Germ-line and somatic DICER1 mutations in pineoblastoma

L. De Kock, N. Sabbaghian, H.A. Druker, E. Weber, N.M. Hamel, S. Miller, C.S. Choong, Nicholas Gottardo, Ursula Kees, S.P. Rednam, L.P. Van Hest, M.C.J. Jongmans, S.N. Jhangiani, J.R. Lupski, M.R. Zacharin, D. Bouron-Dal Soglio, A. Huang, J.R. Priest, A. Perry, S. MuellerS.A. Albrecht, D.F. Malkin, R.G. Grundy, W.D. Foulkes

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120 Citations (Scopus)


© 2014, Springer-Verlag Berlin Heidelberg. 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.
Original languageEnglish
Pages (from-to)583-595
JournalActa Neuropathologica
Issue number4
Publication statusPublished - 2014


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