Abstract
INTRODUCTION: Genome-wide methylation analyses recently revealed distinct epigenetic pineoblastoma (PBL) subtypes. The aim of the study was to shed further light onto the genetic characteristics underlying the pathogenesis of pineoblastoma subtypes. METHODS: Cytogenetic alterations of tumor samples of 76 patients with a diagnosis of PBL confirmed by reference neuropathology and methylation-based subtyping were analyzed by high-resolution genome-wide molecular inversion probe analysis. Seventy-two cases were screened for mutations by next-generation DNA panel sequencing. Survival data of 49 patients were available. Patients ≥4y received postoperative RT followed by maintenance chemotherapy (n=42); infants (<4y) were primarily treated on RT-sparing regimens with intensified chemotherapy. RESULTS: According to epigenetic consensus PBL subtypes (Liu et al., 2021), our cohort consisted of 48 PBL-miRNA1 (1A=40; 1B=8), 17 PBL-miRNA2, 4 PBL-MYC/FOXR2, and 7 PBL-RB1 samples. PBL-miRNA subtype tumors had characteristic alterations in microRNA-processing genes; DICER1 mutations (n=18) and homozygous deletions of the DROSHA locus (n=17) were most abundant, followed by DROSHA mutations (n=12). Most frequent cytogenetic aberrations in PBL-miRNA were whole chromosome (chr.) 7 gain (n=30) and chr. 14 loss (n=21). DICER1 mutations were significantly associated with chr. 14 loss (p<0.001). Twenty-one cases showed gains of chr. 14, 8 additional cases gains of the OTX2 oncogene (chr. 14q). In the miRNA subtypes we identified cases with polyploid cytogenetics (n=15). Of note, only one of the 8 patients with polyploid tumors and survival data died, while the remaining patients of the miRNA subtypes had a 5-year PFS/OS of 61.46±9.27/63.24±9.23% (14 of 35 died) after a median follow-up time of 5.52 years. However, this comparison did not reach statistical significance (p=0.25). CONCLUSION: The epigenetically defined PBL-miRNA subtypes are characterized by distinct cytogenetic and mutational events. A possible prognostic role for a superior (e.g. polyploidy) or inferior outcome requires investigation in prospective clinical trials.