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.
- Urinary Bladder
- GENE AMPLIFICATION
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MB and AT are joint first authors.
GM and AA are joint senior authors.
Handling editor Runjan Chetty.
Contributors All authors contributed equally to all stages of the work.
Funding Internal funding from Department of Diagnostics and Public Health (MB, FUR 2018-2019) has been used in part for study-related facilities.
Disclaimer This study did not receive any funding from the National Institutes of Health (NIH), the Wellcome Trust and the Howard Hughes Medical Institute (HHNI).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval This study was approved by the institutional review board of the University of Verona in accordance with the Declaration of Helsinki of 1975.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement No data are available.
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