TY - JOUR
T1 - MDM2 gene amplification as selection tool for innovative targeted approaches in PD-L1 positive or negative muscle-invasive urothelial bladder carcinoma
AU - Brunelli, Matteo
AU - Tafuri, Alessandro
AU - Cima, Luca
AU - Cerruto, Maria Angela
AU - Milella, Michele
AU - Zivi, Andrea
AU - Buti, Sebastiano
AU - Bersanelli, Melissa
AU - Fornarini, Giuseppe
AU - Vellone, Valerio Gaetano
AU - Rebuzzi, Sara Elena
AU - Procopio, Giuseppe
AU - Verzoni, Elena
AU - Bracarda, Sergio
AU - Sabbatini, Roberto
AU - Baldessari, Cinzia
AU - Eccher, Albino
AU - Passalacqua, Rodolfo
AU - Perrucci, Bruno
AU - Giganti, Maria Olga
AU - Donini, Maddalena
AU - Panni, Stefano
AU - Tucci, Marcello
AU - Prati, Veronica
AU - Ortega, Cinzia
AU - Caliò, Anna
AU - Alongi, Filippo
AU - Munari, Enrico
AU - Pappagallo, Giovanni
AU - Iacovelli, Roberto
AU - Mosca, Alessandra
AU - Porta, Camillo
AU - Martignoni, Guido
AU - Antonelli, Alessandro
N1 - Publisher Copyright:
© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - GENE AMPLIFICATION
KW - IMMUNOHISTOCHEMISTRY
KW - Molecular
KW - Pathology
KW - Urinary Bladder
UR - http://www.scopus.com/inward/record.url?scp=85095946972&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85095946972&partnerID=8YFLogxK
U2 - 10.1136/jclinpath-2020-207089
DO - 10.1136/jclinpath-2020-207089
M3 - Article
C2 - 33144356
AN - SCOPUS:85095946972
JO - Journal of Clinical Pathology - Clinical Molecular Pathology
JF - Journal of Clinical Pathology - Clinical Molecular Pathology
SN - 0021-9746
ER -