Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis through distinct mechanisms in Wilms tumours

Nat Commun. 2014 Sep 5;2:4802. doi: 10.1038/ncomms5802.

Abstract

Wilms tumour is the most common childhood kidney cancer. Here we report the whole-exome sequencing of 44 Wilms tumours, identifying missense mutations in the microRNA (miRNA)-processing enzymes DROSHA and DICER1, and novel mutations in MYCN, SMARCA4 and ARID1A. Examination of tumour miRNA expression, in vitro processing assays and genomic editing in human cells demonstrates that DICER1 and DROSHA mutations influence miRNA processing through distinct mechanisms. DICER1 RNase IIIB mutations preferentially impair processing of miRNAs deriving from the 5'-arm of pre-miRNA hairpins, while DROSHA RNase IIIB mutations globally inhibit miRNA biogenesis through a dominant-negative mechanism. Both DROSHA and DICER1 mutations impair expression of tumour-suppressing miRNAs, including the let-7 family, important regulators of MYCN, LIN28 and other Wilms tumour oncogenes. These results provide new insights into the mechanisms through which mutations in miRNA biogenesis components reprogramme miRNA expression in human cancer and suggest that these defects define a distinct subclass of Wilms tumours.

MeSH terms

  • Child
  • Child, Preschool
  • Cohort Studies
  • DEAD-box RNA Helicases / genetics*
  • Female
  • HEK293 Cells
  • Humans
  • Infant
  • Kidney Neoplasms / genetics*
  • Male
  • MicroRNAs / metabolism*
  • Mutation, Missense
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ribonuclease III / genetics*
  • Sequence Analysis, DNA
  • Wilms Tumor / genetics*

Substances

  • MicroRNAs
  • DICER1 protein, human
  • DROSHA protein, human
  • Ribonuclease III
  • DEAD-box RNA Helicases

Associated data

  • GEO/GSE56955