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David C Christiani - One of the best experts on this subject based on the ideXlab platform.
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polymorphisms in ercc1 and ercc2 xpd genes and carcinogen dna adducts in human lung
Lung Cancer, 2015Co-Authors: Li Su, David C ChristianiAbstract:Objectives In this exploratory study, we aimed to investigate whether polymorphisms in excision repair cross-complementing group 1 (ERCC1) and excision repair cross-complementing group 2/xeroderma pigmentosum group D (ERCC2/XPD) in the nucleotide excision repair (NER) pathways associated with DNA adducts in human lung tissue. We also analyzed the association stratified by the major histologic subtypes of non-small cell lung cancer (NSCLC): adenocarcinoma (ADC) and squamous cell carcinoma (SQCC).
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abstract 4479 polymorphisms in the nucleotide excision repair genes ercc1 and ercc2 xpd and carcinogen dna adducts in human lung
Cancer Research, 2012Co-Authors: Li Su, John C Wain, Eugene J. Mark, David C ChristianiAbstract:Objectives Excision repair cross-complementing group 1 (ERCC1) and excision repair cross-complementing group 2/xeroderma pigmentosum group D (ERCC2/XPD) in the nucleotide excision repair (NER) pathways that removes DNA damage caused by tobacco smoking carcinogen such as polycyclic aromatic hydrocarbons (PAHs). However, no studies have examined their role in DNA adducts in target human lung tissue, a dosimeter for lung cancer risk. Therefore, we investigated whether the polymorphisms in SNPs in NER pathways associated with the DNA adduct formation in human lung tissue. We further analyzed these relationship divided by adenocarcinoma and squamous cell carcinoma, main type of non-small cell lung cancer (NSCLC). Methods The study population consisted of 135 lung cancer patients from the Massachusetts General Hospital (MGH). Genotyping was completed for SNPs in ERCC1 [C8092A (rs3212986) and C118T (rs11615)] and ERCC2/XPD [Asp312Asn (rs1799793) and Lys751Gln (rs1052559)] using PCR-RFLP method and the PCR with fluorescent allele-specific oligonucleotide probes (TaqMan method). DNA adduct levels were measured as relative adduct levels per 1010 nucleotides by 32P-postlabeling in the lung. Multiple regression models were used to estimate adjusted percent change in DNA adduct levels associated with genotypes of the NER genes ERCC1 and ERCC2/XPD. Results After adjusting for potential confounders, DNA adduct levels in lung increased by 73.5% [95% confidence interval (CI), –22.6 to 288.9] for the ERCC2/XPD rs1799793AA genotype and by 43.7% (95% CI, –30.0 to 194.6) for ERCC2/XPD rs1052559GG genotype compared with their corresponding wild type homozygous genotypes in overall lung cancer patients, but it did not reach statistical significance. We found that DNA adducts levels in lung increased by 166.6% (95% CI, –5.0 to 648.3, P = 0.07) for ERCC2/XPD rs1799793AA genotype in patients with squamous cell carcinoma and the trend was borderline significant (P for trend = 0.06). Conclusions Polymorphisms of DNA repair genes, ERCC2/XPD Asp312Asn, may affect increased level of DNA adducts in the lung. Further large scale studies are needed to confirm our findings. Supported by NIH grants CA074386, CA092824, and CA90578. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4479. doi:1538-7445.AM2012-4479
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no evidence of an association of ercc1 and ercc2 polymorphisms with clinical outcomes of platinum based chemotherapies in non small cell lung cancer a meta analysis
Lung Cancer, 2011Co-Authors: Alexandra Voutsina, Carmelo Tibaldi, Rafael Rosell, David C Christiani, Rebecca Suk Heist, Richard BootonAbstract:BACKGROUND: The nucleotide excision repair (NER) pathway modulates platinum-based chemotherapeutic efficacy by removing drug-induced DNA damage. METHODS: To summarize published data on the association between NER genes and responses to platinum-based chemotherapies in non-small cell lung cancer (NSCLC), we performed a meta-analysis of 17 published studies of ERCC1 C118T/C8092A and ERCC2 Lys751Gln/Asp312Asn polymorphisms, including 2097 cancer patients. Primary outcomes included objective response (TR) (i.e., complete response+partial response vs. stable disease+progressive disease), progression-free survival (PFS) and overall survival (OS). We calculated odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI) to estimate the risk or hazard. RESULTS: We found that none of the ERCC1 C118T/C8092A and ERCC2 Lys751Gln/Asp312Asn polymorphisms alone was statistically significantly associated with objective response, PFS and OS in NSCLC patients. CONCLUSION: There is no evidence to support the use of NER ERCC1 C118T/C8092A and ERCC2 Lys751Gln/Asp312Asn polymorphisms as prognostic predictors of platinum-based chemotherapies in NSCLC.
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genetic modifiers of carcinogen dna adducts in target lung and peripheral blood mononuclear cells
Carcinogenesis, 2010Co-Authors: Misun Lee, John C Wain, Eugene J. Mark, David C ChristianiAbstract:Measurement of carcinogen DNA adducts in blood has been used as a surrogate for the target lung tissue. We aimed to examine whether genetic polymorphisms in several metabolic pathway genes modify the relation between DNA adducts in target lung and blood. One hundred and thirty-five early-stage lung cancer patients from the Massachusetts General Hospital were studied. DNA adducts were measured by the 32 P-postlabeling assay in lung and blood mononuclear cells (MNCs) in a subset of 53 who had paired blood samples. Single-nucleotide polymorphisms (SNPs) were assessed in genes involved in phase II (GSTs, NAT2, EPHX and NQO1), DNA repair (ERCC1, ERCC2 and XRCC1) and DNA methylation (MTHFR C677T and A1298C) pathways. There was a significant correlation between DNA adduct levels in lung and blood within the different genotypes, with one exception. Significant modifications in adducts were found by variants in genes for phase II metabolism [NAT2 (1.51 for rapid versus 0.76 for slow, P = 0.022)], DNA repair [ERCC1 C118T (P = 0.014), ERCC2 (P = 0.003) and XRCC1 (P = 0.025)] and MTHFR [C677T (P = 0.005) and A1298C (P = 0.005)]. The relation between DNA adducts in blood MNCs and target lung tissue was significantly modified by the single-nucleotide polymorphisms in the three main pathways. Despite the relatively small sample size, our results suggest that genetic factors may need to be considered when assessing the association of DNA adducts using surrogate tissue in studies of lung cancer. Further studies are needed to better understand their role and the mechanisms.
Weiyu Liao - One of the best experts on this subject based on the ideXlab platform.
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combined effect of ercc1 and ercc2 polymorphisms on overall survival in non squamous non small cell lung cancer patients treated with first line pemetrexed platinum
Lung Cancer, 2018Co-Authors: Weiyu Liao, Chaochi Ho, Tzuhsiu Tsai, Jinyuan Shih, Kuanyu Chen, Chongjen YuAbstract:Abstract Objectives Polymorphisms of DNA repair genes may affect DNA repair capacity and the sensitivity of platinum doublets chemotherapy in non-small-cell lung cancer (NSCLC). We prospectively evaluated whether single nucleotide polymorphisms (SNPs) of ERCC1, ERCC2, XRCC1, and XRCC3 were associated with treatment outcome in advanced non-squamous NSCLC patients receiving pemetrexed/platinum as their first-line chemotherapy. Materials and methods Genotyping of six SNPs in four DNA repair genes in 58 patients treated with first-line pemetrexed/platinum was performed using TaqMan SNP Genotyping Assays. Results The wild-type ERCC1 8092 (C/C) was significantly associated with a better objective response compared to the variant genotypes (C/A + A/A) (48% vs 10%, P = .005). In the multivariate Cox proportional hazards model, we found that individuals with a wild-type genotype of ERCC1 Asn118Asn, ERCC1 C8092A and ERCC2 Asp312Asn had significantly better overall survival (OS) than those with a heterozygous or homozygous variant genotype. On the other hand, the heterozygous variant genotype of ERCC2 Lys751Gln was associated with better OS than that of the wild-type genotype. We further explored the combined effect of SNPs on OS, and found a significant allele/dose-dependent trend toward decreasing OS in patients with an increasing number of unfavorable alleles among four SNPs in ERCC1 and ERCC2. The median OS of patients with two or three unfavorable alleles (30.1 and 30.5 months, respectively) was significantly longer than that of patients with 4 unfavorable alleles (11.8 months, log-rank test for trend, P = .001). Conclusion A combination of ERCC1 and ERCC2 polymorphisms may predict OS among pemetrexed/platinum treated advanced non-squamous NSCLC patients.
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combined effect of ercc1 and ercc2 polymorphisms on overall survival in non squamous non small cell lung cancer patients treated with first line pemetrexed platinum
Lung Cancer, 2018Co-Authors: Weiyu Liao, Chaochi Ho, Tzuhsiu Tsai, Jinyuan Shih, Kuanyu Chen, Chongjen YuAbstract:Abstract Objectives Polymorphisms of DNA repair genes may affect DNA repair capacity and the sensitivity of platinum doublets chemotherapy in non-small-cell lung cancer (NSCLC). We prospectively evaluated whether single nucleotide polymorphisms (SNPs) of ERCC1, ERCC2, XRCC1, and XRCC3 were associated with treatment outcome in advanced non-squamous NSCLC patients receiving pemetrexed/platinum as their first-line chemotherapy. Materials and methods Genotyping of six SNPs in four DNA repair genes in 58 patients treated with first-line pemetrexed/platinum was performed using TaqMan SNP Genotyping Assays. Results The wild-type ERCC1 8092 (C/C) was significantly associated with a better objective response compared to the variant genotypes (C/A + A/A) (48% vs 10%, P = .005). In the multivariate Cox proportional hazards model, we found that individuals with a wild-type genotype of ERCC1 Asn118Asn, ERCC1 C8092A and ERCC2 Asp312Asn had significantly better overall survival (OS) than those with a heterozygous or homozygous variant genotype. On the other hand, the heterozygous variant genotype of ERCC2 Lys751Gln was associated with better OS than that of the wild-type genotype. We further explored the combined effect of SNPs on OS, and found a significant allele/dose-dependent trend toward decreasing OS in patients with an increasing number of unfavorable alleles among four SNPs in ERCC1 and ERCC2. The median OS of patients with two or three unfavorable alleles (30.1 and 30.5 months, respectively) was significantly longer than that of patients with 4 unfavorable alleles (11.8 months, log-rank test for trend, P = .001). Conclusion A combination of ERCC1 and ERCC2 polymorphisms may predict OS among pemetrexed/platinum treated advanced non-squamous NSCLC patients.
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genetic polymorphism of xrcc1 arg399gln is associated with survival in non small cell lung cancer patients treated with gemcitabine platinum
Journal of Thoracic Oncology, 2012Co-Authors: Weiyu Liao, Jinyuan Shih, Geechen Chang, Yukai Cheng, James Chihhsin Yang, Yuhmin ChenAbstract:Introduction Elevated DNA-repair capacity has been related to chemoresistance of platinum doublet chemotherapy in non–small-cell lung cancer (NSCLC). We evaluated whether single nucleotide polymorphisms of DN- repair genes excision repair cross-complementing group 1 ( ERCC1 ), ERCC2 , x-ray repair cross-complementing group 1 ( XRCC1 ), XRCC3 , and RRM1 associate with treatment outcome in NSCLC patients receiving gemcitabine plus platinum as their first-line chemotherapy. Methods Genotyping for eight polymorphisms in five DNA-repair genes was performed with the GenomeLab nucleotide polymorphismstream Genotyping System in 62 advanced NSCLC patients in a training set and 45 patients in a validation set treated with gemcitabine/platinum. Results In the training set, the wild-type genotype of XRCC1 Arg399Gln (G/G) was associated with decreased median overall survival (OS) (22 months, 95% confidence interval [CI], 10–34 months versus not reached, log-rank test, p = 0.005) than those carrying variant genotypes (G/A+A/A). In addition, there was a statistically significant longer median OS in patients carrying wild-type ERCC2 Asp312Asn genotype (G/G) (51 months, 95% CI, 19–82 months versus 10 months, log-rank test, p XRCC1 Arg399Gln (G/A+A/A versus G/G, hazard ratio [HR] 0.290; 95%CI, 0.12–0.705, p = 0.006) and ERCC2 Asp312Asn (G/A versus G/G, HR 14.04; 95% CI, 2.253–87.513, p = 0.005) polymorphisms on patients' OS. In the validation set, only XRCC1 399 Conclusions Genetic polymorphism of XRCC1 Arg399Gln may be a candidate for contributing interindividual difference in the OS of gemcitabine/platinum-treated advanced NSCLC patients.
Chongjen Yu - One of the best experts on this subject based on the ideXlab platform.
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combined effect of ercc1 and ercc2 polymorphisms on overall survival in non squamous non small cell lung cancer patients treated with first line pemetrexed platinum
Lung Cancer, 2018Co-Authors: Weiyu Liao, Chaochi Ho, Tzuhsiu Tsai, Jinyuan Shih, Kuanyu Chen, Chongjen YuAbstract:Abstract Objectives Polymorphisms of DNA repair genes may affect DNA repair capacity and the sensitivity of platinum doublets chemotherapy in non-small-cell lung cancer (NSCLC). We prospectively evaluated whether single nucleotide polymorphisms (SNPs) of ERCC1, ERCC2, XRCC1, and XRCC3 were associated with treatment outcome in advanced non-squamous NSCLC patients receiving pemetrexed/platinum as their first-line chemotherapy. Materials and methods Genotyping of six SNPs in four DNA repair genes in 58 patients treated with first-line pemetrexed/platinum was performed using TaqMan SNP Genotyping Assays. Results The wild-type ERCC1 8092 (C/C) was significantly associated with a better objective response compared to the variant genotypes (C/A + A/A) (48% vs 10%, P = .005). In the multivariate Cox proportional hazards model, we found that individuals with a wild-type genotype of ERCC1 Asn118Asn, ERCC1 C8092A and ERCC2 Asp312Asn had significantly better overall survival (OS) than those with a heterozygous or homozygous variant genotype. On the other hand, the heterozygous variant genotype of ERCC2 Lys751Gln was associated with better OS than that of the wild-type genotype. We further explored the combined effect of SNPs on OS, and found a significant allele/dose-dependent trend toward decreasing OS in patients with an increasing number of unfavorable alleles among four SNPs in ERCC1 and ERCC2. The median OS of patients with two or three unfavorable alleles (30.1 and 30.5 months, respectively) was significantly longer than that of patients with 4 unfavorable alleles (11.8 months, log-rank test for trend, P = .001). Conclusion A combination of ERCC1 and ERCC2 polymorphisms may predict OS among pemetrexed/platinum treated advanced non-squamous NSCLC patients.
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combined effect of ercc1 and ercc2 polymorphisms on overall survival in non squamous non small cell lung cancer patients treated with first line pemetrexed platinum
Lung Cancer, 2018Co-Authors: Weiyu Liao, Chaochi Ho, Tzuhsiu Tsai, Jinyuan Shih, Kuanyu Chen, Chongjen YuAbstract:Abstract Objectives Polymorphisms of DNA repair genes may affect DNA repair capacity and the sensitivity of platinum doublets chemotherapy in non-small-cell lung cancer (NSCLC). We prospectively evaluated whether single nucleotide polymorphisms (SNPs) of ERCC1, ERCC2, XRCC1, and XRCC3 were associated with treatment outcome in advanced non-squamous NSCLC patients receiving pemetrexed/platinum as their first-line chemotherapy. Materials and methods Genotyping of six SNPs in four DNA repair genes in 58 patients treated with first-line pemetrexed/platinum was performed using TaqMan SNP Genotyping Assays. Results The wild-type ERCC1 8092 (C/C) was significantly associated with a better objective response compared to the variant genotypes (C/A + A/A) (48% vs 10%, P = .005). In the multivariate Cox proportional hazards model, we found that individuals with a wild-type genotype of ERCC1 Asn118Asn, ERCC1 C8092A and ERCC2 Asp312Asn had significantly better overall survival (OS) than those with a heterozygous or homozygous variant genotype. On the other hand, the heterozygous variant genotype of ERCC2 Lys751Gln was associated with better OS than that of the wild-type genotype. We further explored the combined effect of SNPs on OS, and found a significant allele/dose-dependent trend toward decreasing OS in patients with an increasing number of unfavorable alleles among four SNPs in ERCC1 and ERCC2. The median OS of patients with two or three unfavorable alleles (30.1 and 30.5 months, respectively) was significantly longer than that of patients with 4 unfavorable alleles (11.8 months, log-rank test for trend, P = .001). Conclusion A combination of ERCC1 and ERCC2 polymorphisms may predict OS among pemetrexed/platinum treated advanced non-squamous NSCLC patients.
Gaetano R Barile - One of the best experts on this subject based on the ideXlab platform.
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the ERCC6 gene and age related macular degeneration
PLOS ONE, 2010Co-Authors: Dominique C Baas, Dominiek D G Despriet, Theo G M F Gorgels, Julie Bergeronsawitzke, Andre G Uitterlinden, Albert Hofman, Cornelia M Van Duijn, Joanna E Merriam, Theodore R Smith, Gaetano R BarileAbstract:Background: Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in the developed countries and is caused by both environmental and genetic factors. A recent study (Tuo et al., PNAS) reported an association between AMD and a single nucleotide polymorphism (SNP) (rs3793784) in the ERCC6 (NM_000124) gene. The risk allele also increased ERCC6 expression. ERCC6 is involved in DNA repair and mutations in ERCC6 cause Cockayne syndrome (CS). Amongst others, photosensitivity and pigmentary retinopathy are hallmarks of CS. Methodology/Principal Findings: Separate and combined data from three large AMD case-control studies and a prospective population-based study (The Rotterdam Study) were used to analyse the genetic association between ERCC6 and AMD (2682 AMD cases and 3152 controls). We also measured ERCC6 mRNA levels in retinal pigment epithelium (RPE) cells of healthy and early AMD affected human donor eyes. Rs3793784 conferred a small increase in risk for late AMD in the Dutch population (The Rotterdam and AMRO-NL study), but this was not replicated in two non-European studies (AREDS, Columbia University). In addition, the AMRO-NL study revealed no significant association for 9 other variants spanning ERCC6. Finally, we determined that ERCC6 expression in the human RPE did not depend on rs3793784 genotype, but, interestingly, on AMD status: Early AMD-affected donor eyes had a 50% lower ERCC6 expression than healthy donor eyes (P=0.018). Conclusions/Significance: Our meta-analysis of four Caucasian cohorts does not replicate the reported association between SNPs in ERCC6 and AMD. Nevertheless, our findings on ERCC6 expression in the RPE suggest that ERCC6 may be functionally involved in AMD. Combining our data with those of the literature, we hypothesize that the AMD-related reduced transcriptional activity of ERCC6 may be caused by diverse, small and heterogeneous genetic and/or environmental determinants.
Emily Y Chew - One of the best experts on this subject based on the ideXlab platform.
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synergic effect of polymorphisms in ERCC6 5 flanking region and complement factor h on age related macular degeneration predisposition
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Jingsheng Tuo, Baitang Ning, Christine M Bojanowski, Zhongning Lin, Robert J Ross, George F Reed, Defen Shen, Xiaodong Jiao, Min Zhou, Emily Y ChewAbstract:This study investigates age-related macular degeneration (AMD) genetic risk factors through identification of a functional single-nucleotide polymorphism (SNP) and its disease association. We chose ERCC6 because of its roles in the aging process, DNA repair, and ocular degeneration from the gene disruption. Bioinformatics indicated a putative binding-element alteration on the sequence containing C−6530>G SNP in the 5′ flanking region of ERCC6 from Sp1 on the C allele to SP1, GATA-1, and OCT-1 on the G allele. Electrophoretic mobility shift assays displayed distinctive C and G allele-binding patterns to nuclear proteins. Luciferase expression was higher in the vector construct containing the G allele than that containing the C allele. A cohort of 460 advanced AMD cases and 269 age-matched controls was examined along with pathologically diagnosed 57 AMD and 18 age-matched non-AMD archived cases. ERCC6 C−6530>G was associated with AMD susceptibility, both independently and through interaction with an SNP (rs380390) in the complement factor H (CFH) intron reported to be highly associated with AMD. A disease odds ratio of 23 was conferred by homozygozity for risk alleles at both ERCC6 and CFH compared with homozygozity for nonrisk alleles. Enhanced ERCC6 expression was observed in lymphocytes from healthy donors bearing ERCC6 C−6530>G alleles. Intense immunostaining of ERCC6 was also found in AMD eyes from ERCC6 C−6530>G carriers. The strong AMD predisposition conferred by the ERCC6 and CFH SNPs may result from biological epistasis, because ERCC6 functions in universal transcription as a component of RNA pol I transcription complex.