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.

Micrornas in prostate cancer: an overview

“…DNA damage and oncogenic stress strongly induced miR-34 expression in a p53-dependent manner. The distinctive features of p53 activity are promoted by miR-34 activation [ 94 – 95 ]: induction of cell cycle block and apoptosis through down-modulation of different proteins (CDK4, CDK6, cyclin D1, cyclin E2, E2F3 and BCL2) [ 96 – 98 ].…”

Genomic landscape of platinum resistant and sensitive testicular cancers

“…The molecular basis of platinum response in TGCT remains poorly understood. Defective homologous recombination and mitochondrial priming have both recently been proposed as possible mechanisms 12,[17][18][19] . Increased frequency of TP53 mutation and higher mutational burden has variously been reported in resistant tumours 13,14 .…”

p53 and MDM2 expression in primary and metastatic testicular germ cell tumors: Association with clinical outcome

“…9 SE are highly sensitive to both radiation and chemotherapy, in contrast to NS, which show higher expression (especially EC) of players involved in DNA repair (like ATM), having been advanced as a justification for their higher propensity to subsequently develop cisplatin resistance. 10 Cisplatin resistance is, indeed, a major clinical challenge, and it is imperative to uncover novel biomarkers for predicting its emergence as well as new therapeutic strategies. It has been associated with factors suggesting malfunction of DNA repair, such as increased microsatellite instability (MSI), BRAF mutations (although these have been shown to be very rare events-or event absent-in TGCTs in more recent studies 11,12 ), and/or abnormal activity of the p53-MDM2 pathway.…”

“…19 The prognostic significance of p53 and MDM2 expression in TGCTs remains a controversial topic, needing further investigation, as the few studies published thus far (mostly centered on primary tumor samples) disclosed multiple and, sometimes, opposite conclusions. 10,20 As there is also a need to better understand the role of p53, MDM2 and their interaction in the pathophysiology of TGCTs, we sought to objectively quantify p53 and MDM2 expression in a clinically and pathologically well-characterized cohort of primary and metastatic TGCTs and to determine associations with clinicopathological and prognostic parameters, including survival.…”