MDM2 gene amplification as selection tool for innovative targeted approaches in PD-L1 positive or negative muscle-invasive urothelial bladder carcinoma

Matteo Brunelli, Alessandro Tafuri, Luca Cima, Maria Angela Cerruto, Michele Milella, Andrea Zivi, Sebastiano Buti, Melissa Bersanelli, Giuseppe Fornarini, Valerio Gaetano Vellone, Sara Elena Rebuzzi, Giuseppe Procopio, Elena Verzoni, Sergio Bracarda, Roberto Sabbatini, Cinzia Baldessari, Albino Eccher, Rodolfo Passalacqua, Bruno Perrucci, Maria Olga GigantiMaddalena Donini, Stefano Panni, Marcello Tucci, Veronica Prati, Cinzia Ortega, Anna Caliò, Filippo Alongi, Enrico Munari, Giovanni Pappagallo, Roberto Iacovelli, Alessandra Mosca, Camillo Porta, Guido Martignoni, Alessandro Antonelli

Research output: Contribution to journalArticlepeer-review

Abstract

Aims: According to The Cancer Genome Atlas (TCGA), around 9% of bladder carcinomas usually show abnormalities of the murine double minute 2 (MDM2) gene, but a few studies have been investigated them. We profiled MDM2 gene amplification in a series of urothelial carcinomas (UC) considering the molecular subtypes and expression of programmed death ligand 1 (PD-L1). Methods: 117 patients with muscle-invasive UC (pT2-3) without (N0) or with (N+) lymph-node metastases were revised. Only cases with availability of in toto specimens and follow-up were studied. Tissue microarray was built. p53, ER, RB1, GATA-3, CK20, CK5/6, CD44 and PD-L1 (clone sp263) immunoexpression was evaluated. Fluorescent in situ hybridisation was assessed by using the HER-2/neu, FGFR-3, CDKN2A and MDM2 probes. True (ratio 12q/CEP12 >2) MDM2 gene amplification was distinguished from polyploidy/gains (ratio <2, absolute copy number of MDM-2 >2). MDM2 and PD-L1 values were correlated to the TCGA molecular phenotypes. Statistical analysis was performed. Results: 6/50 (12%) cases (5 N0 and 1 N+) were amplified for MDM2 without matching to molecular phenotypes. Of 50, 14 (37%) cases expressed PD-L1 at 1% cut-off; 3/50 (9%) at >50% cut-off; of these, 2 cases on side of neoplasia among inflammatory cells. Only one out of six (17%) cases amplified for MDM2 showed expression (>50% cut-off) of PD-L1. MDM2 amplification was independent to all documented profiles (k test=0.3) and was prevalent in recurrent UC. Conclusion: MDM2 amplification has been seen in both PD-L1 positive and negative muscle-invasive bladder UC independently from the TCGA molecular phenotypes. MDM2 and PD-L1 might be assessed in order to predict a better response to combo/single targeted therapies.

Original languageEnglish
JournalJournal of Clinical Pathology
DOIs
Publication statusAccepted/In press - 2020

Keywords

  • GENE AMPLIFICATION
  • IMMUNOHISTOCHEMISTRY
  • Molecular
  • Pathology
  • Urinary Bladder

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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