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

Abstract

Background Testicular germ cell tumors (TGCTs) are highly sensitive to platinum‐based chemotherapy, and wild‐type p53 seems to play a pivotal role in this susceptibility. On the other hand, overexpression of MDM2 seems to entail treatment resistance and unfavorable prognosis. Objectives We aimed to describe p53 and MDM2 immunoexpression in a well‐characterized cohort of primary and metastatic TGCTs and evaluate associations with clinicopathological and prognostic variables, including survival. Materials and methods 237 primary tumor samples and 12 metastases were evaluated for p53 and MDM2 immunoexpression using digital image analysis. Clinical records of all patients were reviewed for baseline clinical/pathologic characteristics and follow‐up. Results A significant positive correlation between p53 and MDM2 H‐scores was found (rs = 0.590, P < .0001). Non‐seminomas showed significantly higher expression levels of both p53 and MDM2 (P = .0002, P < .0001), which peaked in embryonal carcinomas and choriocarcinomas. Percentage of immunoexpressing cells and H‐score were significantly higher in chemo‐treated metastases compared with chemo‐naïve primary tumors for MDM2 (P ≤ .0001 for both), but not for p53 (P = .919 and P = .703, respectively). Cases with higher MDM2 immunoexpression showed a statistically significant trend for association with poorer prognosis (P = .043). Relapse/progression‐free survival at 12 months post‐diagnosis was lower in the “MDM2‐high” (≥P50) vs. the “MDM2‐low” (<P50) expression groups. Discussion and Conclusion In TGCTs, MDM2 overexpression may indicate a more aggressive tumor phenotype, with propensity for therapy resistance and recurrence. If validated in larger multi‐institutional studies with precise quantification, it may be envisioned as a useful predictive biomarker of poor response to cisplatin.

Mechanisms of TP53 Pathway Inactivation in Embryonic and Somatic Cells—Relevance for Understanding (Germ Cell) Tumorigenesis

“…In addition, despite the curative success of GCTs due to their sensitivity to chemotherapeutics such as cisplatin, GCTs may acquire resistance which, with the lack of targeted treatment, is inherently difficult to treat and exemplifies a significant shortcoming in current GCT treatment [383]. Thus, a significant proportion of GCT research aims to identify the underlying cause of GCT resistance, and it has been suggested that the deregulation of the P53 pathway may be a contributing factor [15,18,39,40,42]. Correspondingly, multiple mechanisms of P53 pathway deregulation have been observed in GCTs including rare TP53 mutations and elevated P21, MDM2, and/or MDM4 levels, which have also been associated with resistance to cisplatin [22,27,34,37,39,384].…”

“…For instance, GCTs most often express high levels of wild-type (WT) TP53, and it has been suggested that the P53 pathway is (partially) responsible for their characteristic to enter apoptosis in response to platinum-based chemotherapeutics (e.g., cisplatin) which is reminiscent of ES cells in response to DNA damage [10,18,21,23,[25][26][27][28][29][33][34][35][36][37]. In addition, it has been suggested that the P53 pathway is deregulated through multiple mechanisms in GCTs that have acquired resistance to chemotherapy, including cisplatin [15,18,[38][39][40][41][42].…”

Cisplatin Resistance in Testicular Germ Cell Tumors: Current Challenges from Various Perspectives

“…Moreover, there have been several reports that MDM2 amplifications are enriched in cisplatin-resistant tumors by inactivating p53 and its proapoptotic program, which is supported by the efficacy of MDM2 inhibitor Nutlin-3 in cisplatin-resistant cases, promoting sensitivity to cisplatin [ 108 , 109 , 110 ]. Studies focusing solely on immunohistochemistry for p53 and MDM2 in primary tumors have been conflicting, some failing to show ability to predict disease recurrence after cisplatin treatment and others showing up- and downregulations of MDM2/p53, respectively [ 70 , 111 , 112 , 113 ]. Current knowledge indicates the p53 pathway as a contributor to the cisplatin resistance phenotype but not solely responsible for cisplatin resistance.…”

Ki67 and LSD1 Expression in Testicular Germ Cell Tumors Is Not Associated with Patient Outcome: Investigation Using a Digital Pathology Algorithm

“…Their common precursor is germ cell neoplasia in situ (GCNIS), and they are divided into seminomas (SE) and non-seminomas (NS). The latter comprise a complex array of subtypes that include embryonal carcinoma (EC), choriocarcinoma (CH), yolk sac tumor (YST), and teratoma (TE) [1][2][3][4][5][6][7]. Overall, TGCTs represent a model of curable disease, with most patients presenting with stage I disease (around 70%), but approximately 75% of these are cured with orchiectomy alone, without the need for subsequent adjuvant treatments [4,8,9].…”

“…Overall, TGCTs represent a model of curable disease, with most patients presenting with stage I disease (around 70%), but approximately 75% of these are cured with orchiectomy alone, without the need for subsequent adjuvant treatments [4,8,9]. For those who require systemic therapy, TGCTs present extreme sensitivity to cisplatin-based chemotherapy, due to their unique molecular background [3,10]. However, a significant group of patients relapse, most frequently within the first two years after initial diagnosis [9,11].…”