Germ-line and somatic DICER1 mutations in pineoblastoma

• DOI: 10.1007/s00401-014-1318-7
• Publication Date: 2014-07-14T10:03:23Z
• Authors: 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 ...; Marjolijn C. Jong...; Shalini Jhangiani; James R. Lupski; Margaret Zacharin; Dorothée Bouron-D...; Annie Huang; John R. Priest; Arie Perry; Sabine Mueller; Steffen Albrecht; David Malkin; Richard G. Grundy; William D. Foulkes
• Keywords: Male; Ribonuclease III; Adolescent; Clinical Sciences; DNA Mutational Analysis; DICER1; Pineal Gland; DEAD-box RNA Helicases; Young Adult; 03 medical and health sciences; 616; Genetics; 2.1 Biological and endogenous factors; Humans; Genetic Testing; Aetiology; Preschool; Pineoblastoma; OMIM #601200; Child; Germ-Line Mutation; Cancer; Family Health; 0303 health sciences; Neurology & Neurosurgery; Biomedical and Clinical Sciences; Brain Neoplasms; Human Genome; Neurosciences; Pineal gland; Infant; 3. Good health; miRNA processing; Child, Preschool; Mutation; Paediatric brain tumours; Female; Childhood cancer; Pinealoma

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.