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Increased levels of XPA might be the basis of cisplatin resistance in germ cell tumours

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  • Z. Cierna
  • V. Miskovska
  • J. Roska
  • D. Jurkovicova
  • L.B. Pulzova
  • Z. Sestakova
  • L. Hurbanova
  • K. Machalekova
  • M. Chovanec
  • K. Rejlekova
  • D. Svetlovska
  • K. Kalavska
  • K. Kajo
  • P. Babal
  • J. Mardiak
  • T.A. Ward
  • M. Mego
  • Miroslav Chovanec
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Article number17
<mark>Journal publication date</mark>6/01/2020
<mark>Journal</mark>BMC Cancer
Issue number1
Volume20
Number of pages12
Publication StatusPublished
<mark>Original language</mark>English

Abstract

Background
Germ cell tumours (GCTs) represent a highly curable malignity as they respond well to cisplatin (CDDP)-based chemotherapy. Nevertheless, a small proportion of GCT patients relapse or do not respond to therapy. As this might be caused by an increased capacity to repair CDDP-induced DNA damage, identification of DNA repair biomarkers predicting inadequate or aberrant response to CDDP, and thus poor prognosis for GCT patients, poses a challenge. The objective of this study is to examine the expression levels of the key nucleotide excision repair (NER) factors, XPA, ERCC1 and XPF, in GCT patients and cell lines.

Methods
Two hundred seven GCT patients’ specimens with sufficient follow-up clinical-pathological data and pairwise combinations of CDDP-resistant and -sensitive GCT cell lines were included. Immunohistochemistry was used to detect the ERCC1, XPF and XPA protein expression levels in GCT patients’ specimen and Western blot and qRT-PCR examined the protein and mRNA expression levels in GCT cell lines.

Results
GCT patients with low XPA expression had significantly better overall survival than patients with high expression (hazard ratio = 0.38, 95% confidence interval: 0.12–1.23, p = 0.0228). In addition, XPA expression was increased in the non-seminomatous histological subtype, IGCCCG poor prognosis group, increasing S stage, as well as the presence of lung, liver and non-pulmonary visceral metastases. Importantly, a correlation between inadequate or aberrant CDDP response and XPA expression found in GCT patients was also seen in GCT cell lines.

Conclusions
XPA expression is an additional independent prognostic biomarker for stratifying GCT patients, allowing for improvements in decision-making on treatment for those at high risk of refractoriness or relapse. In addition, it could represent a novel therapeutic target in GCTs.