ERCC2 Single Nucleotide Polymorphisms Research Articles

163P - Excision repair cross-complementation group 1 and 2 (ERCC1/2) Single nucleotide polymorphisms and chemotherapy treatment outcome in Cholangiocarcinoma

BackgroundERCC1 and ERCC2 are major enzymes involved in nucleotide excision repair (NER). Single nucleotide polymorphisms (SNPs) affect the mRNA level and stability resulting in an alteration in protein translation. ERCC1/2 SNPs potentially association with survival in various cancers but the data in CCA was limited. MethodsWe did a retrospective review and genomic DNA analysis from FFPE tissue of patients diagnosed locally advanced or metastatic CCA who received palliative chemotherapy. The target SNPs included ERCC1 C19007T, C8092A and ERCC2 C312T, A2251C. ResultsGenomic DNA analysis was done in 64 patients but only 54 patients received platinum-based chemotherapy were use in the survival analysis. The ERCC1 C19007T CT SNP had a trend to have better OS than wild-type (CC), 8.8 vs 6.3 months respectively, the HR was statistically significant in multivariate survival analysis (HR 0.47 (0.23-0.94), p = 0.032). The ERCC1 C8092A both homozygous (AA) and heterozygous (CA) SNPs had shorter OS compare with wild-type (CC), 6.2, 8.0 and 9.5 months respectively, there was a trend to statistically significant between CT and CC group HR 1.83 (0.96-3.51), p = 0.067. These findings also observe in response rate and disease control rate. Conversely, ERCC2 SNPs did not associate with the outcome. ConclusionsERCC1 C19007T and ERCC1 C8092A SNPs are associated with the overall survival but not the ERCC2 SNPs in cholangiocarcinoma patients receiving platinum-based chemotherapy. Longer survival is seen in ERCC1 C19007T heterozygous SNP (CT) but shorter in ERCC1 C8092A. Clinical trial identificationHuman Ethics Committee of Khon Kaen University (HE611254). Legal entity responsible for the studyThe author. FundingHas not received any funding. DisclosureThe author has declared no conflicts of interest.

Polymorphisms of DNA repair genes are associated with colorectal cancer in patients with Lynch syndrome.

Background DNA repair genes are crucial for maintaining genomic stability by preventing mutagenesis and carcinogenesis. The present retrospective cohort study aimed at investigating whether MLH1,APEX1,MUTYH,OGG1,NUDT1,XRCC5, XPA, and ERCC2 single nucleotide polymorphisms (SNPs) are associated with colorectal cancer (CRC) in Chinese population with Lynch syndrome.MethodsFrom Amsterdam criteria family registry, we identified 270 patients with Lynch syndrome. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between DNA repair SNPs and CRC were calculated using a weighted Cox proportional hazard regression model.ResultsHeterozygous variants of rs1799832 in NUDT1 (HR = 2.97, 95% CI = 1.51–5.83) and rs13181 in ERCC2 (HR = 2.69, 95% CI = 1.10–6.55) were significantly associated with an increased risk of CRC compared with wild‐type homozygous CC and TT genotypes, respectively. However, the variant CG+GG genotype of MUTYH rs3219489 was associated with a decreased risk of CRC (HR = 0.49, 95% CI = 0.26–0.91) compared with the homozygous CC wild‐type counterparts.ConclusionOur findings revealed that polymorphisms of DNA repair genes that include NUDT1,ERCC2, and MUTYH are associated with CRC in patients with Lynch syndrome in Chinese population. Further studies with large sample size are needed to confirm our findings.

ERCC1 and ERCC2 Variants Predict Survival in Gastric Cancer Patients

Purpose ERCC1 and ERCC2 play critical roles in the nucleotide excision repair pathway that effectively repairs DNA damage induced by chemotherapeutic agents. Therefore, functional single nucleotide polymorphisms (SNPs) in these genes could have an impact on clinical outcomes in cancer patients who received chemotherapy. However, few studies have simultaneously investigated the roles of ERCC1 and ERCC2 SNPs in clinical outcomes in gastric cancer patients.Experimental DesignWe genotyped by the TaqMan assay three common, potentially functional ERCC1 (rs3212986) and ERCC2 SNPs (rs13181 and rs1799793) in 360 gastric cancer patients. We used both Kaplan-Meier tests and Cox proportional hazards models to evaluate the effects of ERCC1 and ERCC2 genotypes and haplotypes on clinical outcomes.ResultsWe found that, compared with ERCC2 rs1799793 GG+AG genotypes, the homozygous variant AA genotype was associated with significantly poorer overall survival (OS) (AA vs. GG+AG, log-rank P = 0.012) and significantly higher risk of death (AA vs. GG+AG, Adjusted hazards ratio [HR] 2.13; 95% CI, 1.28 to 3.56; P = 0.004). In combined analyses, patients with any one of the three unfavorable genotypes (i.e. ERCC1 rs3212986 TT, ERCC2 rs13181 GG and rs1799793 AA) had statistically significant hazards of poor prognosis (Adjusted HR, 1.54; 95% CI, 1.06 to 2.25; P = 0.025), compared with those without any unfavorable genotypes. Furthermore, the haplotype A-G-G (rs1799793/rs13181/rs3212986) had a significant impact on OS (Adjusted HR, 1.57; 95% CI, 1.11 to 2.21; P = 0.011), compared with the common haplotype G-T-G.Conclusion ERCC1 and ERCC2 functional SNPs may jointly affect OS in Caucasian gastric cancer patients. Additional large prospective studies are essential to confirm our findings.

Genetic variation in DNA repair genes and prostate cancer risk: results from a population-based study.

DNA repair pathways are crucial to prevent accumulation of DNA damage and maintain genomic stability. Alterations of this pathway have been reported in many cancers. An increase in oxidative DNA damage or decrease in DNA repair capacity with aging or due to germline genetic variation may affect prostate cancer risk. Pooled data from two population-based studies (1,457 cases and 1,351 controls) were analyzed to examine associations between 28 single-nucleotide polymorphisms (SNPs) in nine DNA repair genes (APEX1, BRCA2, ERCC2, ERCC4, MGMT, MUTYH, OGG1, XPC, and XRCC1) and prostate cancer risk. We also explored whether associations varied by smoking, by family history or clinical features of prostate cancer. There were no associations between these SNPs and overall risk of prostate cancer. Risks by genotype also did not vary by smoking or by family history of prostate cancer. Although two SNPs in BRCA2 (rs144848, rs1801406) and two SNPs in ERCC2 (rs1799793, rs13181) showed stronger associations with high Gleason score or advanced-stage tumors when comparing homozygous men carrying the minor versus major allele, results were not statistically significantly different between clinically aggressive and non-aggressive tumors. Overall, this study found no associations between prostate cancer and the SNPs in DNA repair genes. Given the complexity of this pathway and its crucial role in maintenance of genomic stability, a pathway-based analysis of all 150 genes in DNA repair pathways, as well as exploration of gene-environment interactions may be warranted.

Common variations in ERCC2 are associated with response to cisplatin chemotherapy and clinical outcome in osteosarcoma patients

Platinum agents cause DNA cross-linking. Nucleotide excision repair genes play a key role in DNA damage repair. This study aims to investigate whether polymorphisms in these genes are associated with tumor response and survival in cisplatin-treated osteosarcoma patients. Eight single nucleotide polymorphisms in ERCC2, XPC, XPA, ERCC1, ERCC4 and ERCC5 genes were analyzed in 91 patients diagnosed with osteosarcoma and treated with cisplatin. A significant association with tumor response, after correction for multiple testing, was found for the Lys751Gln polymorphism in the ERCC2 gene. We found that only 45% of patients with at least one polymorphic G allele responded compared with 80% of patients homozygous for the common T allele (odds ratio=4.9, 95% confidence interval=1.64-14.54, adjusted P-value=0.047). In addition, carrying at least one ERCC2 Lys751GlnG allele was significantly associated with shorter event-free survival (median=184 months, compared with 240 months for TT homozygotes; hazard ratio=5.76, 95% confidence interval=1.30-25.55; P-value=0.021). Although ototoxicity was only recorded in 32 patients, we found weak evidence of an association with the CC genotype of XPC Lys939Gln (P-value= 0.042). This is the first pharmacogenetic study focused on osteosarcoma treatment providing evidence that polymorphic variants in DNA repair genes could be useful predictors of response to cisplatin chemotherapy in osteosarcoma patients.

Genotyping of Patients with Sporadic and Radiation-Associated Meningiomas

Ionizing radiation is the most established risk factor for meningioma formation. Our aim was to evaluate the main effect of selected candidate genes on the development of meningioma and their possible interaction with ionizing radiation in the causation of this tumor. The total study population included 440 cases and controls: 150 meningioma patients who were irradiated for tinea capitis in childhood, 129 individuals who were similarly irradiated but did not develop meningioma, 69 meningioma patients with no previous history of irradiation, and 92 asymptomatic population controls. DNA from peripheral blood samples was genotyped for single nucleotide polymorphisms (SNP) in 12 genes: NF2, XRCC1, XRCC3, XRCC5, ERCC2, Ki-ras, p16, cyclin D1, PTEN, E-cadherin, TGFB1, and TGFBR2. SNP analysis was done using the MassArray system (Sequenom, San Diego, CA) and computerized analysis by SpectroTYPER. Logistic regressions were applied to evaluate main effect of each gene on meningioma formation and interaction between gene and radiation. Intragenic SNPs in the Ki-ras and ERCC2 genes were associated with meningioma risk (odds ratio, 1.76; 95% confidence interval, 1.07-2.92 and odds ratio, 1.68; 95% confidence interval, 1.00-2.84, respectively). A significant interaction was found between radiation and cyclin D1 and p16 SNPs (P for interaction = 0.005 and 0.057, respectively). Our findings suggest that Ki-ras and ERCC2 SNPs are possible markers for meningioma formation, whereas cyclin D1 and p16 SNPs may be markers of genes that have an inverse effect on the risk to develop meningioma in irradiated and nonirradiated populations.