Department of Pediatric Hematology and Oncology, University Hospital Essen, Essen, Germany.
Algorithms for Reproducible Bioinformatics, Genome Informatics, Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Commun Biol. 2024 Jul 30;7(1):919. doi: 10.1038/s42003-024-06596-6.
Retinoblastoma are childhood eye tumors arising from retinal precursor cells. Two distinct retinoblastoma subtypes with different clinical behavior have been described based on gene expression and methylation profiling. Using consensus clustering of DNA methylation analysis from 61 retinoblastomas, we identify a MYCN-driven cluster of subtype 2 retinoblastomas characterized by DNA hypomethylation and high expression of genes involved in protein synthesis. Subtype 2 retinoblastomas outside the MYCN-driven cluster are characterized by high expression of genes from mesodermal development, including NKX2-5. Knockdown of MYCN expression in retinoblastoma cell models causes growth arrest and reactivates a subtype 1-specific photoreceptor signature. These molecular changes suggest that removing the driving force of MYCN oncogenic activity rescues molecular circuitry driving subtype 1 biology. The MYCN-RB gene signature generated from the cell models better identifies MYCN-driven retinoblastoma than MYCN amplification and can identify cases that may benefit from MYCN-targeted therapy. MYCN drives tumor progression in a molecularly defined retinoblastoma subgroup, and inhibiting MYCN activity could restore a more differentiated and less aggressive tumor biology.
视网膜母细胞瘤是起源于视网膜前体细胞的儿童眼部肿瘤。基于基因表达和甲基化谱分析，已经描述了两种具有不同临床行为的不同视网膜母细胞瘤亚型。通过对 61 例视网膜母细胞瘤的 DNA 甲基化分析进行共识聚类，我们确定了一个由 MYCN 驱动的 2 型视网膜母细胞瘤亚群，其特征是 DNA 低甲基化和参与蛋白质合成的基因高表达。MYCN 驱动的亚群之外的 2 型视网膜母细胞瘤的特征是中胚层发育相关基因的高表达，包括 NKX2-5。在视网膜母细胞瘤细胞模型中敲低 MYCN 表达会导致生长停滞，并重新激活 1 型特有的光感受器特征。这些分子变化表明，去除 MYCN 致癌活性的驱动力可以挽救驱动 1 型生物学的分子电路。该细胞模型生成的 MYCN-RB 基因特征比 MYCN 扩增更能识别 MYCN 驱动的视网膜母细胞瘤，并可以识别可能受益于 MYCN 靶向治疗的病例。MYCN 驱动一个分子定义明确的视网膜母细胞瘤亚组的肿瘤进展，抑制 MYCN 活性可能会恢复更具分化和侵袭性较小的肿瘤生物学。
