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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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Harvard

Waszak, SM, Northcott, PA, Buchhalter, I, Robinson, GW, Sutter, C, Groebner, S, Grund, KB, Brugières, L, Jones, DTW, Pajtler, KW, Morrissy, AS, Kool, M, Sturm, D, Chavez, L, Ernst, A, Brabetz, S, Hain, M, Zichner, T, Segura-Wang, M, Weischenfeldt, J, Rausch, T, Mardin, BR, Zhou, X, Baciu, C, Lawerenz, C, Chan, JA, Varlet, P, Guerrini-Rousseau, L, Fults, DW, Grajkowska, W, Hauser, P, Jabado, N, Ra, Y-S, Zitterbart, K, Shringarpure, SS, De La Vega, FM, Bustamante, CD, Ng, H-K, Perry, A, MacDonald, TJ, Hernáiz Driever, P, Bendel, AE, Bowers, DC, McCowage, G, Chintagumpala, MM, Cohn, R, Hassall, T, Fleischhack, G, Eggen, T, Wesenberg, F, Feychting, M, Lannering, B, Schüz, J, Johansen, C, Andersen, TV, Röösli, M, Kuehni, CE, Grotzer, M, Kjaerheim, K, Monoranu, CM, Archer, TC, Duke, E, Pomeroy, SL, Shelagh, R, Frank, S, Sumerauer, D, Scheurlen, W, Ryzhova, MV, Milde, T, Kratz, CP, Samuel, D, Zhang, J, Solomon, DA, Marra, M, Eils, R, Bartram, CR, von Hoff, K, Rutkowski, S, Ramaswamy, V, Gilbertson, RJ, Korshunov, A, Taylor, MD, Lichter, P, Malkin, D, Gajjar, A, Korbel, JO & Pfister, SM 2018, 'Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort' Lancet Oncology, vol. 19, no. 6, pp. 785-798. https://doi.org/10.1016/S1470-2045(18)30242-0

APA

CBE

Waszak SM, Northcott PA, Buchhalter I, Robinson GW, Sutter C, Groebner S, Grund KB, Brugières L, Jones DTW, Pajtler KW, Morrissy AS, Kool M, Sturm D, Chavez L, Ernst A, Brabetz S, Hain M, Zichner T, Segura-Wang M, Weischenfeldt J, Rausch T, Mardin BR, Zhou X, Baciu C, Lawerenz C, Chan JA, Varlet P, Guerrini-Rousseau L, Fults DW, Grajkowska W, Hauser P, Jabado N, Ra Y-S, Zitterbart K, Shringarpure SS, De La Vega FM, Bustamante CD, Ng H-K, Perry A, MacDonald TJ, Hernáiz Driever P, Bendel AE, Bowers DC, McCowage G, Chintagumpala MM, Cohn R, Hassall T, Fleischhack G, Eggen T, Wesenberg F, Feychting M, Lannering B, Schüz J, Johansen C, Andersen TV, Röösli M, Kuehni CE, Grotzer M, Kjaerheim K, Monoranu CM, Archer TC, Duke E, Pomeroy SL, Shelagh R, Frank S, Sumerauer D, Scheurlen W, Ryzhova MV, Milde T, Kratz CP, Samuel D, Zhang J, Solomon DA, Marra M, Eils R, Bartram CR, von Hoff K, Rutkowski S, Ramaswamy V, Gilbertson RJ, Korshunov A, Taylor MD, Lichter P, Malkin D, Gajjar A, Korbel JO, Pfister SM. 2018. Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort. Lancet Oncology. 19(6):785-798. https://doi.org/10.1016/S1470-2045(18)30242-0

MLA

Vancouver

Author

Waszak, Sebastian M ; Northcott, Paul A ; Buchhalter, Ivo ; Robinson, Giles W ; Sutter, Christian ; Groebner, Susanne ; Grund, Kerstin B ; Brugières, Laurence ; Jones, David T W ; Pajtler, Kristian W ; Morrissy, A Sorana ; Kool, Marcel ; Sturm, Dominik ; Chavez, Lukas ; Ernst, Aurelie ; Brabetz, Sebastian ; Hain, Michael ; Zichner, Thomas ; Segura-Wang, Maia ; Weischenfeldt, Joachim ; Rausch, Tobias ; Mardin, Balca R ; Zhou, Xin ; Baciu, Cristina ; Lawerenz, Christian ; Chan, Jennifer A ; Varlet, Pascale ; Guerrini-Rousseau, Lea ; Fults, Daniel W ; Grajkowska, Wiesława ; Hauser, Peter ; Jabado, Nada ; Ra, Young-Shin ; Zitterbart, Karel ; Shringarpure, Suyash S ; De La Vega, Francisco M ; Bustamante, Carlos D ; Ng, Ho-Keung ; Perry, Arie ; MacDonald, Tobey J ; Hernáiz Driever, Pablo ; Bendel, Anne E ; Bowers, Daniel C ; McCowage, Geoffrey ; Chintagumpala, Murali M ; Cohn, Richard ; Hassall, Timothy ; Fleischhack, Gudrun ; Eggen, Tone ; Wesenberg, Finn ; Feychting, Maria ; Lannering, Birgitta ; Schüz, Joachim ; Johansen, Christoffer ; Andersen, Tina V ; Röösli, Martin ; Kuehni, Claudia E ; Grotzer, Michael ; Kjaerheim, Kristina ; Monoranu, Camelia M ; Archer, Tenley C ; Duke, Elizabeth ; Pomeroy, Scott L ; Shelagh, Redmond ; Frank, Stephan ; Sumerauer, David ; Scheurlen, Wolfram ; Ryzhova, Marina V ; Milde, Till ; Kratz, Christian P ; Samuel, David ; Zhang, Jinghui ; Solomon, David A ; Marra, Marco ; Eils, Roland ; Bartram, Claus R ; von Hoff, Katja ; Rutkowski, Stefan ; Ramaswamy, Vijay ; Gilbertson, Richard J ; Korshunov, Andrey ; Taylor, Michael D ; Lichter, Peter ; Malkin, David ; Gajjar, Amar ; Korbel, Jan O ; Pfister, Stefan M. / Spectrum and prevalence of genetic predisposition in medulloblastoma : a retrospective genetic study and prospective validation in a clinical trial cohort. In: Lancet Oncology. 2018 ; Vol. 19, No. 6. pp. 785-798.

Bibtex

@article{7cfb35943183492391ff06ae63fa084f,
title = "Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort",
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 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.",
keywords = "Journal Article",
author = "Waszak, {Sebastian M} and Northcott, {Paul A} and Ivo Buchhalter and Robinson, {Giles W} and Christian Sutter and Susanne Groebner and Grund, {Kerstin B} and Laurence Brugi{\`e}res and Jones, {David T W} and Pajtler, {Kristian W} and Morrissy, {A Sorana} and Marcel Kool and Dominik Sturm and Lukas Chavez and Aurelie Ernst and Sebastian Brabetz and Michael Hain and Thomas Zichner and Maia Segura-Wang and Joachim Weischenfeldt and Tobias Rausch and Mardin, {Balca R} and Xin Zhou and Cristina Baciu and Christian Lawerenz and Chan, {Jennifer A} and Pascale Varlet and Lea Guerrini-Rousseau and Fults, {Daniel W} and Wiesława Grajkowska and Peter Hauser and Nada Jabado and Young-Shin Ra and Karel Zitterbart and Shringarpure, {Suyash S} and {De La Vega}, {Francisco M} and Bustamante, {Carlos D} and Ho-Keung Ng and Arie Perry and MacDonald, {Tobey J} and {Hern{\'a}iz Driever}, Pablo and Bendel, {Anne E} and Bowers, {Daniel C} and Geoffrey McCowage and Chintagumpala, {Murali M} and Richard Cohn and Timothy Hassall and Gudrun Fleischhack and Tone Eggen and Finn Wesenberg and Maria Feychting and Birgitta Lannering and Joachim Sch{\"u}z and Christoffer Johansen and Andersen, {Tina V} and Martin R{\"o}{\"o}sli and Kuehni, {Claudia E} and Michael Grotzer and Kristina Kjaerheim and Monoranu, {Camelia M} and Archer, {Tenley C} and Elizabeth Duke and Pomeroy, {Scott L} and Redmond Shelagh and Stephan Frank and David Sumerauer and Wolfram Scheurlen and Ryzhova, {Marina V} and Till Milde and Kratz, {Christian P} and David Samuel and Jinghui Zhang and Solomon, {David A} and Marco Marra and Roland Eils and Bartram, {Claus R} and {von Hoff}, Katja and Stefan Rutkowski and Vijay Ramaswamy and Gilbertson, {Richard J} and Andrey Korshunov and Taylor, {Michael D} and Peter Lichter and David Malkin and Amar Gajjar and Korbel, {Jan O} and Pfister, {Stefan M}",
note = "Copyright {\circledC} 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.",
year = "2018",
month = "6",
day = "1",
doi = "10.1016/S1470-2045(18)30242-0",
language = "English",
volume = "19",
pages = "785--798",
journal = "Lancet Oncology",
issn = "1470-2045",
publisher = "The/Lancet Publishing Group",
number = "6",

}

RIS

TY - JOUR

T1 - Spectrum and prevalence of genetic predisposition in medulloblastoma

T2 - a retrospective genetic study and prospective validation in a clinical trial cohort

AU - Waszak, Sebastian M

AU - Northcott, Paul A

AU - Buchhalter, Ivo

AU - Robinson, Giles W

AU - Sutter, Christian

AU - Groebner, Susanne

AU - Grund, Kerstin B

AU - Brugières, Laurence

AU - Jones, David T W

AU - Pajtler, Kristian W

AU - Morrissy, A Sorana

AU - Kool, Marcel

AU - Sturm, Dominik

AU - Chavez, Lukas

AU - Ernst, Aurelie

AU - Brabetz, Sebastian

AU - Hain, Michael

AU - Zichner, Thomas

AU - Segura-Wang, Maia

AU - Weischenfeldt, Joachim

AU - Rausch, Tobias

AU - Mardin, Balca R

AU - Zhou, Xin

AU - Baciu, Cristina

AU - Lawerenz, Christian

AU - Chan, Jennifer A

AU - Varlet, Pascale

AU - Guerrini-Rousseau, Lea

AU - Fults, Daniel W

AU - Grajkowska, Wiesława

AU - Hauser, Peter

AU - Jabado, Nada

AU - Ra, Young-Shin

AU - Zitterbart, Karel

AU - Shringarpure, Suyash S

AU - De La Vega, Francisco M

AU - Bustamante, Carlos D

AU - Ng, Ho-Keung

AU - Perry, Arie

AU - MacDonald, Tobey J

AU - Hernáiz Driever, Pablo

AU - Bendel, Anne E

AU - Bowers, Daniel C

AU - McCowage, Geoffrey

AU - Chintagumpala, Murali M

AU - Cohn, Richard

AU - Hassall, Timothy

AU - Fleischhack, Gudrun

AU - Eggen, Tone

AU - Wesenberg, Finn

AU - Feychting, Maria

AU - Lannering, Birgitta

AU - Schüz, Joachim

AU - Johansen, Christoffer

AU - Andersen, Tina V

AU - Röösli, Martin

AU - Kuehni, Claudia E

AU - Grotzer, Michael

AU - Kjaerheim, Kristina

AU - Monoranu, Camelia M

AU - Archer, Tenley C

AU - Duke, Elizabeth

AU - Pomeroy, Scott L

AU - Shelagh, Redmond

AU - Frank, Stephan

AU - Sumerauer, David

AU - Scheurlen, Wolfram

AU - Ryzhova, Marina V

AU - Milde, Till

AU - Kratz, Christian P

AU - Samuel, David

AU - Zhang, Jinghui

AU - Solomon, David A

AU - Marra, Marco

AU - Eils, Roland

AU - Bartram, Claus R

AU - von Hoff, Katja

AU - Rutkowski, Stefan

AU - Ramaswamy, Vijay

AU - Gilbertson, Richard J

AU - Korshunov, Andrey

AU - Taylor, Michael D

AU - Lichter, Peter

AU - Malkin, David

AU - Gajjar, Amar

AU - Korbel, Jan O

AU - Pfister, Stefan M

N1 - Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.

PY - 2018/6/1

Y1 - 2018/6/1

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1016/S1470-2045(18)30242-0

DO - 10.1016/S1470-2045(18)30242-0

M3 - Journal article

VL - 19

SP - 785

EP - 798

JO - Lancet Oncology

JF - Lancet Oncology

SN - 1470-2045

IS - 6

ER -

ID: 53806063