Authors:
de Kock L, Sabbaghian N, Druker H, Weber E, Hamel N, Miller S, Choong CS, Gottardo NG, Kees UR, et al.
Authors notes:
Acta Neuropathologica. 2014;128(4):583-595
Keywords:
Childhood cancer, DICER1, miRNA processing, Mutation, Paediatric brain tumours, Pineal gland, 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.