TY  - JOUR
AU  - Ryl, Tatsiana
AU  - Afanasyeva, Elena
AU  - Hartmann, Till
AU  - Schwermer, Melanie
AU  - Schneider, Markus
AU  - Schröder, Christopher
AU  - Wagemanns, Maren
AU  - Bister, Arthur
AU  - Kanber, Deniz
AU  - Steenpass, Laura
AU  - Schramm, Kathrin
AU  - Jones, Barbara
AU  - Jones, David
AU  - Biewald, Eva
AU  - Astrahantseff, Kathy
AU  - Hannenberg, Helmut
AU  - Rahmann, Sven
AU  - Lohmann, Dietmar R
AU  - Schramm, Alexander
AU  - Ketteler, Petra
TI  - A MYCN-driven de-differentiation profile identifies a subgroup of aggressive retinoblastoma.
JO  - Communications biology
VL  - 7
IS  - 1
SN  - 2399-3642
CY  - London
PB  - Springer Nature
M1  - DKFZ-2024-01550
SP  - 919
PY  - 2024
AB  - 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.
KW  - Humans
KW  - Retinoblastoma: genetics
KW  - Retinoblastoma: pathology
KW  - N-Myc Proto-Oncogene Protein: genetics
KW  - N-Myc Proto-Oncogene Protein: metabolism
KW  - DNA Methylation
KW  - Retinal Neoplasms: genetics
KW  - Retinal Neoplasms: pathology
KW  - Retinal Neoplasms: metabolism
KW  - Gene Expression Regulation, Neoplastic
KW  - Cell Line, Tumor
KW  - Cell Dedifferentiation: genetics
KW  - Female
KW  - Male
KW  - Child, Preschool
KW  - N-Myc Proto-Oncogene Protein (NLM Chemicals)
KW  - MYCN protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39079981
DO  - DOI:10.1038/s42003-024-06596-6
UR  - https://inrepo02.dkfz.de/record/291942
ER  -