Meta-analysis of pineal region tumours demonstrates molecular subgroups with distinct clinico-pathological features: a consensus study

Abstract

Pineoblastomas (PB) are rare, aggressive pineal gland tumours with poor global OS of 50–70% and only 15–49% OS for patients <4 years, despite intensive treatments. Recently, three independent groups (German Cancer Research Centre, Rare Brain Tumour Consortium/SickKids, St. Jude Children’s Research Hospital) collectively analyzed large tumour cohorts and revealed molecular sub-groups of PB. To harmonize and better characterize clinico-pathologic associations of these sub-groups, we undertook a meta-analysis of molecular and clinical data of the combined cohorts. Unsupervised consensus cluster analyses of global methylation data from 227 unique cases identified five robust molecular sub-groups of pineal region tumours: PB_miRNA_1, PB_miRNA_2, PB_MYC/FOXR2, and PB_RB, mainly comprised of pediatric WHO grade 4 PBs and PNETs; and a fifth group: named PPTID, comprised of mainly pineal parenchymal tumours of intermediate differentiation, a WHO grade 2–3 tumour common in adults. PB_miRNA_1 and PB_miRNA_2 tumours, primarily arising in children (median ages 7.7, 11.4y, respectively), were characterized by alterations of miRNA biogenesis genes DICER1, DROSHA, and DGCR8. PB_MYC/FOXR2 and PB_RB groups, arising in infants/toddlers (median ages 1.4, 2.0y, respectively), were distinguished by recurrent MYC gain/amplification and RB1 loss, respectively. The PPTID group affected mainly adults (median age 33y) and exhibited limited CNAs. Higher rates of metastasis were observed with PB_miRNA_1 (42%), PB_MYC/FOXR2 (38%), and PB_RB (75%) tumours, compared to PB_miRNA_2 (20%) and PPTID (25%). Results from ongoing integrative survival analyses of this large cohort will provide critical data for design of future clinical trials.