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Massively parallel screen uncovers many rare 3’ UTR variants regulating mRNA abundance of cancer driver genes [prime_editing_3utr]

ABSTRACT: Understanding the function of rare non-coding genetic variants represents a significant challenge. Here, we developed MapUTR, a screen to identify rare 3’ UTR variants affecting mRNA abundance post-transcriptionally. Among 17,301 rare variants, an average of 24.5% were functional, with 70% in cancer-related genes, many in critical cancer pathways. This observation motivated a further interrogation of 11,929 cancer somatic mutations, uncovering 3,928 (33%) functional mutations in well-established cancer driver genes, such as CDKN2A. Functional MapUTR variants were enriched in miRNA targets and protein-RNA interaction sites. Based on MapUTR, we define a new metric, untranslated tumor mutation burden (uTMB), reflecting the amount of somatic functional MapUTR variants of a tumor. We showed the potential of uTMB in predicting patient survival. Through prime editing, we characterized three variants in cancer-relevant genes (MFN2, FOSL2, and IRAK1), illustrating their cancer-driving potential. Our study elucidates the function of thousands of non-coding variants, nominates non-coding cancer driver mutations, and demonstrates their potential contributions to cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE232570 | GEO | 2024/02/06

REPOSITORIES: GEO

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Massively parallel screen uncovers many rare 3’ UTR variants regulating mRNA abundance of cancer driver genes [rare_cosmic]

Project description:Understanding the function of rare non-coding genetic variants represents a significant challenge. Here, we developed MapUTR, a screen to identify rare 3’ UTR variants affecting mRNA abundance post-transcriptionally. Among 17,301 rare variants, an average of 24.5% were functional, with 70% in cancer-related genes, many in critical cancer pathways. This observation motivated a further interrogation of 11,929 cancer somatic mutations, uncovering 3,928 (33%) functional mutations in well-established cancer driver genes, such as CDKN2A. Functional MapUTR variants were enriched in miRNA targets and protein-RNA interaction sites. Based on MapUTR, we define a new metric, untranslated tumor mutation burden (uTMB), reflecting the amount of somatic functional MapUTR variants of a tumor. We showed the potential of uTMB in predicting patient survival. Through prime editing, we characterized three variants in cancer-relevant genes (MFN2, FOSL2, and IRAK1), illustrating their cancer-driving potential. Our study elucidates the function of thousands of non-coding variants, nominates non-coding cancer driver mutations, and demonstrates their potential contributions to cancer.

2024-02-06 | GSE232572 | GEO

Massively parallel screen uncovers many rare 3’ UTR variants regulating mRNA abundance of cancer driver genes [rare_3utr_gnomad.motif_activity]

2024-02-06 | GSE232571 | GEO

Tumour mutations in long noncoding RNAs enhance cell fitness

Project description:Tumour DNA contains thousands of somatic single nucleotide variants (SNVs) in non-protein-coding elements, yet their functional significance remains poorly understood. Amongst the most highly mutated elements are long noncoding RNAs (lncRNAs), functional transcripts with known roles in carcinogenesis. To search for driver mutations in lncRNAs, we apply an integrative driver discovery algorithm to SNVs from 2583 primary tumours and 3527 metastases to reveal 54 potential “driver lncRNAs”. Our algorithm confirms a particularly high mutation rate in the iconic cancer lncRNA, NEAT1, which has been ascribed by recent studies to passenger effects. We directly test the functionality of NEAT1 SNVs using in cellulo mutagenesis, identifying discrete regions where mutations reproducibly increase cell proliferation in diverse cell backgrounds, both cancerous and normal. In particular, mutations in the 5’ region alter ribonucleoprotein assembly and boost the population of subnuclear paraspeckles, thus mechanistically linking mutations to cellular proliferation. We then used RNA-pull down followed by mass spectrometry to identify the protein interactor changing between the wild type and mutant form of NEAT1.

2023-07-20 | PXD034007 | Pride

Phosphoproteomics of truncated FGFR2, a clinically actionable oncogene in multiple cancers

Project description:Somatic hotspot mutations and structural amplifications and fusions affecting fibroblast growth factor receptor 2 (FGFR2) occur in multiple cancer types. However, clinical responses to FGFR inhibitors (FGFRi) have remained variable, emphasizing a need to better understand which FGFR2 alterations are oncogenic and targetable. Here we applied transposon-based screening and tumor modelling in mice to uncover truncation of exon (E) 18 of Fgfr2 as a potent driver mutation. Human oncogenomic datasets revealed a diverse set of FGFR2 alterations, including rearrangements (REs), E1-E17 partial amplifications, and E18 nonsense and frameshift mutations, each causing transcription of E18-truncated FGFR2 (FGFR2deltaE18). Somatic modelling in mice and human tumor cell lines using a compendium of FGFR2deltaE18 and full-length variants identified FGFR2deltaE18-truncation as potent single-driver alteration in cancer. Here we show the phosphoproteomic landscape of FGFR2 variants in murine epithelial cell (MEC) lines and mouse tumors. Global (STY) phosphoproteomics using IMAC and phosphotyrosine phosphoproteomics using pTyr IP’s are combined with DIA protein expression data to uncover oncogenic signaling of clinically-relevant FGFR2 variants.

2022-06-06 | PXD031711 | Pride

Widespread perturbation of ETS factor binding sites in cancer [CASCADE_HOOK_SIGGERS_v3]

Project description:Although >90% of somatic mutations reside in non-coding regions, few have been reported as cancer drivers. To predict driver non-coding variants (NCVs), we present a novel transcription factor (TF)-aware burden test (TFA-BT) based on a model of coherent TF function in promoters. We applied our TFA-BT to NCVs from the Pan-Cancer Analysis of Whole Genomes cohort and predicted 2,555 driver NCVs in the promoters of 813 genes across 20 cancer-types. These genes are enriched in cancer-related gene ontologies, essential genes, and genes associated with cancer prognosis. We found that 765 candidate driver NCVs alter transcriptional activity, 510 lead to differential binding of TF-cofactor regulatory complexes, and that they primarily impact the binding of ETS factors. Finally, we show that different NCVs within a promoter often affect transcriptional activity through shared mechanisms. Our integrated computational and experimental approach shows that cancer NCVs are widespread and that ETS factors are commonly disrupted.

2023-01-09 | GSE222435 | GEO

Widespread perturbation of ETS factor binding sites in cancer [SCREEN_HOOK_SIGGERS_v2]

2023-01-09 | GSE222434 | GEO

Widespread perturbation of ETS factor binding sites in cancer

2023-01-10 | GSE218478 | GEO

Cistrome-partitioning reveals convergence of somatic mutations and risk-variants on master transcription regulators in primary prostate tumors

Project description:Thousands of noncoding somatic Single Nucleotide Variants (SNVs) of unknown function are reported in tumors. Partitioning the genome according to cistromes, reveals the enrichment of somatic SNVs in prostate tumors as opposed to adjacent normal tissue cistromes of master transcription regulators, including AR, FOXA1 and HOXB13. This parallels enrichment of prostate cancer genetic predispositions over these transcription regulators’ tumor cistromes, exemplified at the 8q24 locus harboring both risk-variants and somatic SNVs in cis-regulatory elements, upregulating MYC expression and altering the binding of transcription regulators to DNA. However, Massively-Parallel Reporter Assays reveal that few SNVs can alter the transactivation potential of individual CREs. Instead, SNVs accumulate, similarly to inherited riskvariants, in cistromes of master transcription regulators required for prostate cancer development. Significance Difficulties in inferring the biological significance of noncoding mutations have limited their inclusion in precision genomics medicine pipelines. Most attempts to delineate a role for noncoding mutations relied on detecting evidence for positive selection within individual CREs, such as reported for the TERT gene promoter. By considering the enrichment of noncoding mutations in cistromes as opposed to individual CREs, we reveal their specificity towards master transcription regulators that promote prostate cancer development, a feature shared with inherited risk-variants. Overall, our work provides a blueprint for the functional interpretation of noncoding mutations in genomic tests relying on defining cis-regulatory units according to cistrome-partitioning to identify cancer driver transcription regulators.

2019-12-01 | GSE137527 | GEO

The origins and consequences of UPF1 variants in pancreatic adenosquamous carcinoma

Project description:Pancreatic adenosquamous carcinoma (PASC) is an aggressive cancer whose mutational origins are poorly understood. An early study reported high-frequency somatic mutations affecting UPF1, a core nonsense-mediated mRNA decay (NMD) factor, in PASC, but subsequent studies did not observe these lesions. The corresponding controversy about whether UPF1 mutations are important contributors to PASC has been exacerbated by a paucity of functional studies. Here, we modeled two UPF1 mutations to find no significant effects on pancreatic cancer growth, acquisition of adenosquamous features, UPF1 splicing, UPF1 protein levels, or NMD efficiency. We subsequently discovered that ~40% of UPF1 mutations reportedly present in PASCs are identical to standing genetic variants in the human population, suggesting that they may be non-pathogenic inherited variants rather than pathogenic mutations. Our data suggest that UPF1 is not a common functional driver of PASC and motivate further attempts to identify unique genetic features defining these malignancies.

2020-12-19 | GSE163517 | GEO

Targeted resequencing of cis-regulatory elements in human leukemia

Project description:Mutations in protein-coding genes are well established as the basis for human cancer, yet it remains elusive how alterations within non-coding genome, a substantial fraction of which contain cis-regulatory elements, contribute to cancer pathophysiology largely due to lack of high throughput assays to assess their functional effects. Here we developed an integrative approach to systematically identify and characterize non-coding regulatory variants in human hematopoietic malignancies by combining targeted resequencing, mutation discovery, CRISPR-based enhancer-selective epigenome editing, and enhancer reporter assays. We identify 4,629 recurrent non-coding alterations and 939 mutation-associated pathogenic enhancers controlling proto-oncogenes or tumor suppressors. Enhancer variants at KRAS and PER2 co-localize with nuclear receptor (NR) binding sites and modulate transcriptional activities in response to NR signaling in leukemia cells. NR binding sites frequently associate with non-coding variants across cancer types. Hence, recurrent non-coding somatic variants connect enhancer dysregulation with nuclear receptor signaling in hematopoietic malignancies.

2020-04-22 | GSE125939 | GEO

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