ERCC1 SNPs Research Articles

Association of DNA repair gene variants with colorectal cancer: risk, toxicity, and survival

BackgroundSingle nucleotide polymorphisms (SNPs) in DNA repair genes have a potential clinical value in predicting treatment outcomes. In the current study, we examined the association of SNPs in the genes XRCC1-rs25487, ERCC1-rs11615, ERCC2-rs238406, and ERCC2-rs13181 with colorectal cancer (CRC) risk, relapse-free survival (RFS), overall survival (OS), and toxicity during chemotherapy.MethodsSNPs were analysed in 590 CRC cases and 300 controls using TaqMan technology. The association of SNPs with CRC risk and toxicity during chemotherapy was analysed using Chi2 test. The Kaplan–Meier method and log-rank test was used to measure the effects of the SNPs on RFS and OS.ResultsThe CC genotype of ERCC2-rs238406 and the ERCC2-rs13181 C allele were associated with a significantly increased risk of CRC. The ERCC1-rs11615 genotype T/T was associated with stomatitis in adjuvant chemotherapy (p = 0.03). Also, more patients with the ERCC2-rs13181 C allele needed dose reduction compared to patients with the A/A genotype (p = 0.02). In first line chemotherapy, more patients with the ERCC1-rs11615 C allele suffered from nausea compared to those with the T/T genotype (p = 0.04) and eye reactions and thrombocytopenia were more common in patients with the ERCC2-rs13181 C allele compared to the A/A genotype (p = 0.006 and p = 0.004, respectively). ERCC2- rs238406 C/C was also associated with a higher frequency of thrombocytopenia (p = 0.03). A shorter 5-year OS was detected in stage I & II CRC patients with the ERCC2- rs238406 C allele (p = 0.02). However, there was no significant association between the SNPs and 5-year RFS.ConclusionsBoth SNPs in ERCC2 were associated with risk of CRC as well as toxicity during first line treatment. In addition, ERCC2- rs238406 was linked to OS in early stage CRC. The ERCC1-rs11615 variant was associated with toxicity during adjuvant chemotherapy. The results add support to previous findings that SNPs in ERCC1 and ERCC2 have a prognostic and predictive value in clinical management of CRC.

SNPs in ERCC1, ERCC2, and XRCC1 genes of the DNA repair pathway and risk of male infertility in the Asian populations: association study, meta-analysis, and trial sequential analysis.

We investigated if substitutions in the ERCC1, ERCC2, and XRCC1 genes of the DNA repair pathway correlate with non-obstructive azoospermia and male infertility. A total of 548 azoospermic infertile males and 410 fertile controls were genotyped for XRCC1 399A > G, 280G > A, and ERCC1 C > A 3' UTR and 541 azoospermic infertile males and 416 fertile controls were genotyped for ERCC2 751A > C using iPLEX Gold Assay. Meta-analyses were performed on XRCC1 399A > G (1022 cases and 1004 controls), ERCC1 C > A 3' UTR (879 cases and 1059 controls), and ERCC2 751A > C (914 cases and 850 controls) polymorphisms to quantitatively estimate the significance of the association between these polymorphisms and the risk of infertility. Statistically significant association between ERCC2 751A > C SNP and male infertility was found using the codominant model (p= 0.03). Results of meta-analysis suggested a lack of correlation with male infertility risk, which could be due to pooling of studies from different ethnic populations. Due to limited the number of studies, a stratified analysis for different ethnic groups could not be performed. In conclusion, AA genotype of 751A > C SNP in ERCC2 correlated with a higher risk of male infertility and may contribute to an increased risk of azoospermia and male infertility in Indian men.

ERCC1 SNPs as Potential Predictive Biomarkers in Non-Small Cell Lung Cancer Patients Treated With Platinum-Based Chemotherapy

Polymorphisms in ERCC1, XPD, and XRCC1 were examined for (a) association with the clinical outcome of 107 non-small cell lung cancer patients receiving front-line platinum-based chemotherapy, and (b) correlation with the ERCC1 mRNA levels of 176 chemo-naive primary tumors. The ERCC1-C8092 allele and the number of ERCC1 polymorphic variants (C8092A and Asn118Asn) were associated with progression-free survival. In non-squamous histology, tumoral ERCC1 mRNA levels were lower in patients homozygous for ERCC1-C8092 as compared with the patients carrying the A allele (p = .024). These findings merit investigation in larger cohorts of patients treated with uniform regimens.

Analysis of ERCC1 and ERCC2 gene variants in osteosarcoma, colorectal and breast cancer.

The Asn118Asn (rs11615) variant in the ERCC1 gene, and the Lys751Gln (rs13181) and Asp312Asn (rs1799793) variants in the ERCC2 gene have been associated with the development of varied types of cancer. The aim of the present study was to test for any association between the ERCC1 and ERCC2 gene variants and three different types of cancer in Mexican-mestizo patients. Patients and their respective controls were formed into three groups: The osteosarcoma group, with 28 patients and 97 controls; the colorectal group, with 108 patients and 119 controls; and the breast cancer group, with 71 patients and 74 controls. Genotyping was performed using TaqMan probes and quantitative polymerase chain reaction. Allele and genotype frequencies were compared using a χ2 test. Only one SNP (rs1799793) was found to be associated with breast cancer. This is the first study analyzing the SNPs in ERCC1 and ERCC2 genes and the susceptibility to cancer in Mexican-mestizo patients with osteosarcoma, and colorectal and breast cancer.

Association between ERCC1 and ERCC2 gene polymorphisms and chemotherapy response and overall survival in osteosarcoma.

We aimed to evaluate the influence of four SNPs in ERCC1 and ERCC2 on the response to cisplatin-based treatment and on clinical outcome in patients with osteosarcoma. We identified 186 patients with osteosarcoma diagnosed between April 2009 and April 2011 who were eligible for inclusion in our study. Genotyping of ERCC1 rs11615, rs3212986, and rs2298881; and ERCC2 rs1799793 and rs13181 was conducted by a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. By conditional logistic regression analysis, patients carrying the CC genotypes of ERCC1 rs11615 and rs2298881 were shown to be more likely to have good response to chemotherapy when compared with patients carrying wild-type genotypes; the ORs (95%CIs) were 2.56 (1.02-7.35) and 3.01 (1.07-9.71), respectively. By Cox regression analysis, individuals carrying the CC genotype of ERCC1 rs11615 were associated with longer overall survival time and decreased risk of death from osteosarcoma; the hazards ratio (95%CI) was 0.32 (0.07-0.98). In summary, our results suggested that the ERCC1 rs11615 and rs2298881 polymorphisms play important roles in the response to chemotherapy mediated by the DNA repair pathway and in the clinical outcome of osteosarcoma.

Pharmacogenetics of the DNA repair pathways in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy

Genetic variants in DNA repair genes may play a role in the effectiveness of platinum-based chemotherapy in non-small cell lung cancer (NSCLC). We analyzed 17 SNPs in eight genes (ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, XPA, XRCC1 and XRCC2) involved in DNA repair mechanisms and its association with outcome in NSCLC. This prospective study included patients with stages III and IV treated with platinum-based chemotherapy. All patients (n = 161) received cisplatin or carboplatin plus a third-generation drug. Additionally, stage IIIA and IIIB patients (n = 74) received concomitant or sequential radiotherapy. Germline polymorphisms were analyzed using the BioMark system in blood DNA samples. We found that in stage III patients, response was significantly associated with SNPs in ERCC1 and in ERCC3 genes, while radiotherapy-derived toxicity correlated with SNPs in the ERCC2 gene. In stage IV patients, response was associated with a genetic variant in the ERCC4 gene and survival with a SNP in the XRCC1 gene. The complexity of the DNA repair mechanisms along with the heterogeneity in the treatment of lung cancer could explain the role of multiple genes as putative biomarkers of patient outcome.

Association of DNA repair gene polymorphisms with response to chemotherapy and prognosis of gastric cancer in a Chinese population.

We conducted a study to investigate the role of excision repair cross-complimentary group 1 gene (ERCC1)-xeroderma pigmentosum complementation group F (XPF) gene polymorphisms in response to chemotherapy and clinical outcome of gastric patients. Three SNPs in ERCC1 (rs11615, rs3212986, and rs2298881) and two SNPs in XPF (rs2276465 and rs6498486) were extracted using Tiangen DNA kit (Tiangen Biotech, Beijing, China) according to the manufacturer's instructions. The median follow-up time was 36.4 months, and ranged from 2-60 months. During the follow-up period, 112 patients died from gastric cancer. Individuals carrying ERCC1 rs11615 AA and XPF rs6498486 CC genotypes were associated with poorer response to chemotherapy when compared with wild-type genotype, with the ORs (95 % CI) of 0.48 (0.25-0.94) and 0.38 (0.14-1.00). In the Cox proportional hazards model, individuals carrying ERCC1 rs11615 GA and AA genotype had 1.91 and 2.66 risk of death when compared with those carrying GG genotype. Patients carrying the XPF rs6498486 AC and CC genotype were associate with 2.17 and 4.91-fold risk of death when compared with wild-type genotype. In conclusion, we found that ERCC1 rs11615 and XPF rs2276465 may substantially contribute to the future design of individualized cancer treatment in gastric cancer patients.

Genetic variation in ERCC1 and XPF genes and breast cancer risk.

Breast cancer is one of the most frequently diagnosed cancer in women worldwide, and we conducted a case-control study by genotyping seven potentially functional SNPs, three in ERCC1 and four in XPF, in a Chinese population of 417 breast cancer cases and 417 cancer-free controls. Three SNPs in ERCC1 and four SNPs in XPF were genotyped by using the Taqman Universal PCR Master Mix in the GeneAmp(®) PCR System 9700 with Dual 384-Well Sample Block Module, and assays were performed on a 384-well plate on the Sequenom MassARRAY platform. We found that elevated breast cancer risk was associated with those who had a family history of breast cancer and history of breast disease, and those who were over 25 years old at first full-term pregnancy. We found that decreased risk of breast cancer was associated with those who had a history of full-term pregnancies. Compared with the ERCC1 rs11615 T/T genotype, a significantly higher risk of breast cancer was found in the C/C genotype in codominant and dominant models after adjusting for potential risk factors. Similarly, we found that ERCC1 rs3212986 C/C genotype was associated with an increased risk of breast cancer in codominant, dominant and recessive models. Our study indicated that the ERCC1 rs11615 and rs2298881 polymorphisms are associated with breast cancer in a Chinese population. Further studies with large sample size are greatly needed to elucidate the SNPs of ERCC1 and XPF genes in the development of breast cancer.

Association of Four ERCC1 and ERCC2 SNPs with Survival of Bone Tumour Patients

SNPs of ERCC1 and ERCC2 genes have been found to be associated with response to platinum therapy in different clinical settings. In the current study, we investigated the relationship of SNPs in ERCC1 and ERCC2 to cisplatin response and survival in osteosarcoma patients. 267 consecutive patients diagnosed with osteosarcoma between January 2003 to January 2005 were followed up until the end of January 2010. ERCC1 Asn118Asn, ERCC1 Gln504Lys, ERCC2 Asp312Asn and ERCC2 Lys751Gln polymorphisms were detected based upon the Sequenom MassARRAY platform. For ERCC1 Asn118Asn, the variant genotype T/T was strongly significantly associated with a higher event free survival when compared with the wild-type C/C, with an adjusted OR (95% CI) of 0.39 (0.14-0.95). ERCC2 751 A/A genotype showed increased event free survival of osteosarcoma (HR=0.44; 95%CI=0.10-0.87). However, we did not find significant association of ERCC1 Gln504Lys and ERCC2 Asp312Asn polymorphisms with prognosis of osteosarcoma. We first report associations of four SNPs, ERCC1 Asn118Asn, ERCC1 Gln504Lys, ERCC2 Asp312Asn and ERCC2 Lys751Gln, with risk of death from osteosarcoma in a Chinese population, indicating ERCC1 118T/T and ERCC2 A/A may be used as surrogate markers for clinical outcome of osteosarcoma treatment with cisplatin.

Intratumoral lymphocyte density in serous ovarian carcinoma is superior to ERCC1 expression for predicting response to platinum-based therapy

Intratumoral immune cells and ERCC1 expression are likely to play a role in the response of ovarian carcinoma to chemotherapy, but their impact on therapy outcome is still unclear. Therefore, 41 cases of optimally resected high grade serous ovarian carcinomas were examined retrospectively for stromal and intraepithelial lymphocyte populations and ERCC1 status in relation to response to platinum-based therapy. Based on RECIST criteria, 27 patients were classified as responsive and 14 as therapy resistant, respectively. Using immunohistochemistry for CD3, CD8, CD4, TIA1, MUM1 and FOX P3 on representative tumor sections, we quantitatively evaluated the intratumoral density of lymphocyte subpopulations. In addition, ERCC1 protein and mRNA expression were determined by immunohistochemistry using the Steffensen score and quantitative RT-PCR, respectively. Furthermore, ERCC1 SNP's C8092A and codon 118 were analysed. Response to chemotherapy was significantly associated with higher numbers of stromal CD3+ (mean 21.33 lymphocytes/HPF versus 8.21 lymphocytes/HPF, p = 0.002) and CD8+ lymphocytes (mean 9.22 lymphocytes/HPF versus 4.57 lymphocytes/HPF, p = 0.013). Counts of intraepithelial CD3+ and CD8+ lymphocytes, stromal and intraepithelial FOXP3+ and TIA1+ cells, CD4+ lymphocytes, and MUM1+ plasma cells did not reach statistical significance. Neither ERCC1 protein expression (p = 0.232) nor SNPs codon 118 and C8092A of the ERCC1 gene (p = 0.269 and p = 0.543) showed an association with therapy response. The same was true for ERCC1 mRNA levels (p = 0.896), probably due to intratumoral lymphocyte contamination. In conclusion, the density of CD3+ and CD8+ T-cells in tumor stroma proved to be a significant predictor for response to platinum-based therapy, whereas examination of ERCC1 failed to identify therapy-responsive patients.

ERCC1 polymorphisms in patients with advanced bladder cancer treated with platinum-based chemotherapy.

e15066 Background: Platinum-based combination chemotherapy represents the standard treatment for advanced urothelial cancer. Determination of prognosis is based on clinical characteristics: ECOG PS and sites of metastases. ERCC1 is involved in the repair of DNA adducts formed by platinum analogues. Recent data suggest that tissue expression of ERCC1 may have prognostic significance. We studied the prognostic relevance of ERCC1 polymorphisms in the blood from patients with advanced bladder cancer treated with platinum-based chemotherapy. Methods: Patients with inoperable (cT4b, N2, N3) or metastatic bladder cancer were included. Treatment consisted of cisplatin-based chemotherapy (n=65) in the context of a randomized trial of HECOG (HD MVAC vs. HD Cem/Cis) or carboplatin/gemcitabine (n=12) for unfit-for-cisplatin patients. DNA was extracted from blood and was amplified using nested PCR and SNPs C19007T and C8092A were studied. The findings were expressed as C/C (normal), C/T and C/A (heterozygous SNP) and T/T and A/A (homozygous SNP). Results: Seventy patients have been included in this analysis. Median PFS was 11 months (95% CI: 8-14) and median OS 15 months (95% CI: 7-22). SNP C17009T: C/C 18 (26%), C/T 34 (48%), T/T 18 (26%); SNP C8092A: C/C 20 (28%), C/A 44 (63%), A/A 6 (9%). Female patients had higher C19007T T/T and lower C/C expression (60% vs. 20% and 10% vs. 28%, p=0.026). Heterozygous C8092A polymorphism was associated with higher frequency of locoregional relapse (95% vs. 77%, p=0.048) and higher frequency of Hb > 10mg/dL (98% vs. 81%, p=0.046). There was no association of SNPs with objective responses. The presence of distant metastases was associated with significantly lower PFS and OS (13 vs. 8 months, p=0.047 and 20 vs. 12 months, p=0.043). Neither SNP17009 nor SNP8092A was associated with a significant difference in PFS or OS. Conclusions: ERCC1 SNPs are present in the majority of patients with advanced baldder cancer. C8092A SNP is associated with prognostically important clinical characteristics but in this cohort of patients treated with platinum-based chemotherapy did not show any predictive or prognostic significance. No significant financial relationships to disclose.

Effect of ERCC1 Polymorphisms and the Modification by Smoking on the Survival of Non-Small Cell Lung Cancer Patients

A few reports for ERCC1 SNPs were conducted in patients treated with cisplatin chemotherapy. The aim of this study is to determine whether the SNPs are a prognostic factor related to the treatment or not and if smoking level of the patients have any relationship to the SNPs' effect on the survival. Peripheral blood lymphocytes of 423 consecutive non-small cell lung cancer patients were examined: 245 of the patients received cisplatin combination chemotherapy and 178 received only conservative care. We examined ERCC1 SNPs (codon 118 C/T and 8092 C/A). Whereas ERCC1 118 SNP had no effect on the survival in patients' given no treatment, an effect of the SNP was observed in the treatment group, especially in stage III. When smoking was considered, the risk effect of the T allele was shown to be significantly associated with the group that had more than 50 pack yr (p=0.03). As for the ERCC1 8092 C/A, no significant effects were observed in the treated group and the non-treatment group. These findings may suggest that the ERCC1 118 SNP is an useful prognostic factor related to cisplatin therapy and the effect of this polymorphism appears to be modified by smoking.