Abstract LB-204: Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis in Wilms tumors

Abstract

Abstract Wilms tumor is the most common pediatric kidney cancer and the fourth most common childhood cancer overall. It is treated with a combination of surgery, chemotherapy, and radiation, and, while most children are cured, survival remains poor in those with advanced-stage disease. Known driver mutations (in WT1, WTX, and CTNNB1) account for only one-third of Wilms tumor cases. To better define the genomic landscape of Wilms tumor, we performed whole-exome sequencing of 44 Wilms tumors. We also sequenced matched germline DNA by whole-exome sequencing (15 cases) or targeted Sanger sequencing of candidate mutations (29 cases) to identify somatic mutations. Through this approach, we identified recurrent somatic mutations in MYCN, DROSHA, and DICER1 which were mutually exclusive with known Wilms tumor mutations in WT1 and CTNNB1. The ribonucleases DROSHA and DICER1 perform two key steps in the biogenesis of microRNAs (miRNAs), which are ∼22-nt non-coding RNAs that regulate the stability and translation of target mRNAs. DROSHA and DICER1 mutations occurred at or near conserved metal-binding residues in their ribonuclease (RNase) IIIB domains. In vitro processing assays modeling these mutations showed that they partially or completely disrupt the ribonuclease activity of DROSHA and DICER1. In addition, next-generation sequencing of small RNAs in these tumors revealed that the DICER1 mutations preferentially impaired processing of miRNAs derived from the 5′ arm of pre-miRNA hairpins, including the let-7 tumor suppressor miRNA family. Although DROSHA-mutant tumors did not exhibit skewed expression of 5′ vs. 3′-derived miRNAs, expression of let-7 and other putative tumor suppressor miRNAs was reduced in these tumors as well. While germline and somatic mutations in DICER1 have been reported in some cancers, this is the first report of recurrent DROSHA mutations in any human tumor type. Moreover, these results suggest that impairment of miRNA processing by somatic mutation of DROSHA and DICER1 defines a novel subclass of Wilms tumor. Citation Format: Dinesh Rakheja, Kenneth S. Chen, Yangjian Liu, Tsung-Cheng Chang, Abhay A. Shukla, James Malter, Joshua T. Mendell, James F. Amatruda. Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis in Wilms tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-204. doi:10.1158/1538-7445.AM2014-LB-204