title: Biallelic FANCD1/BRCA2 mutations predisposing to glioblastoma multiforme with multiple oncogenic amplifications.
abstract: Fanconi anaemia (FA) caused by biallelic mutation in FANCD1/BRCA2 is rare but carries a high risk of early onset cancer. Medulloblastoma is well described in this cohort but reports of other brain tumours are uncommon. The molecular profile of tumours from FA patients is not well reported. A glioblastoma multiforme (GBM) from a 3-year-old patient with FA and confirmed biallelic BRCA2 mutations was submitted for methylation analysis. This revealed strong clustering with the K27 mutation subgroup and copy number analysis showed gains of chromosomes 1q, 4q, part of 7q, part of 8q and 17q with resultant amplifications of MDM4, CDK6, MET, MYC and PPM1D (WIP1). We also describe for the first time the germline mutation in BRCA2 c.8057T > C resulting in p.Leu2686Pro in our patient with confirmed FA. Biallelic BRCA2 mutations have predisposed to an aggressive and universally fatal subtype of childhood GBM in our patient. Copy number alterations and multiple oncogenic amplifications may be secondary to inherent chromosomal instability and this raises the question of what role BRCA2 may play in the development of GBM in children without FA.
authors.affiliation: Children's Cancer Centre, Royal Children's Hospital, Melbourne, Victoria 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Victoria 3052, Australia. Electronic address: ajdodgshun@gmail.com.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dodgshun
authors.affiliation: Murdoch Children's Research Institute, Melbourne, Victoria 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sexton-Oates
authors.affiliation: Murdoch Children's Research Institute, Melbourne, Victoria 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Saffery
authors.affiliation: Children's Cancer Centre, Royal Children's Hospital, Melbourne, Victoria 3052, Australia; Murdoch Children's Research Institute, Melbourne, Victoria 3052, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Sullivan
mesh_terms: D024682:BRCA2 Protein / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics*; D002675:Child, Preschool; D005784:Gene Amplification; D024522:Genes, BRCA2; D005909:Glioblastoma / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human
keywords: BRCA2; Fanconi anaemia; Glioblastoma multiforme