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

Bryan K. Li, Alexandre Vasiljevic, Christelle Dufour, Fupan Yao, Ben L.B. Ho, Mei Lu, Eugene I. Hwang, Sridharan Gururangan, Jordan R. Hansford, Maryam Fouladi, Sumihito Nobusawa, Annie Laquerriere, Marie Bernadette Delisle, Jason Fangusaro, Fabien Forest, Helen Toledano, Palma Solano-Paez, Sarah Leary, Diane Birks, Lindsey M. HoffmanAlexandru Szathmari, Cécile Faure-Conter, Xing Fan, Daniel Catchpoole, Li Zhou, Kris Ann P. Schultz, Koichi Ichimura, Guillaume Gauchotte, Nada Jabado, Chris Jones, Delphine Loussouarn, Karima Mokhtari, Audrey Rousseau, David S. Ziegler, Shinya Tanaka, Scott L. Pomeroy, Amar Gajjar, Vijay Ramaswamy, Cynthia Hawkins, Richard G. Grundy, D. Ashley Hill, Eric Bouffet, Annie Huang*, Anne Jouvet

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)223-241
Number of pages19
JournalActa Neuropathologica
Issue number2
StatePublished - 1 Feb 2020
Externally publishedYes


  • MYC
  • PNET
  • Pineoblastoma
  • RB
  • miRNA


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