Journal Article

DKFZ-2024-01550

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A MYCN-driven de-differentiation profile identifies a subgroup of aggressive retinoblastoma.

Ryl, T. ; Afanasyeva, E. ; Hartmann, T. ; Schwermer, M. ; Schneider, M. ; Schröder, C. ; Wagemanns, M. ; Bister, A. ; Kanber, D. ; Steenpass, L. ; Schramm, K.DKFZ* ; Jones, B.DKFZ* ; Jones, D.DKFZ* ; Biewald, E. ; Astrahantseff, K. ; Hannenberg, H. ; Rahmann, S. ; Lohmann, D. R. ; Schramm, A. ; Ketteler, P.

2024
Springer Nature London

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Please use a persistent id in citations: doi:10.1038/s42003-024-06596-6

Abstract: 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.

Keyword(s): Humans (MeSH) ; Retinoblastoma: genetics (MeSH) ; Retinoblastoma: pathology (MeSH) ; N-Myc Proto-Oncogene Protein: genetics (MeSH) ; N-Myc Proto-Oncogene Protein: metabolism (MeSH) ; DNA Methylation (MeSH) ; Retinal Neoplasms: genetics (MeSH) ; Retinal Neoplasms: pathology (MeSH) ; Retinal Neoplasms: metabolism (MeSH) ; Gene Expression Regulation, Neoplastic (MeSH) ; Cell Line, Tumor (MeSH) ; Cell Dedifferentiation: genetics (MeSH) ; Female (MeSH) ; Male (MeSH) ; Child, Preschool (MeSH) ; N-Myc Proto-Oncogene Protein ; MYCN protein, human

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Contributing Institute(s):

1. Pädiatrische Gliomforschung (B360)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2024

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