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

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.

• Authors: 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, Gaetano Facchini
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 51 Pg. 85641-85649 (Dec 20 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27821802 (Publication Type: Journal Article, Review)

Chemical References

• Poly(ADP-ribose) Polymerase Inhibitors
• TP53 protein, human
• Tumor Suppressor Protein p53
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2
• Cisplatin

Topics

• Animals
• Cisplatin (therapeutic use)
• DNA Damage
• DNA Repair (drug effects)
• Drug Resistance, Neoplasm (genetics)
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Neoplasms, Germ Cell and Embryonal (drug therapy, genetics, metabolism, pathology)
• Poly(ADP-ribose) Polymerase Inhibitors (therapeutic use)
• Proto-Oncogene Proteins c-mdm2 (genetics, metabolism)
• Signal Transduction
• Testicular Neoplasms (drug therapy, genetics, metabolism, pathology)
• Tumor Suppressor Protein p53 (genetics, metabolism)