Multiplexed functional genomic analysis of 5' untranslated region mutations across the spectrum of prostate cancer.
Yiting LimSonali AroraSamantha L SchusterLukas CoreyMatthew FitzgibbonCynthia L WladykaXiaoying WuIlsa M ColemanJeffrey J DelrowEva CoreyLawrence D TruePeter S NelsonGavin HaAndrew C HsiehPublished in: Nature communications (2021)
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.
Keyphrases
- gene expression
- prostate cancer
- high throughput
- dna methylation
- genome wide
- single cell
- dna binding
- signaling pathway
- endothelial cells
- radical prostatectomy
- copy number
- pi k akt
- clinical trial
- study protocol
- cell proliferation
- endoplasmic reticulum stress
- papillary thyroid
- induced pluripotent stem cells
- squamous cell