Abstract 2504: Next generation sequencing identifies novel potential biomarkers for DICER1 syndrome

Abstract

Abstract MicroRNAs (miRNAs) are small RNA molecules that play a critical role in regulating gene expression. The DICER1 enzyme is a key component of the microRNA biogenesis pathway. Reflecting this central role, patients who inherit or acquire mutations in the DICER1 gene have an increased risk of developing a spectrum of benign and malignant tumors —thereby earning the recognition as a pediatric cancer predisposition syndrome known as DICER1 syndrome (OMIM 601200). DICER1 syndrome is definitively diagnosed by DNA sequencing demonstrating presence of a loss of function mutation on one copy of DICER1 plus a “hotspot” mutation on the other copy of DICER1. As tumor and germline DNA sequencing can pose logistical and/or cost difficulties, a complementary diagnostic method based on marker expression is valuable for both diagnostics and surveillance. Biomarkers that are candidate therapeutic targets are also appealing as these may offer a more tailored approach for therapy. As there are no approved biomarkers for identification of DICER1-associated tumors, we performed RNAseq and miRNAseq in an engineered murine mesenchymal cell model that incorporates a specific DICER1 hotspot mutation to identify candidates. We validated candidate biomarkers at the RNA (Eya2, Vipr1, miR-139-3p, and miR-30d-3p) and protein (Eya2, and Vipr1) levels in vitro, to provide proof of principle data for their eventual clinical utility. The miRNA candidate biomarkers levels were evaluated in both total and small extracellular vesicle-enriched fractions. These novel data pave the way for additional tools for diagnosis and surveillance in patients with DICER1 syndrome. Citation Format: Mona K. Wu, Raphael D. Lopez, Mikako Warren, Rachana Shah, Paolo Neviani, James F. Amatruda. Next generation sequencing identifies novel potential biomarkers for DICER1 syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2504.