High expression of ERCC5 predicts a poor prognosis in hepatocellular carcinoma.
ABSTRACT: Human cells exposed to environmental or endogenous carcinogens can develop DNA damage. This DNA damage may contribute to a susceptibility to cancer; therefore, it is important to repair these defects. The nucleotide excision repair pathway (NER) is a versatile DNA repair pathway that eliminates a wide variety of helix-distorting base lesions induced by environmental or endogenous carcinogenic sources. The excision repair cross-complementation group 5 (ERCC5) gene is a central component of NER. Ectopic expression of ERCC5 has been linked to different types of cancers, including hepatocellular carcinoma (HCC). However, previous reports, mainly based on mRNA level and the role of ERCC5 in cancer, remain conflicting and unclear. In this study, we examined 104 cases of HCC for immunohistochemistry to explore the role of ERCC5 protein in HCC. We found the expression of ERCC5 protein was significantly increased in tumor tissues compared to paracancerous ones (P<0.01). The percentage of positive staining of ERCC5 in tumor tissues was 28.8% (30/104), while only 4.8% (5/104) in paracancerous tissues. Patients with low ERCC5 expression levels had a better overall survival rate and remained disease-free longer (both P<0.01). In addition, univariate and multivariate analysis showed a high expression of ERCC5 protein and large tumor size predict a poor prognosis for patients with HCC (P<0.05).
Project description:Background:The current study aims at using the whole genome expression profile chips for systematically investigating the diagnostic and prognostic values of excision repair cross-complementation (ERCC) genes in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Materials and methods:Whole genome expression profile chips were obtained from the GSE14520. The receiver-operating characteristic (ROC) curve, survival analysis, and nomogram were used to investigate the diagnostic and prognostic values of ERCC genes. Investigation of the potential function of ERCC8 was carried out by gene set enrichment analysis (GSEA) and genome-wide coexpression analysis. Results:ROC analysis suggests that six ERCC genes (ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, and ERCC8) were dysregulated and may have potential to distinguish between HBV-related HCC tumor and paracancerous tissues (area under the curve of ROC ranged from 0.623 to 0.744). Survival analysis demonstrated that high ERCC8 expression was associated with a significantly decreased risk of recurrence (adjusted P=0.021; HR=0.643; 95% CI=0.442-0.937) and death (adjusted P=0.049; HR=0.631; 95% CI=0.399-0.998) in HBV-related HCC. Then, we also developed two nomograms for the HBV-related HCC individualized prognosis predictions. GSEA suggests that the high expression of ERCC8 may have involvement in the energy metabolism biological processes. As the genome-wide coexpression analysis and functional assessment of ERCC8 suggest, those coexpressed genes were significantly enriched in multiple biological processes of DNA damage and repair. Conclusion:The present study indicates that six ERCC genes (ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, and ERCC8) were dysregulated between HBV-related HCC tumor and paracancerous tissues and that the mRNA expression of ERCC8 may serve as a potential biomarker for the HBV-related HCC prognosis.
Project description:Excision repair cross‑complementing rodent repair deficiency, complementation group 5 (ERCC5, XPG) is a key molecule in DNA damage repair. We analyzed the contribution of ERCC5 rs751402 polymorphism in increased susceptibility to hepatocellular carcinoma (HCC). A total of 96 patients diagnosed with HCC and 336 healthy controls provided blood samples for analysis of rs751402 genotypes. Demographic data and information on habitual use of tobacco and alcohol were collected. After adjusting for covariates, rs751402 homozygocity for allele C was found to confer a statistically significant protection [adjusted odds ratio (AOR)=0.56; 95% CI, 0.35‑0.89; p=0.01] against HCC, whereas rs751402 T alleles were associated with increased risk (AOR=1.69; 95% CI, 0.74‑3.87). Individuals with the inherited ERCC rs751402 CC genotype may experience significant protection against HCC, whereas individuals with T alleles appear to be exposed to higher risk.
Project description:ERCC5 plays crucial role in excision repair DNA damage induced by UV in NER pathway. Single neuleotide polymorphism in ERCC5 were responsible for different cancers. Therefore, current study evaluated the relationship between ERCC5 (rs1047768 T>C) polymorphism and the risk of breast cancer in Pakistani population. The rs1047768 polymorphism was screened among 175 females including one hundred breast cancer cases and age matched seventy-five healthy controls. Genotyping was performed with Tetra amplification-refractory mutation system (ARMS) PCR and products were observed through electrophoresis. Multivariate logistic regression was used to calculate odds ratio (OR) and 95% confidence interval (95% CI) investigating relationship between genotypes, clinical parameters and risk of breast cancer. Statistical analysis exhibited significant relationship between the TC genotype (OR=7.2, 95% CI=1.5-34.3) and increased breast cancer risk. Moreover, family history (OR=6.25; 95% CI= 2.61-15.00) and late menopause (OR=2.41; 95% CI=1.20-4.83) were found to be breast cancer associated risk factors. In conclusion, ERCC5 (rs1047768 T>C) polymorphism may contribute towards increased risk of breast cancer in Pakistani population.
Project description:Excision repair cross-complementation group 5 (ERCC5) gene plays an important role in nucleotide excision repair, and dysregulation of ERCC5 is associated with increased lung cancer risk. Haplotype and diplotype analyses were conducted in normal bronchial epithelial cells (NBEC) to better understand mechanisms responsible for interindividual variation in transcript abundance regulation of ERCC5 We determined genotypes at putative ERCC5 cis-regulatory SNPs (cis-rSNP) rs751402 and rs2296147, and marker SNPs rs1047768 and rs17655. ERCC5 allele-specific transcript abundance was assessed by a recently developed targeted sequencing method. Syntenic relationships among alleles at rs751402, rs2296147, and rs1047768 were assessed by allele-specific PCR followed by Sanger sequencing. We then assessed association of ERCC5 allele-specific expression at rs1047768 with haplotype and diplotype structure at cis-rSNPs rs751402 and rs2296147. Genotype analysis revealed significantly (P < 0.005) higher interindividual variation in allelic ratios in cDNA samples relative to matched gDNA samples at both rs1047768 and rs17655. By diplotype analysis, mean expression was higher at the rs1047768 alleles syntenic with rs2296147 T allele compared with rs2296147 C allele. Furthermore, mean expression was lower at rs17655 C allele, which is syntenic with G allele at a linked SNP rs873601 (D' = 0.95). These data support the conclusions that in NBEC, T allele at SNP rs2296147 upregulates ERCC5, variation at rs751402 does not alter ERCC5 regulation, and that C allele at SNP rs17655 downregulates ERCC5 Variation in ERCC5 transcript abundance associated with allelic variation at these SNPs could result in variation in NER function in NBEC and lung cancer risk.
Project description:Hundreds of single nucleotide polymorphisms (SNPs) of the genes encoding nucleotide excision repair (NER) proteins are involved in every step of the DNA recognition-unwinding-incision process, which may affect cancer risk. However, only a limited number of studies have examined the association of NER SNPs with hepatocellular cancer (HCC) risk.In screening stage, single-locus analysis showed that six SNPs in five genes were associated with HCC risk, including three risk SNPs (XPA rs10817938, XPC rs1870134 and ERCC2 rs238417) and three protective SNPs (ERCC1 rs2298881 and rs3212961, and ERCC5 rs873601). In verification stage, only XPC rs1870134 was verified to be associated with HCC risk (P = 4.7 × 10-4). Furthermore, multivariate logistic regression and MDR analysis consistently revealed a gene-gene interaction among ERCC1 rs2298881 and XPC rs1870134 SNPs associated with HCC risk (Pinteraction = 0.023). When analyzing the effect of the positive SNP on the mRNA expression, we found XPC rs1870134 GG genotype which was associated with an increased HCC risk showed lower XPC mRNA expression.This study designed as "screening-verification" experiments and included a total of 1472 participants (570 HCC patients vs. 902 controls). We explored 39 SNPs in eight genes involved in NER Pathways, including XPA, XPC, DDB2, ERCC3, ERCC2, ERCC1, ERCC4 and ERCC5, using Sequenom MassARRAY and KASPar platform. Eighty-six cases of HCC and the neighboring noncancerous tissues were subjected to the measurement of mRNA expression level of the promising gene.XPC promoter rs1870134 SNP and SNP-SNP interaction were associated with HCC risk.
Project description:The nucleotide excision repair (NER) pathway plays a major role in the repair of DNA damaged by exogenous agents, such as chemotherapeutic and radiotherapeutic agents. Thus, we investigated the association between key potentially functional single nucleotide polymorphisms (SNPs) in the NER pathway and clinical outcomes in oral squamous cell carcinoma (OSCC) patients treated with concurrent chemoradiotherapy (CCRT). Thirteen SNPs in five key NER genes were genotyped in 319 male OSCC patients using iPLEX MassARRAY. Cox proportional hazards models and Kaplan?Meier survival curves were used to estimate the risk of death or recurrence. Carriers of the XPC rs2228000 TT genotype showed a borderline significant increased risk of poor overall survival under the recessive model (hazard ratio (HR) = 1.81, 95% confidence interval (CI) = 0.99?3.29). The CC genotypes of ERCC5 rs17655 (HR = 1.54, 95% CI = 1.03?2.29) and ERCC1 rs735482 (HR = 1.65, 95% CI = 1.06?2.58) were associated with an increased risk of worse disease-free survival under the recessive model. In addition, participants carrying both the CC genotypes of ERCC5 rs17655 and ERCC1 rs735482 exhibited an enhanced susceptibility for recurrence (HR = 2.60, 95% CI = 1.11?6.09). However, no statistically significant interaction was observed between them. Our findings reveal that the ERCC5 rs17655 CC and ERCC1 rs735482 CC genotypes were associated with an increased risk of recurrence in male patients with OSCC treated with CCRT. Therefore, CCRT may not be beneficial, and alternative treatments are required for such patients.
Project description:Nucleotide excision repair (NER) plays a critical role in maintaining genome integrity. This study aimed to investigate the expression of NER genes and their associations with colorectal cancer (CRC) development.Expressions of NER genes in CRC and normal tissues were analysed by ONCOMINE. The Cancer Genome Atlas (TCGA) data were downloaded to explore relationship of NER expression with clinicopathological parameters and survival of CRC.ERCC1, ERCC2, ERCC5, and DDB2 were upregulated while ERCC4 was downregulated in CRC. For colon cancer, high ERCC3 expression was related to better T stage; ERCC5 expression indicated deeper T stage and distant metastasis; DDB2 expression suggested earlier TNM stage. For rectal cancer, ERCC2 expression correlated with favourable T stage; XPA expression predicted worse TNM stage. ERCC2 expression was associated with worse overall survival (OS) in colon cancer (HR = 1.53, P = 0.043). Colon cancer patients with high ERCC4 expression showed favorable OS in males (HR = 0.54, P = 0.035). High XPC expression demonstrated decreased death hazards in rectal cancer (HR = 0.40, P = 0.026).ERCC1, ERCC2, ERCC4, ERCC5, and DDB2 were differently expressed in CRC and normal tissues; ERCC2, ERCC3, ERCC5, XPA, and DDB2 correlated with clinicopathological parameters of CRC, while ERCC2, ERCC4, and XPC might predict CRC prognosis.
Project description:BACKGROUND: Excision repair cross complementing group 5 (ERCC5 or XPG) plays an important role in regulating DNA excision repair, removal of bulky lesions caused by environmental chemicals or UV light. Mutations in this gene cause a rare autosomal recessive syndrome, and its functional single nucleotide polymorphisms (SNPs) may alter DNA repair capacity phenotype and cancer risk. However, a series of epidemiological studies on the association between the ERCC5 Asp1104His polymorphism (rs17655, G>C) and cancer susceptibility generated conflicting results. METHODOLOGY/PRINCIPAL FINDINGS: To derive a more precise estimation of the association between the ERCC5 Asp1104His polymorphism and overall cancer risk, we performed a meta-analysis of 44 published case-control studies, in which a total of 23,490 cases and 27,168 controls were included. To provide additional biological plausibility, we also assessed the genotype-gene expression correlation from the HapMap phase II release 23 data with 270 individuals from 4 ethnic populations. When all studies were pooled, we found no statistical evidence for a significantly increased cancer risk in the recessive genetic models (His/His vs. Asp/Asp: OR?=?0.99, 95% CI: 0.92-1.06, P?=?0.242 for heterogeneity or His/His vs. Asp/His + Asp/Asp: OR?=?0.98, 95% CI: 0.93-1.03, P?=?0.260 for heterogeneity), nor in further stratified analyses by cancer type, ethnicity, source of controls and sample size. In the genotype-phenotype correlation analysis from 270 individuals, we consistently found no significant correlation of the Asp1104His polymorphism with ERCC5 mRNA expression. CONCLUSIONS/SIGNIFICANCE: This meta-analysis suggests that it is unlikely that the ERCC5 Asp1104His polymorphism may contribute to individual susceptibility to cancer risk.
Project description:Background and Objective: Excision repair cross complementing (ERCC) group genes play important roles in the nucleotide excision repair (NER) way, which can effectively remove bulky lesions and reduce UV-caused DNA damage by environmental chemicals. Polymorphisms in ERCCs were thought to be related to prostate cancer (PCa) risk. However, it has been unclear whether this relationship is consistent. This study aimed to obtain the overall profile regarding the associations between ERCCs polymorphisms and PCa risk. Materials and Methods: We identified relevant studies by a systematic search of PubMed, Medline, Embase, Google Scholar databases, Web of Science and Wanfang databases up to April 8, 2018. Odds ratios (ORs) with 95% confidential intervals (95%CIs) were conducted to evaluate the associations. All the statistical analyses were conducted basing on STATA 12.0 software. Results: Finally, a total of 29 previous studies published in 17 publications were included for four polymorphisms in two DNA repair genes (ERCC2-rs1799793, ERCC2-rs238406, ERCC2-rs13181 and ERCC5-rs17655). Overall, we observed no significant connection between these four polymorphisms and PCa risk. However, after stratifying the studies by ethnicity, ERCC2-rs1799793 polymorphism was associated with an increased risk of PCa in Asian patients and the relationship was subsequently validated with the allelic model, the homozygous model and the recessive model when extracting the data of Asian patients for specific analyses (B vs. A: OR = 1.537, 95%CI: 1.240-1.906, PA< 0.001; BB vs. AA: OR = 2.089, 95%CI: 1.388-3.145, PA< 0.001 and BB vs. BA + AA: OR = 1.929, 95%CI: 1.313-2.835, PA= 0.020). Furthermore, subgroup analyses were also conducted by Hardy-Weinberg Equilibrium (HWE) and source of control, negative results were identified for ERCC2-rs238406, ERCC2-rs13181 and ERCC5-rs17655 polymorphisms (PA> 0.050). Conclusion: To sum up, our work demonstrated that ERCC2-rs1799793 polymorphism is positively associated with PCa risk in Asian population. Further larger-scale studies with subjects of the same ethnicity and biological characteristics are required to verify these findings.
Project description:BACKGROUND: Excision repair cross complementing group 5 (ERCC5 or XPG) plays an important role in regulating DNA excision repair; its functional single nucleotide polymorphisms (SNPs) may alter DNA repair capacity and thus contribute to cancer risk. METHODOLOGY/PRINCIPAL FINDINGS: In a hospital-based case-control study of 1115 esophageal squamous cell carcinoma (ESCC) cases and 1117 cancer-free controls, we genotyped three potentially functional SNPs of ERCC5 (SNPs, rs2296147T>C, rs2094258C>T and rs873601G>A) and estimated crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for their associations with risk of ESCC using unconditional logistic regression models. We also calculated false-positive report probabilities (FPRPs) for significant findings. We found that compared with the TT genotype, ERCC5 rs2296147 C variant genotypes were associated with a significantly lower ESCC risk (CT: adjusted OR?=?0.76, 95% CI?=?0.63-0.93, CT/CC: adjusted OR?=?0.80, 95% CI?=?0.67-0.96); however, this risk was not observed for the other two SNPs (rs2094258C>T and rs873601 G>A), nor in further stratification and haplotype analysis. CONCLUSIONS/SIGNIFICANCES: These findings suggested that ERCC5 polymorphisms may contribute to risk of ESCC in Eastern Chinese populations, but the effect was weak and needs further validation by larger population-based case-control studies.