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Raymond Taetle - One of the best experts on this subject based on the ideXlab platform.
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characterization of illudin s sensitivity in dna repair deficient chinese hamster cells unusually high sensitivity of ercc2 and ercc3 dna helicase deficient mutants in comparison to other chemotherapeutic agents
Biochemical Pharmacology, 1994Co-Authors: Michael J Kelner, Mary Rutherford, Jill Goldstein, Kyra M Samson, Robin Starr, Leita A. Estes, Mark A. Montoya, Trevor C Mcmorris, Raymond TaetleAbstract:Abstract Illudins, novel natural products with a structure unrelated to any other known chemical, display potent in vitro and in vivo anti-cancer activity against even multi-drug resistant tumors, and are metabolically activated to an unstable intermediate that binds to DNA. The DNA damage produced by illudins, however, appears to differ from that of other known DNA damaging toxins. The sensitivity pattern of the various UV-sensitive cell lines differs from previously studied DNA cross-linking agents. Normally, the ERCC1- (excision repair cross complementing) and ERCC4-deficient cell lines are most sensitive to DNA cross-linking agents, with ERCC2-, ERCC3- and ERCC5-deficient cell lines having minimal sensitivity. With illudins the pattern is reversed, with ERCC2 and ERCC3 being the most sensitive. The sensitivity to illudins in complementation groups 1 through 3 is due to a deficiency of the ERCC1-3 gene products, as cellular drug accumulation studies revealed no differences in transport capacity or total drug accumulation. Also, a transgenic cell line in which ERCC2 activity was expressed through an expression vector regained its relative resistance to the illudins. The EM9 cell line, which displays sensitivity to monoadduct producing chemicals, was not sensitive. Thus, excision repair is involved in repair of illudin-induced damage and, unlike other anti-cancer agents, the involvement of ERCC2 and ERCC3 helicases is critical for repair to occur. The requirement for ERCC2 and ERCC3, combined with the finding that ERCC1 but not ERCC2 is upregulated in drug-resistant tumors, may explain the efficacy of illudins against drug-resistant tumors. The inhibition of DNA synthesis in cells within minutes after exposure to illudins at nanomolar concentrations may be related to the finding that the ERCC3 gene product is actually the p89 helicase component of the BTF2 (TFII) basic transcription factor and the high sensitivity of ERCC3-deficient cells to illudins.
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characterization of illudin s sensitivity in dna repair deficient chinese hamster cells unusually high sensitivity of ercc2 and ercc3 dna helicase deficient mutants in comparison to other chemotherapeutic agents
Biochemical Pharmacology, 1994Co-Authors: Michael J Kelner, Mary Rutherford, Jill Goldstein, Kyra M Samson, Robin Starr, Leita A. Estes, Mark A. Montoya, Trevor C Mcmorris, Raymond TaetleAbstract:Abstract Illudins, novel natural products with a structure unrelated to any other known chemical, display potent in vitro and in vivo anti-cancer activity against even multi-drug resistant tumors, and are metabolically activated to an unstable intermediate that binds to DNA. The DNA damage produced by illudins, however, appears to differ from that of other known DNA damaging toxins. The sensitivity pattern of the various UV-sensitive cell lines differs from previously studied DNA cross-linking agents. Normally, the ERCC1- (excision repair cross complementing) and ERCC4-deficient cell lines are most sensitive to DNA cross-linking agents, with ERCC2-, ERCC3- and ERCC5-deficient cell lines having minimal sensitivity. With illudins the pattern is reversed, with ERCC2 and ERCC3 being the most sensitive. The sensitivity to illudins in complementation groups 1 through 3 is due to a deficiency of the ERCC1-3 gene products, as cellular drug accumulation studies revealed no differences in transport capacity or total drug accumulation. Also, a transgenic cell line in which ERCC2 activity was expressed through an expression vector regained its relative resistance to the illudins. The EM9 cell line, which displays sensitivity to monoadduct producing chemicals, was not sensitive. Thus, excision repair is involved in repair of illudin-induced damage and, unlike other anti-cancer agents, the involvement of ERCC2 and ERCC3 helicases is critical for repair to occur. The requirement for ERCC2 and ERCC3, combined with the finding that ERCC1 but not ERCC2 is upregulated in drug-resistant tumors, may explain the efficacy of illudins against drug-resistant tumors. The inhibition of DNA synthesis in cells within minutes after exposure to illudins at nanomolar concentrations may be related to the finding that the ERCC3 gene product is actually the p89 helicase component of the BTF2 (TFII) basic transcription factor and the high sensitivity of ERCC3-deficient cells to illudins.
Eddie Reed - One of the best experts on this subject based on the ideXlab platform.
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inhibition of gli1 results in altered c jun activation inhibition of cisplatin induced upregulation of ERCC1 xpd and xrcc1 and inhibition of platinum dna adduct repair
Oncogene, 2012Co-Authors: Kenji Kudo, Elaine Gavin, Shamik Das, Lauren Amable, Lalita A Shevde, Eddie ReedAbstract:Inhibition of Gli1 results in altered c-Jun activation, inhibition of cisplatin-induced upregulation of ERCC1, XPD and XRCC1, and inhibition of platinum–DNA adduct repair
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ethnic disparities in americans of european descent versus americans of african descent related to polymorphic ERCC1 ercc2 xrcc1 and parp1
Molecular Cancer Therapeutics, 2008Co-Authors: Douglas K. Price, Tristan M Sissung, Eddie Reed, William D FiggAbstract:Nucleotide excision repair (NER) and base excision repair (BER) pathways are DNA repair pathways that are important in carcinogenesis and in response to DNA-damaging chemotherapy. ERCC1 and ERCC2 are important molecular markers for NER; XRCC1 and PARP1 are important molecular markers for BER. Functional polymorphisms have been described that are associated with altered expression levels of these genes and with altered DNA repair capability. We assayed genomic DNA from 156 Americans of European descent and 164 Americans of African descent for the allelic frequencies of specific polymorphisms of ERCC1 N118N (500C>T), ERCC1 C8092A, ERCC2 K751Q (2282A>C), XRCC1 R399Q (1301G>A), XRCC1 R194W (685C>T), and PARP1 V762A (2446T>C). Differences were observed between Americans of European descent and Americans of African descent in the allelic frequencies of the ERCC1 N118N polymorphism ( P < 0.000001). Differences were also observed between these two ethnic groups for ERCC2 K751Q ( P = < 0.006675), XRCC1 R399Q ( P < 0.000001), and PARP1 V762A ( P = 0.000001). The ERCC1 N118N polymorphic variant that is seen most commonly in Americans of European descent is associated with a measurable reduction in NER function. ERCC1-mediated reduction in NER functionality affects the repair of cisplatin-DNA lesions. [Mol Cancer Ther 2008;7(5):1246–50]
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loss of heterozygosity in human ovarian cancer on chromosome 19q
Gynecologic Oncology, 1997Co-Authors: Annette Bicher, Eddie Reed, Kristen Ault, Alec C Kimmelman, David M Gershenson, Bertrand C LiangAbstract:Abnormalities in the function of oncogenes and tumor suppressor genes have been associated with many human malignancies. The recognition of sites of loss of heterozygosity (LOH) has led to the identification of such genes. We previously reported that abnormalities of mRNA expression of ERCC1 and ERCC2 may be characteristic of epithelial ovarian carcinoma and brain tumors. This led to an investigation of chromosome 19q13.2-q13.4 which contains these DNA repair genes. A 7-Mb region was analyzed using six microsatellite repeats. Loss of heterozygosity has been identified in 53% (8/15) of cases at marker D19S246 which lies in a 2-Mb segment between HRC and KLK1. The genetic material both centromeric and telomeric to the region of loss was conserved. This area is telomeric to three DNA repair genes where LIG1 is 1-Mb centromeric and ERCC1 and ERCC2 are 3.5- and 4.0-Mb centromeric, respectively. These findings represent the first report of a biologically significant rate of LOH on chromosome 19q13.2-q13.4 in human ovarian carcinoma.
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comparative analyses of relative ercc3 and ercc6 mrna levels in gliomas and adjacent non neoplastic brain
Molecular Carcinogenesis, 1996Co-Authors: Meenakshi Dabholkar, Frieda Bostickbruton, Justine A Vionnet, John R Silber, Mitchel S. Berger, Larry Overton, Carol L Thompson, Eddie ReedAbstract:Nucleotide excision repair (NER) is an ordered process in nonmalignant cells, in both human and nonhuman systems. We previously reported that in human brain there is discordant mRNA expression of excision repair cross-complementing (ERCC) 1 and ERCC2 in malignant tissues, concurrent with excellent concordance of these genes in nonmalignant tissues from the same patients. Here we have extended these studies to compare low-grade tumors to high-grade tumors and to include ERCC3 (which links DNA repair with DNA transcription) and ERCC6 (which is essential for gene-specific repair). Glial tumor and adjacent normal brain specimens from 19 individuals were studied. Paired malignant and nonmalignant tissues were obtained from 12 of these patients. For ERCC3, there was excellent concordance of mRNA expression between malignant and nonmalignant tissues from the same individuals (P = 0.003). For ERCC6, no concordance was observed (P = 0.314). Tumor tissue from patients with high-grade gliomas exhibited marked discordance of mRNA expression patterns in situations in which good concordance was observed in tumor tissue from low-grade gliomas. We previously established that malignant brain tumors show increased disorder of genes in the NER process, as compared with nonmalignant tissues. These data suggest that increasing disorder in the NER process may occur as cells move from low-grade to high-grade malignancy.
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malignant and nonmalignant brain tissues differ in their messenger rna expression patterns for ERCC1 and ercc2
Cancer Research, 1995Co-Authors: Meenakshi Dabholkar, Justine A Vionnet, John R Silber, Jing Jie Yu, Charles E Egwuagu, Mitchel S. Berger, Eddie ReedAbstract:Perturbation of the DNA repair process appears to be responsible for the occurrence of a number of human diseases, which are usually associated with a propensity to develop internal malignancies and/or disorders of the central nervous system. We have been interested in the possibility that a subtle abnormality in DNA repair competency might be associated with the transformation of nonmalignant cells to the malignant state. To study this question, we assayed malignant and nonmalignant brain tissues from 19 individuals for mRNA expression levels of the human DNA repair genes ERCC1, ERCC2 , and XPAC and for differential splicing of the ERCC1 transcript. We separately compared expression levels of these genes in the following situations: concordance of expression within malignant tissues; concordance of expression within nonmalignant tissues; concordance between malignant and nonmalignant tissues within individuals of the cohort; and concordance of gene expression between two nonmalignant tissue sites within a single individual. Linear regression analyses of mRNA values obtained suggested orderly concordance of these three DNA repair genes in nonmalignant tissues within the patient cohort and an excellent concordance of these genes between two separate biopsy sites from the same individual. In contrast, malignant tissues showed disruption of concordance between the full-length ERCC1 transcript and ERCC2 , which have excision and helicase functions, respectively. Furthermore, within the same individuals, malignant tissues were discordant with nonmalignant tissues for ERCC1 and ERCC2 , although concordance for XPAC was preserved. These data suggest that one molecular characteristic of human malignancy may be the disruption of the normal relationship between the excision and the helicase functions of the nucleotide excision repair pathway.
David C Christiani - One of the best experts on this subject based on the ideXlab platform.
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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.
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polymorphisms in the dna repair genes xrcc1 and ercc2 smoking and lung cancer risk
Cancer Epidemiology Biomarkers & Prevention, 2003Co-Authors: Wei Zhou, John C Wain, Li Su, David P Miller, Sally W Thurston, Li Lian Xu, Thomas J Lynch, David C ChristianiAbstract:XRCC1 (X-ray cross-complementing group 1) and ERCC2 (excision repair cross-complementing group 2) are two major DNA repair proteins. Polymorphisms of these two genes have been associated with altered DNA repair capacity and cancer risk. We have described statistically significant interactions between the ERCC2 polymorphisms ( Asp312Asn and Lys751Gln ) and smoking in lung cancer risk. In this case-control study of 1091 Caucasian lung cancer patients and 1240 controls, we explored the gene-environment interactions between the XRCC1 Arg399Gln polymorphism, alone or in combination with the two ERCC2 polymorphisms, and cumulative smoking exposure in the development of lung cancer. The results were analyzed using logistic regression models, adjusting for relevant covariates. Overall, the adjusted odds ratio (OR) of XRCC1 Arg399Gln polymorphism ( Gln/Gln versus Arg/Arg ) was 1.3 [95% confidence interval (CI), 1.0–1.8]. Stratified analyses revealed that the ORs decreased as pack-years increased. For nonsmokers, the adjusted OR was 2.4 (95% CI, 1.2–5.0), whereas for heavy smokers (≥55 pack-years), the OR decreased to 0.5 (95% CI, 0.3–1.0). When the three polymorphisms were evaluated together, the adjusted ORs of the extreme genotype combinations of variant alleles (individuals with 5 or 6 variant alleles) versus wild genotype (individuals with 0 variant alleles) were 5.2 (95% CI, 1.7–16.6) for nonsmokers and 0.3 (95% CI, 0.1–0.8) for heavy smokers, respectively. Similar gene-smoking interaction associations were found when pack-years of smoking (or smoking duration and smoking intensity) was fitted as a continuous variable. In conclusion, cumulative cigarette smoking plays an important role in altering the direction and magnitude of the associations between the XRCC1 and ERCC2 polymorphisms and lung cancer risk.
Michael J Kelner - One of the best experts on this subject based on the ideXlab platform.
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characterization of illudin s sensitivity in dna repair deficient chinese hamster cells unusually high sensitivity of ercc2 and ercc3 dna helicase deficient mutants in comparison to other chemotherapeutic agents
Biochemical Pharmacology, 1994Co-Authors: Michael J Kelner, Mary Rutherford, Jill Goldstein, Kyra M Samson, Robin Starr, Leita A. Estes, Mark A. Montoya, Trevor C Mcmorris, Raymond TaetleAbstract:Abstract Illudins, novel natural products with a structure unrelated to any other known chemical, display potent in vitro and in vivo anti-cancer activity against even multi-drug resistant tumors, and are metabolically activated to an unstable intermediate that binds to DNA. The DNA damage produced by illudins, however, appears to differ from that of other known DNA damaging toxins. The sensitivity pattern of the various UV-sensitive cell lines differs from previously studied DNA cross-linking agents. Normally, the ERCC1- (excision repair cross complementing) and ERCC4-deficient cell lines are most sensitive to DNA cross-linking agents, with ERCC2-, ERCC3- and ERCC5-deficient cell lines having minimal sensitivity. With illudins the pattern is reversed, with ERCC2 and ERCC3 being the most sensitive. The sensitivity to illudins in complementation groups 1 through 3 is due to a deficiency of the ERCC1-3 gene products, as cellular drug accumulation studies revealed no differences in transport capacity or total drug accumulation. Also, a transgenic cell line in which ERCC2 activity was expressed through an expression vector regained its relative resistance to the illudins. The EM9 cell line, which displays sensitivity to monoadduct producing chemicals, was not sensitive. Thus, excision repair is involved in repair of illudin-induced damage and, unlike other anti-cancer agents, the involvement of ERCC2 and ERCC3 helicases is critical for repair to occur. The requirement for ERCC2 and ERCC3, combined with the finding that ERCC1 but not ERCC2 is upregulated in drug-resistant tumors, may explain the efficacy of illudins against drug-resistant tumors. The inhibition of DNA synthesis in cells within minutes after exposure to illudins at nanomolar concentrations may be related to the finding that the ERCC3 gene product is actually the p89 helicase component of the BTF2 (TFII) basic transcription factor and the high sensitivity of ERCC3-deficient cells to illudins.
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characterization of illudin s sensitivity in dna repair deficient chinese hamster cells unusually high sensitivity of ercc2 and ercc3 dna helicase deficient mutants in comparison to other chemotherapeutic agents
Biochemical Pharmacology, 1994Co-Authors: Michael J Kelner, Mary Rutherford, Jill Goldstein, Kyra M Samson, Robin Starr, Leita A. Estes, Mark A. Montoya, Trevor C Mcmorris, Raymond TaetleAbstract:Abstract Illudins, novel natural products with a structure unrelated to any other known chemical, display potent in vitro and in vivo anti-cancer activity against even multi-drug resistant tumors, and are metabolically activated to an unstable intermediate that binds to DNA. The DNA damage produced by illudins, however, appears to differ from that of other known DNA damaging toxins. The sensitivity pattern of the various UV-sensitive cell lines differs from previously studied DNA cross-linking agents. Normally, the ERCC1- (excision repair cross complementing) and ERCC4-deficient cell lines are most sensitive to DNA cross-linking agents, with ERCC2-, ERCC3- and ERCC5-deficient cell lines having minimal sensitivity. With illudins the pattern is reversed, with ERCC2 and ERCC3 being the most sensitive. The sensitivity to illudins in complementation groups 1 through 3 is due to a deficiency of the ERCC1-3 gene products, as cellular drug accumulation studies revealed no differences in transport capacity or total drug accumulation. Also, a transgenic cell line in which ERCC2 activity was expressed through an expression vector regained its relative resistance to the illudins. The EM9 cell line, which displays sensitivity to monoadduct producing chemicals, was not sensitive. Thus, excision repair is involved in repair of illudin-induced damage and, unlike other anti-cancer agents, the involvement of ERCC2 and ERCC3 helicases is critical for repair to occur. The requirement for ERCC2 and ERCC3, combined with the finding that ERCC1 but not ERCC2 is upregulated in drug-resistant tumors, may explain the efficacy of illudins against drug-resistant tumors. The inhibition of DNA synthesis in cells within minutes after exposure to illudins at nanomolar concentrations may be related to the finding that the ERCC3 gene product is actually the p89 helicase component of the BTF2 (TFII) basic transcription factor and the high sensitivity of ERCC3-deficient cells to illudins.
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.