Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 Aug;14(4):352-9.
doi: 10.1016/j.clgc.2015.12.029. Epub 2015 Dec 24.

Expression Levels of DNA Damage Repair Proteins Are Associated With Overall Survival in Platinum-Treated Advanced Urothelial Carcinoma

Stephanie A Mullane  1 , Lillian Werner  2 , Elizabeth A Guancial  3 , Rosina T Lis  4 , Edward C Stack  4 , Massimo Loda  5 , Philip W Kantoff  6 , Toni K Choueiri  6 , Jonathan Rosenberg  7 , Joaquim Bellmunt  8
Affiliations

Expression Levels of DNA Damage Repair Proteins Are Associated With Overall Survival in Platinum-Treated Advanced Urothelial Carcinoma

Stephanie A Mullane et al. Clin Genitourin Cancer. 2016 Aug.

Abstract

Background: Combination platinum chemotherapy is standard first-line therapy for metastatic urothelial carcinoma (mUC). Defining the platinum response biomarkers for patients with mUC could establish personalize medicine and provide insights into mUC biology. Although DNA repair mechanisms have been hypothesized to mediate the platinum response, we sought to analyze whether increased expression of DNA damage genes would correlate with worse overall survival (OS) in patients with mUC.

Patients and methods: We retrospectively identified a clinically annotated cohort of patients with mUC, who had been treated with first-line platinum combination chemotherapy. A tissue microarray was constructed from formalin-fixed paraffin-embedded tissue from the primary tumor before treatment. Immunohistochemical analysis of the following DNA repair proteins was performed: ERCC1, RAD51, BRCA1/2, PAR, and PARP-1. Nuclear and cytoplasmic expression was analyzed using multispectral imaging. Nuclear staining was used for the survival analysis. Cox regression analysis was used to evaluate the associations between the percentage of positive nuclear staining and OS in multivariable analysis, controlling for known prognostic variables.

Results: In a cohort of 104 patients with mUC, a greater percentage of nuclear staining of ERCC1 (hazard ratio [HR], 2.7; 95% confidence interval [CI], 1.5-4.9; P = .0007), RAD51 (HR, 5.6; 95% CI, 1.7-18.3; P = .005), and PAR (HR, 2.2; 95% CI, 1.1-4.4; P = .026) was associated with worse OS. BRCA1, BRCA2, and PARP-1 expression was not associated with OS (P = .76, P = .38, and P = .09, respectively). A greater percentage of combined ERCC1 and RAD51 nuclear staining was strongly associated with worse OS (P = .005).

Conclusion: A high percentage of nuclear staining of ERCC1, RAD51, and PAR, assessed by immunohistochemistry, correlated with worse OS for patients with mUC treated with first-line platinum combination chemotherapy, supporting the evidence of the DNA repair pathways' role in the prognosis of mUC. We also report new evidence that RAD51 and PAR might play a role in the platinum response. Additional prospective studies are required to determine the prognostic or predictive nature of these biomarkers in mUC.

Keywords: Bladder cancer; DNA damage; Immunohistochemistry; Platinum chemotherapy.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: All authors declare that they have no interests or involvements that have a bearing on the submitted paper, including support for the work under consideration (financial or in kind from any third party, company or organization whose finances or reputation may be affected by the publication of the work). They also declare that none of them has an existing or planned employment relationship or consultancy with an organization whose finances or reputation may be affected by the publication of the work. They all also state that none of them or their spouses, parents or children has a financial interest (personal shareholdings, consultancies, patents or patent applications) whose value could be affected by the publication.

Figures

Figure 1
Figure 1. Multispectral analysis of ERCC1 IHC
A. ERCC1 IHC was carried out on a UC TMA. TMA cores were scanned using the CRi Vectra™. B. The acquired images were analyzed usig the CRi InForm software package where InForm identifies tumor cells; creates a false-color image with the identity of individual tumor nuclei (green) and associated cytoplasm (multicolor); and performs image analysis.
Figure 2
Figure 2
OS by percentage of cells with positive nuclear ERCC1 staining
Figure 3
Figure 3
OS by percentage of cells with positive nuclear PAR staining
Figure 4
Figure 4
OS by percentage of cells with positive nuclear RAD51 staining
Figure 5
Figure 5
OS by percentage of cells with positive nuclear RAD51 and ERCC1 staining
See this image and copyright information in PMC

References

    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29. - PubMed
    1. Burger M, et al. ICUD-EAU International Consultation on Bladder Cancer 2012: Non-muscle-invasive urothelial carcinoma of the bladder. Eur Urol. 2013;63(1):36–44. - PubMed
    1. Collaboration, A.B.C.A.M.-a. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol. 2005;48(2):202–5. discussion 205–6. - PubMed
    1. Roberts JT, et al. Long-term survival results of a randomized trial comparing gemcitabine/cisplatin and methotrexate/vinblastine/doxorubicin/cisplatin in patients with locally advanced and metastatic bladder cancer. Ann Oncol. 2006;17(Suppl 5):v118–22. - PubMed
    1. Kaufman DS, Shipley WU, Feldman AS. Bladder cancer. Lancet. 2009;374(9685):239–49. - PubMed

MeSH terms