Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2017

Open Access 01-12-2017 | Research article

Increased ERCC1 expression is linked to chromosomal aberrations and adverse tumor biology in prostate cancer

Authors: Frank Jacobsen, Billurvan Taskin, Nathaniel Melling, Charlotte Sauer, Corinna Wittmer, Claudia Hube-Magg, Martina Kluth, Ronald Simon, Dirk Pehrke, Burkhard Beyer, Thomas Steuber, Imke Thederan, Guido Sauter, Thorsten Schlomm, Waldemar Wilczak, Katharina Möller, Sören A. Weidemann, Susanne Burdak-Rothkamm

Published in: BMC Cancer | Issue 1/2017

Login to get access

Abstract

Background

Animal model experiments have suggested a role of the DNA repair protein ERCC1 (Excision Repair Cross-Complementation Group 1) in prostate cancer progression.

Methods

To better understand the impact of ERCC1 protein expression in human prostate cancer, a preexisting tissue microarray (TMA) containing more than 12,000 prostate cancer specimens was analyzed by immunohistochemistry and data were compared with tumor phenotype, PSA recurrence and several of the most common genomic alterations (TMPRSS2:ERG fusions: deletions of PTEN, 6q, 5q, 3p).

Results

ERCC1 staining was seen in 64.7% of 10,436 interpretable tissues and was considered weak in 37.1%, moderate in 22.6% and strong in 5% of tumors. High-level ERCC1 staining was linked to advanced pT stage, high Gleason grade, positive lymph nodes, high pre-operative serum PSA, and positive surgical margin status (p < 0.0001 each). High ERCC1 expression was strongly associated with an elevated risk of PSA recurrence (p < 0.0001). This was independent of established prognostic features. A subgroup analysis of cancers defined by comparable quantitative Gleason grades revealed that the prognostic impact was mostly driven by low-grade tumors with a Gleason 3 + 3 or 3 + 4 (Gleason 4: ≤5%). High ERCC1 expression was strongly associated with the presence of genomic alterations and expression levels increased with the number of deletions present in the tumor. These latter data suggest a functional relationship of ERCC1 expression with genomic instability.

Conclusion

The results of our study demonstrate that expression of ERCC1 - a potential surrogate for genomic instability - is an independent prognostic marker in prostate cancer with particular importance in low-grade tumors.
Appendix
Available only for authorised users
Literature
1.
2.
Matsunaga T, Mu D, Park CH, Reardon JT, Sancar A. Human DNA repair excision nuclease. Analysis of the roles of the subunits involved in dual incisions by using anti-XPG and anti-ERCC1 antibodies. J Biol Chem. 1995;270(35):20862–9.CrossRefPubMed
3.
Sijbers AM, van der Spek PJ, Odijk H, van den Berg J, van Duin M, Westerveld A, Jaspers NG, Bootsma D, Hoeijmakers JH. Mutational analysis of the human nucleotide excision repair gene ERCC1. Nucleic Acids Res. 1996;24(17):3370–80.CrossRefPubMedPubMedCentral
4.
Cheng L, Guan Y, Li L, Legerski RJ, Einspahr J, Bangert J, Alberts DS, Wei Q. Expression in normal human tissues of five nucleotide excision repair genes measured simultaneously by multiplex reverse transcription-polymerase chain reaction. Cancer Epidemiol Biomark Prev. 1999;8(9):801–7.
5.
Klatte T, Seitz C, Rink M, Roupret M, Xylinas E, Karakiewicz P, Susani M, Shariat SF. ERCC1 as a prognostic and predictive biomarker for Urothelial carcinoma of the bladder following radical Cystectomy. J Urol. 2015;194(5):1456–62.CrossRefPubMed
6.
Ciaparrone M, Caspiani O, Bicciolo G, Signorelli D, Simonelli I, de Campora L, Mazzarella G, Mecozzi A, Pianelli C, Camaioni A, et al. Predictive role of ERCC1 expression in head and neck Squamous cell carcinoma patients treated with surgery and adjuvant Cisplatin-based Chemoradiation. Oncology. 2015;89(4):227–34.CrossRefPubMed
7.
Deng Q, Yang H, Lin Y, Qiu Y, Gu X, He P, Zhao M, Wang H, Xu Y, Lin Y, et al. Prognostic value of ERCC1 mRNA expression in non-small cell lung cancer, breast cancer, and gastric cancer in patients from southern China. Int J Clin Exp Pathol. 2014;7(12):8312–21.PubMedPubMedCentral
8.
Li S, Wu J, Chen Y, Tang W, Peng Q, Deng Y, Xie L, Wang J, Huang S, Li R, et al. ERCC1 expression levels predict the outcome of platinum-based chemotherapies in advanced bladder cancer: a meta-analysis. Anti-Cancer Drugs. 2014;25(1):106–14.CrossRefPubMed
9.
Maithel SK, Coban I, Kneuertz PJ, Kooby DA, El-Rayes BF, Kauh JS, Sarmiento J, Staley CA 3rd, Volkan Adsay N. Differential expression of ERCC1 in pancreas adenocarcinoma: high tumor expression is associated with earlier recurrence and shortened survival after resection. Ann Surg Oncol. 2011;18(9):2699–705.CrossRefPubMed
10.
Matoka DJ, Yao V, Harya DS, Gregg JL, Robinson AR, Niedernhofer LJ, Parwani AV, Maier C, Bacich DJ. Deficiency of DNA repair nuclease ERCC1-XPF promotes prostate cancer progression in a tissue recombination model. Prostate. 2012;72(11):1214–22.CrossRefPubMed
11.
Henriquez-Hernandez LA, Valenciano A, Foro-Arnalot P, Alvarez-Cubero MJ, Cozar JM, Suarez-Novo JF, Castells-Esteve M, Fernandez-Gonzalo P, De-Paula-Carranza B, Ferrer M, et al. Single nucleotide polymorphisms in DNA repair genes as risk factors associated to prostate cancer progression. BMC Med Genet. 2014;15:143.CrossRefPubMedPubMedCentral
12.
Sauter G, Steurer S, Clauditz TS, Krech T, Wittmer C, Lutz F, Lennartz M, Janssen T, Hakimi N, Simon R, et al. Clinical utility of quantitative Gleason grading in prostate biopsies and prostatectomy specimens. Eur Urol. 2016;69(4):592–8.CrossRefPubMed
13.
Schlomm T, Iwers L, Kirstein P, Jessen B, Kollermann J, Minner S, Passow-Drolet A, Mirlacher M, Milde-Langosch K, Graefen M, et al. Clinical significance of p53 alterations in surgically treated prostate cancers. Mod Pathol. 2008;21(11):1371–9.CrossRefPubMed
14.
Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S, Torhorst J, Mihatsch MJ, Sauter G, Kallioniemi OP. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med. 1998;4(7):844–7.CrossRefPubMed
15.
Heumann A, Kaya O, Burdelski C, Hube-Magg C, Kluth M, Lang DS, Simon R, Beyer B, Thederan I, Sauter G, et al. Up regulation and nuclear translocation of Y-box binding protein 1 (YB-1) is linked to poor prognosis in ERG-negative prostate cancer. Sci Rep. 2017;7(1):2056.CrossRefPubMedPubMedCentral
16.
Minner S, Wittmer C, Graefen M, Salomon G, Steuber T, Haese A, Huland H, Bokemeyer C, Yekebas E, Dierlamm J, et al. High level PSMA expression is associated with early PSA recurrence in surgically treated prostate cancer. Prostate. 2011;71(3):281–8.CrossRefPubMed
17.
Burkhardt L, Fuchs S, Krohn A, Masser S, Mader M, Kluth M, Bachmann F, Huland H, Steuber T, Graefen M, et al. CHD1 is a 5q21 tumor suppressor required for ERG rearrangement in prostate cancer. Cancer Res. 2013;73(9):2795–805.CrossRefPubMed
18.
Kluth M, Hesse J, Heinl A, Krohn A, Steurer S, Sirma H, Simon R, Mayer PS, Schumacher U, Grupp K, et al. Genomic deletion of MAP3K7 at 6q12-22 is associated with early PSA recurrence in prostate cancer and absence of TMPRSS2:ERG fusions. Mod Pathol. 2013;26(7):975–83.CrossRefPubMed
19.
Krohn A, Diedler T, Burkhardt L, Mayer PS, De Silva C, Meyer-Kornblum M, Kotschau D, Tennstedt P, Huang J, Gerhauser C, et al. Genomic deletion of PTEN is associated with tumor progression and early PSA recurrence in ERG fusion-positive and fusion-negative prostate cancer. Am J Pathol. 2012;181(2):401–12.CrossRefPubMed
20.
Burdelski C, Menan D, Tsourlakis MC, Kluth M, Hube-Magg C, Melling N, Minner S, Koop C, Graefen M, Heinzer H, et al. The prognostic value of SUMO1/Sentrin specific peptidase 1 (SENP1) in prostate cancer is limited to ERG-fusion positive tumors lacking PTEN deletion. BMC Cancer. 2015;15:538.CrossRefPubMedPubMedCentral
21.
Kluth M, Runte F, Barow P, Omari J, Abdelaziz ZM, Paustian L, Steurer S, Christina Tsourlakis M, Fisch M, Graefen M, et al. Concurrent deletion of 16q23 and PTEN is an independent prognostic feature in prostate cancer. Int J Cancer. 2015;137(10):2354–63.CrossRefPubMed
22.
Krohn A, Seidel A, Burkhardt L, Bachmann F, Mader M, Grupp K, Eichenauer T, Becker A, Adam M, Graefen M, et al. Recurrent deletion of 3p13 targets multiple tumour suppressor genes and defines a distinct subgroup of aggressive ERG fusion-positive prostate cancers. J Pathol. 2013;231(1):130–41.CrossRefPubMed
23.
Ellis SD, Blackard B, Carpenter WR, Mishel M, Chen RC, Godley PA, Mohler JL, Bensen JT. Receipt of National Comprehensive Cancer Network guideline-concordant prostate cancer care among African American and Caucasian American men in North Carolina. Cancer. 2013;119(12):2282–90.CrossRefPubMedPubMedCentral
24.
Yacoub A, McKinstry R, Hinman D, Chung T, Dent P, Hagan MP. Epidermal growth factor and ionizing radiation up-regulate the DNA repair genes XRCC1 and ERCC1 in DU145 and LNCaP prostate carcinoma through MAPK signaling. Radiat Res. 2003;159(4):439–52.CrossRefPubMed
25.
Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson A, Kampf C, Sjostedt E, Asplund A, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419.CrossRefPubMed
26.
Yamada Y, Boku N, Nishina T, Yamaguchi K, Denda T, Tsuji A, Hamamoto Y, Konishi K, Tsuji Y, Amagai K, et al. Impact of excision repair cross-complementing gene 1 (ERCC1) on the outcomes of patients with advanced gastric cancer: correlative study in Japan clinical oncology group trial JCOG9912. Ann Oncol. 2013;24(10):2560–5.CrossRefPubMed
27.
Vare D, Groth P, Carlsson R, Johansson F, Erixon K, Jenssen D. DNA interstrand crosslinks induce a potent replication block followed by formation and repair of double strand breaks in intact mammalian cells. DNA Repair (Amst). 2012;11(12):976–85.CrossRef
28.
Hasty P, Montagna C. Chromosomal rearrangements in cancer: detection and potential causal mechanisms. Mol Cell Oncol. 2014;1(1):e29904.
29.
Brase JC, Johannes M, Mannsperger H, Falth M, Metzger J, Kacprzyk LA, Andrasiuk T, Gade S, Meister M, Sirma H, et al. TMPRSS2-ERG -specific transcriptional modulation is associated with prostate cancer biomarkers and TGF-beta signaling. BMC Cancer. 2011;11:507.CrossRefPubMedPubMedCentral
30.
Jhavar S, Brewer D, Edwards S, Kote-Jarai Z, Attard G, Clark J, Flohr P, Christmas T, Thompson A, Parker M, et al. Integration of ERG gene mapping and gene-expression profiling identifies distinct categories of human prostate cancer. BJU Int. 2009;103(9):1256–69.CrossRefPubMed
31.
Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, Arora VK, Kaushik P, Cerami E, Reva B, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18(1):11–22.CrossRefPubMedPubMedCentral
32.
Naim V, Wilhelm T, Debatisse M, Rosselli F. ERCC1 and MUS81-EME1 promote sister chromatid separation by processing late replication intermediates at common fragile sites during mitosis. Nat Cell Biol. 2013;15(8):1008–15.CrossRefPubMed
33.
Gaillard H, Garcia-Muse T, Aguilera A. Replication stress and cancer. Nat Rev Cancer. 2015;15(5):276–89.CrossRefPubMed
34.
Macheret M, Halazonetis TD. DNA replication stress as a hallmark of cancer. Annu Rev Pathol. 2015;10:425–48.CrossRefPubMed
35.
Ficarra V, Martignoni G, Maffei N, Brunelli M, Novara G, Zanolla L, Pea M, Artibani W. Original and reviewed nuclear grading according to the Fuhrman system: a multivariate analysis of 388 patients with conventional renal cell carcinoma. Cancer. 2005;103(1):68–75.CrossRefPubMed
36.
Grignon DJ. The current classification of urothelial neoplasms. Mod Pathol. 2009;22(Suppl 2):S60–9.CrossRefPubMed
37.
Pierorazio PM, Walsh PC, Partin AW, Epstein JI. Prognostic Gleason grade grouping: data based on the modified Gleason scoring system. BJU Int. 2013;111(5):753–60.CrossRefPubMedPubMedCentral
Metadata
Title
Increased ERCC1 expression is linked to chromosomal aberrations and adverse tumor biology in prostate cancer
Authors
Frank Jacobsen
Billurvan Taskin
Nathaniel Melling
Charlotte Sauer
Corinna Wittmer
Claudia Hube-Magg
Martina Kluth
Ronald Simon
Dirk Pehrke
Burkhard Beyer
Thomas Steuber
Imke Thederan
Guido Sauter
Thorsten Schlomm
Waldemar Wilczak
Katharina Möller
Sören A. Weidemann
Susanne Burdak-Rothkamm
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3489-9

Other articles of this Issue 1/2017

BMC Cancer 1/2017 Go to the issue

Research article

Frequency of Human papillomavirus in women attending cervical cancer screening program in Chile

Study protocol

Partnering around cancer clinical trials (PACCT): study protocol for a randomized trial of a patient and physician communication intervention to increase minority accrual to prostate cancer clinical trials

Research article

Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens

Research article

Single-cell mRNA profiling reveals transcriptional heterogeneity among pancreatic circulating tumour cells

Research article

Differential expression of estrogen receptor subtypes and variants in ovarian cancer: effects on cell invasion, proliferation and prognosis

Research article

A lowered 26S proteasome activity correlates with mantle lymphoma cell lines resistance to genotoxic stress
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits