The Experts below are selected from a list of 2856 Experts worldwide ranked by ideXlab platform

David C Christiani - One of the best experts on this subject based on the ideXlab platform.

  • polymorphisms in ercc1 and ERCC2 xpd genes and carcinogen dna adducts in human lung
    Lung Cancer, 2015
    Co-Authors: Li Su, David C Christiani
    Abstract:

    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).

  • abstract 4479 polymorphisms in the nucleotide excision repair genes ercc1 and ERCC2 xpd and carcinogen dna adducts in human lung
    Cancer Research, 2012
    Co-Authors: Li Su, John C Wain, Eugene J Mark, David C Christiani
    Abstract:

    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

  • 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, 2011
    Co-Authors: Alexandra Voutsina, Carmelo Tibaldi, David C Christiani, Rebecca S Heist, Rafael Rosell, Richard Booton
    Abstract:

    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.

Jerard Hurwitz - One of the best experts on this subject based on the ideXlab platform.

  • isolation and characterization of two human transcription factor iih tfiih related complexes ERCC2 cak and tfiih
    Proceedings of the National Academy of Sciences of the United States of America, 1996
    Co-Authors: Joyce T Reardon, Hui Ge, Emma Gibbs, Aziz Sancar, Jerard Hurwitz
    Abstract:

    Abstract Transcription factor IIH (TFIIH) is a multisubunit protein complex essential for both the initiation of RNA polymerase class II (pol II)-catalyzed transcription and nucleotide excision repair of DNA. Recent studies have shown that TFIIH copurifies with the cyclin-dependent kinase (cdk)-activating kinase complex (CAK) that includes cdk7, cyclin H, and p36/MAT1. Here we report the isolation of two TFIIH-related complexes: TFIIH* and ERCC2/CAK. TFIIH* consists of a subset of the TFIIH complex proteins including ERCC3 (XPB), p62, p44, p41, and p34 but is devoid of detectable levels of ERCC2 (XPD) and CAK. ERCC2/CAK was isolated as a complex that exhibits CAK activity that cosediments with the three CAK components (cdk7, cyclin H, and p36/MAT1) as well as the ERCC2 (XPD) protein. TFIIH* can support pol II-catalyzed transcription in vitro with lower efficiency compared with TFIIH. This TFIIH*-dependent transcription reaction was stimulated by ERCC2/CAK. The ERCC2/CAK and TFIIH* complexes are each active in DNA repair as shown by their ability to complement extracts prepared from ERCC2 (XPD)- and ERCC3 (XPB)-deficient cells, respectively, in supporting the excision of DNA containing a cholesterol lesion. These data suggest that TFIIH* and ERCC2/CAK interact to form the TFIIH holoenzyme capable of efficiently assembling the pol II transcription initiation complex and directly participating in excision repair reactions.

  • Isolation and characterization of two human transcription factor IIH (TFIIH)-related complexes: ERCC2/CAK and TFIIH.
    Proceedings of the National Academy of Sciences of the United States of America, 1996
    Co-Authors: Joyce T Reardon, Hui Ge, Emma Gibbs, Aziz Sancar, Jerard Hurwitz
    Abstract:

    Abstract Transcription factor IIH (TFIIH) is a multisubunit protein complex essential for both the initiation of RNA polymerase class II (pol II)-catalyzed transcription and nucleotide excision repair of DNA. Recent studies have shown that TFIIH copurifies with the cyclin-dependent kinase (cdk)-activating kinase complex (CAK) that includes cdk7, cyclin H, and p36/MAT1. Here we report the isolation of two TFIIH-related complexes: TFIIH* and ERCC2/CAK. TFIIH* consists of a subset of the TFIIH complex proteins including ERCC3 (XPB), p62, p44, p41, and p34 but is devoid of detectable levels of ERCC2 (XPD) and CAK. ERCC2/CAK was isolated as a complex that exhibits CAK activity that cosediments with the three CAK components (cdk7, cyclin H, and p36/MAT1) as well as the ERCC2 (XPD) protein. TFIIH* can support pol II-catalyzed transcription in vitro with lower efficiency compared with TFIIH. This TFIIH*-dependent transcription reaction was stimulated by ERCC2/CAK. The ERCC2/CAK and TFIIH* complexes are each active in DNA repair as shown by their ability to complement extracts prepared from ERCC2 (XPD)- and ERCC3 (XPB)-deficient cells, respectively, in supporting the excision of DNA containing a cholesterol lesion. These data suggest that TFIIH* and ERCC2/CAK interact to form the TFIIH holoenzyme capable of efficiently assembling the pol II transcription initiation complex and directly participating in excision repair reactions.

Eliezer M Van Allen - One of the best experts on this subject based on the ideXlab platform.

  • abstract pr18 somatic ERCC2 mutations nucleotide excision repair ner function and cisplatin response in muscle invasive bladder cancer mibc
    Molecular Cancer Research, 2017
    Co-Authors: Kent W Mouw, Alexis W Damish, Zoe Frazier, Elizaveta Reznichenko, Jonathan E Rosenberg, Jeanbernard Lazaro, Paz Polak, Levi A Garraway, Gad Getz, Eliezer M Van Allen
    Abstract:

    ERCC2 is a core member of the nucleotide excision repair (NER) pathway, a highly conserved and remarkably versatile DNA repair pathway responsible for repairing intrastrand DNA adducts created by genotoxic agents such as UV irradiation and platinum-based chemotherapies. Recent large-scale genomic efforts have shown that somatic ERCC2 missense mutations are present in approximately 20% of all primary muscle-invasive bladder cancers (MIBC). We previously showed that ERCC2 mutations are associated with treatment response and overall survival in MIBC patients treated with cisplatin-based chemotherapy. Initial functional studies on a subset of the observed ERCC2 mutations suggest that the mutations confer loss of normal cellular NER capacity. However, sequencing of additional MIBC cohorts has revealed that mutations occur across the ERCC2 gene, and the functional effects of the majority of these mutations remain unknown. In order to understand the functional landscape of ERCC2 mutations in MIBC, we have developed a high-throughput fluorescence-based assay to test the functional consequences of mutations in ERCC2 and other NER genes on cellular NER capacity. We apply this approach to all observed ERCC2 mutations across three published MIBC cohorts and find that the majority of ERCC2 mutations result in complete or near-complete loss of cellular NER. In addition, by correlating our functional results with available clinical data, we find interesting examples of cases in which ERCC2 status and cisplatin response are decoupled, highlighting the importance of using functional data to complement genomic and clinical endpoints in the search for reliable predictive biomarkers. This abstract is also being presented as Poster A29. Citation Format: Kent Mouw, Jean-Bernard Lazaro, Alexis Damish, Elizaveta Reznichenko, Zoe Frazier, David Liu, Jaegil Kim, Paz Polak, Levi Garraway, Gad Getz, Jonathan Rosenberg, Eliezer Van Allen, Alan D9Andrea. Somatic ERCC2 mutations, nucleotide excision repair (NER) function, and cisplatin response in muscle-invasive bladder cancer (MIBC) [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr PR18.

  • somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle invasive urothelial carcinoma
    Cancer Discovery, 2014
    Co-Authors: Kent W Mouw, Eliezer M Van Allen, Gopa Iyer, Nikhil Wagle, Hikmat Alahmadie, Irina Ostrovnaya
    Abstract:

    Cisplatin-based chemotherapy is the standard of care for patients with muscle-invasive urothelial carcinoma. Pathologic downstaging to pT0/pTis after neoadjuvant cisplatin-based chemotherapy is associated with improved survival, although molecular determinants of cisplatin response are incompletely understood. We performed whole-exome sequencing on pretreatment tumor and germline DNA from 50 patients with muscle-invasive urothelial carcinoma who received neoadjuvant cisplatin-based chemotherapy followed by cystectomy (25 pT0/pTis “responders,” 25 pT2+ “nonresponders”) to identify somatic mutations that occurred preferentially in responders. ERCC2 , a nucleotide excision repair gene, was the only significantly mutated gene enriched in the cisplatin responders compared with nonresponders ( q < 0.01). Expression of representative ERCC2 mutants in an ERCC2 -deficient cell line failed to rescue cisplatin and UV sensitivity compared with wild-type ERCC2. The lack of normal ERCC2 function may contribute to cisplatin sensitivity in urothelial cancer, and somatic ERCC2 mutation status may inform cisplatin-containing regimen usage in muscle-invasive urothelial carcinoma. Significance: Somatic ERCC2 mutations correlate with complete response to cisplatin-based chemosensitivity in muscle-invasive urothelial carcinoma, and clinically identified mutations lead to cisplatin sensitivity in vitro . Nucleotide excision repair pathway defects may drive exceptional response to conventional chemotherapy. Cancer Discov; 4(10); 1140–53. ©2014 AACR . See related commentary by Turchi et al., [p. 1118][1] This article is highlighted in the In This Issue feature, [p. 1103][2] [1]: /lookup/volpage/4/1118?iss=10 [2]: /lookup/volpage/4/1103?iss=10

Qiang Li - One of the best experts on this subject based on the ideXlab platform.

  • ERCC2 helicase domain mutations confer nucleotide excision repair deficiency and drive cisplatin sensitivity in muscle invasive bladder cancer
    Clinical Cancer Research, 2019
    Co-Authors: Qiang Li, Alexis W Damish, Zoe Frazier, Elizaveta Reznichenko, Atanas Kamburov, Andrew C Bell, Huiyong Zhao
    Abstract:

    Purpose: DNA damaging agents comprise the backbone of systemic treatment for many tumor types; however, few reliable predictive biomarkers are available to guide use of these agents. In muscle-invasive bladder cancer (MIBC), cisplatin-based chemotherapy improves survival, yet response varies widely among patients. Here, we sought to define the role of the nucleotide excision repair (NER) gene ERCC2 as a biomarker predictive of response to cisplatin in MIBC. Experimental Design: Somatic missense mutations in ERCC2 are associated with improved response to cisplatin-based chemotherapy; however, clinically identified ERCC2 mutations are distributed throughout the gene and the impact of individual ERCC2 variants on NER capacity and cisplatin sensitivity is unknown. We developed a microscopy-based NER assay to profile ERCC2 mutations observed retrospectively in prior studies and prospectively within the context of an institution-wide tumor profiling initiative. In addition, we created the first ERCC2-deficient bladder cancer preclinical model for studying the impact of ERCC2 loss-of-function. Results: We used our functional assay to test the NER capacity of clinically observed ERCC2 mutations and found that most ERCC2 helicase domain mutations cannot support NER. Further, we show that introducing an ERCC2 mutation into a bladder cancer cell line abrogates NER activity and is sufficient to drive cisplatin sensitivity in an orthotopic xenograft model. Conclusions: Our data support a direct role for ERCC2 mutations in driving cisplatin response, define the functional landscape of ERCC2 mutations in bladder cancer, and provide an opportunity to apply combined genomic and functional approaches to prospectively guide therapy decisions in bladder cancer.

  • effect of defective ERCC2 on cisplatin and ionizing radiation ir sensitivity in bladder cancer cells
    Journal of Clinical Oncology, 2017
    Co-Authors: Qiang Li, Andrew C Bell, Emmet Jordan, Eugene J Pietzak, Guido Dalbagni, Bernard H Bochner, Jonathan E Rosenberg, Dean F Bajorin, David B Solit, Nadeem Riaz
    Abstract:

    333Background: Genetic alterations within ERCC2 correlate with extraordinary responses to neoadjuvant cisplatin-based chemotherapy and bladder-sparing ionizing radiation (IR) in muscle-invasive bladder cancer (MIBC). Two studies correlated ERCC2 mutations with pathologic response to chemotherapy and improved disease-free and bladder intact survival following trimodality therapy. We sought to characterize the biological significance of these mutations in bladder cancer cells using CRISPR/Cas9-mediated ablation of ERCC2 function. Methods: The ERCC2 T484A/M point mutation was the most common alteration (4 of 36 patients) within a prospectively collected cohort of 299 bladder cancer patients sequenced at our institution. We infected the ERCC2 wild-type KU19-19 bladder cancer cell line with a CRISPR/Cas9 lentivirus targeting residues 481-487 of ERCC2 and identified a cell clone harboring an ERCC2 in-frame deletion (M483_T484del). Following exposure to cisplatin and IR, cell viability was examined using Cell-ti...

Eddie Reed - One of the best experts on this subject based on the ideXlab platform.

  • ethnic disparities in americans of european descent versus americans of african descent related to polymorphic ercc1 ERCC2 xrcc1 and parp1
    Molecular Cancer Therapeutics, 2008
    Co-Authors: Douglas K Price, Eddie Reed, Tristan M Sissung, William D Figg
    Abstract:

    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]

  • Genomic copy number changes of DNA repair genes ERCC1 and ERCC2 in human gliomas
    Journal of Neuro-Oncology, 1995
    Co-Authors: Bertrand C. Liang, Donald A. Ross, Eddie Reed
    Abstract:

    Abnormalities of the genomic region of chromosome 19q13.2–13.4 are a common occurrence in brain malignancies and contain a possible tumor suppressor gene involved in gliomas. Since abnormalities of DNA repair are associated with malignancy, we assessed DNA status of the nucleotide excision repair genes located in this area, viz. ERCC1 and ERCC2. Radiodensitometry was used to assess gene copy number in samples obtained from brain tumor specimens from 24 patients. Nine tumors were of lower grade histology (3 pilocytic astrocytomas, 2 gangliogliomas, 4 astrocytomas); 15 tumors were pathologiclly higher grade (4 anaplastic astrocytomas, 11 glioblastomas). Tumor samples were obtained prior to radiation or chemotherapy. Abnormalities of gene copy number of ERCC1 and ERCC2 were observed in 11/24 specimens (46%). Whereas increased and decreased copy numbers were observed for ERCC1, only decreases in copy number of ERCC2 were seen. Three tumors (all lower grade) showed concurrent allelic loss of ERCC1 and ERCC2. Abnormalities of copy number for these genes were not associated with response to subsequent therapy nor survival. However, allelic loss of ERCC2 was associated with younger age at diagnosis when compared to those specimens which did not show loss. There were no significant differences between lower grade and higher grade tumors with respect to these investigations. Abnormalities in copy number of ERCC1 and ERCC2 are common in glial tumors. Further study of this genomic region is necessary to define the importance of these observations in tumor pathophysiology and treatment.

  • Genomic copy number changes of DNA repair genes ERCC1 and ERCC2 in human gliomas
    Journal of Neuro-oncology, 1995
    Co-Authors: Bertrand C. Liang, Donald A. Ross, Eddie Reed
    Abstract:

    Abnormalities of the genomic region of chromosome 19q13.2–13.4 are a common occurrence in brain malignancies and contain a possible tumor suppressor gene involved in gliomas. Since abnormalities of DNA repair are associated with malignancy, we assessed DNA status of the nucleotide excision repair genes located in this area, viz. ERCC1 and ERCC2.

  • malignant and nonmalignant brain tissues differ in their messenger rna expression patterns for ercc1 and ERCC2
    Cancer Research, 1995
    Co-Authors: Meenakshi Dabholkar, Charles E Egwuagu, Mitchel S Berger, Justine A Vionnet, John R Silber, Jing Jie Yu, Eddie Reed
    Abstract:

    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.

  • ercc1 and ERCC2 expression in malignant tissues from ovarian cancer patients
    Journal of the National Cancer Institute, 1992
    Co-Authors: Meenakshi Dabholkar, Christine A Weber, Frieda Bostickbruton, Vilhelm A Bohr, Charles E Egwuagu, Eddie Reed
    Abstract:

    Abstract ERCC1 and ERCC2 are human DNA repair genes that are associated with in vitro resistance to selected DNA-damaging agents. Fresh tumor tissues from 26 patients with ovarian cancer were analyzed for the RNA levels of expression of these genes to determine possible clinical relevance. Tumor tissues were harvested from patients immediately before they entered a cisplatin- or carboplatin-based treatment protocol. Clinical response was assessed by standard criteria. Gene expression level was assessed by slot blot analysis, using beta-actin as a control. Relative expression levels were determined by comparing each tumor sample with a Chinese hamster ovary cell line that had a stable transfection of the human ERCC1 gene. Patients who were clinically resistant to platinum-based therapy had a 2.6-fold higher expression level of ERCC1 in their tumor tissue than did patients who responded to that therapy (P = .015). Results obtained by slot blot analysis were qualitatively confirmed by polymerase chain reaction analysis. Relative levels of expression of ERCC2 did not differ significantly between responders and nonresponders. We conclude that ERCC1 expression levels in human tumor tissue may have a role in clinical resistance to platinum compounds. These data appear to be consistent with the assertion that ERCC1 serves as an excision nuclease, whereas ERCC2 serves as a helicase.