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

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

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 

Citation

Li, B. K., Vasiljevic, A., Dufour, C., Yao, F., Ho, B. L. B., Lu, M., …Jouvet, A. (2020). Pineoblastoma segregates into molecular sub-groups with distinct clinico-pathologic features: a Rare Brain Tumor Consortium registry study. Acta Neuropathologica, 139(2), 223–241. https://doi.org/10.1007/s00401-019-02111-y

• Journal Article Type: Article
• Acceptance Date: Nov 14, 2019
• Online Publication Date: Dec 9, 2019
• Publication Date: 2020-02
• Deposit Date: Jan 6, 2020
• Publicly Available Date: Dec 10, 2020
• Journal: Acta Neuropathologica
• Print ISSN: 0001-6322
• Electronic ISSN: 1432-0533
• Publisher: Springer Verlag
• Peer Reviewed: Peer Reviewed
• Volume: 139
• Issue: 2
• Pages: 223–241
• DOI: https://doi.org/10.1007/s00401-019-02111-y
• Public URL: https://nottingham-repository.worktribe.com/output/3674368
• Publisher URL: https://link.springer.com/article/10.1007%2Fs00401-019-02111-y
• Additional Information: Received: 9 October 2019; Revised: 13 November 2019; Accepted: 14 November 2019; First Online: 9 December 2019; : ; : The authors declare that they have no conflict of interest.