Multiplexed functional genomic analysis of 5' untranslated region mutations across the spectrum of prostate cancer.

Autor: Lim Y; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Arora S; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Schuster SL; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.; Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, USA., Corey L; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Fitzgibbon M; Genomics and Bioinformatics Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Wladyka CL; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Wu X; Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Coleman IM; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Delrow JJ; Genomics and Bioinformatics Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Corey E; Department of Urology, University of Washington, Seattle, WA, USA., True LD; Department of Urology, University of Washington, Seattle, WA, USA.; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA., Nelson PS; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.; Departments of Medicine and Genome Sciences, University of Washington, Seattle, WA, USA., Ha G; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Hsieh AC; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. ahsieh@fredhutch.org.; Departments of Medicine and Genome Sciences, University of Washington, Seattle, WA, USA. ahsieh@fredhutch.org.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Jul 09; Vol. 12 (1), pp. 4217. Date of Electronic Publication: 2021 Jul 09.
DOI: 10.1038/s41467-021-24445-6
Abstrakt: The functional consequences of genetic variants within 5' untranslated regions (UTRs) on a genome-wide scale are poorly understood in disease. Here we develop a high-throughput multi-layer functional genomics method called PLUMAGE (Pooled full-length UTR Multiplex Assay on Gene Expression) to quantify the molecular consequences of somatic 5' UTR mutations in human prostate cancer. We show that 5' UTR mutations can control transcript levels and mRNA translation rates through the creation of DNA binding elements or RNA-based cis-regulatory motifs. We discover that point mutations can simultaneously impact transcript and translation levels of the same gene. We provide evidence that functional 5' UTR mutations in the MAP kinase signaling pathway can upregulate pathway-specific gene expression and are associated with clinical outcomes. Our study reveals the diverse mechanisms by which the mutational landscape of 5' UTRs can co-opt gene expression and demonstrates that single nucleotide alterations within 5' UTRs are functional in cancer.
(© 2021. The Author(s).)
Databáze: MEDLINE
Externí odkaz: