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Pineoblastoma segregates into molecular sub-groups with distinct clinico-pathologic features: a Rare Brain Tumor
Bryan K Li1,2,3, Alexandre Vasiljevic4,5, Christelle Dufour6
1Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, 555 University Ave., 10421B, Black, Toronto, ON, M5G 1X8, Canada.
Abstract:
Pineoblastomas (PBs) 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 sub-groups. Copy number, whole exome and targeted sequencing, and miRNA expression analyses were used to evaluate the clinico-pathologic significance of each sub-group. 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 sub-group, 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 exhibits 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.
Insights
Pineoblastomas (PBs) are rare pediatric brain tumors. Molecular sub-grouping reveals distinct clinical features and survival outcomes, guiding tailored treatment for better patient outcomes.
Area of Science:
- Pediatric neuro-oncology
- Cancer genomics
- Molecular pathology
Background:
- Pineoblastomas (PBs) are aggressive pediatric brain tumors with poor survival.
- Current treatment strategies offer modest efficacy for this rare orphan cancer.
- Understanding PB heterogeneity is crucial for developing novel therapeutic approaches.
Purpose of the Study:
- To define the clinical and molecular spectra of pineoblastomas.
- To identify distinct molecular subgroups within PBs.
- To correlate molecular subgroups with clinical features and patient survival.
Main Methods:
- Global DNA methylation profiling of 93 pediatric brain tumors (PB, sPNETs, PPTIDs).
- Copy number, whole exome, targeted sequencing, and miRNA expression analyses.
- Clinical data collection from 29 international centers.
Main Results:
- Five distinct molecular subgroups of PB were identified.
- Subgroups 1 and 2 showed high rates of miRNA biogenesis gene alterations (DICER1, DROSHA, DGCR8).
- RB and MYC subgroups exhibited alterations in the MYC-miR-17/92-RB1 pathway.
- Age < 3 years, metastatic disease, and chr 16q loss were negative prognostic factors.
Conclusions:
- Pineoblastomas exhibit significant molecular heterogeneity.
- Molecular subgroups are associated with distinct clinical phenotypes and survival rates.
- Molecular subtyping can inform treatment de-escalation for favorable-risk PBs.
