies, while GSTT1+ carriers with the XRCC1Arg399Gln allele showed lower NPB frequencies. Consistent with GSTM1, GSTT1Null carriers with XRCC3Thr241Met showed increased NBUDS frequency. With the rise of gold mining activities, these approaches are vital to identify and safeguard populations vulnerable to Hg's toxic effects.

The Role of DNA Repair (XPC, XPD, XPF, and XPG) Gene Polymorphisms in the Development of Myeloproliferative Neoplasms.

Background and Objectives: Several polymorphisms have been described in various DNA repair genes. Nucleotide excision DNA repair (NER) detects defects of DNA molecules and corrects them to restore genome integrity. We hypothesized that the XPC, XPD, XPF, and XPG gene polymorphisms influence the appearance of myeloproliferative neoplasms (MPNs). Materials and Methods: We investigated the XPC 1496C>T (rs2228000, XPC Ala499Val), XPC 2920A>C (rs228001, XPC Lys939Gln), XPD 2251A>C (rs13181, XPD Lys751Gln), XPF-673C>T (rs3136038), XPF 11985A>G (rs254942), and XPG 3507G>C (rs17655, XPG Asp1104His) polymorphisms by polymerase chain reaction-restriction fragment length polymorphism analysis in 393 MPN patients [153 with polycythemia vera (PV), 201 with essential thrombocythemia (ET), and 39 with primary myelofibrosis (PMF)] and 323 healthy controls. Results: Overall, we found that variant genotypes of XPD 2251A>C were associated with an increased risk of MPN (OR = 1.54, 95% CI = 1.15-2.08, p = 0.004), while XPF-673C>T and XPF 11985A>G were associated with a decreased risk of developing MPN (OR = 0.56, 95% CI = 0.42-0.76, p < 0.001; and OR = 0.26, 95% CI = 0.19-0.37, p < 0.001, respectively). Conclusions: In light of our findings, XPD 2251A>C polymorphism was associated with the risk of developing MPN and XPF-673C>T and XPF 11985A>G single nucleotide polymorphisms (SNPs) may have a protective role for MPN, while XPC 1496C>T, XPC 2920A>C, and XPG 3507G>C polymorphisms do not represent risk factors in MPN development.

XRCC1 and hOGG1 polymorphisms and endometrial carcinoma: A meta-analysis.

Endometrial carcinoma's (EC) etiology is complex and involves DNA repair gene polymorphisms like XRCC1-Arg399Gln and hOGG1-Ser326Cys, but their association with the disease is unclear. Following PRISMA, we conducted a systematic review and meta-analysis, collecting data from four databases. The studies needed to be population-based case-control studies examining the association between the named polymorphisms and EC. Quality was assessed with the Newcastle-Ottawa Scale. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated, and subgroup analyses were conducted based on ethnicity. Seven studies were included. Both polymorphisms were found to significantly increase EC risk, particularly in Caucasians. XRCC1-Arg399Gln showed a dominant model OR of 1.14 (95% CI: 1.01-1.29) and a homozygous model OR of 1.59 (95% CI: 1.12-2.25). The heterozygote model OR for hOGG1-Ser326Cys was 1.29 (95% CI: 1.02-1.63), and the allele OR was 1.31 (95% CI: 1.07-1.60). XRCC1-Arg399Gln and hOGG1-Ser326Cys may increase EC risk, primarily in Caucasian women, emphasizing the role of DNA repair in disease susceptibility. More extensive studies are needed to validate these findings in diverse ethnicities and investigate other DNA repair gene polymorphisms.

Abstract B086: Association of breast cancer-relevant DNA repair genes with postmenopausal breast cancer risk in UK Biobank

Abstract Purpose. Several polymorphisms have been described in DNA damage signaling and repair genes and some of the polymorphisms have been implicated in genetic susceptibility to breast cancer. However, there is no consensus result yet for most of these polymorphisms. In this study, we focused on evaluating selected SNPs in BRCA1, BRCA2, ATM, XRCC1, XRCC2, XRCC3, and XPD (ERCC2) genes that have been previously reported to be associated with breast cancer risk and are available in the UK Biobank. Methods. This study included 150,929 postmenopausal women (5,969 with BCa) from UK Biobank, a population-based prospective cohort. Cancer diagnoses were ascertained through the linkage to the UK National Health Service Central Registers. DNA was extracted from blood samples collected from participants at enrollment in UK Biobank. Samples were genotyped using the Applied Biosystems UK BiLEVE Axiom Array or the Applied Biosystems UK Biobank Axiom Array. The positions of markers in the data are in GRCh37 coordinates. SNPs with frequency &amp;lt; 1% in the study population were excluded from analyses. We included the following SNPs in the final analyses: XRCC3-rs861539, BRCA1-rs16942, BRCA1-rs4986852, XRCC1-rs25487, XRCC1-rs25489, XRCC1-rs1799782, XPD (ERCC2)-rs13181, XPD (ERCC2)-rs1799793, XRCC2-rs3218536, ATM-rs1800056, ATM-rs1800057, BRCA2-rs144848, BRCA2-rs4987117, and BRCA2-rs11571833. Information on breast cancer risk factors was collected at baseline. Cox proportional hazards regression models were used to analyze the association between each SNP and breast cancer risk while adjusting for known breast cancer risk factors. The risk estimates were presented as hazard rations (HRs) and their corresponding 95% confidence intervals (CIs). Results. The mean age of the study population at enrollment was 60.1 years (range 40-71 years). Heterozygous carriers of BRCA2-rs11571833 T allele were found to have an increased risk of breast cancer (HR=1.22, 95% CI 1.02, 1.46, p-trend = 0.033) compared to the homozygous carriers of the BRCA2-rs11571833 A allele. No other significant associations between other SNPs and breast cancer risk were found. Conclusions. We found a significant association between SNP BRCA2-rs11571833 and postmenopausal breast cancer risk. Our findings contribute to the existing evidence on the association of high-risk polymorphisms in DNA damage signaling and repair genes with postmenopausal breast cancer risk. Citation Format: Carmen Smotherman, Brian Sprague, Dejana Braithwaite, Huaizhen Qin, Lusine Yaghjyan. Association of breast cancer-relevant DNA repair genes with postmenopausal breast cancer risk in UK Biobank [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B086.

Abstract A030: DNA repair gene polymorphism(s): Association with relapse of oral squamous cell carcinoma

Abstract Differences in DNA repair capacity have been linked to the risk and prognosis of cancer. In specific types of cancer, certain variations known as Single Nucleotide Polymorphisms (SNPs) within DNA repair genes can influence the effectiveness of treatments. This phenomenon has been observed in patients with Oral Squamous Cell Carcinoma (OSCC), especially in those undergoing chemotherapy and radiation therapy. One such gene, Excision Repair Cross-Complementation 5 (ERCC5), contains a SNP (rs17655) G&amp;gt;C, leading to a missense variation and a change in amino acid from D to H. This variation has been noted in various cancer types. Hence, this study aimed to investigate the presence of this DNA repair gene polymorphism (rs17655) and its association with OSCC. To achieve this goal, blood samples were collected from OSCC patients exposed to chemotherapy and radiation therapy, as well as from OSCC patients not exposed to these treatments, following approval from the relevant institutional review committees. Informed consent was obtained from 100 patients, and an equal number of age and gender-matched controls. Genomic DNA was extracted using the salting-out method and analyzed for quality and quantity through agarose gel electrophoresis and nanodrop spectrophotometry. Primers were designed using online primer designing software. Genetic variations were identified using Tetra Primers-Amplifies Refractory Mutation System Polymerase Chain Reaction (t-ARMS PCR), and the amplified products were visualized via agarose gel electrophoresis. The genotypic frequency analysis of rs17655 revealed a higher prevalence of the homozygous mutant type (CC) in the blood samples of OSCC patients, both exposed and non-exposed to chemotherapy and radiation therapy. In contrast, the homozygous wild type (GG) was more prevalent among the control group. Statistical analysis, including a chi-square test (χ 2 = 36.76, p &amp;lt; 0.001) and odds ratio (10.27), demonstrated a significant association between the rs17655 polymorphism and oral squamous cell carcinoma, indicating an increased risk of OSCC due to this genetic variation. These genomic variants have the potential to serve as biomarkers for predicting clinical outcomes in OSCC patients undergoing chemotherapy and radiotherapy. Citation Format: Umaiya Abdali, Saima Saleem. DNA repair gene polymorphism(s): Association with relapse of oral squamous cell carcinoma [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 A030.

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 of Genetic Polymorphisms in Base excision Repair Pathways and Cervical Cancer Risk Factors in a Tertiary Care Centre

Background and Objective: Cervical cancer is one of the most frequent neoplastic disorders affecting women, with about half a million new cases diagnosed globally each year. Reduced DNA repair capacity (DRC) is linked to an increased risk of cancer, particularly cervical cancer. DNA repair gene polymorphisms may play a role in genomic instability and carcinogenesis. Cervical cancer is linked to a number of risk factors that have been verified. The goal of this study was to compare genotypes of DNA repair genes XRCC1-194, XRCC1-280, XRCC1-399, and XRCC3-241 with distinct histological subtypes in patients and controls.Material and Methods: To test this theory, 168 cervical cancer patients with histological confirmed cases and 184 healthy control women was inducted in the study. For genotyping we used CTPP method (Arg194Trp, Arg280His, and Arg399Gln &amp; XRCC3-T241M). Results: A positive association was observed between the polymorphisms of XRCC1 genes, that is, in codons 194 [P=0.03, odds ratio (OR) =2.39, 95% confidence interval (CI)=5.2–1.1], 280 (P=0.01, OR=4.1, 95% CI=11.5–1.3), and 399 (P=0.01, OR=3.4, 95% CI=8.6–1.3) in cervical cancer As well as risk factor like early age of pregnancy, high number of parity are also likely to be contributing in disease development.Conclusion: Our results suggested that, XRCC1399 gene is an important candidate gene for susceptibility to cervical cancer. Although the sample size was small, the present study indicate a statistical association between cervical cancer and XRCC1 SNPs. Future studies are needed that may provide a better understanding of the association between gene polymorphism and cervical carcinoma risk factors are assessed.

A review and metanalysis of metronomic oral single-agent cyclophosphamide for treating advanced ovarian carcinoma in the era of precision medicine.

Oral metronomic cyclophosphamide has been used as a single agent or in combination with other drugs for several solid tumors with interesting results in disease palliation and mild to moderate toxicity, notably in patients with recurrent epithelial ovarian cancer (EOC) progressing after systemic chemotherapy. In this paper, we report a review and a metanalysis of heterogeneous data published up to date. The literature search was restricted to single-agent MOC. The analysis was conducted through March 2023 by consulting PubMed, Embase, Google Scholar, and The Cochrane Library databases. Research string and Medical Subject Headings included "ovarian tumor," "ovarian carcinoma," or "ovarian cancer," "fallopian tube cancer," "primary peritoneal cancer," "oral chemotherapy," and "metronomic cyclophosphamide." All articles were assessed for quality by at least two investigators independently, and a < 18 patients sample size cutoff was chosen as a lower limit with a Cohen's kappa statistical coefficient for accuracy and reliability. Metanalysis of selected papers was carried out according to a fixed model. The percentage of agreement between investigators on literature study selection was very high, reaching 96.9% with a Cohen's k of 0.929. MOC pooled objective response rate (ORR) and disease control rate for recurrent or platinum-refractory ovarian cancer were 18.8% (range 4-44%) and 36.2% (range 16-58.8%), respectively. The mean progressive-free survival and overall survival were 3.16 months (range 1.9 to 5.0 months) and 8.7 months (range 8 to 13 months), respectively. The fixed model metanalysis of selected studies showed a 16% median ORR (12-20% CI, p < 0.001). Single-agent oral cyclophosphamide in EOC holds promise as a treatment option, even in the era of precision medicine. Genetic factors, such as DNA repair gene polymorphisms, may influence treatment response. Combining cyclophosphamide with biological agents such as PARP inhibitors or immunotherapy agents is an area of active investigation.

Role of rs873601 Polymorphisms in Prognosis of Lung Cancer Patients Treated with Platinum-Based Chemotherapy.

Lung cancer is still the most lethal malignancy in the world, according to the report of Cancer Statistics in 2021. Platinum-based chemotherapy combined with immunotherapy is the first-line treatment in lung cancer patients. However, the 5-year survival rate is always affected by the adverse reactions and drug resistance caused by platinum-based chemotherapy. DNA damage and repair system is one of the important mechanisms that can affect the response to chemotherapy and clinical outcomes in lung cancer patients. The objective of this study is to find the relationship between the polymorphisms of DNA repair genes with the prognosis of platinum-based chemotherapy in lung cancer patients. We performed genotyping in 17 single nucleotide polymorphisms (SNPs) of Excision Repair Cross-Complementation group (ERCC) genes and X-ray Repair Cross-Complementing (XRCC) genes of 345 lung cancer patients via Sequenom MassARRAY. We used Cox proportional hazard models, state, and plink to analyze the associations between SNPs and the prognosis of lung cancer patients. We found that the ERCC5 rs873601 was associated with the overall survival time in lung cancer patients treated with platinum-based chemotherapy (p = 0.031). There were some polymorphisms that were related to the prognosis in specific subgroups of lung cancer. Rs873601 showed a great influence on the prognosis of patients more than 55 years, Small Cell Lung Cancer (SCLC), and smoking patients. Rs2444933 was associated with prognosis in age less than 55 years, SCLC, metastasis, and stage III/IV/ED patients. Rs3740051 played an important role in the prognosis of SCLC and metastasis patients. Rs1869641 was involved in the prognosis of SCLC patients. Rs1051685 was related to the prognosis in non-metastasis patients. The ERCC5 rs873601 (G>A) was a valuable biomarker for predicting the prognosis in lung cancer patients treated with platinum-based chemotherapy.

Variability of DNA Repair and Oxidative Stress Genes Associated with Worst Pain in Breast Cancer Survivors on Aromatase Inhibitors.

Pain is a problem affecting women with breast cancer (HR+BrCa) receiving aromatase inhibitor (AI) therapy. We investigated the relationship between single-nucleotide polymorphisms (SNPs) in DNA repair and oxidative stress genes and perceived worst pain after 6 months of AI therapy. We explored 39 SNPs in genes involved in DNA repair (ERCC2, ERCC3, ERCC5, and PARP1) and oxidative stress (CAT, GPX1, SEPP1, SOD1, and SOD2) in women with HR+BrCa receiving adjuvant therapy (AI ± chemotherapy; n = 138). Pain was assessed via the Brief Pain Inventory. Hurdle regression was used to evaluate the relationship between each associated allele and (1) the probability of pain and (2) the severity of worst pain. ERCC2rs50872 and ERCC5rs11069498 were associated with the probability of pain and had a significant genetic risk score (GRS) model (p = 0.003). ERCC2rs50872, ERCC5rs11069498, ERCC5rs4771436, ERCC5rs4150360, PARP1rs3219058, and SEPP1rs230819 were associated with the severity of worst pain, with a significant GRS model (conditional mean estimate = 0.45; 95% CI = 0.29, 0.60; p < 0.001). These results suggest DNA repair and oxidative stress pathways may play a role in the probability of pain and the severity of worst pain. As healthcare delivery moves towards the model of precision healthcare, nurses may, in the future, be able to use these results to tailor patient care based on GRS.

DNA Double-Strand Break Response and Repair Gene Polymorphisms May Influence Therapy Results and Prognosis in Head and Neck Cancer Patients.

Radiotherapy and cisplatin-based chemotherapy belong to the main treatment modalities for head and neck squamous cell carcinoma (HNSCC) and induce cancer cell death by generating DNA damage, including the most severe double-strand breaks (DSBs). Alterations in DSB response and repair genes may affect individual DNA repair capacity and treatment sensitivity, contributing to the therapy resistance and poor prognosis often observed in HNSCC. In this study, we investigated the association of a panel of single-nucleotide polymorphisms (SNPs) in 20 DSB signaling and repair genes with therapy results and prognosis in 505 HNSCC patients treated non-surgically with DNA damage-inducing therapies. In the multivariate analysis, there were a total of 14 variants associated with overall, locoregional recurrence-free or metastasis-free survival. Moreover, we identified 10 of these SNPs as independent predictors of therapy failure and unfavorable prognosis in the whole group or in two treatment subgroups. These were MRE11 rs2155209, XRCC5 rs828907, RAD51 rs1801321, rs12593359, LIG4 rs1805388, CHEK1 rs558351, TP53 rs1042522, ATM rs1801516, XRCC6 rs2267437 and NBN rs2735383. Only CHEK1 rs558351 remained statistically significant after correcting for multiple testing. These results suggest that specific germline variants related to DSB response and repair may be potential genetic modifiers of therapy effects and disease progression in HNSCC treated with radiotherapy and cisplatin-based chemoradiation.

DNA repair genes, air pollution, and breast cancer risk

PurposeWe investigated if selected polymorphisms in DNA repair genes modify the association between air pollution and breast cancer (BCa) risk. MethodsWe included 150,929 postmenopausal women (5969 with BCa) from UK Biobank, a population-based prospective cohort. Information on BCa risk factors was collected at baseline. Cox proportional hazards regression was used to examine interactions of exposure for which we previously found associations with BCa in this cohort (2007 PM10 and cumulative average PM10) with 15 SNPs, adjusting for BCa risk factors. The associations between PM10 and BCa risk were stratified by genotype level. ResultsThe positive associations of 2007 PM10 and cumulative average PM10 with BCa risk were stronger in women with one or two copies of XRCC2 rs3218536C allele versus none (2007 PM10 Hazard Ratio (HR) per 1 µg/m3 = 1.04, 95% Confidence Interval (CI) 1.02–1.07, HR = 1.01, 95% CI 1.00–1.02, respectively, versus HR = 0.94, 95% CI 0.83–1.06, p-interaction = 0.02; cumulative average PM10 HR per 1 µg/m3 = 1.11, 95% CI 1.07–1.15, HR = 1.07, 95% CI 1.05–1.08 versus HR = 0.92, 95% CI 0.78–1.09, p-interaction = 0.05). The association of cumulative average PM10 with BCa was stronger in women with two copies of XRCC1 rs25489 T allele versus one or none (HR = 3.04, 95% CI 1.54–5.96 vs. HR = 1.06, 95% CI 1.02–1.11 and HR = 1.07, 95% CI 1.06–1.09; p-interaction = 0.06). ConclusionsOur results suggest stronger associations of 2007 PM10 and cumulative average PM10 with postmenopausal BCa risk in carriers of XRCC2 rs3218536C allele and stronger associations of cumulative average PM10 in those with two copies of XRCC1 rs25489 T allele.

Single Nucleotide Polymorphisms in DNA Repair Genes (XRCC1, XRCC2, XRCC3) and Their Association with Radiotherapy Toxicity among Head and Neck Cancer Patients:A Study from South-Western Maharashtra.

The genetic polymorphisms in DNA repair genes and their correlation with normal tissue toxicity in response to radiation therapy has not been consistently proven in many of the studies done in head and neck cancers (HNC). This study was intended to investigate the association of most common single nucleotide polymorphisms of DNA repair genes with acute radiation induced toxicities such as skin reactions and oral mucositis in normal tissue from HNC patients receiving radiotherapy from South-Western Maharashtra. Two hundred HNC patients receiving radiotherapy were enrolled in this study and the radiation injuries in the form of skin reactions and oral mucositis were recorded. Three single nucleotide polymorphisms (SNPs) rs1799782, rs25489) rs25487 of XRCC1 gene, rs3218536in XRCC2 gene and rs861539 SNP of XRCC3 gene were studied by PCR-RFLP and direct DNA sequencing. Results: The univariate analysis of SNPs of XRCC1, XRCC2 and XRCC3, the obtained results verified that XRCC1 polymorphism at 194Trp of exon 6 (OR=0.69, 95% CI: 0.28-1.71; p=0.433), codon 280 at exon 9 ((OR=1.05, 95% CI: 0.42-2.63; p=0.911) and codon 399 of at exon 10(OR=1.06, 95% CI: 0.52-2.15; p=0.867) and XRCC2 polymorphism at codon 188 at exon 3 (OR=1.07, 95% CI: 0.46-2.47; p=0.866) and 241Met variant genotype of XRCC3 (OR=2.63 95% CI: 0.42-16.30; p=0.298) showed no association with degree of radiotherapy associated dermatitis or mucositis in HNC patients. The findings from this study postulated that none of rs1799782, rs25489, rs25487 SNPs of XRCC1, rs3218536 SNP of XRCC2 nor rs861539 SNP of XRCC3 were associated with increased toxicity of radiotherapy in HNC patients of south-western Maharashtra.<br />.

Polymorphism of DNA repair genes (APEX1 T444G RS1130409) in obese gout patients in the male population of the trans-baikal territory in Russia

Polymorphism of DNA repair genes (APEX1 T444G RS1130409) in obese gout patients in the male population of the trans-baikal territory in Russia

Evaluation of Systemic Genotoxic/Oxidative and Proinflammatory Effects in Workers of a Titanium Dioxide Production Plant.

This study is aimed at evaluating whether the occupational exposure to TiO2 during the industrial production process is able to induce genotoxic, oxidative, and inflammatory effects on blood, biomonitoring the same workers that showed micronucleus induction in the exfoliated buccal cells, as previous published. The final aim was to find sensitive and suitable biomarkers to evaluate potential early toxicity of occupational exposure to TiO2. On the same 40 workers involved in the manufacture of TiO2 pigment, 5 office workers, and 18 controls previously studied, we used formamidopyrimidine glycosylase- (Fpg-) comet assay on lymphocytes to evaluate genotoxic/oxidative effects and detected cytokine (IL-6, IL-8, and TNFα) release by ELISA to evaluate proinflammation. Moreover, we studied the possible influence of single nucleotide polymorphisms of XRCC1 and hOGG1 DNA repair genes and of GST metabolism-related genes (GSTT1 and GSTM1) on the evaluated effects. We did not find statistically significant differences in the mean values of the analysed Fpg-comet assay parameters; only the percentage of DNA damaged cells appearing in the test as comets (% comets) resulted higher in the exposed workers compared to controls. Also, the data analysed taking into account the specific task (bagging, industrial cleaning, mobile operations, maintaining, and production) showed differences only for % comets which resulted higher in industrial cleaners compared to controls. We found variations of IL-6 and IL-8 levels in the exposed workers with concentrations that were lower for IL-6 and higher for IL-8 compared to the control group. XRCC1, hOGG1, and GSTT1 polymorphisms did not influence neither comet parameters nor cytokine release. These findings demonstrate that TiO2 production process is able to induce slight proinflammatory effects in terms of IL-8 increased release but not significant genotoxic/oxidative effects on lymphocytes, which do not seem to be a target of TiO2, prevalently inhalable particles, generated in the studied production site.

A Significant Increasing Risk Association between Cigarette Smoking and XPA and XPC Genes Polymorphisms.

Cigarette smoking (CS) is a major cause of various serious diseases due to tobacco chemicals. There is evidence suggesting that CS has been linked with the DNA damage repair system, as it can affect genomic stability, inducing genetic changes in the genes involved in the repair system, specifically the nucleotide excision repair (NER) pathway, affecting the function and/or regulation of these genes. Single nucleotide polymorphism (SNP), along with CS, can affect the work of the NER pathway and, therefore, could lead to different diseases. This study explored the association of four SNPs in both XPA and XPC genes with CS in the Saudi population. The Taq Man genotyping assay was used for 220 healthy non-smokers (control) and 201 healthy smokers to evaluate four SNPs in the XPA gene named rs10817938, rs1800975, rs3176751, and rs3176752 and four SNPs in the XPC gene called rs1870134, rs2228000, rs2228001, and rs2607775. In the XPA gene, SNP rs3176751 showed a high-risk association with CS-induced diseases with all clinical parameters, including CS duration, CS intensity, gender, and age of smokers. On the other hand, SNP rs1800975 showed a statistically significant low-risk association with all clinical parameters. In addition, rs10817938 showed a high-risk association only with long-term smokers and a low-risk association only with younger smokers. A low-risk association was found in SNP rs3176752 with older smokers. In the XPC gene, SNP rs2228001 showed a low-risk association only with female smokers. SNP rs2607775 revealed a statistically significant low-risk association with CS-induced diseases, concerning all parameters, except for male smokers. However, SNP rs2228000 and rs1870134 showed no association with CS. Overall, the study results demonstrated possible significant associations (effector/and protector) between CS and SNPs polymorphisms in DNA repair genes, such as XPA and XPC, except for rs2228000 and rs1870134 polymorphisms.

Meta-Analysis of 49 SNPs Covering 25,446 Cases and 41,106 Controls Identifies Polymorphisms in Hormone Regulation and DNA Repair Genes Associated with Increased Endometrial Cancer Risk.

Endometrial cancer (EC) is among the most common gynecological disorders globally. As single nucleotide polymorphisms (SNPs) play an important role in the causation of EC, therefore, a comprehensive meta-analysis of 49 SNPs covering 25,446 cases and 41,106 controls was performed to identify SNPs significantly associated with increased EC risk. PubMed was searched to identify case control studies and meta-analysis was performed to compute the pooled odds ratio (OR) at 95% confidence interval (CI). Cochran's Q-test and I2 were used to study heterogeneity, based on which either a random or a fixed effect model was implemented. The meta-analysis identified 11 SNPs (from 10 genes) to be significantly associated with increased EC risk. Among these, seven SNPs were significant in at least three of the five genetic models, as well as three of the polymorphisms (rs1801320, rs11224561, and rs2279744) corresponding to RAD51, PGR, and MDM2 genes, which contained more than 1000 EC cases each and exhibited increased risk. The current meta-analysis indicates that polymorphisms associated with various hormone related genes-SULT1A1 (rs1042028), PGR (rs11224561), and CYP19A1 (rs10046 and rs4775936); DNA repair genes-ERCC2 (rs1799793), OGG1 (rs1052133), MLH1 (rs1800734), and RAD51 (rs1801320) as well as genes like MDM2 (rs2279744), CCND1 (rs9344), and SERPINE1 (rs1799889), are significantly associated with increased EC risk.

Polymorphisms in DNA Repair Genes and Association with Rheumatoid Arthritis in a Pilot Study on a Central European Population.

Rheumatoid arthritis (RA) is a chronic, multifactorial autoimmune disease characterized by chronic arthritis, a tendency to develop joint deformities, and involvement of extra-articular tissues. The risk of malignant neoplasms among patients with RA is the subject of ongoing research due to the autoimmune pathogenesis that underlies RA, the common etiology of rheumatic disease and malignancies, and the use of immunomodulatory therapy, which can alter immune system function and thus increase the risk of malignant neoplasms. This risk can also be increased by impaired DNA repair efficiency in individuals with RA, as reported in our recent study. Impaired DNA repair may reflect the variability in the genes that encode DNA repair proteins. The aim of our study was to evaluate the genetic variation in RA within the genes of the DNA damage repair system through base excision repair (BER), nucleotide excision repair (NER), and the double strand break repair system by homologous recombination (HR) and non-homologous end joining (NHEJ). We genotyped a total of 28 polymorphisms in 19 genes encoding DNA repair-related proteins in 100 age- and sex-matched RA patients and healthy subjects from Central Europe (Poland). Polymorphism genotypes were determined using the Taq-man SNP Genotyping Assay. We found an association between the RA occurrence and rs25487/XRCC1, rs7180135/RAD51, rs1801321/RAD51, rs963917/RAD51B, rs963918/RAD51B, rs2735383/NBS1, rs132774/XRCC6, rs207906/XRCC5, and rs861539/XRCC3 polymorphisms. Our results suggest that polymorphisms of DNA damage repair genes may play a role in RA pathogenesis and may be considered as potential markers of RA.