title: Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers.
abstract: BACKGROUND
  Germline truncating mutations in DICER1, an endoribonuclease in the RNase III family that is essential for processing microRNAs, have been observed in families with the pleuropulmonary blastoma-family tumor and dysplasia syndrome. Mutation carriers are at risk for nonepithelial ovarian tumors, notably sex cord-stromal tumors.
  
  
  METHODS
  We sequenced the whole transcriptomes or exomes of 14 nonepithelial ovarian tumors and noted closely clustered mutations in the region of DICER1 encoding the RNase IIIb domain of DICER1 in four samples. We then sequenced this region of DICER1 in additional ovarian tumors and in certain other tumors and queried the effect of the mutations on the enzymatic activity of DICER1 using in vitro RNA cleavage assays.
  
  
  RESULTS
  DICER1 mutations in the RNase IIIb domain were found in 30 of 102 nonepithelial ovarian tumors (29%), predominantly in Sertoli-Leydig cell tumors (26 of 43, or 60%), including 4 tumors with additional germline DICER1 mutations. These mutations were restricted to codons encoding metal-binding sites within the RNase IIIb catalytic centers, which are critical for microRNA interaction and cleavage, and were somatic in all 16 samples in which germline DNA was available for testing. We also detected mutations in 1 of 14 nonseminomatous testicular germ-cell tumors, in 2 of 5 embryonal rhabdomyosarcomas, and in 1 of 266 epithelial ovarian and endometrial carcinomas. The mutant DICER1 proteins had reduced RNase IIIb activity but retained RNase IIIa activity.
  
  
  CONCLUSIONS
  Somatic missense mutations affecting the RNase IIIb domain of DICER1 are common in nonepithelial ovarian tumors. These mutations do not obliterate DICER1 function but alter it in specific cell types, a novel mechanism through which perturbation of microRNA processing may be oncogenic. (Funded by the Terry Fox Research Institute and others.).
authors.affiliation: British Columbia Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: Alireza
authors.initials: A
authors.lastname: Heravi-Moussavi
authors.forename: Michael S
authors.initials: MS
authors.lastname: Anglesio
authors.forename: S-W Grace
authors.initials: SW
authors.lastname: Cheng
authors.forename: Janine
authors.initials: J
authors.lastname: Senz
authors.forename: Winnie
authors.initials: W
authors.lastname: Yang
authors.forename: Leah
authors.initials: L
authors.lastname: Prentice
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Fejes
authors.forename: Christine
authors.initials: C
authors.lastname: Chow
authors.forename: Alicia
authors.initials: A
authors.lastname: Tone
authors.forename: Steve E
authors.initials: SE
authors.lastname: Kalloger
authors.forename: Nancy
authors.initials: N
authors.lastname: Hamel
authors.forename: Andrew
authors.initials: A
authors.lastname: Roth
authors.forename: Gavin
authors.initials: G
authors.lastname: Ha
authors.forename: Adrian N C
authors.initials: AN
authors.lastname: Wan
authors.forename: Sarah
authors.initials: S
authors.lastname: Maines-Bandiera
authors.forename: Clara
authors.initials: C
authors.lastname: Salamanca
authors.forename: Barbara
authors.initials: B
authors.lastname: Pasini
authors.forename: Blaise A
authors.initials: BA
authors.lastname: Clarke
authors.forename: Anna F
authors.initials: AF
authors.lastname: Lee
authors.forename: Cheng-Han
authors.initials: CH
authors.lastname: Lee
authors.forename: Chengquan
authors.initials: C
authors.lastname: Zhao
authors.forename: Robert H
authors.initials: RH
authors.lastname: Young
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Aparicio
authors.forename: Poul H B
authors.initials: PH
authors.lastname: Sorensen
authors.forename: Michelle M M
authors.initials: MM
authors.lastname: Woo
authors.forename: Niki
authors.initials: N
authors.lastname: Boyd
authors.forename: Steven J M
authors.initials: SJ
authors.lastname: Jones
authors.forename: Martin
authors.initials: M
authors.lastname: Hirst
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
authors.forename: Blake
authors.initials: B
authors.lastname: Gilks
authors.forename: Sohrab P
authors.initials: SP
authors.lastname: Shah
authors.forename: William D
authors.initials: WD
authors.lastname: Foulkes
authors.forename: Gregg B
authors.initials: GB
authors.lastname: Morin
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
mesh_terms: D002296:Carcinosarcoma / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D018095:Germ-Line Mutation; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D020125:Mutation, Missense; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics*; D012208:Rhabdomyosarcoma / Q000235:genetics; D043244:Ribonuclease III / Q000235:genetics*; D017422:Sequence Analysis, DNA; D018310:Sertoli-Leydig Cell Tumor / Q000235:genetics*
chemical_list: D035683:MicroRNAs; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases