Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort

• Type of Material: Article
• Authors: Sebastian M Waszak, European Molecular Biology Laboratory; Paul A Northcott, German Cancer Research Center; Ivo Buchhalter, German Cancer Research Center; Giles W Robinson, St Jude Children's Research Hospital; Christian Sutter, Heidelberg University; Susanne Groebner, German Cancer Research Center; Kerstin B Grund, Heidelberg University; Laurence Brugières, Gustave Roussy Cancer Campus; David T W Jones, German Cancer Research Center; Kristian W Pajtler, Heidelberg University; A Sorana Morrissy, University of Calgary; Marcel Kool, German Cancer Research Center; Dominik Sturm, Heidelberg University; Lukas Chavez, German Cancer Research Center; Aurelie Ernst, German Cancer Research Center; Sebastian Brabetz, Heidelberg University; Michael Hain, German Cancer Research Center; Thomas Zichner, European Molecular Biology Laboratory; Maia Segura-Wang, European Molecular Biology Laboratory; Joachim Weischenfeldt, Biotech Research and Innovation Centre; Tobias Rausch, European Molecular Biology Laboratory; Balca R Mardin, European Molecular Biology Laboratory; Xin Zhou, St Jude Children's Research Hospital; Cristina Baciu, Toronto General Hospital; Christian Lawerenz, German Cancer Research Center; Tobey MacDonald, Emory University; David Malkin, The Hospital for Sick Children; Amar Gajjar, St Jude Children's Research Hospital; Jan O Korbel, European Molecular Biology Laboratory; Stefan M Pfister, Heidelberg University
• Language: English
• Date: 2018-05-09
• Publisher: Elsevier: Lancet
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/S1470-2045(18)30242-0
• Title of Journal or Parent Work: Lancet Oncology
• ISSN: 1470-2045
• Volume: 19
• Issue: 6
• Start Page: 785
• End Page: 798
• Grant/Funding Information: This study was done with the support of the Ontario Institute for Cancer Research through funding provided by the Government of Ontario; This project was supported by the PedBrain Tumor Project contributing to the ICGC, funded by German Cancer Aid (109252), the German Federal Ministry of Education and Research (BMBF; 01KU1201A and 01KU1201C), and additionally through BMBF grants BioTop (01EK1502A and 01EK1502B), ICGC-Data Mining (01KU1505F), MedSys (0315416C) and NGFNplus (01GS0883).; CEFALO was supported by grants from the Swedish Council for Health, Working Life and Welfare (2004-0504, 2007-0224), the Swedish Research Council (K2008-70X-15366-04-3), the Swedish Cancer Society (09 0666), the Swedish Childhood Cancer Foundation (PROJ06/050, PROJ09/086), the Swedish Radiation Protection Authority (SSI P 1572), the Danish Strategic Research Council (2103-05-0006, 2064-04-0010), the Swiss Federal Office of Public Health (05.001626), the Swiss Research Foundation on Mobile Communication (A2006.18), the Swiss National Science Foundation (PDFMP3_122873), and the Research Council of Norway (175163/V40).; Additional support came from the German Cancer Research Center-Heidelberg Center for Personalized Oncology (German Cancer Research Centre [DKFZ]-HIPO), the St Jude Comprehensive Cancer Center Core Grant (CA 21765), the American Lebanese Syrian Associated Charities, German Cancer Aid (111234), and the German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung; A2013/46 DKS2014.12).; The Medulloblastoma Advanced Genomics International Consortium (or MAGIC) project is financially supported by Genome Canada, Genome BC, Terry Fox Research Institute, Ontario Institute for Cancer Research, Pediatric Oncology Group Ontario, Funds from The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre, Montreal Children's Hospital Foundation, Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, BRAIN Child, MDT's Garron Family Endowment, and BC Childhood Cancer Parents Association.; Tissue banking was supported by funds from the Faculty of Medicine, Masaryk University (Brno, Czech Republic); See publication for full funding statement
• Keywords: Oncology; LANDSCAPE; TP53 MUTATION; FANCONI-ANEMIA; CHILDREN; CHILDHOOD-CANCER; Science & Technology; BREAST-CANCER; PALB2; SUBGROUPS; Life Sciences & Biomedicine; SOMATIC MUTATIONS; BRAIN-TUMORS
• Research Categories: Health Sciences, Oncology

Abstract

Background: Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines. Methods: In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma. Findings: We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHHsubgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHHsubgroup). Patients with germline APC mutations developed MBWNTand accounted for most (five [71%] of seven) cases of MBWNTthat had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHHsubgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40–69) and 5-year overall survival was 65% (95% CI 52–81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes. Interpretation: Genetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNTand MBSHHbecause these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics.