The genetic landscape of high-risk neuroblastoma

Trevor J Pugh, Olena Morozova, Edward F Attiyeh, Shahab Asgharzadeh, Jun S Wei, Daniel Auclair, Scott L Carter, Kristian Cibulskis, Megan Hanna, Adam Kiezun, Jaegil Kim, Michael S Lawrence, Lee Lichenstein, Aaron McKenna, Chandra Sekhar Pedamallu, Alex H Ramos, Erica Shefler, Andrey Sivachenko, Carrie Sougnez, Chip Stewart, Adrian Ally, Inanc Birol, Readman Chiu, Richard D Corbett, Martin Hirst, Shaun D Jackman, Baljit Kamoh, Alireza Hadj Khodabakshi, Martin Krzywinski, Allan Lo, Richard A Moore, Karen L Mungall, Jenny Qian, Angela Tam, Nina Thiessen, Yongjun Zhao, Kristina A Cole, Maura Diamond, Sharon J Diskin, Yael P Mosse, Andrew C Wood, Lingyun Ji, Richard Sposto, Thomas Badgett, Wendy B London, Yvonne Moyer, Julie M Gastier-Foster, Malcolm A Smith, Jaime M Guidry Auvil, Daniela S Gerhard, Michael D Hogarty, Steven J M Jones, Eric S Lander, Stacey B Gabriel, Gad Getz, Robert C Seeger, Javed Khan, Marco A Marra, Matthew Meyerson, John M Maris

Neuroblastoma is a malignancy of the developing sympathetic nervous system that often presents with widespread metastatic disease, resulting in survival rates of less than 50%. To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 affected individuals (cases) using a combination of whole-exome, genome and transcriptome sequencing as part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Here we report a low median exonic mutation frequency of 0.60 per Mb (0.48 nonsilent) and notably few recurrently mutated genes in these tumors. Genes with significant somatic mutation frequencies included ALK (9.2% of cases), PTPN11 (2.9%), ATRX (2.5%, and an additional 7.1% had focal deletions), MYCN (1.7%, causing a recurrent p.Pro44Leu alteration) and NRAS (0.83%). Rare, potentially pathogenic germline variants were significantly enriched in ALK, CHEK2, PINK1 and BARD1. The relative paucity of recurrent somatic mutations in neuroblastoma challenges current therapeutic strategies that rely on frequently altered oncogenic drivers.