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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE149489 | GEO | 2021/05/17

REPOSITORIES: GEO

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

Project description: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.

| S-EPMC8270899 | biostudies-literature

Multiplexed functional genomic analysis of somatic 5' untranslated region mutations across the spectrum of human prostate cancer (PLUMAGE)

Project description:The functional consequences of cancer patient-derived genetic variants within the 5’ untranslated regions (UTRs) on a genome-wide scale and their effects on mRNA transcript and translation levels are poorly understood. To systematically interrogate the mutational landscape of 5’ UTRs across cancer patients with localized to metastatic disease, we analyzed the genomes of 226 prostate cancer patients and observed thousands of mutations, many of which impact known cis-regulatory elements. We developed a high-throughput multi-layer massively parallel sequencing-based method called PLUMAGE (Pooled full-length UTR Multiplex Assay on Gene Expression) to simultaneously quantify the effects of 545 5’ UTR somatic mutations across recurrently mutated or cancer-related genes from our patient cohort. Our method enabled unprecedented insights into how 5’ UTR mutations can control multiple levels of gene expression simultaneously. In particular, we identified 190 mutations that significantly altered 5’ UTR function, either by creating new DNA binding elements, disrupting known translation regulatory motifs, or simultaneously impacting both transcript levels and mRNA translation. Furthermore, we also determined that 5’ UTR mutations to the MAP kinase signaling pathway are significantly associated with early metastasis. This study is the first to comprehensively interrogate the functional 5’ UTR mutational landscape of a human cancer revealing the importance of untranslated regions in regulating multiple levels of oncogenic gene expression and provides a high-throughput functional genomics solution applicable to many genetically driven diseases.

2021-05-17 | GSE149487 | GEO

Multiplexed functional genomic analysis of somatic 5' untranslated region mutations across the spectrum of human prostate cancer (RNASeq)

Project description:The functional consequences of genetic variants within 5’ untranslated regions (UTRs) on a genome-wide scale are poorly understood in disease. We developed a high-throughput multi-layer massively parallel sequencing-based method called PLUMAGE (Pooled full-length UTR Multiplex Assay on Gene Expression) to quantify the molecular consequences of somatic 5’ UTR mutations found across 229 prostate cancer patients with localized to metastatic disease. We show that 5’ UTR mutations can control both transcript levels and mRNA translation rates through the creation of new DNA binding elements or RNA-based cis-regulatory motifs. We also discover that single point mutations can simultaneously impact both transcript levels and mRNA translation of the same gene. Using gene editing technology, we validate that a single point mutation in the oncogenic CKS2 5’ UTR can increase mRNA specific translation. Turning to a molecular pathway critical for cancer, we provide evidence that functional 5’ UTR mutations in the MAP kinase signaling pathway can upregulate pathway-specific gene expression and are associated with distinct clinical outcomes. Our study reveals the diverse mechanisms by which the mutational landscape of 5’ UTRs can co-opt multiple levels of gene expression and demonstrates that single nucleotide alternations within leader sequences are functional in cancer.

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Multiplexed functional genomic analysis of somatic 5' untranslated region mutations across the spectrum of human prostate cancer (Ribosome Profiling)

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Multiplexed functional genomic analysis of somatic 5’ untranslated region mutations across the spectrum of human prostate cancer (Exome-Seq)

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

Project description:Multiplexed functional genomic analysis of somatic 5’ untranslated region mutations across the spectrum of human prostate cancer

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Multiplexed functional genomic analysis of somatic 5' untranslated region mutations across the spectrum of human prostate cancer (RNASeq)

Project description:Multiplexed functional genomic analysis of somatic 5' untranslated region mutations across the spectrum of human prostate cancer (RNASeq)

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Multiplexed functional genomic analysis of somatic 5' untranslated region mutations across the spectrum of human prostate cancer (PLUMAGE)

Project description:Multiplexed functional genomic analysis of somatic 5' untranslated region mutations across the spectrum of human prostate cancer (PLUMAGE)

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Multiplexed functional genomic analysis of somatic 5’ untranslated region mutations across the spectrum of human prostate cancer (Exome-Seq)

Project description:Multiplexed functional genomic analysis of somatic 5’ untranslated region mutations across the spectrum of human prostate cancer (Exome-Seq)

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Multiplexed functional genomic analysis of somatic 5' untranslated region mutations across the spectrum of human prostate cancer (Ribosome Profiling)

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