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Moscovitz, Yana

University of British Columbia

DICER1 syndrome is a rare genetic disorder that predisposes individuals to hereditary cancers, with tumours arising in organs such as the lung, gynecologic tract, thyroid, kidney, and brain. This syndrome is driven by germline loss-of-function mutations in the DICER1 gene, typically inherited in an autosomal dominant manner. Tumours acquire somatic mutations affecting the RNase IIIb domain on the alternate allele, resulting in compound heterozygosity. These mutations impair DICER1's ability to cleave precursor miRNAs, disrupting microRNA biogenesis, an essential process for gene expression regulation. While the role of DICER1 mutations in tumour initiation is well-established, the mechanisms underlying tumour progression remain poorly understood. To address this gap, a genetically engineered mouse model harbouring a specific Dicer1 RNase IIIb mutation was developed. Tumours in this model displayed histological and molecular characteristics resembling those of human DICER1-associated cancers, including renal cystic nephroma, Wilms tumours, and anaplastic sarcoma of the kidney. Exome sequencing indicated that tumour progression may be influenced by accumulating secondary mutations, such as alterations in Trp53 and Kras. Syngeneic models and cell lines derived from these tumours were established, offering a robust platform to evaluate therapeutic strategies. This study demonstrates that the Dicer1 RNase IIIb mouse model faithfully recapitulates DICER1-associated tumourigenesis and progression. By enabling the investigation of tumour biology and therapeutic testing, this model provides a foundation for identifying targeted treatments for DICER1 syndrome-associated cancers.

Text

2025-04-28

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/90881

Medical Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/