Genomic correlates of outcome in pleuropulmonary blastoma

The National Cancer Institute awarded The University of Texas Southwestern Medical Center $1,041,962 on September 12, 2025, under the Cancer Cause and Prevention Research program (CFDA 93.393) to conduct genomic and functional research on DICER1 variants in pleuropulmonary blastoma, the most common pediatric lung cancer.

The research examines clinical and functional impacts of DICER1 hotspot variants across three specific aims: validating prognostic significance by correlating hotspot variants with clinical outcome and patient-derived xenograft engraftment; testing whether different variants have distinct effects on 5P microRNA production through tumor analysis and cell-based modeling; and evaluating therapeutic strategies targeting oncogenic DICER1 variants. PPB typically exhibits a loss-of-function variant on one DICER1 allele and a missense variant on the second allele at one of five hotspot positions. Preliminary data suggest these hotspots differ in clinical prognosis, PDX engraftment capability, and 5P microRNA expression, with severe impairment of 5P micrornas leading to elevated expression of genes targeted by these micrornas, including MYC.

Work is performed in Dallas, Texas, with a period of performance through August 31, 2030. Children's Health Care (doing business as Children's Minnesota) serves as a sub-recipient, with Dr. Schultz overseeing patient enrollment and clinical data and biospecimen collection from treating institutions, Ms. Harris managing IRB regulatory practices and grant administration, Mr. Deonovic facilitating study design and analyses, Ms. Mallinger overseeing patient enrollment and biospecimen procurement, and Ms. Abraham coordinating participant consent and clinical data abstraction. The sub-award was dated January 9, 2026.

Abstract

Pleuropulmonary blastoma (PPB) is the most common pediatric lung cancer in children and one of the sentinel manifestations of DICER1-related tumor predisposition. While some patients with PPB may be treated with surgery alone, children with advanced PPB require an intense combination of surgery, chemotherapy and often radiation. Unresectable or recurrent disease is associated with a poor prognosis. Currently, there are no molecular factors sufficiently predictive to allow risk stratification in advanced PPB and no ways to rationally target oncogenic DICER1 variants. The DICER1 enzyme normally produces mature micrornas by cleaving the two arms of a pre-microrna hairpin, and ppbs typically exhibit a loss-of-function variant on one DICER1 allele and a missense variant on the second allele, predominantly affecting one of five specific "hotspot" positions. These hotspot variants in DICER1 impair cleavage of micrornas derived from the 5P arms of pre-microrna hairpins ("5P micrornas") but allow cleavage of 3P micrornas. Although these hotspots have previously been thought of as interchangeable, our analysis suggests that hotspot variants differ in clinical prognosis, ability to engraft as patient-derived xenografts (PDXS), and expression of 5P micrornas. More severe impairment of 5P micrornas leads to higher levels of genes targeted by 5P micrornas, including MYC. Thus, here we will examine the clinical and functional impact of DICER1 variants in PPB with the following specific aims: aim 1. To validate the prognostic significance of DICER1 variants in PPB, we will correlate hotspot with clinical outcome and PDX engraftment in a larger set of tumors. Aim 2. To test whether DICER1 variants have different effects on 5P microrna production, we will analyze more tumors, and we will model hotspot variants in cell-free assays and in cell lines. Aim 3. To evaluate therapeutic strategies for targeting MYC in PPB, we will test silencing and inhibition of MYC cofactors in PPB cell lines and xenografts. The overall goal of our research program is to improve outcomes for patients with PPB and other DICER1-related cancers. If successful, this project could advance molecular risk stratification in PPB and identify novel therapeutic approaches to target these tumors.