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

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Authors

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.

Year of publication 2018
Type Article in Periodical
Magazine / Source Lancet Oncology
MU Faculty or unit

Faculty of Medicine

Citation
Doi http://dx.doi.org/10.1016/S1470-2045(18)30242-0
Keywords Medulloblastoma
Description 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.
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