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

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

doi:10.1186/s12885-017-3489-9

Abstract

BackgroundAnimal model experiments have suggested a role of the DNA repair protein ERCC1 (Excision Repair Cross-Complementation Group 1) in prostate cancer progression.MethodsTo 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).ResultsERCC1 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.ConclusionThe 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.

Highlights

Animal model experiments have suggested a role of the DNA repair protein Excision repair cross-complementation (ERCC1) (Excision Repair Cross-Complementation Group 1) in prostate cancer progression
Technical issues A total of 11,665 (93.9%) patients had follow up data and 10,436 (84%) of samples were interpretable in the tissue microarray (TMA) analysis (Table 1)
Positive nuclear ERCC1 staining was seen in 64.7% of 10,436 interpretable tissue samples, and was graded as weak in 37.1%, moderate in 22.6%, and strong in 5% of tumors

Summary

Introduction

Animal model experiments have suggested a role of the DNA repair protein ERCC1 (Excision Repair Cross-Complementation Group 1) in prostate cancer progression. While most patients will never suffer symptoms from their disease, prostate cancer is still the third most common cause of cancer related death of men in most Western countries [1]. Jacobsen et al BMC Cancer (2017) 17:504 in many cancer types such as urothelial carcinoma [5], head and neck squamous cell carcinoma [6] and nonsmall cell lung cancer [7]. For these entities it has been proposed that ERCC1 overexpression may serve as a prognostic and/or predictive tumor marker [5,6,7,8,9]

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Discussion

Conclusion