title: Recurrent somatic mutation in DROSHA induces microRNA profile changes in Wilms tumour.
abstract: Wilms tumour (WT) is an embryonal kidney neoplasia for which very few driver genes have been identified. Here we identify DROSHA mutations in 12% of WT samples (26/222) using whole-exome sequencing and targeted sequencing of 10 microRNA (miRNA)-processing genes. A recurrent mutation (E1147K) affecting a metal-binding residue of the RNase IIIb domain is detected in 81% of the DROSHA-mutated tumours. In addition, we identify non-recurrent mutations in other genes of this pathway (DGCR8, DICER1, XPO5 and TARBP2). By assessing the miRNA expression pattern of the DROSHA-E1147K-mutated tumours and cell lines expressing this mutation, we determine that this variant leads to a predominant downregulation of a subset of miRNAs. We confirm that the downregulation occurs exclusively in mature miRNAs and not in primary miRNA transcripts, suggesting that the DROSHA E1147K mutation affects processing of primary miRNAs. Our data underscore the pivotal role of the miRNA biogenesis pathway in WT tumorigenesis, particularly the major miRNA-processing gene DROSHA.
authors.affiliation: 1] Genomics and Molecular Biology Laboratory, International Research Center, A. C. Camargo Cancer Center, São Paulo, S.P., 01508-010, Brazil [2].
authors.forename: Giovana T
authors.initials: GT
authors.lastname: Torrezan
authors.affiliation: 1] Genomics and Molecular Biology Laboratory, International Research Center, A. C. Camargo Cancer Center, São Paulo, S.P., 01508-010, Brazil [2].
authors.forename: Elisa N
authors.initials: EN
authors.lastname: Ferreira
authors.affiliation: Genomics and Molecular Biology Laboratory, International Research Center, A. C. Camargo Cancer Center, São Paulo, S.P., 01508-010, Brazil.
authors.forename: Adriana M
authors.initials: AM
authors.lastname: Nakahata
authors.affiliation: Genomics and Molecular Biology Laboratory, International Research Center, A. C. Camargo Cancer Center, São Paulo, S.P., 01508-010, Brazil.
authors.forename: Bruna D F
authors.initials: BD
authors.lastname: Barros
authors.affiliation: Genomics and Molecular Biology Laboratory, International Research Center, A. C. Camargo Cancer Center, São Paulo, S.P., 01508-010, Brazil.
authors.forename: Mayra T M
authors.initials: MT
authors.lastname: Castro
authors.affiliation: Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, S.P., 01308-060, Brazil.
authors.forename: Bruna R
authors.initials: BR
authors.lastname: Correa
authors.affiliation: Genomics and Molecular Biology Laboratory, International Research Center, A. C. Camargo Cancer Center, São Paulo, S.P., 01508-010, Brazil.
authors.forename: Ana C V
authors.initials: AC
authors.lastname: Krepischi
authors.affiliation: Genomics and Molecular Biology Laboratory, International Research Center, A. C. Camargo Cancer Center, São Paulo, S.P., 01508-010, Brazil.
authors.forename: Eloisa H R
authors.initials: EH
authors.lastname: Olivieri
authors.affiliation: Department of Pathology, A. C. Camargo Cancer Center, São Paulo, S.P., 01509-900, Brazil.
authors.forename: Isabela W
authors.initials: IW
authors.lastname: Cunha
authors.affiliation: Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Uri
authors.initials: U
authors.lastname: Tabori
authors.affiliation: Cancer Control Alberta, Alberta Health Services, Edmonton, Alberta, Canada AB T5J 3H1.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Grundy
authors.affiliation: Department of Pediatrics, A. C. Camargo Cancer Center, São Paulo, S.P., 01509-010, Brazil.
authors.forename: Cecilia M L
authors.initials: CM
authors.lastname: Costa
authors.affiliation: Pediatric Hematology-Oncology Research Program, Instituto Nacional de Cancer, INCA, Rio de Janeiro, R.J., 20231-050, Brazil.
authors.forename: Beatriz
authors.initials: B
authors.lastname: de Camargo
authors.affiliation: Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, S.P., 01308-060, Brazil.
authors.forename: Pedro A F
authors.initials: PA
authors.lastname: Galante
authors.affiliation: Genomics and Molecular Biology Laboratory, International Research Center, A. C. Camargo Cancer Center, São Paulo, S.P., 01508-010, Brazil.
authors.forename: Dirce M
authors.initials: DM
authors.lastname: Carraro
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D043244:Ribonuclease III / Q000737:chemistry / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D009396:Wilms Tumor / Q000235:genetics*
chemical_list: D035683:MicroRNAs; C517918:DROSHA protein, human; D043244:Ribonuclease III