Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma
Alan Mackay, Anna Burford, Diana Carvalho, Elisa Izquierdo, Janat Fazal-Salom, Kathryn R. Taylor, Lynn Bjerke, Matthew Clarke, Mara Vinci, Meera Nandhabalan, Sara Temelso, Sergey Popov, Valeria Molinari, Pichai Raman, Angela J. Waanders, Harry J. Han, Saumya Gupta, Lynley V. Marshall, Stergios Zacharoulis, Sucheta Vaidya, Henry Mandeville, Leslie Bridges, Andrew J. Martin, Safa Al‐Sarraj, Christopher Chandler, Ho‐Keung Ng, Xingang Li, Kun Mu, Saoussen Trabelsi, Dorra H’mida-Ben Brahim, Alexei N. Kisljakov, Д. М. Коновалов, Andrew S. Moore, Ángel M. Carcaboso, Mariona Suñol, Carmen de Torres, Ofelia Cruz, Jaume Mora, Л. И. Шац, João N. Stávale, Lucas Tadeu Bidinotto, Rui Manuel Reis, Natacha Entz‐Werlé, Michael Farrell, Jane Cryan, Darach Crimmins, John Caird, Jane Pears, Michelle Monje, Marie‐Anne Debily, David Castel, Jacques Grill, Cynthia Hawkins, Hamid Nikbakht, Nada Jabado, Suzanne J. Baker, Stefan M. Pfister, David Jones, Maryam Fouladi, André O. von Bueren, Michael Baudis, Adam Resnick, Chris Jones
Abstract
We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification.