Journal article
Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis through distinct mechanisms in Wilms tumours
Nature communications, Vol.2(1), pp.4802-4802
09/05/2014
DOI: 10.1038/ncomms5802
PMCID: PMC4159681
PMID: 25190313
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.
Details
- Title: Subtitle
- Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis through distinct mechanisms in Wilms tumours
- Creators
- Dinesh Rakheja - 1] Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA Division of Pathology and Laboratory Medicine, Children's Medical Center, Dallas, Texas 75235, USA Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAKenneth S Chen - 1] Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA Gill Center for Cancer and Blood Disorders, Children's Medical Center, Dallas, Texas 75235, USAYangjian Liu - 1] Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAAbhay A Shukla - 1] Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAVanessa Schmid - Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USATsung-Cheng Chang - Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAShama Khokhar - Division of Pathology and Laboratory Medicine, Children's Medical Center, Dallas, Texas 75235, USAJonathan E Wickiser - 1] Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA Gill Center for Cancer and Blood Disorders, Children's Medical Center, Dallas, Texas 75235, USANitin J Karandikar - Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAJames S Malter - Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAJoshua T Mendell - 1] Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAJames F Amatruda - 1] Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA Gill Center for Cancer and Blood Disorders, Children's Medical Center, Dallas, Texas 75235, USA Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.2(1), pp.4802-4802
- Publisher
- England
- DOI
- 10.1038/ncomms5802
- PMID
- 25190313
- PMCID
- PMC4159681
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Grant note
- R01 CA135731 / NCI NIH HHS R01 CA120185 / NCI NIH HHS P01 CA134292 / NCI NIH HHS T32 CA136515 / NCI NIH HHS
- Language
- English
- Date published
- 09/05/2014
- Academic Unit
- Pathology
- Record Identifier
- 9984046908302771
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