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

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

Author information

1
1] Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [3] Division of Pathology and Laboratory Medicine, Children's Medical Center, Dallas, Texas 75235, USA [4] Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [5].
2
1] Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [3] Gill Center for Cancer and Blood Disorders, Children's Medical Center, Dallas, Texas 75235, USA [4].
3
1] Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2].
4
1] Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
5
Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
6
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
7
Division of Pathology and Laboratory Medicine, Children's Medical Center, Dallas, Texas 75235, USA.
8
1] Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Gill Center for Cancer and Blood Disorders, Children's Medical Center, Dallas, Texas 75235, USA.
9
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
10
1] Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
11
1] Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [3] Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [4] Gill Center for Cancer and Blood Disorders, Children's Medical Center, Dallas, Texas 75235, USA [5] Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.

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.

PMID:
25190313
PMCID:
PMC4159681
DOI:
10.1038/ncomms5802
[Indexed for MEDLINE]
Free PMC Article

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