Multi-level functional genomics reveals molecular and cellular oncogenicity of patient-based 3' untranslated region mutations.

Autor:	Schuster SL; Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98195, USA; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Arora S; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Wladyka CL; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Itagi P; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Corey L; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Young D; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Stackhouse BL; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Kollath L; Department of Urology, University of Washington, Seattle, WA 98195, USA., Wu QV; Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Corey E; Department of Urology, University of Washington, Seattle, WA 98195, USA., True LD; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA., Ha G; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA., Paddison PJ; Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98195, USA; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Hsieh AC; Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98195, USA; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Department of Medicine, University of Washington, Seattle, WA 98195, USA. Electronic address: ahsieh@fredhutch.org.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2023 Aug 29; Vol. 42 (8), pp. 112840. Date of Electronic Publication: 2023 Jul 28.
DOI:	10.1016/j.celrep.2023.112840
Abstrakt:	3' untranslated region (3' UTR) somatic mutations represent a largely unexplored avenue of alternative oncogenic gene dysregulation. To determine the significance of 3' UTR mutations in disease, we identify 3' UTR somatic variants across 185 advanced prostate tumors, discovering 14,497 single-nucleotide mutations enriched in oncogenic pathways and 3' UTR regulatory elements. By developing two complementary massively parallel reporter assays, we measure how thousands of patient-based mutations affect mRNA translation and stability and identify hundreds of functional variants that allow us to define determinants of mutation significance. We demonstrate the clinical relevance of these mutations, observing that CRISPR-Cas9 endogenous editing of distinct variants increases cellular stress resistance and that patients harboring oncogenic 3' UTR mutations have a particularly poor prognosis. This work represents an expansive view of the extent to which disease-relevant 3' UTR mutations affect mRNA stability, translation, and cancer progression, uncovering principles of regulatory functionality and potential therapeutic targets in previously unexplored regulatory regions. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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