Attenuated XPC expression is not associated with impaired DNA repair in bladder cancer.

Kishan A T Naipal,Roland Kanaar,Geert J L H Van Leenders,Serena T Bruens,Joris Pothof,Dik C Van Gent,Nicole S Verkaik,Joost Boormans,Nicolaas G J Jaspers,Inger Brandsma,Anja Raams,Jan H J Hoeijmakers

doi:10.1371/journal.pone.0126029

Kishan A T Naipal, Roland Kanaar + Show 10 more

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https://doi.org/10.1371/journal.pone.0126029

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Journal: PloS one	Publication Date: Apr 30, 2015
Citations: 10	License type: CC BY 4.0

Affiliation: Erasmus MC, Cancer Genomics Centre

Abstract

Bladder cancer has a high incidence with significant morbidity and mortality. Attenuated expression of the DNA damage response protein Xeroderma Pigmentosum complementation group C (XPC) has been described in bladder cancer. XPC plays an essential role as the main initiator and damage-detector in global genome nucleotide excision repair (NER) of UV-induced lesions, bulky DNA adducts and intrastrand crosslinks, such as those made by the chemotherapeutic agent Cisplatin. Hence, XPC protein might be an informative biomarker to guide personalized therapy strategies in a subset of bladder cancer cases. Therefore, we measured the XPC protein expression level and functional NER activity of 36 bladder tumors in a standardized manner. We optimized conditions for dissociation and in vitro culture of primary bladder cancer cells and confirmed attenuated XPC expression in approximately 40% of the tumors. However, NER activity was similar to co-cultured wild type cells in all but one of 36 bladder tumors. We conclude, that (i) functional NER deficiency is a relatively rare phenomenon in bladder cancer and (ii) XPC protein levels are not useful as biomarker for NER activity in these tumors.

Highlights

Bladder cancer (BC) is the fifth most common malignancy in Europe with an incidence of more than 150,000 cases resulting in more than 50,000 deaths per year [1]
In line with previous studies [13,14], we found that attenuated Xeroderma Pigmentosum complementation group C (XPC) protein expression is a common phenomenon in BC, both in dissociated tumor cells as well as in FFPE samples
We confirm that XPC expression varied widely among primary BC samples but surprisingly, we found that lowered XPC protein levels did not generally influence nucleotide excision repair (NER) capacity in BC

Summary

Introduction

Bladder cancer (BC) is the fifth most common malignancy in Europe with an incidence of more than 150,000 cases resulting in more than 50,000 deaths per year [1]. Bladder tumors present either as non-muscle-invasive (NMIBC) (70%) or as muscle-invasive bladder cancer (MIBC) (30%) [2]. MIBC is a potentially lethal disease with a 5-year survival rate of 50–60% [3]. Therapy of MIBC involves mainly surgery and systemic chemotherapeutic treatments, the latter mainly for recurrent and metastatic disease. There is a clear clinical need for the development of new systemic treatment strategies for MIBC, as the survival of MIBC patients has not improved over the past decades. Treatments targeting tumor-specific pathways have shown to be effective in various cancers, such as breast, PLOS ONE | DOI:10.1371/journal.pone.0126029. Treatments targeting tumor-specific pathways have shown to be effective in various cancers, such as breast, PLOS ONE | DOI:10.1371/journal.pone.0126029 April 30, 2015

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