Diminished MYCN Dosage Endows Cavitary Transformation in Retinoblastoma

IF 3.2 Q1 OPHTHALMOLOGY

Ophthalmology science Pub Date : 2025-05-06 DOI:10.1016/j.xops.2025.100820

Mingpeng Xu MD , Hanhan Shi MD, PhD , Yongning Shen BS , Ludi Yang MD , Yu Luan MD , Xiang Gu MD , Xuyang Wen MD, PhD , Chuandi Zhou MD, PhD , Renbing Jia MD, PhD , Xunda Ji MD, PhD , Peiquan Zhao MD, PhD , Minglei Han MD, PhD , Jiayan Fan MD, PhD , Peiwei Chai MD, PhD

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Abstract

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 Disclosure(s)

The author(s) have no proprietary or commercial interest in any materials discussed in this article.

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减少MYCN剂量可使视网膜母细胞瘤发生腔体转化

目的：腔体视网膜母细胞瘤（CRB）是一种独特的视网膜母细胞瘤（RB）变体，其特征是存在半透明腔，通过眼科检查可识别。本研究旨在阐明CRB的临床意义和分子特征，从而增强我们对这种独特亚型RB的理解。设计一项结合空间蛋白质组学分析的多中心、巢式病例对照、回顾性队列研究。在一项包含1360名RB患者的纵向研究中，从2008年6月到2022年2月进行了13年的时间框架，在46名患者的48只眼睛的肿瘤中检测到腔隙。从138名年龄匹配的非crb患者中选择180只眼睛作为对照，保持1:3的病例对照比。激光捕获的空间蛋白质组学分析用于探索该特定亚型中的关键分子变化。通过腺相关病毒（AAV） 2介导的基因治疗，在患者来源的异种移植物模型中实现了MYCN的沉默。干预：去核、化疗和局灶治疗。主要观察指标：总生存期和无转移生存期。结果腹腔RB与无转移生存期（P = 0.007）和总生存期（P = 0.03）的提高以及高分化状态比例(P <；0.001)，玻璃体植入发生率降低（P = 0.02）。空间蛋白质组学分析、免疫荧光和免疫组织病理学显示，MYCN在CRB中的表达低于非CRB。在患者来源的异种移植物中使用AAV沉默MYCN再现了CRB的这些表型，包括半透明腔的形成和圆锥形莲座的出现。结论本研究建立了一种新的遗传-表型关联，揭示MYCN表达减少可诱导半透明空腔的形成。这种表型表明一种侵袭性较低、分化良好的CRB亚型，预后较好。财务披露作者在本文中讨论的任何材料中没有专有或商业利益。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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