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

doi:10.1016/S1470-2045(18)30242-0

Multicenter Study

. 2018 Jun;19(6):785-798.

doi: 10.1016/S1470-2045(18)30242-0. Epub 2018 May 9.

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

Sebastian M Waszak¹, Paul A Northcott², Ivo Buchhalter³, Giles W Robinson⁴, Christian Sutter⁵, Susanne Groebner⁶, Kerstin B Grund⁵, Laurence Brugières⁷, David T W Jones⁸, Kristian W Pajtler⁹, A Sorana Morrissy¹⁰, Marcel Kool⁸, Dominik Sturm⁹, Lukas Chavez⁶, Aurelie Ernst¹¹, Sebastian Brabetz⁹, Michael Hain¹¹, Thomas Zichner¹, Maia Segura-Wang¹, Joachim Weischenfeldt¹², Tobias Rausch¹, Balca R Mardin¹, Xin Zhou¹³, Cristina Baciu¹⁴, Christian Lawerenz¹⁵, Jennifer A Chan¹⁶, Pascale Varlet¹⁷, Lea Guerrini-Rousseau⁷, Daniel W Fults¹⁸, Wiesława Grajkowska¹⁹, Peter Hauser²⁰, Nada Jabado²¹, Young-Shin Ra²², Karel Zitterbart²³, Suyash S Shringarpure²⁴, Francisco M De La Vega²⁴, Carlos D Bustamante²⁴, Ho-Keung Ng²⁵, Arie Perry²⁶, Tobey J MacDonald²⁷, Pablo Hernáiz Driever²⁸, Anne E Bendel²⁹, Daniel C Bowers³⁰, Geoffrey McCowage³¹, Murali M Chintagumpala³², Richard Cohn³³, Timothy Hassall³⁴, Gudrun Fleischhack³⁵, Tone Eggen³⁶, Finn Wesenberg³⁷, Maria Feychting³⁸, Birgitta Lannering³⁹, Joachim Schüz⁴⁰, Christoffer Johansen⁴¹, Tina V Andersen⁴², Martin Röösli⁴³, Claudia E Kuehni⁴⁴, Michael Grotzer⁴⁵, Kristina Kjaerheim³⁶, Camelia M Monoranu⁴⁶, Tenley C Archer⁴⁷, Elizabeth Duke⁴⁸, Scott L Pomeroy⁴⁷, Redmond Shelagh⁴⁴, Stephan Frank⁴⁹, David Sumerauer⁵⁰, Wolfram Scheurlen⁵¹, Marina V Ryzhova⁵², Till Milde⁵³, Christian P Kratz⁵⁴, David Samuel⁵⁵, Jinghui Zhang¹³, David A Solomon²⁶, Marco Marra⁵⁶, Roland Eils⁵⁷, Claus R Bartram⁵, Katja von Hoff⁵⁸, Stefan Rutkowski⁵⁹, Vijay Ramaswamy⁶⁰, Richard J Gilbertson⁶¹, Andrey Korshunov⁶², Michael D Taylor⁶³, Peter Lichter⁶⁴, David Malkin⁶⁰, Amar Gajjar⁴, Jan O Korbel¹, Stefan M Pfister⁶⁵

Affiliations

¹ European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
² Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
³ Division of Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany; Division of Applied Bioinformatics, German Cancer Research Center, Heidelberg, Germany.
⁴ Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
⁵ Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
⁶ Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁷ Department of Children and Adolescents Oncology, Gustave Roussy Cancer Campus, Villejuif, France.
⁸ Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Hopp Children's Cancer Center at the NCT Heidelberg, Heidelberg, Germany.
⁹ Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Hopp Children's Cancer Center at the NCT Heidelberg, Heidelberg, Germany.
¹⁰ Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
¹¹ Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany.
¹² Biotech Research and Innovation Centre, Copenhagen, Denmark; Finsen Laboratory, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
¹³ Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
¹⁴ University Health Network-Toronto General Hospital, Toronto, ON, Canada.
¹⁵ Data Management Facility, German Cancer Research Center, Heidelberg, Germany.
¹⁶ Department of Pathology and Laboratory Medicine, Department of Oncology, and Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada.
¹⁷ Department of Neuropathology, Sainte-Anne Hospital, Paris, France.
¹⁸ Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, UT, USA.
¹⁹ Department of Pathology, Children's Memorial Health Institute, Warsaw, Poland.
²⁰ 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
²¹ Department of Pediatrics, McGill University, Montreal, QC, Canada.
²² Department of Neurosurgery, Asan Medical Center, Seoul, South Korea.
²³ Department of Paediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic; Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
²⁴ Departments of Genetics and Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
²⁵ Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
²⁶ Division of Neuropathology, Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
²⁷ Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA, USA.
²⁸ Klinik für Pädiatrie mS Onkologie und Hämatologie, Charité, Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
²⁹ Department of Pediatric Hematology and Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA.
³⁰ Division of Pediatric Hematology-Oncology, University of Texas Southwestern Medical School, Dallas, TX, USA.
³¹ Department of Paediatric Oncology, The Children's Hospital at Westmead, Sydney, NSW, Australia.
³² Department of Pediatric Hematology and Oncology, Texas Children's Hospital, Houston, TX, USA.
³³ Department of Paediatric Oncology, Sydney Children's Hospital, Sydney, NSW, Australia.
³⁴ Department of Paediatric Oncology, Lady Cilento Children's Hospital, South Brisbane, QLD, Australia.
³⁵ Pediatric Oncology and Hematology, Pediatrics III, University Hospital of Essen, Essen, Germany.
³⁶ Cancer Registry of Norway, Oslo, Norway.
³⁷ Department of Pediatric Medicine, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Cancer Registry of Norway, Oslo, Norway.
³⁸ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
³⁹ Department of Pediatrics, University of Gothenburg, The Queen Silvia Children's Hospital, Gothenburg, Sweden.
⁴⁰ Section of Environment and Radiation, International Agency for Research on Cancer, Lyon, France.
⁴¹ Oncology Clinic, Finsen Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Unit of Survivorship, Copenhagen, Denmark.
⁴² Danish Cancer Society Research Center, Copenhagen, Denmark.
⁴³ Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland; Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland.
⁴⁴ Swiss Childhood Cancer Registry, Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
⁴⁵ Department of Pediatric Oncology, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
⁴⁶ Comprehensive Cancer Center Mainfranken, Würzburg, Germany; Department of Neuropathology, Institute of Pathology, University of Würzburg, Würzburg, Germany.
⁴⁷ Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
⁴⁸ Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
⁴⁹ Institute of Neuropathology, University Hospital Basel, Basel, Switzerland.
⁵⁰ Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czech Republic.
⁵¹ Cnopf'sche Kinderklinik, Nuremberg, Germany.
⁵² Department of Neuropathology, Burdenko Neurosurgical Institute, Moscow, Russia.
⁵³ Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany; Clinical Cooperation Unit Pediatric Oncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Hopp Children's Cancer Center at the NCT Heidelberg, Heidelberg, Germany.
⁵⁴ Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
⁵⁵ Valley Children's Hospital, Madera, CA, USA.
⁵⁶ Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
⁵⁷ Division of Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany.
⁵⁸ Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Klinik für Pädiatrie mS Onkologie und Hämatologie, Charité, Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
⁵⁹ Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁶⁰ Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada.
⁶¹ Department of Oncology and Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
⁶² Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center, Heidelberg, Germany.
⁶³ Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada.
⁶⁴ Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁶⁵ Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Hopp Children's Cancer Center at the NCT Heidelberg, Heidelberg, Germany. Electronic address: s.pfister@kitz-heidelberg.de.

PMID: 29753700
PMCID: PMC5984248
DOI: 10.1016/S1470-2045(18)30242-0

Multicenter Study

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

Sebastian M Waszak et al. Lancet Oncol. 2018 Jun.

. 2018 Jun;19(6):785-798.

doi: 10.1016/S1470-2045(18)30242-0. Epub 2018 May 9.

Authors

Affiliations

¹ European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
² Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
³ Division of Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany; Division of Applied Bioinformatics, German Cancer Research Center, Heidelberg, Germany.
⁴ Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
⁵ Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
⁶ Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁷ Department of Children and Adolescents Oncology, Gustave Roussy Cancer Campus, Villejuif, France.
⁸ Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Hopp Children's Cancer Center at the NCT Heidelberg, Heidelberg, Germany.
⁹ Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Hopp Children's Cancer Center at the NCT Heidelberg, Heidelberg, Germany.
¹⁰ Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
¹¹ Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany.
¹² Biotech Research and Innovation Centre, Copenhagen, Denmark; Finsen Laboratory, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
¹³ Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
¹⁴ University Health Network-Toronto General Hospital, Toronto, ON, Canada.
¹⁵ Data Management Facility, German Cancer Research Center, Heidelberg, Germany.
¹⁶ Department of Pathology and Laboratory Medicine, Department of Oncology, and Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada.
¹⁷ Department of Neuropathology, Sainte-Anne Hospital, Paris, France.
¹⁸ Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, UT, USA.
¹⁹ Department of Pathology, Children's Memorial Health Institute, Warsaw, Poland.
²⁰ 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
²¹ Department of Pediatrics, McGill University, Montreal, QC, Canada.
²² Department of Neurosurgery, Asan Medical Center, Seoul, South Korea.
²³ Department of Paediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic; Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
²⁴ Departments of Genetics and Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
²⁵ Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
²⁶ Division of Neuropathology, Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
²⁷ Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA, USA.
²⁸ Klinik für Pädiatrie mS Onkologie und Hämatologie, Charité, Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
²⁹ Department of Pediatric Hematology and Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA.
³⁰ Division of Pediatric Hematology-Oncology, University of Texas Southwestern Medical School, Dallas, TX, USA.
³¹ Department of Paediatric Oncology, The Children's Hospital at Westmead, Sydney, NSW, Australia.
³² Department of Pediatric Hematology and Oncology, Texas Children's Hospital, Houston, TX, USA.
³³ Department of Paediatric Oncology, Sydney Children's Hospital, Sydney, NSW, Australia.
³⁴ Department of Paediatric Oncology, Lady Cilento Children's Hospital, South Brisbane, QLD, Australia.
³⁵ Pediatric Oncology and Hematology, Pediatrics III, University Hospital of Essen, Essen, Germany.
³⁶ Cancer Registry of Norway, Oslo, Norway.
³⁷ Department of Pediatric Medicine, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Cancer Registry of Norway, Oslo, Norway.
³⁸ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
³⁹ Department of Pediatrics, University of Gothenburg, The Queen Silvia Children's Hospital, Gothenburg, Sweden.
⁴⁰ Section of Environment and Radiation, International Agency for Research on Cancer, Lyon, France.
⁴¹ Oncology Clinic, Finsen Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Unit of Survivorship, Copenhagen, Denmark.
⁴² Danish Cancer Society Research Center, Copenhagen, Denmark.
⁴³ Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland; Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland.
⁴⁴ Swiss Childhood Cancer Registry, Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
⁴⁵ Department of Pediatric Oncology, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
⁴⁶ Comprehensive Cancer Center Mainfranken, Würzburg, Germany; Department of Neuropathology, Institute of Pathology, University of Würzburg, Würzburg, Germany.
⁴⁷ Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
⁴⁸ Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
⁴⁹ Institute of Neuropathology, University Hospital Basel, Basel, Switzerland.
⁵⁰ Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czech Republic.
⁵¹ Cnopf'sche Kinderklinik, Nuremberg, Germany.
⁵² Department of Neuropathology, Burdenko Neurosurgical Institute, Moscow, Russia.
⁵³ Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany; Clinical Cooperation Unit Pediatric Oncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Hopp Children's Cancer Center at the NCT Heidelberg, Heidelberg, Germany.
⁵⁴ Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
⁵⁵ Valley Children's Hospital, Madera, CA, USA.
⁵⁶ Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
⁵⁷ Division of Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany.
⁵⁸ Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Klinik für Pädiatrie mS Onkologie und Hämatologie, Charité, Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
⁵⁹ Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁶⁰ Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada.
⁶¹ Department of Oncology and Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
⁶² Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center, Heidelberg, Germany.
⁶³ Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada.
⁶⁴ Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁶⁵ Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Hopp Children's Cancer Center at the NCT Heidelberg, Heidelberg, Germany. Electronic address: s.pfister@kitz-heidelberg.de.

PMID: 29753700
PMCID: PMC5984248
DOI: 10.1016/S1470-2045(18)30242-0

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 (MB_WNT), SHH (MB_SHH), group 3 (MB_Group3), and group 4 (MB_Group4). 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 MB_SHH subgroup (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 MB_SHH subgroup). Patients with germline APC mutations developed MB_WNT and accounted for most (five [71%] of seven) cases of MB_WNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MB_SHH. Germline TP53 mutations presented only in childhood patients in the MB_SHH subgroup 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 MB_SHH, MB_Group3, and MB_Group4 molecular 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 MB_WNT and MB_SHH because 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.

Funding: German Cancer Aid; German Federal Ministry of Education and Research; German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung); European Research Council; National Institutes of Health; Canadian Institutes for Health Research; German Cancer Research Center; St Jude Comprehensive Cancer Center; American Lebanese Syrian Associated Charities; Swiss National Science Foundation; European Molecular Biology Organization; Cancer Research UK; Hertie Foundation; Alexander and Margaret Stewart Trust; V Foundation for Cancer Research; Sontag Foundation; Musicians Against Childhood Cancer; BC Cancer Foundation; Swedish Council for Health, Working Life and Welfare; Swedish Research Council; Swedish Cancer Society; the Swedish Radiation Protection Authority; Danish Strategic Research Council; Swiss Federal Office of Public Health; Swiss Research Foundation on Mobile Communication; Masaryk University; Ministry of Health of the Czech Republic; Research Council of Norway; Genome Canada; Genome BC; Terry Fox Research Institute; Ontario Institute for Cancer Research; Pediatric Oncology Group of Ontario; The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre; Montreal Children's Hospital Foundation; The Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, MDT's Garron Family Endowment; BC Childhood Cancer Parents Association; Cure Search Foundation; Pediatric Brain Tumor Foundation; Brainchild; and the Government of Ontario.

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Figures

**Figure 1**
Discovery and replication of medulloblastoma predisposition genes (A) Study design and patient characteristics. (B) Rare variant burden analysis based on 673 patients with medulloblastoma and 53 105 controls from the Exome Aggregation Consortium. Diagnosis of medulloblastoma was the outcome variable. Proportion of patients with a genetic predisposition in our (C) retrospective cohort and (D) prospective cohort. (D) p values indicate statistical differences in the proportion of germline mutation carriers in the retrospective compared with prospective cohort. Infant=age 3 years or younger. Child=age 4–17 years. Adult=age 18 years or older. RR=relative risk. *p<0·001. †p<0·01. ‡p<0·05. §Patients with damaging germline mutations in *APC, PTCH1, SUFU, TP53, PALB2*, and *BRCA2*.

**Figure 2**
Clinical characteristics of patients with a genetic predisposition (A) Molecular tumour subgroups. (B) Age at diagnosis. (C) Family history of cancer. (D) Clinical signs of a genetic predisposition. p values indicate whether there is a difference between patients with different types of genetic predisposition. *Patients with compound heterozygous germline *BRCA2* mutations. †Data are median (IQR). Circle sizes indicate the proportion of patients with a genetic predisposition.

**Figure 3**
Kaplan-Meier curves for survival outcomes of patients with a genetic predisposition (A) Progression-free survival. (B) Overall survival. Log-rank p values indicate differences across all patient groups.

**Figure 4**
Molecular medulloblastoma characteristics for patients with a genetic predisposition (A) Patterns of somatic inactivation of wild-type alleles for all patients with a germline mutation in one of the consensus medulloblastoma predisposition genes. Circle sizes indicate the proportion of patients with a genetic predisposition. (B) Somatic driver events in patients with medulloblastoma in the WNT subgroup (top panel) and age at diagnosis for all patients with germline *APC* mutations and patients in the WNT subgroup with somatic *CTNNB1* mutations (bottom panel). (C) Association between germline *PALB2* (n=5) and *BRCA2* (n=7) mutation status and somatic mutational signatures 1, 3, 5, and 8. EXP=allele-specific gene expression. MUT=somatic inactivation via single nucleotide variation, insertion, or deletion. LOH=loss of heterozygosity. ND=no somatic alteration detected. NS=not significant. HRD=homologous recombination repair deficiency. *Present study and Hamilton and colleagues. †p<0·001. ‡p<0·01. §p<0·05.

**Figure 5**
Proposed clinical guidelines for genetic counselling and testing in medulloblastoma based on clinical and molecular tumour characteristics

See this image and copyright information in PMC

Comment in

Genetic predisposition to medulloblastomas: just follow the tumour genome.
Bourdeaut F, Delattre O. Bourdeaut F, et al. Lancet Oncol. 2018 Jun;19(6):722-723. doi: 10.1016/S1470-2045(18)30289-4. Epub 2018 May 9. Lancet Oncol. 2018. PMID: 29753702 No abstract available.
Study Reveals Germline Genetics of Medulloblastoma.
[No authors listed] [No authors listed] Cancer Discov. 2018 Aug;8(8):OF7. doi: 10.1158/2159-8290.CD-NB2018-079. Epub 2018 Jun 22. Cancer Discov. 2018. PMID: 29934315

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1. Taylor MD, Liu L, Raffel C. Mutations in SUFU predispose to medulloblastoma. Nat Genet. 2002;31:306–310. - PubMed
1. Li FP, Fraumeni JF. Rhabdomyosarcoma in children: epidemiologic study and identification of a familial cancer syndrome. J Natl Cancer Inst. 1969;43:1365–1373. - PubMed

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[1] Johnson KJ, Cullen J, Barnholtz-Sloan JS. Childhood brain tumor epidemiology: a Brain Tumor Epidemiology Consortium review. Cancer Epidemiol Biomarkers Prev. 2014;23:2716–2736. - PMC - PubMed

[2] Johnson KJ, Cullen J, Barnholtz-Sloan JS. Childhood brain tumor epidemiology: a Brain Tumor Epidemiology Consortium review. Cancer Epidemiol Biomarkers Prev. 2014;23:2716–2736. - PMC - PubMed

[3] Northcott PA, Jones DTW, Kool M. Medulloblastomics: the end of the beginning. Nat Rev Cancer. 2012;12:818–834. - PMC - PubMed

[4] Northcott PA, Jones DTW, Kool M. Medulloblastomics: the end of the beginning. Nat Rev Cancer. 2012;12:818–834. - PMC - PubMed

[5] Wolter M, Reifenberger J, Sommer C, Ruzicka T, Reifenberger G. Mutations in the human homologue of the drosophila segment polarity gene patched (PTCH) in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res. 1997;57:2581–2585. - PubMed

[6] Wolter M, Reifenberger J, Sommer C, Ruzicka T, Reifenberger G. Mutations in the human homologue of the drosophila segment polarity gene patched (PTCH) in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res. 1997;57:2581–2585. - PubMed

[7] Taylor MD, Liu L, Raffel C. Mutations in SUFU predispose to medulloblastoma. Nat Genet. 2002;31:306–310. - PubMed

[8] Taylor MD, Liu L, Raffel C. Mutations in SUFU predispose to medulloblastoma. Nat Genet. 2002;31:306–310. - PubMed

[9] Li FP, Fraumeni JF. Rhabdomyosarcoma in children: epidemiologic study and identification of a familial cancer syndrome. J Natl Cancer Inst. 1969;43:1365–1373. - PubMed

[10] Li FP, Fraumeni JF. Rhabdomyosarcoma in children: epidemiologic study and identification of a familial cancer syndrome. J Natl Cancer Inst. 1969;43:1365–1373. - PubMed

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

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

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