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Inherited functional regulatory risk variants for common human cancers [MPRA]

ABSTRACT: Single nucleotide variants (SNVs) in regulatory DNA are linked to inherited cancer risk. Massively parallel reporter assays (MPRA) of 5,031 SNVs linked to 14 neoplasms comprising >90% of human malignancies were performed in pertinent diploid cell types then integrated with matching chromatin accessibility, looping, and eQTL data to identify 411 regulatory SNVs and their putative target eGenes. The latter highlighted specific protein networks in lifetime cancer risk, including mitochondrial translation, proliferation, signaling, adhesion, and immunity. This cancer SNV compendium underscores the importance of studying pathogenic variants in disease-relevant cells and implicates specific dysregulated gene networks in cancer predisposition. It also indicates that inherited cancer risk can impact the same gene via orthogonal genetic mechanisms of dysregulated expression as well as protein coding sequence alteration and demonstrates that a subset of germline-encoded risk genes also enable tumor growth of established cancers.

ORGANISM(S): synthetic construct Homo sapiens

PROVIDER: GSE183301 | GEO | 2024/08/22

REPOSITORIES: GEO

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Inherited functional regulatory risk variants for common human cancers

Project description:Single nucleotide variants (SNVs) in regulatory DNA are linked to inherited cancer risk. Massively parallel reporter assays (MPRA) of 5,031 SNVs linked to 14 neoplasms comprising >90% of human malignancies were performed in pertinent diploid cell types then integrated with matching chromatin accessibility, looping, and eQTL data to identify 411 regulatory SNVs and their putative target eGenes. The latter highlighted specific protein networks in lifetime cancer risk, including mitochondrial translation, proliferation, signaling, adhesion, and immunity. This cancer SNV compendium underscores the importance of studying pathogenic variants in disease-relevant cells and implicates specific dysregulated gene networks in cancer predisposition. It also indicates that inherited cancer risk can impact the same gene via orthogonal genetic mechanisms of dysregulated expression as well as protein coding sequence alteration and demonstrates that a subset of germline-encoded risk genes also enable tumor growth of established cancers.

2024-08-22 | GSE183348 | 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

Single-Mitochondrion Sequencing Uncovers Distinct Mutational Patterns and Heteroplasmy Landscape in Mouse Astrocytes and Neurons

Project description:BACKGROUND: Mitochondrial (mt) heteroplasmy can cause adverse biological consequences when deleterious mtDNA mutations accumulate disrupting ‘normal’ mt-driven processes and cellular functions. To investigate the heteroplasmy of such mtDNA changes we developed a moderate throughput mt isolation procedure to quantify the mt single-nucleotide variant (SNV) landscape in individual mouse neurons and astrocytes In this study we amplified mt-genomes from 1,645 single mitochondria (mts) isolated from mouse single astrocytes and neurons to 1. determine the distribution and proportion of mt-SNVs as well as mutation pattern in specific target regions across the mt-genome,2. assess differences in mtDNA SNVs between neurons and astrocytes, and 3. Study cosegregation of variants in the mouse mtDNA. RESULTS: 1. The data show that specific sites of the mt-genome are permissive to SNV presentation while others appear to be under stringent purifying selection. Nested hierarchical analysis at the levels of mitochondrion, cell, and mouse reveals distinct patterns of inter- and intra-cellular variation for mt-SNVs at different sites. 2. Further, differences in the SNV incidence were observed between mouse neurons and astrocytes for two mt-SNV 9027:G>A and 9419:C>T showing variation in the mutational propensity between these cell types. Purifying selection was observed in neurons as shown by the Ka/Ks statistic, suggesting that neurons are under stronger evolutionary constraint as compared to astrocytes. 3. Intriguingly, these data show strong linkage between the SNV sites at nucleotide positions 9027 and 9461. CONCLUSION: This study suggests that segregation as well as clonal expansion of mt-SNVs is specific to individual genomic loci, which is important foundational data in understanding of heteroplasmy and disease thresholds for mutation of pathogenic variants.

2024-06-24 | GSE218122 | GEO

An integrative analysis of non-coding regulatory DNA variations associated with autism

Project description:A number of genetic studies have identified rare protein-coding DNA variations associated with autism spectrum disorder (ASD), a neurodevelopmental disorder with significant genetic etiology and heterogeneity. In contrast, the contributions of functional, regulatory genetic variations that occur in the extensive non-protein-coding regions of the genome remain poorly understood. Here we developed a genome-wide analysis to identify rare single nucleotide variants (SNVs) that occur in non-coding regions and determined regulatory function and evolutionary conservation of these variants. Using publicly available datasets and computational predictions, we identified SNVs within putative regulatory regions in promoters, transcription factor binding sites, microRNA genes and their target sites. Overall, we found regulatory variants in the ASD cases were enriched in autism-risk genes and genes involved in fetal neurodevelopment. As with previously reported coding mutations, we found an enrichment of regulatory variants associated with dysregulation of neurodevelopmental and synaptic signaling pathways. Among these were rare inherited non-coding SNVs found in the mature sequence of a number of microRNAs predicted to affect the regulation of autism-risk genes. We show a paternally inherited miR-873-5p variant, with reduced NRXN2 binding affinity, overlays a maternally inherited NRXN1 putative loss-of-function coding variation to likely increase genetic liability in an idiopathic ASD case. Our analysis pipeline provides a new resource for identifying loss-of-function regulatory DNA variations that may contribute to the genetic etiology of complex disorders.

2017-04-25 | GSE98088 | GEO

Anti-NR2F1 scCUT&Tag on FAC-sorted Isl1MN-GFP rhombomere 4 neurons from wildtype and HCFP1 Fam5snv/snv E10.5 mouse embryos

Project description:We found hereditary congenital facial paralysis type 1 (HCFP1) is caused by variants that duplicate or change cis regulatory elements (cREs) controlling the neuronal expression of the GATA2 transcription factor. The single nucleotide variants (SNVs) alter a previously uncharacterized cis regulatory element (we named cRE2). A subset of these variants disrupted a consensus sequence for the COUP transcription factor family (NR2F1 and NR2F2). We performed low-input scCUT&Tag with antibodies against NR2F1 and found it bound to the predicted cRE2 sequence in embryonic mouse rhombomere 4 motor neurons in vivo. We generated an HCFP1 SNV mouse model that harbored Mm10:Chr6:88,224,892 A>G in the NR2F1 binding site (Fam5snv/snv) and found it disrupted NR2F1 binding in vivo.

2023-04-04 | GSE223271 | GEO

A Molecular Portrait of Potentially Curable Prostate Cancer

Project description:Herein we describe a molecular portrait of potentially curable, Gleason 7 and intermediate risk prostate cancer based on genome-wide CNV profiles of 96 patients, and subsequent whole-genome sequencing of 28 tumours from 10 patients, using DNA quantities that are achievable in diagnostic biopsies (50 ng). We show that Gleason 7 cancer is highly heterogeneous at the SNV, CNV, and intra-chromosomal translocation levels, and is characterized by a very low number of recurrent SNVs but significant structural variation. We identified a novel recurrent MYCL1 amplification, which was strongly associated with TP53 deletion and prognostic for biochemical recurrence in this cohort. Moreover, we identified clear evidence of divergent tumour evolution in multi focal cancer and, in 2/5 cases evaluated, multiple tumours of independent clonal origin. Taken together, these data represent the first systematic evaluation of the differential genomics of potentially curable prostate cancer, and strongly suggest that a more robust understanding of the relationship between genetic heterogeneity and clinical outcomes is required to effectively develop biomarkers of prognosis based on tumour genomics. Six samples were analyzed in duplicate. Samples included untreated cells, cells transfected with vector only, and cells transfected with 4 different MYCL transcript variants. Expression constructs and vector were purchased from GeneCopoeia

2015-04-20 | E-GEOD-64619 | biostudies-arrayexpress

Single nucleotide variants (SNVs) associated with cutaneous melanoma (CM) risk and prognosis

Project description:Single nucleotide variants (SNVs) associated with cutaneous melanoma (CM) risk and prognosis

| PRJNA533122 | ENA

Homo sapiens

Project description:OncoArray: Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE)

| PRJNA360342 | ENA

OncoArray: Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE)

Project description:OncoArray: Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE)

| PRJNA360341 | ENA

Noncoding somatic and inherited single-nucleotide variants converge to promote ESR1 expression in breast cancer

Project description:Sustained expression of the estrogen receptor-Î± (ESR1) drives two-thirds of breast cancer and defines the ESR1-positive subtype. ESR1 engages enhancers upon estrogen stimulation to establish an oncogenic expression program1. Somatic copy number alterations involving the ESR1 gene occur in approximately 1 % of ESR1-positive breast cancers2â5, suggesting that other mechanisms underlie the persistent expression of ESR1. We report significant enrichment of somatic mutations within the set of regulatory elements (SRE) regulating ESR1 in 7% of ESR1-positive breast cancers. These mutations regulate ESR1 expression by modulating transcription factor binding to the DNA. The SRE includes a recurrently mutated enhancer whose activity is also affected by rs9383590, a functional inherited single-nucleotide variant (SNV) that accounts for several breast cancer riskâassociated loci. Our work highlights the importance of considering the combinatorial activity of regulatory elements as a single unit to delineate the impact of noncoding genetic alterations on single genes in cancer. RNA-Seq was performed in HCC1419 cells heterozygous for the functional SNV, rs9383590, to determine which genes displayed an allelic imbalance within a 1MB window.

2016-08-23 | E-GEOD-74718 | biostudies-arrayexpress

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