Germ-line and somatic DICER1 mutations in pineoblastoma

• Published in: Acta neuropathologica 2014-10, Vol.128 (4), p.583-595
• Main Authors: de Kock, Leanne, Sabbaghian, Nelly, Druker, Harriet, Weber, Evan, Hamel, Nancy, Miller, Suzanne, Choong, Catherine S., Gottardo, Nicholas G., Kees, Ursula R., Rednam, Surya P., van Hest, Liselotte P., Jongmans, Marjolijn C., Jhangiani, Shalini, Lupski, James R., Zacharin, Margaret, Bouron-Dal Soglio, Dorothée, Huang, Annie, Priest, John R., Perry, Arie, Mueller, Sabine, Albrecht, Steffen, Malkin, David, Grundy, Richard G., Foulkes, William D.
• Format: Article
• Language: English
• Subjects: Adolescent; Brain Neoplasms - genetics; Cancer research; Cancer therapies; Child; Child, Preschool; Children & youth; DEAD-box RNA Helicases - genetics; Diabetes; DNA Mutational Analysis; Endocrine system; Endocrinology; Families & family life; Family Health; Family medical history; Female; Genetics; Germ-Line Mutation - genetics; Hematology; Hospitals; Humans; Infant; Leukemia; Male; Medical research; Medicine; Medicine & Public Health; Mutation; Neurosciences; Oncology; Original Paper; Pathology; Pediatrics; Pineal Gland - pathology; Pinealoma - genetics; Ribonuclease III - genetics; Tumors; Young Adult
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-014-1318-7

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.