Clinical, Genomic, and Pharmacological Study of MYCN-Amplified RB1 Wild-Type Metastatic Retinoblastoma

Author:

Zugbi Santiago,Ganiewich Daiana,Bhattacharyya Arpita,Aschero RosarioORCID,Ottaviani Daniela,Sampor Claudia,Cafferata Eduardo,Mena Marcela,Sgroi MarianaORCID,Winter Ursula,Lamas Gabriela,Suñol Mariona,Daroqui Manuel,Baialardo Edgardo,Salas Beatriz,Das AnirbanORCID,Fandiño Adriana,Francis Jasmine,Lubieniecki Fabiana,Lavarino CinziaORCID,Garippa RalphORCID,Podhajcer OsvaldoORCID,Abramson DavidORCID,Radvanyi François,Chantada Guillermo,Llera AndreaORCID,Schaiquevich PaulaORCID

Abstract

An uncommon subgroup of unilateral retinoblastomas with highly aggressive histological features, lacking aberrations in RB1 gene with high-level amplification of MYCN (MCYNamplRB1+/+) 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 MCYNamplRB1+/+ 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 MCYNamplRB1+/+ that may be associated with chemotherapy resistance and in vitro/in vivo models that serve as basis for tailoring therapy in these cases.

Funder

Fondation Nelia et Amadeo Barletta

Amazon Web Services

Publisher

MDPI AG

Subject

Cancer Research,Oncology

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