DOCSLIB.ORG

Original Article Predictive Value of ERCC1, ERCC2, ERCC4, And

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Original Article Predictive Value of ERCC1, ERCC2, ERCC4, And Am J Cancer Res 2018;8(10):2096-2105 www.ajcr.us /ISSN:2156-6976/ajcr0085053 Original Article Predictive value of ERCC1, ERCC2, ERCC4, and glutathione S-Transferase Pi expression for the efficacy and safety of FOLFIRINOX in patients with unresectable pancreatic cancer Shun Tezuka1, Makoto Ueno1, Satoshi Kobayashi1, Manabu Morimoto1, Shinichi Ohkawa1, Akane Hirotani1, Yuichiro Tozuka1, Satoshi Moriya1, Yoshiyasu Nakamura2, Yohei Miyagi2, Makoto Sugimori3, Shin Maeda3 1Department of Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center, Yokohama, Japan; 2De- partment of Molecular Pathology and Genetics, Kanagawa Cancer Center Research Institute, Yokohama, Japan; 3Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan Received September 4, 2018; Accepted September 14, 2018; Epub October 1, 2018; Published October 15, 2018 Abstract: The platinum-based chemotherapy regimen FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxali- platin) is currently used as a standard treatment for patients with unresectable pancreatic cancer. FOLFIRINOX is associated with severe toxicities, including neutropenia, febrile neutropenia, and anorexia; however, there are cur- rently no reliable biomarkers to predict its efficacy and safety. Several studies of patients with various cancers have shown that tumor expression of excision repair cross-complementing (ERCC) proteins and glutathione S-transferase Pi (GSTPi) correlates with the response to platinum-based chemotherapies. Therefore, in this study, we examined the associations between expression of ERCC proteins and GSTPi and the safety and efficacy of FOLFIRINOX in 34 patients with unresectable pancreatic cancer. ERCC1, ERCC2, ERCC4, and GSTPi expression were examined by im- munohistochemical staining of tumor specimens and the results were correlated with overall survival, progression- free survival, response rate, disease control rate, and the frequency of grade 3-4 neutropenia and non-hematologic toxicities. We found that ERCC1, ERCC2, ERCC4, and GSTPi were expressed in tumor samples from 64%, 24%, 18%, and 64% of patients, respectively. Notably, there were no statistically significant associations between the expres- sion pattern of any of the proteins and either the clinical outcomes or the frequency of grade 3-4 neutropenia or grade 3-4 anorexia. Collectively, these data indicate that tumor expression of ERCC1, ERCC2, ERCC4, and GSTPi does not predict the safety or efficacy of FOLFIRINOX in patients with pancreatic cancer. Keywords: Pancreatic cancer, FOLFIRINOX, predictive factor, ERCC1, ERCC2, ERCC4, GSTPi, immunohistochemis- try, biomarker Introduction FOLFIRINOX is associated with severe toxici- ties, including neutropenia, febrile neutropenia, The effectiveness of the platinum-based regi- thrombocytopenia, anorexia, fatigue, and diar- men FOLFIRINOX (oxaliplatin, irinotecan, flu- rhea, which frequently require dose reduction orouracil, and leucovorin) as first-line chemo- or treatment interruption. A phase 2 study of therapy in patients with metastatic pancreatic FOLFIRINOX in Japanese patients with pancre- cancer was first reported in 2011 [1]. In Japan, atic cancer reported high frequencies of toxici- FOLFIRINOX obtained regulatory approval for ties, including grade 3 or 4 neutropenia (77.8% the treatment of pancreatic cancer in Decem- of patients), febrile neutropenia (22.2%), and ber 2013. FOLFIRINOX and nab-paclitaxel plus anorexia (11.1%) [3]. These side effects could gemcitabine are both currently employed as lead limited use of FOLFIRINOX. Recently, a standard chemotherapy regimens for unresect- modified FOLFIRINOX regimen showed satis- able pancreatic cancer in patients with good factory efficacy with less toxicity in pancreatic Eastern Cooperative Oncology Group perfor- cancer patients [4-6]. However, there have be- mance status (ECOG PS) [2]. en no direct comparisons of the safety and ef- Relationship between ERCC and FOLFIRINOX efficacy for pancreatic cancer Table 1. Clinical characteristics of the pa- response to platinum chemotherapies. Another tients (n = 34) potential biomarker is glutathione S-transfer- N (%) ase Pi (GSTPi, also known as GSTP1). GSTs are Age, median (range) 61 (42-73) a family of detoxification enzymes found in all aerobic organisms and play protective roles in Gender preventing cellular damage from toxic com- Male 20 (59) pounds, including chemotherapeutic agents Female 14 (41) [21]. Polymorphisms have been detected in Line many of the genes encoding the main GST iso- 1st line therapy 26 (76) enzymes, including GSTPi. One polymorphism 2nd line therapy 3 (9) in GSTPi is reportedly related to the sensitivity 3rd line therapy 5 (15) of colorectal cancer to platinum-based com- UICC Stage pounds [22]. III 3 (9) IV 31 (91) There have been few reports examining the correlation between ERCC1, ERCC2, ERCC4, Performance status (ECOG) and GSTPi expression and the response to plat- 0 16 (47) inum-based chemotherapies in patients with 1 18 (53) pancreatic cancer [16, 18, 23]. To address this Initial dose modification 17 (50) knowledge gap, we examined the expression of Neutrophil-to-lymphocyte ratio ≥5 8 (24) these four candidate biomarkers in pancrea- Abbreviations: ECOG, Eastern Cooperative Oncology tic cancer specimens from patients treated Group; UICC, Union for International Cancer Control. with FOLFIRINOX and investigated their rela- tionship to various clinicopathological factors, ficacy of FOLFIRINOX, modified FOLFIRINOX, including patient outcomes. and nab-paclitaxel plus gemcitabine, making it Material and methods difficult to select the optimal treatment regi- men for pancreatic cancer patients. There is Patients and study design thus great interest in discovering biomarkers that can predict the efficacy and safety of This was a single-center, retrospective cohort FOLFIRINOX in this disease. study of 34 patients with unresectable pancre- DNA repair is an important role in resistance atic cancer who started treatment with FOLFI- to platinum agents that act inhibiting DNA RINOX between December 2013 and Septem- replication and transcription by binding to a ber 2015. All patients were selected for this DNA molecule in the form of platinum-DNA- study based on histologically confirmed pan- adducts [7]. Excision repair cross-complement- creatic adenocarcinoma and the availability of ing (ERCC) protein 1, ERCC2, and ERCC4 are adequate tissue derived from (i) endoscopic key proteins involved in the nucleotide exci- ultrasonography-guided fine-needle aspiration sion repair pathway, which is a major compo- (EUS-FNA) of the primary pancreatic tumor or nent of the DNA repair response [8, 9]. Previous lymph node metastasis, (ii) fine-needle biopsy work identified a correlation between expres- from liver metastasis, (iii) forceps biopsy of sion of ERCC1 protein or mRNA, as measured bile duct-invasive tumor or duodenum-invasive by immunohistochemistry (IHC) or reverse-tran- tumor, or (iv) previously resected surgical speci- scription polymerase chain reaction (RT-PCR) mens from primary tumors. Clinical data were respectively, and the response to platinum obtained by retrospective chart review. All pa- agents, including oxaliplatin, in patients with tients had an ECOG PS score of 0 or 1 [2] and gastrointestinal cancer, ovarian cancer, and had adequate bone marrow and renal funct- non-small cell lung cancer (NSCLC) [10-19]. A ion. Evaluation of the response to chemothera- single nucleotide polymorphism in ERCC2 (Lys- py (complete response [CR], partial response 751Gln) is associated with the survival of pa- [PR], stable disease [SD], and progressive dis- tients with colon cancer treated by oxaliplatin- ease [PD]) was based on the Response Eva- based regimens [20], supporting the possible luation Criteria In Solid Tumors guidelines [24]. utility of ERCC proteins as biomarkers of the All patients provided informed consent. This 2097 Am J Cancer Res 2018;8(10):2096-2105 Relationship between ERCC and FOLFIRINOX efficacy for pancreatic cancer lin and dehydrated for mount- ing. Evaluation of immunohisto- chemical staining Protein staining was assess- ed independently by two in- vestigators who were blinded to the patients’ identities and clinical outcomes. If the in- vestigators’ opinions differed, the final result was decided by consensus. Slides were analyzed by light microscopy. Staining was scored for inten- sity (1, weak; 2, moderate; 3, strong) and the percentage of cells positively stained (1, 1% Figure 1. Immunohistochemical staining of patient specimens. A-D. Repre- to 9.9%; 2, 10% to <49.9%; 3, sentative images of immunohistochemical staining of the four proteins to illustrate typical intensity and percentage staining scores (both on a scale of 50% to 100%). ERCC1, ERC- 1-3). A. Excision repair cross-complementing (ERCC): intensity score 1, per- C2, and ERCC4 expression centage score 3. B. ERCC2: intensity score 3, percentage score 2. C. ERCC4: was considered to be positive intensity score 3, percentage score 2. D. Glutathione S-transferase Pi, inten- when the intensity and per- sity score 3, percentage score 3. Scale bar = 500 μm. centage scores were 2 or 3 and the tumor cells showed study was approved by the Institutional Review nuclear staining. GSTPi expression was con- Board of Kanagawa Cancer Center. sidered to be positive when the intensity and percentage scores were 2 or 3 and the tumor Immunohistochemistry cells showed nuclear or cytoplasmic staining. IHC was performed using standard
Load more

Recommended publications
  • Open Full Page
    CCR PEDIATRIC ONCOLOGY SERIES CCR Pediatric Oncology Series Recommendations for Childhood Cancer Screening and Surveillance in DNA Repair Disorders Michael F. Walsh1, Vivian Y. Chang2, Wendy K. Kohlmann3, Hamish S. Scott4, Christopher Cunniff5, Franck Bourdeaut6, Jan J. Molenaar7, Christopher C. Porter8, John T. Sandlund9, Sharon E. Plon10, Lisa L. Wang10, and Sharon A. Savage11 Abstract DNA repair syndromes are heterogeneous disorders caused by around the world to discuss and develop cancer surveillance pathogenic variants in genes encoding proteins key in DNA guidelines for children with cancer-prone disorders. Herein, replication and/or the cellular response to DNA damage. The we focus on the more common of the rare DNA repair dis- majority of these syndromes are inherited in an autosomal- orders: ataxia telangiectasia, Bloom syndrome, Fanconi ane- recessive manner, but autosomal-dominant and X-linked reces- mia, dyskeratosis congenita, Nijmegen breakage syndrome, sive disorders also exist. The clinical features of patients with DNA Rothmund–Thomson syndrome, and Xeroderma pigmento- repair syndromes are highly varied and dependent on the under- sum. Dedicated syndrome registries and a combination of lying genetic cause. Notably, all patients have elevated risks of basic science and clinical research have led to important in- syndrome-associated cancers, and many of these cancers present sights into the underlying biology of these disorders. Given the in childhood. Although it is clear that the risk of cancer is rarity of these disorders, it is recommended that centralized increased, there are limited data defining the true incidence of centers of excellence be involved directly or through consulta- cancer and almost no evidence-based approaches to cancer tion in caring for patients with heritable DNA repair syn- surveillance in patients with DNA repair disorders.
    [Show full text]
  • A Mutation in the XPBIERCC3 DNA Repair Transcription Gene, Associated with Trichothiodystrophy
    Am. J. Hum. Genet. 60:320-329, 1997 A Mutation in the XPBIERCC3 DNA Repair Transcription Gene, Associated with Trichothiodystrophy G. Weeda,' E. Eveno,2 1. Donker,' W. Vermeulen,' 0. Chevallier-Lagente,2 A. Tafeb,3 A. Stary,2 J. H. J. Hoeijmakers,1 M. Mezzina,2 and A. Sarasin2 'MGC-Department of Cell Biology and Genetics, Erasmus University, Rotterdam; 2Laboratory of Molecular Genetics, UPR 42 Institut Federatif CNRS-IFC1 -Institut de Recherches sur le Cancer, Vilejuif, France; and 'Unit6 de Dermatologie P6diatrique, Centre Hospitalier Universitaire, Groupe Pellegrin, Hopital des Enfants, Bordeaux Summary Introduction Trichothiodystrophy (TD1) is a rare, autosomal recessive disorder characterized by sulfur-deficient brittle hair and To counteract the deleterious effects of mutagenic and nails, mental retardation, impaired sexual development, and carcinogenic agents, all organisms are equipped with a ichthyosis. Photosensitivity has been reported in -50% of sophisticated network of DNA repair systems that is the cases, but no skin cancer is associated with TI). Virtu- essential for genetic stability. Nucleotide excision repair ally all photosensitive ID patients have a deficiency in (NER)-one of the most studied repair pathways-re- the nucleotide excision repair (NER) of UV-induced DNA moves a wide diversity of DNA lesions, including UV- damage that is indistinguishable from that of xeroderma induced lesions, in a multistep process (Hoeijmakers pigmentosum (XP) complementation group D (XP-D) pa- 1993). tients. DNA repair defects in XP-D are associated with two Two subpathways are recognized in NER: a rapid additional, quite different diseases; XP, a sun-sensitive and preferential repair of the transcribed strand of active cancer-prone repair disorder, and Cockayne syndrome (CS), genes ("transcription-coupled repair") and the less effi- a photosensitive condition characterized by physical and cient global genome repair process (Bohr 1991; Hana- mental retardation and wizened facial appearance.
    [Show full text]
  • RAD51 Paralogs Promote Genomic Integrity and Chemoresistance in Cancer by Facilitating Homologous Recombination
    122 Editorial Page 1 of 6 RAD51 paralogs promote genomic integrity and chemoresistance in cancer by facilitating homologous recombination Janelle Louise Harris, Andrea Rabellino, Kum Kum Khanna QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia Correspondence to: Kum Kum Khanna. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. Email: [email protected]. Provenance: This is an invited Editorial commissioned by Section Editor Yazhou He, MD (Institute of Genetics and Molecular Medicine, Western General Hospital/Usher Institute of Population Health Sciences, University of Edinburgh, Edinburgh, UK). Comment on: Chen X, Li Y, Ouyang T, et al. Associations between RAD51D germline mutations and breast cancer risk and survival in BRCA1/2- negative breast cancers. Ann Oncol 2018;29:2046-51. Submitted Nov 30, 2018. Accepted for publication Dec 10, 2018. doi: 10.21037/atm.2018.12.30 View this article at: http://dx.doi.org/10.21037/atm.2018.12.30 Cancer is a major health burden, however advances in early a loss of function mutation in the DDR gene RAD51D, diagnosis and improved surgery and therapeutic options while such mutations were detected in 0.1% of the healthy have improved outcomes over the past several decades. population. For example, RAD51D mutation carriers had Nevertheless, many radiological and chemotherapeutic higher grade cancers and early relapse compared to wild treatments yield severe side effects, while relapse and types, implicating RAD51D loss as rare but penetrant breast subsequent outgrowth of treatment resistant tumours cancer mutation associated with more aggressive disease. is common. The majority of cancer treatments rely on During cancer progression the disruption of normal inhibition of cancer cells pro-growth signalling, blocking DDR drives accumulation of additional genetic defects that proliferation or inducing DNA damage.
    [Show full text]
  • Clinical Significance of ERCC2, XPC, ERCC5 and XRCC3 Gene Polymorphisms in Diffuse Large B Cell Lymphoma
    DOI: 10.14744/ejmi.2020.56831 EJMI 2020;4(3):332–340 Research Article Clinical Significance of ERCC2, XPC, ERCC5 and XRCC3 Gene Polymorphisms in Diffuse Large B Cell Lymphoma Aykut Bahceci,1 Semra Paydas,2 Melek Ergin,3 Gulsah Seydaoglu,4 Gulsum Ucar5 1Department of Medical Oncology, Dr. Ersin Arslan Training and Research Hospital, Gaziantep, Turkey 2Department of Medical Oncology, Cukurova University Faculty of Medicine, Adana, Turkey 3Department of Patology, Cukurova University Faculty of Medicine, Adana, Turkey 4Department of Biostatistics, Cukurova University Faculty of Medicine, Adana, Turkey 5Department of Pediatric Hematology, Cukurova University Faculty of Medicine, Adana, Turkey Abstract Objectives: DNA repair genes protects the genome from DNA damage both of endogenous and exogenous stress fac- tors. Due to DNA repair gene polymorphisms, there are differences in the repair capacity between several cancer types. The aim of this study is to evaluate the association between some of the DNA repair gene polymorphisms and clinical outcome in Diffuse Large B-Cell Lymphoma (DLBCL). Methods: The association between clinical factors including stage at diagnosis, extra-nodal involvement, tumor bur- den, bone marrow involvement, relapse status, disease-free/overall survival times and DNA repair gene polymorphisms including ERCC2 (Lys751Gln), XPC (Gln939Lys), ERCC5 (Asp1104His) and XRCC3 (Thr241Met) in 58 patients with DLBCL. T-Shift Real-Time PCR was used to detect these mutations. Results: The median survival times were 60 months and 109 months in patients with CC genotype and CA/AA geno- type of XPC gene polymorphism, respectively (p=0.017). More interestingly, median survival times were 9 months and 109 months in patients with CC (XPC)/CC (XRCC3) and CA/AA (XPC)/CT/TT (XRCC3) for both XPC and XRCC3 gene polymorphisms, respectively (p=0.004).
    [Show full text]
  • Predisposition to Hematologic Malignancies in Patients With
    LETTERS TO THE EDITOR carcinomas but no internal cancer by the age of 29 years Predisposition to hematologic malignancies in and 9 years, respectively. patients with xeroderma pigmentosum Case XP540BE . This patient had a highly unusual pres - entation of MPAL. She was diagnosed with XP at the age Germline predisposition is a contributing etiology of of 18 months with numerous lentigines on sun-exposed hematologic malignancies, especially in children and skin, when her family emigrated from Morocco to the young adults. Germline predisposition in myeloid neo - USA. The homozygous North African XPC founder muta - plasms was added to the World Health Organization tion was present. 10 She had her first skin cancer at the age 1 2016 classification, and current management recommen - of 8 years, and subsequently developed more than 40 cuta - dations emphasize the importance of screening appropri - neous basal and squamous cell carcinomas, one melanoma 2 ate patients. Rare syndromes of DNA repair defects can in situ , and one ocular surface squamous neoplasm. She 3 lead to myeloid and/or lymphoid neoplasms. Here, we was diagnosed with a multinodular goiter at the age of 9 describe our experience with hematologic neoplasms in years eight months, with several complex nodules leading the defective DNA repair syndrome, xeroderma pigmen - to removal of her thyroid gland. Histopathology showed tosum (XP), including myelodysplastic syndrome (MDS), multinodular adenomatous/papillary hyperplasia. At the secondary acute myeloid leukemia (AML), high-grade age of 19 years, she presented with night sweats, fatigue, lymphoma, and an extremely unusual presentation of and lymphadenopathy. Laboratory studies revealed pancy - mixed phenotype acute leukemia (MPAL) with B, T and topenia with hemoglobin 6.8 g/dL, platelet count myeloid blasts.
    [Show full text]
  • ERCC2 Helicase Domain Mutations Confer Nucleotide Excision Repair Deficiency and Drive Cisplatin Sensitivity in Muscle-Invasive Bladder Cancer
    Author Manuscript Published OnlineFirst on July 6, 2018; DOI: 10.1158/1078-0432.CCR-18-1001 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ERCC2 Helicase Domain Mutations Confer Nucleotide Excision Repair Deficiency and Drive Cisplatin Sensitivity in Muscle-Invasive Bladder Cancer Qiang Li1,2*, Alexis W Damish3*, Zoë Frazier3*, David Liu4,5,6, Elizaveta Reznichenko3,7, Atanas Kamburov5,8, Andrew Bell9, Huiyong Zhao9, Emmet J. Jordan10, S. Paul Gao10, Jennifer Ma9, Philip H Abbosh11,12, Joaquim Bellmunt4, Elizabeth R Plimack13, Jean-Bernard Lazaro3,7, David B. Solit10,14,15, Dean Bajorin14, Jonathan E. Rosenberg14, Alan D’Andrea3,7,16, Nadeem Riaz9#, Eliezer M Van Allen4,5#, Gopa Iyer14#, Kent W Mouw3,16# 1Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY 2Department of Urology, Roswell Park Cancer Institute, Buffalo, NY 3Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham & Women’s Hospital, Boston, MA 4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 5Broad Institute of Harvard and MIT, Cambridge, MA 6Cancer Center, Massachusetts General Hospital, Boston, MA 7Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA 8Drug Discovery, Bayer AG, Berlin, Germany 9Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 11Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 12Department of Urology, Einstein Medical Center, Philadelphia, PA 13Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA 14Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 15Weill Cornell Medical College, Cornell University, New York, NY 16Ludwig Center at Harvard, Boston, MA *contributed equally #contributed equally Running Title: ERCC2 functional profiling in bladder cancer Conflicts of Interest: J.E.R.
    [Show full text]
  • *.-,C IP 4 8 12 16 20 2!4 28 1 Fraction No
    10538 Correction Proc. Natl. Acad. Sci. USA (1996) Biochemistry. In the article "Isolation and characterization 1996, of Proc. Natl. Acad. Sci. USA (93, 6482-6487), the of two human transcription factor IIH (TFIIH)-related following correction should be noted. Panel C in Fig. 2 complexes: ERCC2/CAK and TFIIH" by Joyce T. Rear- was incorrectly replaced with panel C from Fig. 3. A don, Hui Ge, Emma Gibbs, Aziz Sancar, Jerard Hurwitz, and correct reproduction of Fig. 2 and its legend are reproduced Zhen-Qiang Pan, which appeared in number 13, June 25, below. A 7.4S c E 4.4S c ._ *.-,C IP 4 8 12 16 20 2!4 28 1 Fraction No. E E B Glycerol Gradient Fractions 1 6 8 10 12 14 16 18 20 22 24 0 . 0 0 . 0 0 . 0 -cdk7 t w -cdk7 * S S * . 0. 0. * 0 0 . w -Cyclin H * -Cyclin H 0 6 0 0 0 . 0 . * 0 0 -p36 * am -p36 0..0 0. 0. 0 * 0 0 -ERCC2 __ -ERCC2 1 2 3 4 5 6 7 8 9 10 1 2 3 FIG. 2. (A and B) Cosedimentation of CAK activity with the ERCC2 (XPD) protein. An aliquot of the glycerol gradient-isolated 7.4S peak fractions (94 units) was concentrated and centrifuged through a second 15-35% glycerol gradient. (A) The distribution of CAK activity in the glycerol gradient fractions (3 ,lI) was determined. The sedimentations of protein standards catalase (11.2S), aldolase (7.4S), and BSA (4.4S) are shown. (B) Immunoblot assays of the glycerol gradient fractions (20 ,lI).
    [Show full text]
  • DNA Repair Disorders
    178 Arch Dis Child 1998;78:178–184 REGULAR REVIEW Arch Dis Child: first published as 10.1136/adc.78.2.178 on 1 February 1998. Downloaded from DNA repair disorders C GeoVrey Woods Over the past 30 years a number of rare DNA Exogenous DNA mutants have been classi- repair disorder phenotypes have been deline- cally divided into ultraviolet irradiation, ionis- ated, for example Bloom’s syndrome, ataxia ing irradiation, and alkylating agents. telangiectasia, and Fanconi’s anaemia. In each Ultraviolet irradiation and alkylating agents phenotype it was hypothesised that the under- can cause a number of specific base changes, as lying defect was an inability to repair a particu- well as cross linking bases together. Ionising lar type of DNA damage. For some of these irradiation is thought to generate the majority disorders this hypothesis was supported by of its mutational load by free radical produc- cytogenetics studies using DNA damaging tion. A wide variety of other DNA damaging agents, these tests defined the so-called chro- agents, both natural and man made, are mosome breakage syndromes. A number of the known, many are used as chemotherapeutic aetiological genes have recently been cloned, agents. confirming that some DNA repair disorder phenotypes can be caused by more than one DNA repair gene and vice versa. This review deals only with The DNA double helix seems to have evolved the more common DNA repair disorders. so that mutations, even as small as individual Rarer entities, such as Rothmund-Thomson base damage, are easily recognised. Such syndrome and dyskeratosis congenita, are recognition is usually by a change to the physi- excluded.
    [Show full text]
  • RNA Expression of DNA Damage Response Genes in Muscle-Invasive Bladder Cancer: Influence on Outcome and Response to Adjuvant Cisplatin-Based Chemotherapy
    International Journal of Molecular Sciences Article RNA Expression of DNA Damage Response Genes in Muscle-Invasive Bladder Cancer: Influence on Outcome and Response to Adjuvant Cisplatin-Based Chemotherapy Jonas Herrmann 1,* , Helena Schmidt 1, Katja Nitschke 1, Cleo-Aron Weis 2, Philipp Nuhn 1, Jost von Hardenberg 1, Maurice Stephan Michel 1, Philipp Erben 1 and Thomas Stefan Worst 1 1 Department of Urology, University Medical Centre Mannheim, 68167 Mannheim, Germany; [email protected] (H.S.); [email protected] (K.N.); [email protected] (P.N.); [email protected] (J.v.H.); [email protected] (M.S.M.); [email protected] (P.E.); [email protected] (T.S.W.) 2 Institute for Pathology, University Medical Centre Mannheim, 68167 Mannheim, Germany; [email protected] * Correspondence: [email protected]; Tel.: +49-621-383-2201 Abstract: Background: Perioperative cisplatin-based chemotherapy (CBC) can improve the outcome of patients with muscle-invasive bladder cancer (MIBC), but it is still to be defined which patients benefit. Mutations in DNA damage response genes (DDRG) can predict the response to CBC. The value of DDRG expression as a marker of CBC treatment effect remains unclear. Material and Citation: Herrmann, J.; Schmidt, H.; methods: RNA expression of the nine key DDRG (BCL2, BRCA1, BRCA2, ERCC2, ERCC6, FOXM1, Nitschke, K.; Weis, C.-A.; Nuhn, P.; RAD50, RAD51, and RAD52) was assessed by qRT-PCR in a cohort of 61 MICB patients (median age von Hardenberg, J.; Michel, M.S.; 66 y, 48 males, 13 females) who underwent radical cystectomy in a tertiary care center.
    [Show full text]
  • DNA Repair Pathway Alterations in Bladder Cancer
    Review DNA Repair Pathway Alterations in Bladder Cancer Kent W. Mouw Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham & Women’s Hospital, Harvard Medical School, Boston, MA 02215, USA; [email protected]; Tel.: +1-617-852-9356 Academic Editor: Eddy S. Yang Received: 7 March 2017; Accepted: 23 March 2017; Published: 27 March 2017 Abstract: Most bladder tumors have complex genomes characterized by a high mutation burden as well as frequent copy number alterations and chromosomal rearrangements. Alterations in DNA repair pathways—including the double-strand break (DSB) and nucleotide excision repair (NER) pathways—are present in bladder tumors and may contribute to genomic instability and drive the tumor phenotype. DNA damaging such as cisplatin, mitomycin C, and radiation are commonly used in the treatment of muscle-invasive or metastatic bladder cancer, and several recent studies have linked specific DNA repair pathway defects with sensitivity to DNA damaging-based therapy. In addition, tumor DNA repair defects have important implications for use of immunotherapy and other targeted agents in bladder cancer. Therefore, efforts to further understand the landscape of DNA repair alterations in bladder cancer will be critical in advancing treatment for bladder cancer. This review summarizes the current understanding of the role of DNA repair pathway alterations in bladder tumor biology and response to therapy. Keywords: urothelial cancer; bladder cancer; DNA repair; nucleotide excision repair; mutational signature; genomic instability 1. Introduction 1.1. Bladder Cancer Is a Global Health Problem An estimated 75,000 cases of bladder cancer will be diagnosed in the USA in 2017, making it the fifth most common cancer among adults [1].
    [Show full text]
  • ERCC2 Helicase Domain Mutations Confer Nucleotide Excision Repair Deficiency and Drive Cisplatin Sensitivity in Muscle-Invasive Bladder Cancer Qiang Li1,2, Alexis W
    Published OnlineFirst July 6, 2018; DOI: 10.1158/1078-0432.CCR-18-1001 Personalized Medicine and Imaging Clinical Cancer Research ERCC2 Helicase Domain Mutations Confer Nucleotide Excision Repair Deficiency and Drive Cisplatin Sensitivity in Muscle-Invasive Bladder Cancer Qiang Li1,2, Alexis W. Damish3,Zoe€ Frazier3, David Liu4,5,6, Elizaveta Reznichenko3,7, Atanas Kamburov5,8, Andrew Bell9, Huiyong Zhao9, Emmet J. Jordan10, S. Paul Gao10, Jennifer Ma9, Philip H. Abbosh11,12, Joaquim Bellmunt4, Elizabeth R. Plimack13, Jean-Bernard Lazaro3,7, David B. Solit10,14,15, Dean Bajorin14, Jonathan E. Rosenberg14, Alan D. D'Andrea3,7,16, Nadeem Riaz9, Eliezer M. Van Allen4,5,GopaIyer14, and Kent W. Mouw3,16 Abstract Purpose: DNA-damaging agents comprise the backbone of an institution-wide tumor profiling initiative. In addition, we systemic treatment for many tumor types; however, few reli- created the first ERCC2-deficient bladder cancer preclinical able predictive biomarkers are available to guide use of these model for studying the impact of ERCC2 loss of function. agents. In muscle-invasive bladder cancer (MIBC), cisplatin- Results: We used our functional assay to test the NER based chemotherapy improves survival, yet response varies capacity of clinically observed ERCC2 mutations and found widely among patients. Here, we sought to define the role of that most ERCC2 helicase domain mutations cannot support the nucleotide excision repair (NER) gene ERCC2 as a bio- NER. Furthermore, we show that introducing an ERCC2 muta- marker predictive of response to cisplatin in MIBC. tion into a bladder cancer cell line abrogates NER activity and is Experimental Design: Somatic missense mutations in sufficient to drive cisplatin sensitivity in an orthotopic xeno- ERCC2 are associated with improved response to cisplatin- graft model.
    [Show full text]
  • DNA-Related Pathways Defective in Human Premature Aging
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Crossref Mini-Review TheScientificWorldJOURNAL (2002) 2, 1216–1226 ISSN 1537-744X; DOI 10.1100/tsw.2002.226 DNA-Related Pathways Defective in Human Premature Aging Vilhelm A. Bohr Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Dr., Baltimore, MD 21224 E-mail: [email protected] Received November 27, 2001; Revised March 18, 2002; Accepted March 20, 2002; Published May 7, 2002 One of the major issues in studies on aging is the choice of biological model system. The human premature aging disorders represent excellent model systems for the study of the normal aging process, which occurs at a much earlier stage in life in these individuals than in normals. The patients with premature aging also get the age associated diseases at an early stage in life, and thus age associated disease can be studied as well. It is thus of great interest to understand the molecular pathology of these disorders. KEY WORDS: aging, premature aging, Werner syndrome, Cockayne syndrome, DNA repair DOMAINS: aging, biochemistry, DNA repair, DNA metabolism HUMAN PREMATURE AGING DISORDERS A number of premature aging disorders have been described in humans. In patients with these disorders, aging-like symptoms and age-associated diseases appear much earlier than in the average normal individual; thus, the premature aging disorders are useful models for the study of the aging process. Werner syndrome (WS) is the most characterized premature aging disorder. Patients with WS have a large number of signs and symptoms of normal aging at a younger age than normal individuals.
    [Show full text]