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Role of DNA repair machinery and p53 in the testicular germ cell cancer: a review

Francesco Jacopo Romano _, Sabrina Rossetti, Vincenza Conteduca, Giuseppe Schepisi, Carla Cavaliere, Rossella Di Franco, Elvira La Mantia, Luigi Castaldo, Flavia Nocerino, Gianluca Ametrano, Francesca Cappuccio, Gabriella Malzone, Micaela Montanari, Daniela Vanacore, Vincenzo Quagliariello, Raffaele Piscitelli, Maria Filomena Pepe, Massimiliano Berretta, Carmine D’Aniello, Sisto Perdonà, Paolo Muto, Gerardo Botti, Gennaro Ciliberto, Bianca Maria Veneziani, Francesco De Falco, Piera Maiolino, Michele Caraglia, Maurizio Montella, Ugo De Giorgi and Gaetano Facchini

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Oncotarget. 2016; 7:85641-85649. https://doi.org/10.18632/oncotarget.13063

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Abstract

Francesco Jacopo Romano1, Sabrina Rossetti1,2, Vincenza Conteduca3, Giuseppe Schepisi3, Carla Cavaliere1,4, Rossella Di Franco1,5, Elvira La Mantia1,6, Luigi Castaldo1,7, Flavia Nocerino8, Gianluca Ametrano1,5, Francesca Cappuccio1,9, Gabriella Malzone1,6, Micaela Montanari1,10, Daniela Vanacore1, Vincenzo Quagliariello1, Raffaele Piscitelli1,11, Maria Filomena Pepe1,6, Massimiliano Berretta12, Carmine D’Aniello1,13, Sisto Perdonà7, Paolo Muto5, Gerardo Botti6, Gennaro Ciliberto14, Bianca Maria Veneziani10, Francesco De Falco9, Piera Maiolino11, Michele Caraglia15, Maurizio Montella8, Ugo De Giorgi3 and Gaetano Facchini1,2

1 Progetto ONCONET2.0, Linea Progettuale 14 per L’implementazione della Prevenzione e Diagnosi Precoce del Tumore alla Prostata e Testicolo, Regione Campania, Italy

2 Division of Medical Oncology, Department of Uro-Gynaecological Oncology, Istituto Nazionale Tumori ‘Fondazione G. Pascale’, IRCCS, Naples, Italy

3 Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola, Italy

4 Department of Onco-Ematology Medical Oncology, S.G. Moscati Hospital of Taranto, Taranto, Italy

5 Radiation Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori ‘Fondazione Giovanni Pascale’, IRCCS, Napoli, Italy

6 Pathology Unit, Istituto Nazionale Tumori “Fondazione G. Pascale”-IRCCS, Naples, Italy

7 Department of Uro-Gynaecological Oncology, Division of Urology, Istituto Nazionale Tumori ‘Fondazione G. Pascale’, IRCCS, Naples, Italy

8 Epidemiology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori ‘Fondazione Giovanni Pascale’, IRCCS, Napoli, Italy

9 Psicology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori ‘Fondazione Giovanni Pascale’, IRCCS, Napoli, Italy

10 Department of Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, Naples, Italy

11 Pharmacy Unit, Istituto Nazionale Tumori, Istituto Nazionale Tumori-Fondazione G. Pascale Naples, Italy

12 Department of Medical Oncology, CRO Aviano, National Cancer Institute, Aviano, Italy

13 Division of Medical Oncology, A.O.R.N. dei COLLI “Ospedali Monaldi-Cotugno-CTO”, Napoli, Italy

14 Scientific Directorate, Istituto Nazionale per lo Studio e la Cura dei Tumori ‘Fondazione Giovanni Pascale’, IRCCS, Napoli, Italy

15 Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy

Correspondence to:

Francesco Jacopo Romano, email:

Keywords: testis; germ cell cancer; DDR; ATM; p53

Received: September 12, 2016 Accepted: October 19, 2016 Published: November 03, 2016

Abstract

Notwithstanding the peculiar sensitivity to cisplatin-based treatment, resulting in a very high percentage of cures even in advanced stages of the disease, still we do not know the biological mechanisms that make Testicular Germ Cell Tumor (TGCT) “unique” in the oncology scene. p53 and MDM2 seem to play a pivotal role, according to several in vitro observations, but no correlation has been found between their mutational or expression status in tissue samples and patients clinical outcome. Furthermore, other players seem to be on stage: DNA Damage Repair Machinery (DDR) , especially Homologous Recombination (HR) proteins, above all Ataxia Telangiectasia Mutated (ATM), cooperates with p53 in response to DNA damage, activating apoptotic cascade and contributing to cell “fate”. Homologous Recombination deficiency has been assumed to be a Germ Cell Tumor characteristic underlying platinum-sensitivity, whereby Poly(ADP-ribose) polymerase (PARP), an enzyme involved in HR DNA repair, is an intriguing target: PARP inhibitors have already entered in clinical practice of other malignancies and trials are recruiting TGCT patients in order to validate their role in this disease. This paper aims to summarize evidence, trying to outline an overview of DDR implications not only in TGCT curability, but also in resistance to chemotherapy.


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