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.

Základní údaje

Originální název

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

Autoři

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 a Stefan M. PFISTER

Vydání

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

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30204 Oncology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Impakt faktor

Impact factor: 35.386

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14110/18:00104147

Organizační jednotka

Lékařská fakulta

Klíčová slova anglicky

Medulloblastoma

Štítky

14110321, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 16. 12. 2019 10:43, Mgr. Tereza Miškechová

Anotace

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.

Návaznosti

ROZV/24/LF/2018, interní kód MU

Název: LF - Příspěvek na IP 2108

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, LF - Příspěvek na IP 2108, Interní rozvojové projekty

ROZV/25/LF/2017, interní kód MU

Název: LF - Příspěvek na IP 2017

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, LF - Příspěvek na IP 2017, Interní rozvojové projekty

Citovat

@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 = {https://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  -

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