GENE-06. DISTINCT MOLECULAR SUBGROUPS OF TUMORS OF THE PINEAL REGION CORRELATE WITH CLINICAL PARAMETERS AND GENETIC ALTERATIONS

Abstract

Tumors arising in the pineal region comprise a spectrum of different entities with distinct clinical and histopathological characteristics. Pineocytoma (PC), pineal parenchymal tumors of intermediate differentiation (PPTID) and papillary tumors of the pineal region (PTPR) mainly occur in adult patients and are low to moderately aggressive neoplasms (WHO °I-III). In contrast, pineoblastoma (PB) are high-grade (WHO °IV) malignancies primarily affecting children and adolescents. Especially for patients with unresectable or metastatic disease or at very young age survival outcomes remain poor despite aggressive multimodal treatment regimen. To date, no therapeutically actionable molecular targets have been identified. A subset of PB occur in patients with cancer predisposition syndromes including DICER1 and RB1 germline mutations, the latter in the context of trilateral retinoblastoma (TLRB). We analyzed a cohort of ~230 pineal tumors of different histologies using genome-wide DNA methylation profling and copy-number analysis, as well as gene panel sequencing, miRNA sequencing and gene expression profling. Unsupervised clustering based on DNA methyla-tion profiles revealed clear separation of known histopathological entities (PC, PTPR, PPTID) and, furthermore, distinction of subclasses within these groups. Interestingly, several biologically discrete subgroups emerged within the group of histologically diagnosed PBs or pineal primitive embryonal tu-mors/PNETs, which displayed distinct clinical associations (e.g. age distribution). RB1 alterations were recurrent in a small subgroup (PB-RB) including TLRBs as well as sporadic PB cases (~60%) showing similarities with retino-blastoma. About 45% of cases in the largest PB subgroup (PB-B) harbored alterations within the miRNA processing pathway (affecting DROSHA, DGCR8 or DICER1) suggesting a central role of altered miRNA biogenesis in the development of this group which showed evidence for global reduction of mature miRNA by miRNA-Seq. With this study, we provide a foundation for further clinical, molecular and functional characterization of PB subgroups.