S'abonner

Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort - 02/06/18

Doi : 10.1016/S1470-2045(18)30242-0 
Sebastian M Waszak, PhD af, *, Paul A Northcott, PhD aj, br, *, Ivo Buchhalter, PhD am, ao, Giles W Robinson, MD bs, Christian Sutter, PhD ag, Susanne Groebner, PhD aj, Kerstin B Grund, MD ag, Laurence Brugières, MD v, David T W Jones, PhD aj, ar, Kristian W Pajtler, MD ah, aj, ar, A Sorana Morrissy, PhD d, f, Marcel Kool, PhD aj, ar, Dominik Sturm, MD ah, aj, ar, Lukas Chavez, PhD aj, Aurelie Ernst, PhD an, Sebastian Brabetz, MSc ah, aj, ar, Michael Hain, CITBM an, Thomas Zichner, PhD af, Maia Segura-Wang, PhD af, Joachim Weischenfeldt, PhD q, s, af, Tobias Rausch, PhD af, Balca R Mardin, PhD af, Xin Zhou, PhD bq, Cristina Baciu, PhD l, Christian Lawerenz, PhD ap, Jennifer A Chan, MD e, Pascale Varlet, MD w, Lea Guerrini-Rousseau, MD v, Daniel W Fults, MD bi, Wiesława Grajkowska, ProfMD ax, Peter Hauser, PhD as, Nada Jabado, ProfMD i, Young-Shin Ra, MD at, Karel Zitterbart, MD n, p, Suyash S Shringarpure, PhD bm, Francisco M De La Vega, DSc bm, Carlos D Bustamante, PhD bm, Ho-Keung Ng, MD m, Arie Perry, ProfMD bn, Tobey J MacDonald, ProfMD bl, Pablo Hernáiz Driever ac, Anne E Bendel, MD bj, Daniel C Bowers, MD bo, Geoffrey McCowage, MBBS c, Murali M Chintagumpala, ProfMD bk, Richard Cohn, ProfMBBCh b, Timothy Hassall, MBBS a, Gudrun Fleischhack, MD ae, Tone Eggen, MSc aw, Finn Wesenberg, ProfMD au, av, aw, Maria Feychting, ProfPhD ba, Birgitta Lannering, ProfMD az, Joachim Schüz, PhD x, Christoffer Johansen, ProfMD r, t, Tina V Andersen, MS u, Martin Röösli, ProfPhD bb, bf, Claudia E Kuehni, ProfMD be, Michael Grotzer, ProfMD bc, Kristina Kjaerheim, PhD aw, Camelia M Monoranu, MD z, aa, Tenley C Archer, PhD bg, bh, Elizabeth Duke, MD bh, Scott L Pomeroy, ProfMD bg, bh, Redmond Shelagh, PhD be, Stephan Frank, ProfMD bd, David Sumerauer, MD o, Wolfram Scheurlen, ProfMD y, Marina V Ryzhova, MD ay, Till Milde, MD ah, al, ar, Christian P Kratz, ProfMD ad, David Samuel, MD bp, Jinghui Zhang, PhD bq, David A Solomon, MD bn, Marco Marra, PhD k, Roland Eils, ProfPhD am, Claus R Bartram, ProfMD ag, Katja von Hoff, MD ab, ac, Stefan Rutkowski, ProfMD ab, Vijay Ramaswamy, MD g, j, Richard J Gilbertson, ProfPhD bt, Andrey Korshunov, MD ai, aq, Michael D Taylor, ProfMD h, Peter Lichter, ProfPhD ak, David Malkin, MD g, j, , Amar Gajjar, ProfMD bs, , Jan O Korbel, PhD af, , Stefan M Pfister, ProfMD ah, aj, ar, ,
a Department of Paediatric Oncology, Lady Cilento Children’s Hospital, South Brisbane, QLD, Australia 
b Department of Paediatric Oncology, Sydney Children’s Hospital, Sydney, NSW, Australia 
c Department of Paediatric Oncology, The Children’s Hospital at Westmead, Sydney, NSW, Australia 
d Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada 
e Department of Pathology and Laboratory Medicine, Department of Oncology, and Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada 
f Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada 
g Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada 
h Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada 
i Department of Pediatrics, McGill University, Montreal, QC, Canada 
j Department of Pediatrics, University of Toronto, Toronto, ON, Canada 
k Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada 
l University Health Network-Toronto General Hospital, Toronto, ON, Canada 
m Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China 
n Department of Paediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic 
o Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czech Republic 
p Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic 
q Biotech Research and Innovation Centre, Copenhagen, Denmark 
r Oncology Clinic, Finsen Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark 
s Finsen Laboratory, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark 
t Unit of Survivorship, Copenhagen, Denmark 
u Danish Cancer Society Research Center, Copenhagen, Denmark 
v Department of Children and Adolescents Oncology, Gustave Roussy Cancer Campus, Villejuif, France 
w Department of Neuropathology, Sainte-Anne Hospital, Paris, France 
x Section of Environment and Radiation, International Agency for Research on Cancer, Lyon, France 
y Cnopf’sche Kinderklinik, Nuremberg, Germany 
z Comprehensive Cancer Center Mainfranken, Würzburg, Germany 
aa Department of Neuropathology, Institute of Pathology, University of Würzburg, Würzburg, Germany 
ab Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 
ac 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 
ad Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany 
ae Pediatric Oncology and Hematology, Pediatrics III, University Hospital of Essen, Essen, Germany 
af European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany 
ag Institute of Human Genetics, Heidelberg University, Heidelberg, Germany 
ah Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany 
ai Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany 
aj Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany 
ak Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany 
al Clinical Cooperation Unit Pediatric Oncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany 
am Division of Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany 
an Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany 
ao Division of Applied Bioinformatics, German Cancer Research Center, Heidelberg, Germany 
ap Data Management Facility, German Cancer Research Center, Heidelberg, Germany 
aq Clinical Cooperation Unit Neuropathology, German Cancer Research Center, Heidelberg, Germany 
ar Hopp Children’s Cancer Center at the NCT Heidelberg, Heidelberg, Germany 
as 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary 
at Department of Neurosurgery, Asan Medical Center, Seoul, South Korea 
au Department of Pediatric Medicine, Oslo University Hospital, Oslo, Norway 
av Institute of Clinical Medicine, University of Oslo, Oslo, Norway 
aw Cancer Registry of Norway, Oslo, Norway 
ax Department of Pathology, Children’s Memorial Health Institute, Warsaw, Poland 
ay Department of Neuropathology, Burdenko Neurosurgical Institute, Moscow, Russia 
az Department of Pediatrics, University of Gothenburg, The Queen Silvia Children’s Hospital, Gothenburg, Sweden 
ba Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden 
bb Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland 
bc Department of Pediatric Oncology, University Children’s Hospital Zurich, University of Zurich, Zurich, Switzerland 
bd Institute of Neuropathology, University Hospital Basel, Basel, Switzerland 
be Swiss Childhood Cancer Registry, Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland 
bf Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland 
bg Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA 
bh Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA 
bi Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, UT, USA 
bj Department of Pediatric Hematology and Oncology, Children’s Hospitals and Clinics of Minnesota, Minneapolis, MN, USA 
bk Department of Pediatric Hematology and Oncology, Texas Children’s Hospital, Houston, TX, USA 
bl Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA, USA 
bm Departments of Genetics and Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA 
bn Division of Neuropathology, Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA 
bo Division of Pediatric Hematology-Oncology, University of Texas Southwestern Medical School, Dallas, TX, USA 
bp Valley Children’s Hospital, Madera, CA, USA 
bq Department of Computational Biology, St Jude Children’s Research Hospital, Memphis, TN, USA 
br Department of Developmental Neurobiology, St Jude Children’s Research Hospital, Memphis, TN, USA 
bs Department of Oncology, St Jude Children’s Research Hospital, Memphis, TN, USA 
bt Department of Oncology and Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK 

* Correspondence to: Dr Stefan M Pfister, Hopp Children’s Cancer Center at the NCT Heidelberg, Division of Pediatric Neurooncology, German Cancer Research Center, Heidelberg 69120, Germany Hopp Children’s Cancer Center at the NCT Heidelberg Division of Pediatric Neurooncology German Cancer Research Center Heidelberg 69120 Germany

Summary

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 MBSHH 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 MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that 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 MBSHH 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 MBSHH, MBGroup3, and MBGroup4 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 MBWNT and MBSHH 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.

Le texte complet de cet article est disponible en PDF.

Plan


© 2018  The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Publié par Elsevier Masson SAS. Tous droits réservés.
Ajouter à ma bibliothèque Retirer de ma bibliothèque Imprimer
Export

    Export citations

  • Fichier

  • Contenu

Vol 19 - N° 6

P. 785-798 - juin 2018 Retour au numéro
Article précédent Article précédent
  • Risk-adapted therapy for young children with medulloblastoma (SJYC07): therapeutic and molecular outcomes from a multicentre, phase 2 trial
  • Giles W Robinson, Vasilisa A Rudneva, Ivo Buchhalter, Catherine A Billups, Sebastian M Waszak, Kyle S Smith, Daniel C Bowers, Anne Bendel, Paul G Fisher, Sonia Partap, John R Crawford, Tim Hassall, Daniel J Indelicato, Frederick Boop, Paul Klimo, Noah D Sabin, Zoltan Patay, Thomas E Merchant, Clinton F Stewart, Brent A Orr, Jan O Korbel, David T W Jones, Tanvi Sharma, Peter Lichter, Marcel Kool, Andrey Korshunov, Stefan M Pfister, Richard J Gilbertson, Robert P Sanders, Arzu Onar-Thomas, David W Ellison, Amar Gajjar, Paul A Northcott
| Article suivant Article suivant
  • NGR-hTNF in combination with best investigator choice in previously treated malignant pleural mesothelioma (NGR015): a randomised, double-blind, placebo-controlled phase 3 trial
  • Vanesa Gregorc, Rabab M Gaafar, Adolfo Favaretto, Francesco Grossi, Jacek Jassem, Andreas Polychronis, Paolo Bidoli, Marcello Tiseo, Riyaz Shah, Paul Taylor, Silvia Novello, Alberto Muzio, Alessandra Bearz, Laurent Greillier, Floriana Fontana, Giulia Salini, Antonio Lambiase, Mary O’Brien

Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.

Déjà abonné à cette revue ?

Mon compte


Plateformes Elsevier Masson

Déclaration CNIL

EM-CONSULTE.COM est déclaré à la CNIL, déclaration n° 1286925.

En application de la loi nº78-17 du 6 janvier 1978 relative à l'informatique, aux fichiers et aux libertés, vous disposez des droits d'opposition (art.26 de la loi), d'accès (art.34 à 38 de la loi), et de rectification (art.36 de la loi) des données vous concernant. Ainsi, vous pouvez exiger que soient rectifiées, complétées, clarifiées, mises à jour ou effacées les informations vous concernant qui sont inexactes, incomplètes, équivoques, périmées ou dont la collecte ou l'utilisation ou la conservation est interdite.
Les informations personnelles concernant les visiteurs de notre site, y compris leur identité, sont confidentielles.
Le responsable du site s'engage sur l'honneur à respecter les conditions légales de confidentialité applicables en France et à ne pas divulguer ces informations à des tiers.


Tout le contenu de ce site: Copyright © 2025 Elsevier, ses concédants de licence et ses contributeurs. Tout les droits sont réservés, y compris ceux relatifs à l'exploration de textes et de données, a la formation en IA et aux technologies similaires. Pour tout contenu en libre accès, les conditions de licence Creative Commons s'appliquent.