Clinical and molecular heterogeneity of pineal parenchymal tumors: a consensus study

Background: Recent genomic studies have shed light on the biology and inter-tumoral heterogeneity underlying pineal parenchymal tumors, in particular pineoblastomas (PBs) and pineal parenchymal tumors of intermediate differentiation (PPTIDs). Previous reports, however, had modest sample sizes and lacked power to fully integrate molecular findings, clinical factors and patient outcome. The different subgroup structures proposed also called for a need to reconcile and reach consensus on a robust and relevant classification system. Methods: We performed a meta-analysis on 221 patients with molecularly characterized PBs and PPTIDs. DNA methylation profiles were analyzed through complementary bioinformatic approaches and molecular subgrouping was harmonized. Demographic, clinical and genomic features of patients and samples from these consensus subgroups were annotated. Findings: Four clinically and biologically relevant consensus PB subgroups were defined: PB-miRNA1 (n=96), PB-miRNA2 (n=23), PB-MYC/FOXR2 (n=34) and PB-RB1 (n=25); with PPTID (n=43) remaining as a molecularly distinct entity. Genomic and transcriptomic profiling allowed the characterization of oncogenic drivers for individual subgroups, specifically, alterations in the microRNA processing pathway in PB-miRNA1/2, MYC amplification and FOXR2 overexpression in PB-MYC/FOXR2, RB1 alteration in PB-RB1, and KBTBD4 insertion in PPTID. Age at diagnosis, sex predilection and metastatic status varied significantly among tumor subgroups. While patients from PB-miRNA2 and PPTID had superior outcome, survival for patients with PB-miRNA1 was intermediate and those from PB-MYC/FOXR2 and PB-RB1 dismal. Interpretation: We systematically interrogated the clinical and molecular heterogeneity within pineal parenchymal tumors and proposed a consensus nomenclature for disease subgroups, laying the groundwork for future clinical and preclinical studies as well as routine use in tumor classification.