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.

MDM2 gene amplification as selection tool for innovative targeted approaches in PD-L1 positive or negative muscle-invasive urothelial bladder carcinoma / Brunelli, Matteo; Tafuri, Alessandro; Cima, Luca; Cerruto, Maria Angela; Milella, Michele; Zivi, Andrea; Buti, Sebastiano; Bersanelli, Melissa; Fornarini, Giuseppe; Vellone, Valerio Gaetano; Rebuzzi, Sara Elena; Procopio, Giuseppe; Verzoni, Elena; Bracarda, Sergio; Sabbatini, Roberto; Baldessari, Cinzia; Eccher, Albino; Passalacqua, Rodolfo; Perrucci, Bruno; Giganti, Maria Olga; Donini, Maddalena; Panni, Stefano; Tucci, Marcello; Prati, Veronica; Ortega, Cinzia; Caliò, Anna; Alongi, Filippo; Munari, Enrico; Pappagallo, Giovanni; Iacovelli, Roberto; Mosca, Alessandra; Porta, Camillo; Martignoni, Guido; Antonelli, Alessandro. - In: JOURNAL OF CLINICAL PATHOLOGY. - ISSN 0021-9746. - 75:1(2022), pp. 39-44. [10.1136/jclinpath-2020-207089]

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

Eccher, Albino;
2022

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.
2022
75
1
39
44
MDM2 gene amplification as selection tool for innovative targeted approaches in PD-L1 positive or negative muscle-invasive urothelial bladder carcinoma / Brunelli, Matteo; Tafuri, Alessandro; Cima, Luca; Cerruto, Maria Angela; Milella, Michele; Zivi, Andrea; Buti, Sebastiano; Bersanelli, Melissa; Fornarini, Giuseppe; Vellone, Valerio Gaetano; Rebuzzi, Sara Elena; Procopio, Giuseppe; Verzoni, Elena; Bracarda, Sergio; Sabbatini, Roberto; Baldessari, Cinzia; Eccher, Albino; Passalacqua, Rodolfo; Perrucci, Bruno; Giganti, Maria Olga; Donini, Maddalena; Panni, Stefano; Tucci, Marcello; Prati, Veronica; Ortega, Cinzia; Caliò, Anna; Alongi, Filippo; Munari, Enrico; Pappagallo, Giovanni; Iacovelli, Roberto; Mosca, Alessandra; Porta, Camillo; Martignoni, Guido; Antonelli, Alessandro. - In: JOURNAL OF CLINICAL PATHOLOGY. - ISSN 0021-9746. - 75:1(2022), pp. 39-44. [10.1136/jclinpath-2020-207089]
Brunelli, Matteo; Tafuri, Alessandro; Cima, Luca; Cerruto, Maria Angela; Milella, Michele; Zivi, Andrea; Buti, Sebastiano; Bersanelli, Melissa; Fornarini, Giuseppe; Vellone, Valerio Gaetano; Rebuzzi, Sara Elena; Procopio, Giuseppe; Verzoni, Elena; Bracarda, Sergio; Sabbatini, Roberto; Baldessari, Cinzia; Eccher, Albino; Passalacqua, Rodolfo; Perrucci, Bruno; Giganti, Maria Olga; Donini, Maddalena; Panni, Stefano; Tucci, Marcello; Prati, Veronica; Ortega, Cinzia; Caliò, Anna; Alongi, Filippo; Munari, Enrico; Pappagallo, Giovanni; Iacovelli, Roberto; Mosca, Alessandra; Porta, Camillo; Martignoni, Guido; Antonelli, Alessandro
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