Pituitary blastoma: a pathognomonic feature of germ-line DICER1 mutations
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Individuals harboring germ-line DICER1 mutations are predisposed to a rare cancer syndrome, the DICER1 Syndrome or pleuropulmonary blastoma-familial tumor and dysplasia syndrome [online Mendelian inheritance in man (OMIM) #601200]. In addition, specific somatic mutations in the DICER1 RNase III catalytic domain have been identified in several DICER1-associated tumor types. Pituitary blastoma (PitB) was identified as a distinct entity in 2008, and is a very rare, potentially lethal early childhood tumor of the pituitary gland. Since the discovery by our team of an inherited mutation in DICER1 in a child with PitB in 2011, we have identified 12 additional PitB cases. We aimed to determine the contribution of germ-line and somatic DICER1 mutations to PitB. We hypothesized that PitB is a pathognomonic feature of a germ-line DICER1 mutation and that each PitB will harbor a second somatic mutation in DICER1. Lymphocyte or saliva DNA samples ascertained from ten infants with PitB were screened and nine were found to harbor a heterozygous germ-line DICER1 mutation. We identified additional DICER1 mutations in nine of ten tested PitB tumor samples, eight of which were confirmed to be somatic in origin. Seven of these mutations occurred within the RNase IIIb catalytic domain, a domain essential to the generation of 5p miRNAs from the 5′ arm of miRNA-precursors. Germ-line DICER1 mutations are a major contributor to PitB. Second somatic DICER1 “hits” occurring within the RNase IIIb domain also appear to be critical in PitB pathogenesis.
KeywordsDICER1 Pituitary blastoma miRNA Pediatric tumors
We thank the families involved in this research for their consent to participation and all the clinicians for referring cases and providing samples. We thank Dr. Benoît Lhermitte, Dr. Alistair Lammie, Dr. Cynthia Andoniadou, Dr. Helen Spoudeas, Dr. Oh-Lyong Kim, Dr. Andrew Peet, Dr. Angela Hübner, Dr. Walter Miller, Claudia Retamal-Muñoz, Dr. Bénédict Rilliet, Dr. Ty W. Abel and Dr. Duncan MacGregor for their assistance with ascertainment and analysis of their respective cases. We thank the MUGQIC staff for assisting Pierre Lepage with the Fluidigm Access Array and next-generation sequencing. This research was made possible thanks to the support of the Lady Davis Institute/TD Bank Studentship Award, CCSRI Innovative grant to Dr. William D. Foulkes and K12 CA 090625 to Dr. Adam Esbenshade.
Conflict of interest
The authors have no conflicts of interest to disclose.
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