title: Germ-line and somatic DICER1 mutations in pineoblastoma.
abstract: Germ-line RB-1 mutations predispose to pineoblastoma (PinB), but other predisposing genetic factors are not well established. We recently identified a germ-line DICER1 mutation in a child with a PinB. This was accompanied by loss of heterozygosity (LOH) of the wild-type allele within the tumour. We set out to establish the prevalence of DICER1 mutations in an opportunistically ascertained series of PinBs. Twenty-one PinB cases were studied: Eighteen cases had not undergone previous testing for DICER1 mutations; three patients were known carriers of germ-line DICER1 mutations. The eighteen PinBs were sequenced by Sanger and/or Fluidigm-based next-generation sequencing to identify DICER1 mutations in blood gDNA and/or tumour gDNA. Testing for somatic DICER1 mutations was also conducted on one case with a known germ-line DICER1 mutation. From the eighteen PinBs, we identified four deleterious DICER1 mutations, three of which were germ line in origin, and one for which a germ line versus somatic origin could not be determined; in all four, the second allele was also inactivated leading to complete loss of DICER1 protein. No somatic DICER1 RNase IIIb mutations were identified. One PinB arising in a germ-line DICER1 mutation carrier was found to have LOH. This study suggests that germ-line DICER1 mutations make a clinically significant contribution to PinB, establishing DICER1 as an important susceptibility gene for PinB and demonstrates PinB to be a manifestation of a germ-line DICER1 mutation. The means by which the second allele is inactivated may differ from other DICER1-related tumours.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada.
authors.forename: Leanne
authors.initials: L
authors.lastname: de Kock
authors.forename: Nelly
authors.initials: N
authors.lastname: Sabbaghian
authors.forename: Harriet
authors.initials: H
authors.lastname: Druker
authors.forename: Evan
authors.initials: E
authors.lastname: Weber
authors.forename: Nancy
authors.initials: N
authors.lastname: Hamel
authors.forename: Suzanne
authors.initials: S
authors.lastname: Miller
authors.forename: Catherine S
authors.initials: CS
authors.lastname: Choong
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Gottardo
authors.forename: Ursula R
authors.initials: UR
authors.lastname: Kees
authors.forename: Surya P
authors.initials: SP
authors.lastname: Rednam
authors.forename: Liselotte P
authors.initials: LP
authors.lastname: van Hest
authors.forename: Marjolijn C
authors.initials: MC
authors.lastname: Jongmans
authors.forename: Shalini
authors.initials: S
authors.lastname: Jhangiani
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.forename: Margaret
authors.initials: M
authors.lastname: Zacharin
authors.forename: Dorothée
authors.initials: D
authors.lastname: Bouron-Dal Soglio
authors.forename: Annie
authors.initials: A
authors.lastname: Huang
authors.forename: John R
authors.initials: JR
authors.lastname: Priest
authors.forename: Arie
authors.initials: A
authors.lastname: Perry
authors.forename: Sabine
authors.initials: S
authors.lastname: Mueller
authors.forename: Steffen
authors.initials: S
authors.lastname: Albrecht
authors.forename: David
authors.initials: D
authors.lastname: Malkin
authors.forename: Richard G
authors.initials: RG
authors.lastname: Grundy
authors.forename: William D
authors.initials: WD
authors.lastname: Foulkes
mesh_terms: D000293:Adolescent; D001932:Brain Neoplasms / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D010870:Pineal Gland / Q000473:pathology*; D010871:Pinealoma / Q000235:genetics*; D043244:Ribonuclease III / Q000235:genetics*; D055815:Young Adult
chemical_list: C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases