Clinical, Genomic, and Pharmacological Study of MYCN-Amplified RB1 Wild-Type Metastatic Retinoblastoma
Por:
Zugbi S, Ganiewich D, Bhattacharyya A, Aschero R, Ottaviani D, Sampor C, Cafferata EG, Mena M, Sgroi M, Winter U, Lamas G, Suñol M, Daroqui M, Baialardo E, Salas B, Das A, Fandiño A, Francis JH, Lubieniecki F, Lavarino C, Garippa R, Podhjacer OL, Abramson DH, Radvanyi F, Chantada G, Llera AS and Schaiquevich P
Publicada:
1 sep 2020
Ahead of Print:
22 sep 2020
Resumen:
Simple Summary We present two cases of a subtype of retinoblastoma, a rare ocular tumor in children, presenting without the typical mutation in the RB1 gene but showing amplification of the transcription factor MYCN frequently reported in pediatric malignancies. Even though previous reports suggested that this tumor sybtype could present metastases, patients with metastatic disease were not reported. Our cases had metastasis to the orbit and lymph nodes and poor sensitivity to standard chemotherapy but no dissemination to the central nervous system, as described for patients with mutations in the RB1. We were able to grow the cells of one of our patients in vitro, perform comprehensive genomic analysis that showed previously not reported mutations and other chromosomal alterations. In an animal model, we could reproduce the clinical dissemination and we identified an innovative active drug combination that could help for the treatment of these children with poor prognosis.
An uncommon subgroup of unilateral retinoblastomas with highly aggressive histological features, lacking aberrations in RB1 gene with high-level amplification of MYCN (MCYNampl RB1(+/+)) has only been described as intra-ocular cases treated with initial enucleation. Here, we present a comprehensive clinical, genomic, and pharmacological analysis of two cases of MCYNampl RB1(+/+) with orbital and cervical lymph node involvement, but no central nervous system spread, rapidly progressing to fatal disease due to chemoresistance. Both patients showed in common MYCN high amplification and chromosome 16q and 17p loss. A somatic mutation in TP53, in homozygosis by LOH, and high chromosomal instability leading to aneuploidy was identified in the primary ocular tumor and sites of dissemination of one patient. High-throughput pharmacological screening was performed in a primary cell line derived from the lymph node dissemination of one case. This cell line showed resistance to broad spectrum chemotherapy consistent with the patient's poor response but sensitivity to the synergistic effects of panobinostat-bortezomib and carboplatin-panobinostat associations. From these cells we established a cell line derived xenograft model that closely recapitulated the tumor dissemination pattern of the patient and served to evaluate whether triple chemotherapy significantly prolonged survival of the animals. We report novel genomic alterations in two cases of metastatic MCYNampl RB1(+/+) that may be associated with chemotherapy resistance and in vitro/in vivo models that serve as basis for tailoring therapy in these cases.
Filiaciones:
Zugbi S:
Precision Medicine, Hospital de Pediatría JP Garrahan, Buenos Aires 1245, Argentina
National Scientific and Technical Research Council, CONICET, Buenos Aires 1425, Argentina
Ganiewich D:
Precision Medicine, Hospital de Pediatría JP Garrahan, Buenos Aires 1245, Argentina
Laboratory of Molecular and Cellular Therapy, Instituto Leloir-Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA), Buenos Aires 1405, Argentina
Bhattacharyya A:
Department of Paediatric Haematology and Oncology, Tata Memorial Hospital, Kolkata 700160, India
Aschero R:
Precision Medicine, Hospital de Pediatría JP Garrahan, Buenos Aires 1245, Argentina
National Scientific and Technical Research Council, CONICET, Buenos Aires 1425, Argentina
Ottaviani D:
Institut Curie
PSL Research University, Centre National de la Recherche Scientifique (CNRS), UMR144, Equipe Ligue Contre le Cancer, 75005 Paris, France
Sampor C:
Hematology-Oncology Service, Hospital de Pediatría JP Garrahan, Buenos Aires 1245, Argentina
Cafferata EG:
National Scientific and Technical Research Council, CONICET, Buenos Aires 1425, Argentina
Laboratory of Molecular and Cellular Therapy, Instituto Leloir-Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA), Buenos Aires 1405, Argentina
Mena M:
Precision Medicine, Hospital de Pediatría JP Garrahan, Buenos Aires 1245, Argentina
Sgroi M:
Ophthalmology Service, Hospital de Pediatría JP Garrahan, Buenos Aires 1245, Argentina
Winter U:
Pathology Service, Hospital de Pediatría JP Garrahan, Buenos Aires 1245, Argentina
Lamas G:
Pathology Service, Hospital de Pediatría JP Garrahan, Buenos Aires 1245, Argentina
Suñol M:
Pathology Service, Hospital Sant Joan de Deu, 08950 Barcelona, Spain
Daroqui M:
Cytogenetics Service, Hospital de Pediatría JP Garrahan, Buenos Aires 1245, Argentina
Baialardo E:
Cytogenetics Service, Hospital de Pediatría JP Garrahan, Buenos Aires 1245, Argentina
Salas B:
Paediatric Oncology Service, Hospital Asencio Villaroel, Cochabamba 2500, Bolivia
Das A:
Department of Paediatric Haematology and Oncology, Tata Memorial Hospital, Kolkata 700160, India
Fandiño A:
Ophthalmology Service, Hospital de Pediatría JP Garrahan, Buenos Aires 1245, Argentina
Francis JH:
Ophthalmic Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
Lubieniecki F:
Pathology Service, Hospital de Pediatría JP Garrahan, Buenos Aires 1245, Argentina
Lavarino C:
Pediatric Hematology and Oncology Service, Hospital Sant Joan de Deu, 08950 Barcelona, Spain
Laboratory of Molecular Oncology, Hospital Sant Joan de Déu, Fundación Sant Joan de Déu, 08950 Barcelona, Spain
Garippa R:
Gene editing and screening core facility, Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
Podhjacer OL:
National Scientific and Technical Research Council, CONICET, Buenos Aires 1425, Argentina
Laboratory of Molecular and Cellular Therapy, Instituto Leloir-Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA), Buenos Aires 1405, Argentina
Abramson DH:
Ophthalmic Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
Radvanyi F:
Institut Curie
PSL Research University, Centre National de la Recherche Scientifique (CNRS), UMR144, Equipe Ligue Contre le Cancer, 75005 Paris, France
Chantada G:
Precision Medicine, Hospital de Pediatría JP Garrahan, Buenos Aires 1245, Argentina
National Scientific and Technical Research Council, CONICET, Buenos Aires 1425, Argentina
Laboratory of Molecular Oncology, Hospital Sant Joan de Déu, Fundación Sant Joan de Déu, 08950 Barcelona, Spain
Llera AS:
National Scientific and Technical Research Council, CONICET, Buenos Aires 1425, Argentina
Laboratory of Molecular and Cellular Therapy, Instituto Leloir-Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA), Buenos Aires 1405, Argentina
Schaiquevich P:
Precision Medicine, Hospital de Pediatría JP Garrahan, Buenos Aires 1245, Argentina
National Scientific and Technical Research Council, CONICET, Buenos Aires 1425, Argentina
gold, Green Published
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