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

The Lancet Oncology
Sebastian M WaszakStefan M Pfister

Abstract

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. 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 sig...Continue Reading

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Methods Mentioned

BETA
Exome Sequencing
genotyping
methylation profiling
exome-sequencing

Clinical Trials Mentioned

NCT00085202
NCT01878617
NCT00602667
NCT02417324
NCT02066220

Software Mentioned

Ensembl Variant Effect Predictor ( VEP
delly
normalize
R package survminer
R package suvival
ClinVar
R
R package EMT
R package SomaticSignatures
bedtools

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