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A MYCN-driven de-differentiation profile identifies a subgroup of aggressive retinoblastoma
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A MYCN-driven de-differentiation profile identifies a subgroup of aggressive retinoblastoma
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Journal Article
A MYCN-driven de-differentiation profile identifies a subgroup of aggressive retinoblastoma
2024
Overview
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.
DNA methylation analysis identifies a MYCN-driven subgroup of aggressive retinoblastoma that may benefit from
MYCN
-targeted therapy.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 38/61
/ 38/89
/ 38/91
/ 45
/ Biomedical and Life Sciences
/ Cell Dedifferentiation - genetics
/ Children
/ Female
/ Gene Expression Regulation, Neoplastic
/ Genes
/ Humans
/ Male
/ N-Myc Proto-Oncogene Protein - genetics
/ N-Myc Proto-Oncogene Protein - metabolism
/ Retinal Neoplasms - genetics
/ Retinal Neoplasms - metabolism
