Pineoblastoma segregates into molecular sub-groups with distinct clinico-pathologic features: a Rare Brain Tumor Consortium registry study

Abstract

Pineoblastoma (PB) are rare, aggressive pediatric brain tumors of the pineal gland with modest overall survival despite intensive therapy. We sought to define the clinical and molecular spectra of PB to inform new treatment approaches for this orphan cancer. Tumor, blood, and clinical data from 91 patients with PB or supratentorial primitive neuroectodermal tumor (sPNETs/CNS-PNETs), and 2 pineal parenchymal tumors of intermediate differentiation (PPTIDs) were collected from 29 centres in the Rare Brain Tumor Consortium. We used global DNA methylation profiling to define a core group of PB from 72/93 cases, which were delineated into five molecular subgroups. Copy number, whole exome and targeted sequencing, and miRNA expression analyses were used to evaluate the clinicopathologic significance of each subgroup. Tumors designated as group 1 and 2 almost exclusively exhibited deleterious homozygous loss of function alterations in miRNA biogenesis genes (DICER1, DROSHA, and DGCR8) in 62 and 100% of group 1 and 2 tumors respectively. Recurrent alterations of the oncogenic MYC-miR-17/92-RB1 pathway were observed in the RB and MYC subgroup, respectively characterized by RB1 loss with gain of miR-17/92, and recurrent gain or amplification of MYC. PB sub-groups exhibited distinct clinical features: group 1-3 arose in older children (median ages 5.2-14.0 years) and had intermediate to excellent survival (5-year OS of 68.0-100%), while Group RB and MYC PB patients were much younger (median age 1.3-1.4 years) with dismal survival (5-year OS 37.5% and 28.6%, respectively). We identified age <3 years at diagnosis, metastatic disease, omission of upfront radiation, and chr 16q loss as significant negative prognostic factors across all PBs. Our findings demonstrate that PB exhibit substantial molecular heterogeneity with sub-group associated clinical phenotypes and survival. In addition to revealing novel biology and therapeutics, molecular sub-grouping of PB can be exploited to reduce treatment intensity for patients with favorable biology tumors.

Modeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy

“…Recent molecular classification of PBs identified several subtypes with distinct oncogenic alterations and clinical/pathological features. RB1 loss or amplification of MYC or the miR17-92 cluster is observed in young children (median 1.3-1.4 years) with 5 year OS in this cohort of 28.6% and 37.5%, respectively; whereas loss-of-function alterations in genes involved in miRNA biogenesis (DICER1, DROSHA, and DGCR8) characterize older patients (median age 5.2-14.0 years) with five-year OS of 68-100% 10 .…”

“…3). Thus, the WAP-Cre transgene can be used to model germline mutations in PB, and combined deletion of Rb-p53 o rDicer1-p53 via this deleter line induces histologically similar PBs with distinct kinetics as observed in children 10 .…”

Loss of histone H3 trimethylation on lysine 27 and nuclear expression of transducin‐like enhancer 1 in primary intracranial sarcoma, DICER1‐mutant

“…The CNS manifestations associated with DICER1 tumour predisposition syndrome comprise metastatic pleuropulmonary blastoma (and other extracranial DICER1-related sarcomas), pituitary blastoma, pineoblastoma, ciliary body medulloepithelioma, ETMR-like DICER1-related cerebellar tumour, and primary intracranial sarcoma, DICER1-mutant. 7,[11][12][13][14] Whereas most of these conditions are relatively easy to diagnose with the help of ancillary tests and correlation with imaging information, primary intracranial sarcoma, DICER1-mutant poses diagnostic challenges and has a vast differential diagnosis. All six sarcomas in this series had increased cellularity with at least focal spindle cell morphology and a fascicular growth pattern.…”

ETMR: a tumor entity in its infancy

“…Cancers associated to the DICER1 predisposition syndrome, both benign and malignant, primarily have biallelic loss of function mutations and mutations affecting an RNASE III domain of DICER1 (reviewed in [28]). However, there are also tumors such as Wilms tumor or pineoblastoma that recurrently have mutations leading to a complete loss of function of DICER1 or that have mutations in other members of the miRNA processing pathway such as mutations in DROSHA and DGCR8 [82,84,109,128,135]. These tumors rarely have mutations in the RNase IIIa or RNase IIIb domain of DICER1, suggesting that a general lack of miRNA processing, rather than biased loading of 3p miRNAs, is the driving mechanism in the majority of these tumors [113].…”