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

Yiting Lim, Sonali Arora, Samantha L. Schuster, Lukas Corey, Matthew Fitzgibbon, Cynthia L. Wladyka, Xiaoying Wu, Ilsa M. Coleman, Jeffrey J. Delrow, Eva Corey, Lawrence D. True, Peter S. Nelson, Gavin Ha and Andrew C. Hsieh ()
Additional contact information
Yiting Lim: Fred Hutchinson Cancer Research Center
Sonali Arora: Fred Hutchinson Cancer Research Center
Samantha L. Schuster: Fred Hutchinson Cancer Research Center
Lukas Corey: Fred Hutchinson Cancer Research Center
Matthew Fitzgibbon: Fred Hutchinson Cancer Research Center
Cynthia L. Wladyka: Fred Hutchinson Cancer Research Center
Xiaoying Wu: Fred Hutchinson Cancer Research Center
Ilsa M. Coleman: Fred Hutchinson Cancer Research Center
Jeffrey J. Delrow: Fred Hutchinson Cancer Research Center
Eva Corey: University of Washington
Lawrence D. True: University of Washington
Peter S. Nelson: Fred Hutchinson Cancer Research Center
Gavin Ha: Fred Hutchinson Cancer Research Center
Andrew C. Hsieh: Fred Hutchinson Cancer Research Center

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-24445-6

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