Recurrent somatic mutation in DROSHA induces microRNA profile changes in Wilms tumour

Author(s):Show less -

Torrezan, Giovana T. ^[1] ; Ferreira, Elisa N. ^[1] ; Nakahata, Adriana M. ^[1] ; Barros, Bruna D. F. ^[1] ; Castro, Mayra T. M. ^[1] ; Correa, Bruna R. ^[2] ; Krepischi, Ana C. V. ^[1] ; Olivieri, Eloisa H. R. ^[1] ; Cunha, Isabela W. ^[3] ; Tabori, Uri ^[4] ; Grundy, Paul E. ^[5] ; Costa, Cecilia M. L. ^[6] ; de Camargo, Beatriz ^[7] ; Galante, Pedro A. F. ^[2] ; Carraro, Dirce M. ^[1]

Affiliation

^[1] AC Camargo Canc Ctr, Int Res Ctr, Genom & Mol Biol Lab, BR-01508010 Sao Paulo - Brazil

^[2] Hosp Sirio Libanes, Ctr Mol Oncol, BR-01308060 Sao Paulo - Brazil

^[3] AC Camargo Canc Ctr, Dept Pathol, BR-01509900 Sao Paulo - Brazil

^[4] Hosp Sick Children, Dept Pediat, Toronto, ON M5G 1X8 - Canada

^[5] Alberta Hlth Serv, Canc Control Alberta, Edmonton, AB T5J 3H1 - Canada

^[6] AC Camargo Canc Ctr, Dept Pediat, BR-01509010 Sao Paulo - Brazil

^[7] INCA, Inst Nacl Canc, Pediat Hematol Oncol Res Program, BR-20231050 Rio De Janeiro, RJ - Brazil

• Document type: Journal article
• Source: NATURE COMMUNICATIONS; v. 5, JUN 2014.
• Web of Science Citations: 71

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. (AU)

• FAPESP's process: 10/00223-1 - Genes of signaling pathways involved in the recapitulation of nephrogenesis by Wilms tumor: definition of the mutation spectrum and characterization of regulatory and functional aspects
• Grantee: Dirce Maria Carraro
• Support Opportunities: Regular Research Grants
• FAPESP's process: 06/00054-0 - Gene expression analysis of kidney and liver development stages and their implications in embryonic tumors
• Grantee: Dirce Maria Carraro
• Support Opportunities: Regular Research Grants