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

• Type of Material: Article
• Authors: Bryan K. Li, University of Toronto; Alexandre Vasiljevic, University of Lyon; Christelle Dufour, Institut Gustave Roussy; Fupan Yao, Hospital for Sick Children; Ben L. B. Ho, Hospital for Sick Children; Maryam Lu, Hospital for Sick Children; Eugene I. Hwang, Childrens National Medical Center; Sridharan Gururangan, University of Florida; Jordan R. Hansford, Royal Childrens Hospital; Maryam Fouladi, Cincinnati Childrens Hospital Medical Center; Sumihito Nobusawa, Gunma University; Annie Laquerriere, Normandie Université; Marie-Bernadette Delisle, CHU Toulouse; Jason Fangusaro, Emory University; Fabien Forest, CHU St Etienne; Helen Toledano, Schneider Childrens Medical Center Israel; Palma Solano-Paez, Hospital for Sick Children; Sarah Leary, Seattle Childrens; Diane Birks, University of Colorado; Lindsey M. Hoffman, Phoenix Childrens Hospital; Alexandru Szathmari, Hospital Civils Lyon; Cécile Faure-Conter, IHOPe; Xing Fan, University of Michigan; Daniel Catchpoole, Childrens Hospital Westmead; Li Zhou, Childrens Hospital Westmead; Kris Ann P. Schultz, Childrens Hospital & Clinic Minnesota; Koichi Ichimura, National Cancer Center; Guillaume Gauchotte, CHU Nancy; Nada Jabado, McGill University; Chris Jones, Institute for Cancer Research; Delphine Loussouarn, CHU Nantes; Karima Mokhtari, Hôpital Universitaire Pitie-Salpetriere, Paris; Audrey Rousseau, CHU Angers; David S. Ziegler, Sydney Childrens Hospital; Shinya Tanaka, Hokkaido University; Scott L. Pomeroy, Boston Childrens Hospital; Amar Gajjar, St Jude Childrens Research Hospital; Vijay Ramaswamy, University of Toronto; Cynthia Hawkins, Hospital for Sick Children; Richard G. Grundy, University of Nottingham; D. Ashley Hill, Childrens National Medical Center; Eric Bouffet, University of Toronto; Annie Huang, University of Toronto; Anne Jouvet, CHU Lyon
• Language: English
• Date: 2020-02-01
• Publisher: Springer
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 Springer Nature Switzerland AG
• Final Published Version (URL): http://dx.doi.org/10.1007/s00401-019-02111-y
• Title of Journal or Parent Work: Acta Neuropathologica
• Volume: 139
• Issue: 2
• Start Page: 223
• End Page: 241
• Grant/Funding Information: This project was funded by the Canadian Institutes of Health Research (grant no. 137011) and b.r.a.i.n.child to A. H. D.A.H. is supported by the NIH/NCI (grant 2R01CA143167).; B.K.L. is a Garron Family Cancer Centre Research Fellow.; AH holds a Tier 1 Canada Research Chair.
• Keywords: PPTID; RB; Radiotherapy; Expression; Somatic dicer1 mutations; Clinical Neurology; miRNA; PNET; Neurosciences & Neurology; Prognostic factors; MYC; Trilateral retinoblastoma; Primitive neuroectodermal tumors; Young children; Life Sciences & Biomedicine; Risk; Chemotherapy; Neurosciences; Science & Technology; Pathology; Proliferation; Pineoblastoma
• Research Categories: Health Sciences, Human Development; Health Sciences, Pathology; Health Sciences, Oncology

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.