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

Author

Listed:
  • Giovana T. Torrezan

    (Genomics and Molecular Biology Laboratory, International Research Center, A. C. Camargo Cancer Center)

  • Elisa N. Ferreira

    (Genomics and Molecular Biology Laboratory, International Research Center, A. C. Camargo Cancer Center)

  • Adriana M. Nakahata

    (Genomics and Molecular Biology Laboratory, International Research Center, A. C. Camargo Cancer Center)

  • Bruna D. F. Barros

    (Genomics and Molecular Biology Laboratory, International Research Center, A. C. Camargo Cancer Center)

  • Mayra T. M. Castro

    (Genomics and Molecular Biology Laboratory, International Research Center, A. C. Camargo Cancer Center)

  • Bruna R. Correa

    (Centro de Oncologia Molecular, Hospital Sírio-Libanês)

  • Ana C. V. Krepischi

    (Genomics and Molecular Biology Laboratory, International Research Center, A. C. Camargo Cancer Center)

  • Eloisa H. R. Olivieri

    (Genomics and Molecular Biology Laboratory, International Research Center, A. C. Camargo Cancer Center)

  • Isabela W. Cunha

    (A. C. Camargo Cancer Center)

  • Uri Tabori

    (The Hospital for Sick Children)

  • Paul E. Grundy

    (Cancer Control Alberta, Alberta Health Services, Edmonton)

  • Cecilia M. L. Costa

    (A. C. Camargo Cancer Center)

  • Beatriz de Camargo

    (Pediatric Hematology-Oncology Research Program, Instituto Nacional de Cancer, INCA)

  • Pedro A. F. Galante

    (Centro de Oncologia Molecular, Hospital Sírio-Libanês)

  • Dirce M. Carraro

    (Genomics and Molecular Biology Laboratory, International Research Center, A. C. Camargo Cancer Center)

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.

Suggested Citation

  • Giovana T. Torrezan & Elisa N. Ferreira & Adriana M. Nakahata & Bruna D. F. Barros & Mayra T. M. Castro & Bruna R. Correa & Ana C. V. Krepischi & Eloisa H. R. Olivieri & Isabela W. Cunha & Uri Tabori , 2014. "Recurrent somatic mutation in DROSHA induces microRNA profile changes in Wilms tumour," Nature Communications, Nature, vol. 5(1), pages 1-10, September.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5039
    DOI: 10.1038/ncomms5039
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