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

J 2018

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

WASZAK, Sebastian M., Paul A. NORTHCOTT, Ivo BUCHHALTER, Giles W. ROBINSON, Christian SUTTER et. al.

Basic information

Original name

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

Authors

WASZAK, Sebastian M. (276 Germany), Paul A. NORTHCOTT (276 Germany), Ivo BUCHHALTER (276 Germany), Giles W. ROBINSON (840 United States of America), Christian SUTTER (276 Germany), Susanne GROEBNER (276 Germany), Kerstin B. GRUND (276 Germany), Laurence BRUGIERES (250 France), David T.W. JONES (276 Germany), Kristian W. PAJTLER (276 Germany), A. Sorana MORRISSY (124 Canada), Marcel KOOL (276 Germany), Dominik STURM (276 Germany), Lukas CHAVEZ (276 Germany), Aurelie ERNST (276 Germany), Sebastian BRABETZ (276 Germany), Michael HAIN (276 Germany), Thomas ZICHNER (276 Germany), Maia SEGURA-WANG (276 Germany), Joachim WEISCHENFELDT (208 Denmark), Tobias RAUSCH (276 Germany), Balca R. MARDIN (276 Germany), Xin ZHOU (840 United States of America), Cristina BACIU (124 Canada), Christian LAWERENZ (276 Germany), Jennifer A. CHAN (124 Canada), Pascale VARLET (250 France), Lea GUERRINI-ROUSSEAU (250 France), Daniel W. FULTS (840 United States of America), Wieslawa GRAJKOWSKA (616 Poland), Peter HAUSER (348 Hungary), Nada JABADO (124 Canada), Young-Shin RA (410 Republic of Korea), Karel ZITTERBART (203 Czech Republic, belonging to the institution), Suyash S. SHRINGARPURE (410 Republic of Korea), Francisco M. DE LA VEGA (840 United States of America), Carlos D. BUSTAMANTE (840 United States of America), Ho-Keung NG (156 China), Arie PERRY (840 United States of America), Tobey J. MACDONALD (840 United States of America), Pablo H. DRIEVER (276 Germany), Anne E. BENDEL (840 United States of America), Daniel C. BOWERS (840 United States of America), Geoffrey MCCOWAGE (36 Australia), Murali M. CHINTAGUMPALA (840 United States of America), Richard COHN (36 Australia), Timothy HASSALL (36 Australia), Gudrun FLEISCHHACK (276 Germany), Tone EGGEN (578 Norway), Finn WESENBERG (578 Norway), Maria FEYCHTING (752 Sweden), Birgitta LANNERING (752 Sweden), Joachim SCHUZ (250 France), Christoffer JOHANSEN (208 Denmark), Tina V. ANDERSEN (208 Denmark), Martin ROOSLI (756 Switzerland), Claudia E. KUEHNI (756 Switzerland), Michael GROTZER (756 Switzerland), Kristina KJAERHEIM (578 Norway), Camelia M. MONORANU (276 Germany), Tenley C. ARCHER (840 United States of America), Elizabeth DUKE (840 United States of America), Scott L. POMEROY (840 United States of America), Redmond SHELAGH (756 Switzerland), Stephan FRANK (756 Switzerland), David SUMERAUER (203 Czech Republic), Wolfram SCHEURLEN (276 Germany), Marina V. RYZHOVA (643 Russian Federation), Till MILDE (276 Germany), Christian P. KRATZ (276 Germany), David SAMUEL (840 United States of America), Jinghui ZHANG (840 United States of America), David A. SOLOMON (840 United States of America), Marco MARRA (124 Canada), Roland EILS (276 Germany), Claus R. BARTRAM (276 Germany), Katja von HOFF (276 Germany), Stefan RUTKOWSKI (276 Germany), Vijay RAMASWAMY (124 Canada), Richard J. GILBERTSON (826 United Kingdom of Great Britain and Northern Ireland), Andrey KORSHUNOV (276 Germany), Michael D. TAYLOR (124 Canada), Peter LICHTER (276 Germany), David MALKIN (124 Canada), Amar GAJJAR (840 United States of America), Jan O. KORBEL (276 Germany) and Stefan M. PFISTER (276 Germany, guarantor)

Edition

Lancet Oncology, New York, Elsevier Science INC, 2018, 1470-2045

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30204 Oncology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

Impact factor

Impact factor: 35.386

RIV identification code

RIV/00216224:14110/18:00104147

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1016/S1470-2045(18)30242-0

UT WoS

000434153000044

Keywords in English

Medulloblastoma

Abstract

V originále

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.

Links

ROZV/24/LF/2018, interní kód MU

Name: LF - Příspěvek na IP 2108

Investor: Ministry of Education, Youth and Sports of the CR, Internal development projects

ROZV/25/LF/2017, interní kód MU

Name: LF - Příspěvek na IP 2017

Investor: Ministry of Education, Youth and Sports of the CR, Internal development projects

Citovat

WASZAK, Sebastian M., Paul A. NORTHCOTT, Ivo BUCHHALTER, Giles W. ROBINSON, Christian SUTTER, Susanne GROEBNER, Kerstin B. GRUND, Laurence BRUGIERES, David T.W. JONES, Kristian W. PAJTLER, A. Sorana MORRISSY, Marcel KOOL, Dominik STURM, Lukas CHAVEZ, Aurelie ERNST, Sebastian BRABETZ, Michael HAIN, Thomas ZICHNER, Maia SEGURA-WANG, Joachim WEISCHENFELDT, Tobias RAUSCH, Balca R. MARDIN, Xin ZHOU, Cristina BACIU, Christian LAWERENZ, Jennifer A. CHAN, Pascale VARLET, Lea GUERRINI-ROUSSEAU, Daniel W. FULTS, Wieslawa GRAJKOWSKA, Peter HAUSER, Nada JABADO, Young-Shin RA, Karel ZITTERBART, Suyash S. SHRINGARPURE, Francisco M. DE LA VEGA, Carlos D. BUSTAMANTE, Ho-Keung NG, Arie PERRY, Tobey J. MACDONALD, Pablo H. DRIEVER, Anne E. BENDEL, Daniel C. BOWERS, Geoffrey MCCOWAGE, Murali M. CHINTAGUMPALA, Richard COHN, Timothy HASSALL, Gudrun FLEISCHHACK, Tone EGGEN, Finn WESENBERG, Maria FEYCHTING, Birgitta LANNERING, Joachim SCHUZ, Christoffer JOHANSEN, Tina V. ANDERSEN, Martin ROOSLI, Claudia E. KUEHNI, Michael GROTZER, Kristina KJAERHEIM, Camelia M. MONORANU, Tenley C. ARCHER, Elizabeth DUKE, Scott L. POMEROY, Redmond SHELAGH, Stephan FRANK, David SUMERAUER, Wolfram SCHEURLEN, Marina V. RYZHOVA, Till MILDE, Christian P. KRATZ, David SAMUEL, Jinghui ZHANG, David A. SOLOMON, Marco MARRA, Roland EILS, Claus R. BARTRAM, Katja von HOFF, Stefan RUTKOWSKI, Vijay RAMASWAMY, Richard J. GILBERTSON, Andrey KORSHUNOV, Michael D. TAYLOR, Peter LICHTER, David MALKIN, Amar GAJJAR, Jan O. KORBEL and Stefan M. PFISTER. Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort. Lancet Oncology. New York: Elsevier Science INC, 2018, vol. 19, No 6, p. 785-798. ISSN 1470-2045. Available from: https://dx.doi.org/10.1016/S1470-2045(18)30242-0.

@article{1453857,
   author = {Waszak, Sebastian M. and Northcott, Paul A. and Buchhalter, Ivo and Robinson, Giles W. and Sutter, Christian and Groebner, Susanne and Grund, Kerstin B. and Brugieres, Laurence and Jones, David T.W. and Pajtler, Kristian W. and Morrissy, A. Sorana and Kool, Marcel and Sturm, Dominik and Chavez, Lukas and Ernst, Aurelie and Brabetz, Sebastian and Hain, Michael and Zichner, Thomas and SeguraandWang, Maia and Weischenfeldt, Joachim and Rausch, Tobias and Mardin, Balca R. and Zhou, Xin and Baciu, Cristina and Lawerenz, Christian and Chan, Jennifer A. and Varlet, Pascale and GuerriniandRousseau, Lea and Fults, Daniel W. and Grajkowska, Wieslawa and Hauser, Peter and Jabado, Nada and Ra, YoungandShin and Zitterbart, Karel and Shringarpure, Suyash S. and De La Vega, Francisco M. and Bustamante, Carlos D. and Ng, HoandKeung and Perry, Arie and MacDonald, Tobey J. and Driever, Pablo H. and Bendel, Anne E. and Bowers, Daniel C. and McCowage, Geoffrey and Chintagumpala, Murali M. and Cohn, Richard and Hassall, Timothy and Fleischhack, Gudrun and Eggen, Tone and Wesenberg, Finn and Feychting, Maria and Lannering, Birgitta and Schuz, Joachim and Johansen, Christoffer and Andersen, Tina V. and Roosli, Martin and Kuehni, Claudia E. and Grotzer, Michael and Kjaerheim, Kristina and Monoranu, Camelia M. and Archer, Tenley C. and Duke, Elizabeth and Pomeroy, Scott L. and Shelagh, Redmond and Frank, Stephan and Sumerauer, David and Scheurlen, Wolfram and Ryzhova, Marina V. and Milde, Till and Kratz, Christian P. and Samuel, David and Zhang, Jinghui and Solomon, David A. and Marra, Marco and Eils, Roland and Bartram, Claus R. and Hoff, Katja von and Rutkowski, Stefan and Ramaswamy, Vijay and Gilbertson, Richard J. and Korshunov, Andrey and Taylor, Michael D. and Lichter, Peter and Malkin, David and Gajjar, Amar and Korbel, Jan O. and Pfister, Stefan M.},
   article_location = {New York},
   article_number = {6},
   doi = {http://dx.doi.org/10.1016/S1470-2045(18)30242-0},
   keywords = {Medulloblastoma},
   language = {eng},
   issn = {1470-2045},
   journal = {Lancet Oncology},
   title = {Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort},
   volume = {19},
   year = {2018}
}

TY  - JOUR
ID  - 1453857
AU  - Waszak, Sebastian M. - Northcott, Paul A. - Buchhalter, Ivo - Robinson, Giles W. - Sutter, Christian - Groebner, Susanne - Grund, Kerstin B. - Brugieres, 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, Wieslawa - 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. - Driever, Pablo H. - 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 - Schuz, Joachim - Johansen, Christoffer - Andersen, Tina V. - Roosli, 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. - Hoff, Katja von - Rutkowski, Stefan - Ramaswamy, Vijay - Gilbertson, Richard J. - Korshunov, Andrey - Taylor, Michael D. - Lichter, Peter - Malkin, David - Gajjar, Amar - Korbel, Jan O. - Pfister, Stefan M.
PY  - 2018
TI  - Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort
JF  - Lancet Oncology
VL  - 19
IS  - 6
SP  - 785-798
EP  - 785-798
PB  - Elsevier Science INC
SN  - 14702045
KW  - Medulloblastoma
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.
ER  -

WASZAK, Sebastian M., Paul A. NORTHCOTT, Ivo BUCHHALTER, Giles W. ROBINSON, Christian SUTTER, Susanne GROEBNER, Kerstin B. GRUND, Laurence BRUGIERES, David T.W. JONES, Kristian W. PAJTLER, A. Sorana MORRISSY, Marcel KOOL, Dominik STURM, Lukas CHAVEZ, Aurelie ERNST, Sebastian BRABETZ, Michael HAIN, Thomas ZICHNER, Maia SEGURA-WANG, Joachim WEISCHENFELDT, Tobias RAUSCH, Balca R. MARDIN, Xin ZHOU, Cristina BACIU, Christian LAWERENZ, Jennifer A. CHAN, Pascale VARLET, Lea GUERRINI-ROUSSEAU, Daniel W. FULTS, Wieslawa GRAJKOWSKA, Peter HAUSER, Nada JABADO, Young-Shin RA, Karel ZITTERBART, Suyash S. SHRINGARPURE, Francisco M. DE LA VEGA, Carlos D. BUSTAMANTE, Ho-Keung NG, Arie PERRY, Tobey J. MACDONALD, Pablo H. DRIEVER, Anne E. BENDEL, Daniel C. BOWERS, Geoffrey MCCOWAGE, Murali M. CHINTAGUMPALA, Richard COHN, Timothy HASSALL, Gudrun FLEISCHHACK, Tone EGGEN, Finn WESENBERG, Maria FEYCHTING, Birgitta LANNERING, Joachim SCHUZ, Christoffer JOHANSEN, Tina V. ANDERSEN, Martin ROOSLI, Claudia E. KUEHNI, Michael GROTZER, Kristina KJAERHEIM, Camelia M. MONORANU, Tenley C. ARCHER, Elizabeth DUKE, Scott L. POMEROY, Redmond SHELAGH, Stephan FRANK, David SUMERAUER, Wolfram SCHEURLEN, Marina V. RYZHOVA, Till MILDE, Christian P. KRATZ, David SAMUEL, Jinghui ZHANG, David A. SOLOMON, Marco MARRA, Roland EILS, Claus R. BARTRAM, Katja von HOFF, Stefan RUTKOWSKI, Vijay RAMASWAMY, Richard J. GILBERTSON, Andrey KORSHUNOV, Michael D. TAYLOR, Peter LICHTER, David MALKIN, Amar GAJJAR, Jan O. KORBEL and Stefan M. PFISTER. Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort. \textit{Lancet Oncology}. New York: Elsevier Science INC, 2018, vol.~19, No~6, p.~785-798. ISSN~1470-2045. Available from: https://dx.doi.org/10.1016/S1470-2045(18)30242-0.

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