Serum levels of vitamin A, selenium, and better dietary total antioxidant capacity are related to lower oxidative DNA damage: A cross-sectional study of individuals at cardiovascular risk.

The risk for cardiovascular diseases (CVR) has been associated with oxidative DNA damage, but the genetic and environmental factors involved in the antioxidant and DNA repair system contributing to this damage are unknown. The aim was to evaluate the levels of oxidative DNA damage in CVR subjects and how it is related with some genetic and nutritional factors. The cross-sectional study evaluated 136 individuals of both sexes, aged 20-59 years, with at least one cardiovascular risk factor. The global risk score was used to classify individuals at low, intermediate, and high cardiovascular risk. The dietary total antioxidant capacity (DTAC) was calculated using table with FRAP values. The oxidative DNA damage was verified by the comet assay. The variants null of Glutathione-S-transferases Mu1 and Theta 1(GSTM1 and GSTT1) and rs25487 of X-Ray Repair Cross Complementing Protein 1 (XRCC1) were analyzed by real-time PCR and PCR-RFLP, respectively. The oxidative DNA damage was higher in patients with intermediate/high CVR than in patients with low CVR (P=.01). Individuals with GSTT1/GSTM1 null genotypes or arg/gln+gln/gln genotypes of the XRCC1 (rs25487) gene showed similar levels of oxidative DNA damage compared wild genotype. Multivariate regression analysis demonstrated that oxidative DNA damage in individuals with CVR depends on serum levels of vitamin A, selenium, and DTAC independently of the other factors [F(6.110)=8.213; P<.001; R2=0.330]. These findings suggest that nutritional factors such as DTAC, vitamin A and selenium may have a protective effect against oxidative DNA damage in these individuals.

SAM and folic acid prevent arsenic-induced oxidative and nitrative DNA damage in human lymphoblast cells by modulating expression of inflammatory and DNA repair genes.

Growing evidence suggests that arsenic exposure increases the risk of developing a variety of inflammation-associated chronic diseases and cancers. Our previous study revealed that increased transcript levels of inflammatory genes (i.e. COX2, EGR1, and SOCS3) coupled with hypomethylation of the promoter regions of these genes was associated with increased DNA damage in arsenic-exposed newborns through their early childhood. This study further investigated the ability of the methyl group donors, S-adenosyl methionine (SAM) and folic acid, to prevent promoter hypomethylation that results in decreased mRNA expression of inflammatory genes (COX2, EGR1, and SOCS3), and a reduction in arsenic-induced oxidative and nitrative DNA damage in human lymphoblast cells. Pretreatment with SAM (100 nM, 2 days) increased promoter methylation, reduced the mRNA levels of these inflammatory genes, and decreased both 8-hydroxydeoxyguanosine (8-OHdG) and 8-nitroguanine levels by 50% (p < 0.01) in arsenic-treated cells. In addition, pretreatment with folic acid (10 µM, 7 days), a micronutrient, led to a significant increase in promoter methylation associated with the reduction in mRNA levels of these inflammatory genes and decreased levels of 8-OHdG and 8-nitroguanine by 80% and 90% (p < 0.01), respectively, compared with arsenic treatment alone. Moreover, pretreatments with these methyl group donors increased mRNA expression of an antioxidant defense regulator (Nrf2) and DNA repair genes (hOGG1, XRCC1, and PARP1). This study shows for the first time that SAM or folic acid supplementation can prevent arsenic-induced oxidative and nitrative DNA damage. This suggests the potential use of SAM or folic acid for prevention of arsenic toxicity in human populations.

Ailanthus Altissima-derived Ailanthone enhances Gastric Cancer Cell Apoptosis by Inducing the Repression of Base Excision Repair by Downregulating p23 Expression.

Chemotherapy plays an irreplaceable role in the treatment of GC, but currently available chemotherapeutic drugs are not ideal. The application of medicinal plants is an important direction for new drug discovery. Through drug screening of GC organoids, we determined that ailanthone has an anticancer effect on GC cells in vitro and in vivo. We also found that AIL can induce DNA damage and apoptosis in GC cells. Further transcriptome sequencing of PDX tissue indicated that AIL inhibited the expression of XRCC1, which plays an important role in DNA damage repair, and the results were also confirmed by western blotting. In addition, we found that AIL inhibited the expression of P23 and that inhibition of P23 decreased the expression of XRCC1, indicating that AIL can regulate XRCC1 via P23. The results of coimmunoprecipitation showed that AIL can inhibit the binding of P23 and XRCC1 to HSP90. These findings indicate that AIL can induce DNA damage and apoptosis in GC cells. Meanwhile, AIL can decrease XRCC1 activity by downregulating P23 expression to inhibit DNA damage repair. The present study sheds light on the potential application of new drugs isolated from natural medicinal plants for GC therapy.

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.

The role of H3K9me2-regulated base excision repair genes in the repair of DNA damage induced by arsenic in HaCaT cells and the effects of Ginkgo biloba extract intervention.

Arsenic is an established human carcinogen that can induce DNA damage; however, the precise mechanism remains unknown. Histone modification is of great significance in chemical toxicity and carcinogenesis. To investigate the role of histone H3K9me2 in arsenic-induced DNA damage, HaCaT cells were exposed to sodium arsenite in this study, and the results showed that the enrichment level of H3K9me2 at the N-methylated purine-DNA-glycosylase (MPG), X-ray repair cross-complementary gene 1 (XRCC1), and polyadenylate diphosphate ribose polymerase-1 (PARP1) promoter regions of base-excision repair (BER) genes was increased, which inhibited the expression of these BER genes, thereby inhibiting the repair of DNA damage and aggravating the DNA damage. Furthermore, the molecular mechanism by which H3K9me2 participates in the BER repair of arsenic-induced DNA damage was verified based on functional loss and gain experiments. In addition, Ginkgo biloba extract can upregulate the expression of MPG, XRCC1, and PARP1 and ameliorate cell DNA damage by reducing the enrichment of H3K9me2 at repair gene promoter regions.

Amelioration of PM2.5-induced lung toxicity in rats by nutritional supplementation with biochanin A.

Epidemiological studies have shown that particulate matter with an aerodynamic diameter less than 2.5 µm (PM2.5) is closely associated with human health issues, especially pulmonary diseases such as chronic obstructive pulmonary disease (COPD), asthma and lung cancer. In this study, particles were characterized by scanning electron microscopy (SEM), microbeam energy-dispersive X-ray spectroscopy (EDS), inductively coupled plasma mass spectrometry (ICP-MS) and high-performance liquid chromatography (HPLC). A rat model of PM2.5 exposure was established by nonsurgical intratracheal instillation, and the effects of biochanin A (BCA) treatment were examined. BCA showed a protective effect; it reduced PM2.5-induced apoptosis and the production of proinflammatory factors, such as tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), interleukin-6 (IL-6), and the chemokine interleukin-8 (IL-8), as measured using ELISA. These effects were accompanied by increases in the levels of antioxidant enzymes and decreases in the levels of malondialdehyde (MDA), lactate dehydrogenase (LDH) and alkaline phosphatase (AKP). Furthermore, isobaric tag for relative and absolute quantitation (iTRAQ)-based analytical techniques and bioinformatics tools were used to identify putative biomarkers, including XRCC1, MP2K5, IGJ, and F1LQ12, and the results were verified by Western blot analysis. In conclusion, our findings have scientific significance for the application of flavonoids in preventive and therapeutic strategies for PM2.5-associated pulmonary diseases and for the promotion of human health.

Predictive Value of ERCC1, ERCC2, and XRCC Expression for Patients with Locally Advanced or Metastatic Gastric Cancer Treated with Neoadjuvant mFOLFOX-4 Chemotherapy.

The dismal outcome in patients with locally advanced or metastatic gastric cancer (GC) highlights the need for effective systemic neoadjuvant chemotherapy to improve clinical results. This study evaluated the correlation between the expression of three DNA repair genes, namely the excision repair cross-complementing group 1 (ERCC1), excision repair cross-complementing group 2 (ERCC2), and X-ray repair cross-complementing protein 1 (XRCC1) and the clinical outcome of patients with locally advanced or metastatic GC treated with mFOLFOX-4 neoadjuvant chemotherapy. Fifty-eight patients with histologically confirmed locally advanced or metastatic GC following neoadjuvant mFOLFOX-4 chemotherapy were enrolled between January 2009 and January 2018. We analyzed clinicopathological features and ERCC1, ERCC2, and XRCC1 expression to identify potential predictors of clinical response. Among the 58 patients, 16 (27.6%) were categorized into the response group (partial response) and 42 into the nonresponse group (stable disease in 24 patients and progressive disease in 18 patients). A multivariate analysis showed that ERCC1 overexpression (P = 0.003), ERCC2 overexpression (P = 0.049), and either ERCC1 or ERCC2 overexpression (P = 0.002) were independent predictors of response following mFOLFOX-4 neoadjuvant chemotherapy. Additionally, ERCC1 and ERCC2 overexpression did not only predict the response but also progression-free survival (both P < 0.05) and overall survival (both P < 0.05). ERCC1 and ERCC2 overexpression are promising predictive biomarkers for patients with locally advanced or metastatic GC receiving neoadjuvant mFOLFOX-4 chemotherapy and the potential clinical implication is mandatory for further investigation.

Berberine attenuates XRCC1-mediated base excision repair and sensitizes breast cancer cells to the chemotherapeutic drugs.

Berberine (BBR) is a natural isoquinoline alkaloid, which is used in traditional medicine for its anti-microbial, anti-protozoal, anti-diarrhoeal activities. Berberine interacts with DNA and displays anti-cancer activities, yet its effects on cellular DNA repair and on synthetic treatments with chemotherapeutic drugs remain unclear. In this study, we investigated the effects of BBR on DNA repair and on sensitization of breast cancer cells to different types of DNA damage anti-tumoural drugs. We found BBR arrested cells in the cell cycle S phase and induced DNA breaks. Cell growth analysis showed BBR sensitized MDA-MB-231 cells to cisplatin, camptothecin and methyl methanesulfonate; however, BBR had no synergistic effects with hydroxurea and olaparib. These results suggest BBR only affects specific DNA repair pathways. Western blot showed BBR down-regulated XRCC1 expressions, and the rescued XRCC1 recovered the resistance of cancer cells to BBR. Therefore, we conclude that BBR interferes with XRCC1-mediated base excision repair to sensitize cancer cells to chemotherapeutic drugs. These finding can contribute to understanding the effects of BBR on cellular DNA repair and the clinical employment of BBR in treatment of breast cancer.

Hemoglobin level and XRCC1 polymorphisms to select patients with locally advanced rectal cancer candidate for neoadjuvant chemoradiotherapy with concurrent capecitabine and a platinum salt.

A platinum salt (oxaliplatin or cisplatin) is widely used to enhance chemoradation (CRT) response. The potential of cisplatin in neoadjuvant CRT for locally advanced rectal cancer (LARC) has not been fully investigated. Consecutive patients with histologically confirmed LARC were treated with standard pelvic radiotherapy and concurrent cisplatin plus capecitabine (CisCape CRT). Surgery and eight cycles of adjuvant FOLFOX4 were offered to all patients after CRT. Common biochemical variables and key germline genetic polymorphisms were analyzed as predictors of pathological complete response (pCR). Fifty-one patients were enrolled. pCR (regression AJCC grade 0) was documented in 7 patients (14%), nearly complete response (AJCC grade 1) in 10 pts. There was a strong association between disease-free survival and AJCC grade (p 0.0047). Grade 3-4 toxicities (mainly diarrhea) was observed in 41% of patients. Among all analyzed variables, baseline hemoglobin (Hb) was significantly associated with AJCC grade 0-1 response (p 0.027). As for the pharmacogenetic analysis, XRCC1 rs25487 polymorphism was significantly associated with AJCC grade 0-1, Odds Ratio 25.8, p 0.049. AJCC grade 0-1 response rate for patients with high Hb and/or XRCC1 rs25487 G/G genotype was as high as 57%. Baseline Hb and XRCC1 polymorphisms are valuable selection criteria for the CisCape CRT regimen, given its otherwise meaningful toxicity.

Correlations between microsatellite instability, ERCC1/XRCC1 polymorphism and clinical characteristics, and FOLFOX adjuvant chemotherapy effect of colorectal cancer patients.

Patients with MSI colorectal tumor have good prognosis and cannot benefit from 5-fluorouracil (5-Fu)-based chemotherapy reported by previous studies. While, single nucleotide polymorphisms (SNP) of ERCC1 and XRCC1 have be proved to influence clinical outcome of colorectal cancer patients treated with oxaliplatin-based chemotherapy. We aim to study the correlation between molecular status and clinical- pathological features, and their effect on CRC patients' clinical outcome treated with mFOLFOX6 adjuvant chemotherapy. In this study, MSI status was determined in tumors and paired normal tissues from 101 colorectal cancer (CRC) patients. We also examined SNP of ERCC1 (c. C354T) and XRCC1 (c.G1196A) in 83 and 85 patients' blood. MSI was found to be significantly correlated with well/moderate histopathological differentiation (p = 0.038) and CRC family history (p = 0.003). CEA and CA19-9 levels was positive correlated significantly by Spearman correlation analysis (Pearson's r = 0.823, p < 0.0001). No significant correlation was found between MSI status and ERCC1/XRCC1 polymorphisms. We found greater drop of CEA level in mFOLFOX6 sensitive group than low sensitive group after mFOLFOX6 adjuvant chemotherapy according to MSI status, ERCC1 and XRCC1 SNP. MSI was significantly correlated with well/moderate histopathological differentiation (p = 0.038) and CRC family history (p = 0.003). The MSI status, ERCC1 and XRCC1 polymorphisms may influence the clinical outcome of colorectal cancer patients treated with mFOLFOX6 adjuvant chemotherapy.

The XRCC 1 DNA repair gene modifies the environmental risk of stomach cancer: a hospital-based matched case-control study.

BACKGROUND: Previous studies have found that polymorphisms of the DNA repair gene X-ray repair cross-complementing group 1(XRCC1) and environmental factors are both associated with an increased risk of stomach cancer, but no study has reported on the potential additive effect of these factors among Thai people. The aim of this study was to investigate whether the risk of stomach cancer from XRCC1 gene polymorphisms was modified by environmental factors in the Thai population. METHODS: Hospital-based matched case-control study data were collected from 101 new stomach cancer cases and 202 controls, which were recruited from2002 to 2006 and were matched for gender and age. Genotype analysis was performed using real-time PCR-HRM. The data were analysed by the chi-square test and conditional logistic regression. RESULTS: The Arg/Arg homozygote polymorphism of the XRCC1 gene was associated with an increased risk of stomach cancer in the Thai population (OR adj, 3.7; 95%CI, 1.30-10.72) compared with Gln/Gln homozygosity. The effect of the XRCC1gene on the risk of stomach cancer was modified by both a high intake of vegetable oils and salt (p = 0.036 and p = 0.014), particularly for the Arg/Arg homozygous genotype. There were, however, no additive effects on the risk of stomach cancer between variants of the XRCC1gene and smoking,alcohol or pork oil consumption. CONCLUSIONS: The effect of the XRCC1 gene homozygosity, particularly Arg/Arg, on the risk for stomach cancer was elevated by a high intake of vegetable oils and salt.

Relationship Between Expression of Proteins ERCC1, ERCC2, and XRCC1 and Clinical Outcomes in Patients with Rectal Cancer Treated with FOLFOX-Based Preoperative Chemoradiotherapy.

BACKGROUND: Platinum resistance enhances DNA damage repair through nucleotide excision repair mechanisms involving the excision repair cross-complementing group 1 (ERCC1), X-ray cross-complementing group 1 (XRCC1), and excision repair cross-complementing group 2 (ERCC2). We evaluated the correlation between the expression of these three DNA repair genes and clinical outcomes in patients with rectal cancer receiving FOLFOX-based preoperative chemoradiotherapy (CRT). METHODS: Using immunohistochemistry, we examined the expression of ERCC1, ERCC2, and XRCC1 in pre-CRT cancer tissues from 86 patients with rectal cancer who had undergone curative resection and preoperative CRT with FOLFOX-4 to identify potential predictors of clinical outcomes. RESULTS: Following CRT, 57 and 29 patients were classified as responders (pathological tumor regression grade TRG 0 and TRG 1) and poor responders (TRG 2 and TRG 3), respectively. The multivariate analysis revealed that ERCC1 overexpression was correlated with a poor CRT response [p < 0.0001; odds ratio (OR), 9.397; 95% confidence interval (CI) 2.721-32.457]. Furthermore, a poor response to CRT (pathological TRG of 2-3) (p = 0.18; OR 5.685; 95% CI 1.349-23.954) and abnormal pre-CRT serum carcinoembryonic antigen levels (>5 ng/mL) (p = 0.03; OR 6.288; 95% CI 1.198-33.006) were independent predictors of postoperative relapse. By contrast, ERCC2 and XRCC1 expression did not play predictive roles in the analyzed patients. CONCLUSIONS: ERCC1 overexpression is associated with a poor preoperative CRT response in patients with rectal cancer receiving FOLFOX-based preoperative CRT. ERCC1 is a potential biomarker for identifying patients who can benefit from customized treatment programs.

Influence of Morinda citrifolia (Noni) on Expression of DNA Repair Genes in Cervical Cancer Cells.

BACKGROUND: Previous studies have suggested that Morinda citrifolia (Noni) has potential to reduce cancer risk. OBJECTIVE: The purpose of this study was to investigate the effect of Noni, cisplatin, and their combination on DNA repair genes in the SiHa cervical cancer cell line. MATERIALS AND METHODS: SiHa cells were cultured and treated with 10% Noni, 10 µg/dl cisplatin or their combination for 24 hours. Post culturing, the cells were pelleted, RNA extracted, and processed for investigating DNA repair genes by real time PCR. RESULTS: The expression of nucleotide excision repair genes ERCC1, ERCC2, and ERCC4 and base excision repair gene XRCC1 was increased 4 fold, 8.9 fold, 4 fold, and 5.5 fold, respectively, on treatment with Noni as compared to untreated controls (p<0.05). In contrast, expression was found to be decreased 22 fold, 13 fold, 16 fold, and 23 fold on treatment with cisplatin (p<0.05). However, the combination of Noni and cisplatin led to an increase of 2 fold, 1.6 fold, 3 fold, 1.2 fold, respectively (p<0.05). CONCLUSIONS: Noni enhanced the expression of DNA repair genes by itself and in combination with cisplatin. However, high expression of DNA repair genes at mRNA level only signifies efficient DNA transcription of the above mentioned genes; further investigations are needed to evaluate the DNA repair protein expression.

Complex relationships between occupation, environment, DNA adducts, genetic polymorphisms and bladder cancer in a case-control study using a structural equation modeling.

DNA adducts are considered an integrate measure of carcinogen exposure and the initial step of carcinogenesis. Their levels in more accessible peripheral blood lymphocytes (PBLs) mirror that in the bladder tissue. In this study we explore whether the formation of PBL DNA adducts may be associated with bladder cancer (BC) risk, and how this relationship is modulated by genetic polymorphisms, environmental and occupational risk factors for BC. These complex interrelationships, including direct and indirect effects of each variable, were appraised using the structural equation modeling (SEM) analysis. Within the framework of a hospital-based case/control study, study population included 199 BC cases and 213 non-cancer controls, all Caucasian males. Data were collected on lifetime smoking, coffee drinking, dietary habits and lifetime occupation, with particular reference to exposure to aromatic amines (AAs) and polycyclic aromatic hydrocarbons (PAHs). No indirect paths were found, disproving hypothesis on association between PBL DNA adducts and BC risk. DNA adducts were instead positively associated with occupational cumulative exposure to AAs (p = 0.028), whereas XRCC1 Arg 399 (p<0.006) was related with a decreased adduct levels, but with no impact on BC risk. Previous findings on increased BC risk by packyears (p<0.001), coffee (p<0.001), cumulative AAs exposure (p = 0.041) and MnSOD (p = 0.009) and a decreased risk by MPO (p<0.008) were also confirmed by SEM analysis. Our results for the first time make evident an association between occupational cumulative exposure to AAs with DNA adducts and BC risk, strengthening the central role of AAs in bladder carcinogenesis. However the lack of an association between PBL DNA adducts and BC risk advises that these snapshot measurements are not representative of relevant exposures. This would envisage new scenarios for biomarker discovery and new challenges such as repeated measurements at different critical life stages.

Predictive value of ERCC1, ERCC2, and XRCC1 overexpression for stage III colorectal cancer patients receiving FOLFOX-4 adjuvant chemotherapy.

OBJECTIVES: To determine the correlation between expression of three DNA repair genes and early failure/clinical outcome of stage III colorectal cancer (CRC) patients administrated with FOLFOX-4, including the excision repair cross-complementation group 1 (ERCC1), the excision repair cross-complementing 2 (ERCC2), and X-ray repair cross-complementing protein 1 (XRCC1). MATERIALS AND METHODS: We retrospectively analyzed clinicopathological features and ERCC1, ERCC2, XRCC1 expressions by immunohistochemical staining in 180 stage III CRC patients undergoing curative resection and treated with FOLFOX-4 chemotherapy to identify predictors of postoperative early failure. RESULTS: Among 180 CRC patients, 44 patients were classified into early failure group, and 136 patients were categorized into non-early failure group. A multivariate logistic regression analysis showed that ERCC1 overexpression (P = 0.005), and high postoperative carcinoembryonic antigen (CEA) levels (P = 0.001) were independent predictors of early failure. Additionally, ERCC1 overexpression was not only a predictor of early failure but also for disease-free survival (P < 0.001) and overall survival (P < 0.001). However, no predictive roles of ERCC2 and XRCC1 expression among these analyzed patients. CONCLUSIONS: ERCC1 overexpression is an important predictor of early failure in patients with stage III CRC administrating FOLFOX-4 adjuvant chemotherapy and this marker may help identify patients who would benefit from intensive follow-up and enhance therapeutic programs.

Genetic polymorphisms of ERCC1­118, XRCC1­399 and GSTP1­105 are associated with the clinical outcome of gastric cancer patients receiving oxaliplatin­based adjuvant chemotherapy.

The aim of the present study was to determine whether specific molecular parameters may serve as predictors of treatment outcomes and toxicity of oxaliplatin (OXA)­based chemotherapy, which is used as an adjuvant treatment in resected gastric cancer. All gastric cancer patients examined in the study received an OXA/5­fluorouracil chemotherapeutic regimen. Genetic polymorphisms of certain platinum­related genes were determined by the TaqMan 5' nuclease assay and direct sequencing. Relapse­free survival (RFS), overall survival (OS) and toxicity were evaluated according to each genotype. Following adjustment for the most relevant clinical variables, excision repair cross­complimentary group 1 (ERCC1)­118 and X-ray repair cross-complementing protein 1 (XRCC1­399) demonstrated significant predictive value for RFS and OS. We also demonstrated that carrying at least one variant XRCC1 Arg399Gln or glutathione S-transferase π 1 (GSTP1) Ile105Val allele significantly increased the risk of any grade 3 or 4 hematological toxicity. In particular, carrying at least one variant GSTP1 Ile105Val allele was also significantly correlated with an increased risk of grade 3 or 4 gastrointestinal toxicity and neurotoxicity. Our data suggested that gastric cancer patients harboring ERCC1­118 C/C and XRCC1­399 A/G or A/A genotypes may benefit from receiving OXA­based adjuvant chemotherapy, and carrying at least one variant XRCC1 Arg399Gln or GSTP1 Ile105Val allele may contribute to the occurrence of adverse drug effects associated with OXA­based chemotherapy.

Pharmacogenetic analysis of adjuvant FOLFOX for Korean patients with colon cancer.

PURPOSE: Ethnic diversity of genetic polymorphism can result in individual differences in the efficacy and toxicity of cancer chemotherapy. METHODS: We analyzed 20 germline polymorphisms in 10 genes (TS, MTHFR, ERCC1, XPD, XRCC1, ABCC2, AGXT, GSTP1, GSTT1 and GSTM1) from prospectively enrolled 292 Korean patients treated with adjuvant oxaliplatin plus leucovorin plus 5-fluorouracil (FOLFOX) for colon cancer. RESULTS: In contrast to previous studies in Caucasians, neutropenia (grade 3-4, 60.5 %) was frequently observed, whereas only 16.4 % experienced grade 2 or more sensory neuropathy. Neutropenia was more frequent in MTHFR 677TT [adjusted odds ratio (OR) 2.32, 95 % confidence interval (CI) 1.19-4.55] and ERCC1 19007TT (adjusted OR 4.58, 95 % CI 1.20-17.40) genotypes. Patients harboring XRCC1 23885GG experienced less grade 2-4 neuropathy [adjusted OR 0.52, 95 % CI 0.27-0.99]. MTHFR 677TT (p = 0.002) and XRCC1 23885GG (p = 0.146) genotypes were also more prevalent in Koreans compared to Caucasians. TS 'low' genotype (adjusted HR 1.83, 95 % CI 1.003-3.34) was significantly related to shorter disease-free survival. Overall survival was not significantly different according to the polymorphisms. CONCLUSIONS: Polymorphisms in MTHFR, XRCC1 and TS are related to toxicities and disease-free survival in patients with colon cancer. The ethnic differences in frequencies of genotypes may explain the ethnic difference in toxicity profile following adjuvant FOLFOX chemotherapy.

Association of the Arg194Trp and the Arg399Gln polymorphisms of the XRCC1 gene with risk occurrence and the response to adjuvant therapy among Polish women with breast cancer.

BACKGROUND: The XRCC1 gene encoding the X-ray cross-complementing group 1 protein (XRCC1) is involved in the base excision repair (BER) pathway. METHODS: The aim of this study was to investigate an association of the Arg194Trp and Arg399Gln polymorphisms of the XRCC1 gene with a risk of breast cancer occurrence and the response to adjuvant treatment among Polish women. Overall survival (OS) and disease-free survival (DFS) were investigated in groups of patients with breast cancer treated with (1) all types of adjuvant therapy, (2) concomitant radiotherapy and chemotherapy, (3) chemotherapy alone, or (4) radiotherapy alone. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) was used to evaluate the genotype distribution of the XRCC1 gene among 185 patients with breast cancer and 205 female controls. RESULTS: We showed a higher risk of breast cancer occurrence for the Trp allele and the Arg194Trp genotype of the XRCC1 gene. However there was no significant difference in distribution of the Arg399Gln genotype of XRCC1 between patients and the control group. In the patient subgroup treated with adjuvant therapy, Kaplan-Meier survival analysis showed a significantly higher OS as well as DFS for carriers of the Gln399Gln genotype when compared with carriers of the Arg399Gln and Arg399Arg genotypes. The Gln399Gln genotype was associated with a significantly higher DFS in the subgroup of patients treated with chemotherapy alone or with concomitant radiotherapy and chemotherapy. CONCLUSION: We suggest that the polymorphism of the XRCC1 gene may be considered a predictive factor associated with the risk of occurrence and the survival outcome in breast cancer among Polish women.

[The polymorphism of DNA repair genes XRCC1, XRCC3 and the level of chromosomal aberrations in the Uranium workers].

Association between the polymorphism of DNA repair genes XRCC1 Arg399ln and XRCC3 Thr241Met and the frequency of chromosomal aberrations in the uranium workers was studied. The Gln/Gln genotype of gene XRCC1 was associated with a significant increase in the number of chromosomal aberrations as compared to the corresponding homozygous wild type Arg/Arg (p < 0.05). The frequency of chromosomal aberrations in heterozygous carriers of the XRCC3gene Thr/Met was lower than in the homozygous carriers of the wild type Thr/Thr (p < 0.001).

Prognostic and predictive role of JWA and XRCC1 expressions in gastric cancer.

PURPOSE: To investigate the expression pattern and significance of DNA repair genes JWA and X-ray repair cross complement group 1 (XRCC1) in gastric cancer. EXPERIMENTAL DESIGN: Expressions of JWA and XRCC1 were assessed by immunohistochemistry in a training cohort and they went into a second testing cohort and finally to a validating cohort. Prognostic and predictive role of JWA and XRCC1 expression status in cases treated with surgery alone or combined with adjuvant chemotherapy was evaluated, respectively. RESULTS: JWA and XRCC1 protein levels were significantly downregulated in gastric cancer lesions compared with adjacent noncancerous tissues. Low tumoral JWA or XRCC1 expression significantly correlated with shorter overall survival (OS), as well as with clinicopathologic characteristics in patients without adjuvant treatment. Multivariate regression analysis showed that low JWA and XRCC1 expressions, separately and together, were independent negative markers of OS. Adjuvant fluorouracil-leucovorin-oxaliplatin (FLO) significantly improved OS compared with surgery alone (log-rank test, P = 0.01). However, this effect was evident only in the JWA or XRCC1 low expression group (HR = 0.44; 95% CI: 0.26-0.73; P = 0.002, and HR = 0.44, 95% CI: 0.26-0.75; P = 0.002, respectively); Adjuvant fluorouracil-leucovorin-platinol (FLP) did not improve OS, except in the patients with low JWA and XRCC1 expressions (P = 0.010 for JWA and 0.024 for XRCC1, respectively). CONCLUSIONS: JWA and XRCC1 protein expressions in tumor are novel candidate prognostic markers and predictive factors for benefit from adjuvant platinum-based chemotherapy (FLO or FLP) in resectable human gastric carcinoma.