# Project 4: Prognostic Significance and Therapeutic Potential of DROSHA Mutations in Wilms Tumor

> **NIH NIH P50** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $321,044

## Abstract

Project Summary 
Wilms tumor is the most common pediatric kidney cancer and the 3rd most common solid tumor of childhood. 
Wilms tumor 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. Adverse late effects of chemotherapy 
are common and affect the quality of life of survivors. Better molecular knowledge of Wilms tumor is necessary 
to develop novel therapies that are more effective and less toxic. Known driver mutations (WT1, WTX, and 
CTNNB1) are identified in only one-third of Wilms tumors. Recently, we sequenced a large cohort of Wilms 
tumor specimens and identified recurrent, somatic heterozygous missense mutations in the enzyme DROSHA, 
which were mutually exclusive with known driver mutations in WT1 and CTNNB1. DROSHA is a ribonuclease 
that is essential for the first step in the biogenesis of microRNAs (miRNAs), small RNAs that play critical roles 
in the biology of cancer. Wilms tumor is the first human cancer in which DROSHA mutations have been 
identified. However, it is currently unknown how DROSHA mutations impact miRNA biogenesis and contribute 
to Wilms tumor pathogenesis. DROSHA mutations in Wilms tumors occur at or near conserved metal-binding 
residues in the ribonuclease (RNase) III domains, and impair miRNA processing. Importantly, we discovered 
that Wilms tumors with DROSHA mutations exhibit greatly reduced expression of a specific sub-class of 
miRNAs, including multiple members of the let-7 tumor suppressor miRNA family. let-7 miRNAs regulate 
several known oncogenes in Wilms tumors, including MCYN and LIN28, and therefore loss of expression of 
these miRNAs is likely to contribute to tumorigenesis in this setting. To establish the clinical significance of 
molecular subtype in Wilms tumors, we will correlate the presence of known and novel mutations with clinical 
outcome in a large collection of clinically-annotated Wilms tumor specimens. Our preliminary data suggest that 
heterozygous DROSHA mutations operate through a dominant-negative mechanism. We hypothesize that 
heterozygous DROSHA RNase III missense mutations drive tumorigenesis by impairing the biogenesis of a 
specific set of tumor suppressor miRNAs, reprogramming the miRNA expression program in the developing 
kidney to facilitate Wilms tumor development. We will test this hypothesis using state-of-the-art genomic editing 
techniques to recreate tumor-specific DROSHA mutations in Wilms tumor cells. We will identify and validate 
specific miRNAs whose dysregulated expression drives tumorigenesis. We will test a novel targeted 
therapeutic strategy using genetically-engineered cell lines and mouse models of Wilms tumor. Elucidation of 
these mechanisms will provide critical molecular insights into Wilms tumor and potentially reveal new 
therapeutic approaches based on miRNA delivery or pharmacologic modulation of downstream pathways.

## Key facts

- **NIH application ID:** 9990736
- **Project number:** 5P50CA196516-05
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** JAMES F AMATRUDA
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $321,044
- **Award type:** 5
- **Project period:** 2016-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990736

## Citation

> US National Institutes of Health, RePORTER application 9990736, Project 4: Prognostic Significance and Therapeutic Potential of DROSHA Mutations in Wilms Tumor (5P50CA196516-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9990736. Licensed CC0.

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