• Leanne de Kock, Nelly Sabbaghian, Harriet Druker, Evan Weber, Nancy Hamel, Suzanne Miller, Catherine S Choong, Nicholas G Gottardo, Ursula R Kees, Surya P Rednam, Liselotte P van Hest, Marjolijn C Jongmans, Shalini Jhangiani, James R Lupski, Margaret Zacharin, Dorothée Bouron-Dal Soglio, Annie Huang, John R Priest, Arie Perry, Sabine Mueller, Steffen Albrecht, David Malkin, Richard G Grundy, and William D Foulkes.
• Department of Human Genetics, McGill University, Montreal, QC, Canada.
• Acta Neuropathol. 2014 Oct 1; 128 (4): 583-95.

AbstractGerm-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.

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