Diminished MYCN Dosage Endows Cavitary Transformation in Retinoblastoma.

OBJECTIVE: Cavitary retinoblastoma (CRB) represents a unique variant of retinoblastoma (RB) distinguished by the presence of translucent cavities, which are discernible through ophthalmoscopic examination. The present study was designed to elucidate the clinical implications and molecular signatures of CRB, thereby enhancing our understanding of this distinct subtype of RB. DESIGN: A multicentric, nested case-control, retrospective cohort study combining spatial proteomic analysis. PARTICIPANTS: In a longitudinal study encompassing 1360 RB patients, conducted over a 13-year timeframe from June 2008 to February 2022, cavitary spaces were detected within the tumors of 48 eyes of 46 patients. A control cohort of 180 eyes from 138 age-matched patients with non-CRB was selected, maintaining a 1:3 case-control ratio. Laser-captured spatial proteomic analysis was conducted to explore the pivotal molecular changes within this specific subtype. The silencing of MYCN was achieved using adeno-associated virus (AAV) 2-mediated gene therapy in patient-derived xenograft models. INTERVENTION: Enucleation, chemotherapy, and focal therapy. MAIN OUTCOME MEASURES: Overall survival and metastasis-free survival. RESULTS: Cavitary RB was linked to enhanced metastasis-free survival (P = 0.007) and overall survival (P = 0.03), as well as an increased proportion of well-differentiated status (P < 0.001) and a reduced incidence of vitreous seeding (P = 0.02). Spatial proteomic analysis, immunofluorescence, and immunohistopathology revealed a lower MYCN expression in CRB than in non-CRB. Silencing MYCN in patient-derived xenografts using AAV recapitulated these phenotypes of CRB, including the formation of translucent cavities and the emergence of cone-like rosettes. CONCLUSIONS: This study establishes a novel genetic-phenotypic association, revealing that diminished MYCN expression induces the formation of translucent cavities. This phenotype is indicative of a less aggressive, well-differentiated CRB subtype with a more favorable prognosis. FINANCIAL DISCLOSURES: The author(s) have no proprietary or commercial interest in any materials discussed in this article.