TY  - JOUR
AU  - Goschzik, Tobias
AU  - Yuan, Mathias
AU  - Pfaff, Elke
AU  - Müller, Manuel E B
AU  - Mynarek, Martin
AU  - Dörner, Evelyn
AU  - Jones, David T W
AU  - Pfister, Stefan M
AU  - Rutkowski, Stefan
AU  - Pietsch, Torsten
TI  - Recurrent genetic alterations in epigenetically defined pineoblastoma subtypes.
JO  - Acta Neuropathologica Communications
VL  - 13
IS  - 1
SN  - 2051-5960
CY  - London
PB  - Biomed Central
M1  - DKFZ-2025-02638
SP  - 241
PY  - 2025
AB  - Previous studies have revealed four distinct epigenetic consensus pineoblastoma (PB) subtypes. The aim of this study was to confirm and further extend their respective genetic underpinnings. Cytogenetics of 83 PB were analyzed by high-resolution genome-wide molecular inversion probe analysis and methylation profiling. Seventy-nine cases were screened for mutations by next-generation DNA panel sequencing and for 25 samples mRNA expression was analyzed using NanoString. Additionally, 24 further pineal parenchymal tumors were analyzed. Clinical data of 63 patients was available. Our cohort consisted of 48 PB-miRNA1, 19 PB-miRNA2, 8 PB-MYC/FOXR2, and 8 PB-RB1 cases. PB-miRNA subtype tumors had characteristic alterations in microRNA-processing genes; DICER1 mutations (n = 19/64) and homozygous deletions of the DROSHA locus (n = 18/67) were most abundant, followed by DROSHA mutations (n = 12/64). Most frequent cytogenetic aberrations in PB-miRNA cases were chromosome 7 gains (n = 31/67) and chromosome 14 losses (n = 26/67, including 5 cases with copy-neutral LOH). The latter were significantly associated with DICER1 mutations (p < 0.001). OTX2 gain represented the most frequent alteration that occurred in 37/83 PB of all subtypes. In the PB-miRNA subtypes we identified cases with polyploid cytogenetics (n = 16/67). In contrast to previous publications, we did not find a difference in survival for the PB-miRNA subtypes, whereas PB-MYC/FOXR2 and PB-RB1 in infants showed a worse outcome. Epigenetically defined PB subtypes are characterized by distinct genetic events. Frequent gains of the oncogene OTX2 indicate a role in the pathogenesis of PB independent of its subtype.
KW  - Humans
KW  - Pinealoma: genetics
KW  - Pinealoma: classification
KW  - Pinealoma: pathology
KW  - Female
KW  - Male
KW  - Brain Neoplasms: genetics
KW  - Brain Neoplasms: classification
KW  - Brain Neoplasms: pathology
KW  - Child
KW  - Child, Preschool
KW  - Pineal Gland: pathology
KW  - Adult
KW  - Ribonuclease III: genetics
KW  - Adolescent
KW  - Epigenesis, Genetic: genetics
KW  - MicroRNAs: genetics
KW  - Mutation: genetics
KW  - Young Adult
KW  - Middle Aged
KW  - Infant
KW  - DEAD-box RNA Helicases: genetics
KW  - DNA Methylation
KW  - Otx Transcription Factors: genetics
KW  - DICER1 (Other)
KW  - DROSHA (Other)
KW  - Epigenetic subtypes (Other)
KW  - PPTID (Other)
KW  - Pineoblastoma (Other)
KW  - Ribonuclease III (NLM Chemicals)
KW  - MicroRNAs (NLM Chemicals)
KW  - DICER1 protein, human (NLM Chemicals)
KW  - DEAD-box RNA Helicases (NLM Chemicals)
KW  - Otx Transcription Factors (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41291966
C2  - pmc:PMC12648887
DO  - DOI:10.1186/s40478-025-02140-7
UR  - https://inrepo02.dkfz.de/record/306599
ER  -