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MDM2 gene amplification as selection tool for innovative targeted approaches in PD-L1 positive or negative muscle-invasive urothelial bladder carcinoma
  1. Matteo Brunelli1,2,
  2. Alessandro Tafuri3,
  3. Luca Cima4,
  4. Maria Angela Cerruto3,
  5. Michele Milella5,
  6. Andrea Zivi5,
  7. Sebastiano Buti6,
  8. Melissa Bersanelli6,
  9. Giuseppe Fornarini7,
  10. Valerio Gaetano Vellone7,
  11. Sara Elena Rebuzzi7,
  12. Giuseppe Procopio8,
  13. Elena Verzoni8,
  14. Sergio Bracarda9,
  15. Roberto Sabbatini10,
  16. Cinzia Baldessari10,
  17. Albino Eccher1,
  18. Rodolfo Passalacqua11,
  19. Bruno Perrucci11,
  20. Maria Olga Giganti11,
  21. Maddalena Donini11,
  22. Stefano Panni11,
  23. Marcello Tucci12,
  24. Veronica Prati13,
  25. Cinzia Ortega13,
  26. Anna Caliò1,
  27. Filippo Alongi14,
  28. Enrico Munari15,
  29. Giovanni Pappagallo16,
  30. Roberto Iacovelli17,
  31. Alessandra Mosca18,
  32. Camillo Porta19,20,
  33. Guido Martignoni1,21,
  34. Alessandro Antonelli3
  1. 1Department of Diagnostics and Public Health, Pathology Unit, University and Hospital Trust of Verona, Verona, Italy
  2. 2Department of Diagnostics and Public Health, FISH Lab, University and Hospital Trust of Verona, Verona, Italy
  3. 3Division of Urology, University and Hospital Trust of Verona, Verona, Italy
  4. 4Department of Clinical Services, Pathology Unit, Santa Chiara Hospital, Trento, Italy
  5. 5Division of Oncology, University and Hospital Trust of Verona, Verona, Italy
  6. 6Division of Oncology, University and Hospital Trust of Parma, Parma, Italy
  7. 7Division of Oncology, San Martino Hospital, Genova, Italy
  8. 8Division of Oncology, IRCCS Foundation, Istituto Nazionale dei Tumori di Milano, Milano, Italy
  9. 9Division of Oncology, Santa Maria Hospital, Terni, Italy
  10. 10Department of Oncology, Hematology & Respiratory Diseases, Division of Oncology, University of Modena & Reggio Emilia, Modena, Modena & Reggio Emilia, Italy
  11. 11Division of Oncology, Hospital Trust of Cremona, Cremona, Italy
  12. 12Division of Oncology, Cardinal Massaia Hospital, Asti, Italy
  13. 13Division of Oncology, Institute for Cancer Research and Treatment, Asl Cn2 Alba-Brà, Alba-Brà, Italy
  14. 14Division of Radiotherapy, Ospedale SacroCuore di Negrar di Valpolicella, Negrar, Italy
  15. 15Division of Pathology, Ospedale SacroCuore di Negrar di Valpolicella, Negrar, Italy
  16. 16Clinical Epidemiologist, Silea, Italy
  17. 17Policlinico Universitario Fondazione Andrea Gemelli, Rome, Italy
  18. 18Oncology, Candiolo Cancer Institute, IRCCS-FPO, Torino, Italy
  19. 19Department of Biomedical Sciences and Human Oncology, University of Bari ‘A.Moro’, Bari, Italy
  20. 20Division of Medical Oncology, Policlinico Consorziale di Bari, Bari, Italy
  21. 21Pathology Unit, Pederzoli Hospital, Italy
  1. Correspondence to Professor Matteo Brunelli, Department of Diagnostics and Public Health, Pathology Unit, University and Hospital Trust of Verona, 37134 Verona, Italy; matteo.brunelli{at}univr.it

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.

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

  • MB and AT are joint first authors.

  • GM and AA are joint senior authors.

  • Handling editor Runjan Chetty.

  • Twitter @AlessandraMosc5

  • 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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