Ovarian cancer associated variants
Ontology highlight
ABSTRACT:
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR372915_1.fastq.gz | Fastqsanger.gz | |||
| ERR372915_2.fastq.gz | Fastqsanger.gz | |||
| ERR372916_1.fastq.gz | Fastqsanger.gz | |||
| ERR372916_2.fastq.gz | Fastqsanger.gz | |||
| ERR372917_1.fastq.gz | Fastqsanger.gz |
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Project description:Understanding the regulatory landscape of the human genome is a central question in complex trait genetics. Most single nucleotide polymorphisms (SNPs) associated with cancer risk lie in non protein-coding regions, implicating regulatory DNA elements as functional targets of susceptibility variants. Here, we describe genome-wide annotation of regions of open chromatin and histone modification in fallopian tube and ovarian surface epithelial cells (FTSECs, OSECs), the debated cellular origins of high-grade serous ovarian cancers (HGSOCs), and in endometriosis epithelial cells (EECs), the likely precursor of clear cell ovarian carcinomas (CCOCs). The regulatory architecture of these cell types was compared to normal human mammary epithelial cells (HMECs) and LNCaP prostate cancer cells. We observed similar positional patterns of global enhancer signatures across the three different ovarian cancer precursor cell types, and evidence of tissues specific regulatory signatures to non-gynecological cell types. We found significant enrichment for risk-associated SNPs intersecting regulatory biofeatures at 17 known HGSOC susceptibility loci in FTSECs (P=3.8x10-30) OSECs (P=2.4x10-23) and HMECs (P=6.7x10-15) but not for EECs (P=0.45) or LNCaP cells (P=0.88). Hierarchical clustering of risk SNPs conditioned on the six different cell types indicates FTSECs and OSECs are highly related (96% of samples using multi-scale bootstrapping) indicating both cell types may be precursors of HGSOC. These data represent the first description of regulatory catalogues of normal precursor cells for different ovarian cancer subtypes, and provide unique insights into the tissue specific regulatory variation with respect to the likely functional targets germline genetic susceptibility variants for ovarian cancer FAIRE-Seq and ChIP-Seq of 2 different histone modifications in 5 cell types.
2015-04-22 | E-GEOD-68104 | biostudies-arrayexpress
Project description:Understanding the regulatory landscape of the human genome is a central question in complex trait genetics. Most single nucleotide polymorphisms (SNPs) associated with cancer risk lie in non protein-coding regions, implicating regulatory DNA elements as functional targets of susceptibility variants. Here, we describe genome-wide annotation of regions of open chromatin and histone modification in fallopian tube and ovarian surface epithelial cells (FTSECs, OSECs), the debated cellular origins of high-grade serous ovarian cancers (HGSOCs), and in endometriosis epithelial cells (EECs), the likely precursor of clear cell ovarian carcinomas (CCOCs). The regulatory architecture of these cell types was compared to normal human mammary epithelial cells (HMECs) and LNCaP prostate cancer cells. We observed similar positional patterns of global enhancer signatures across the three different ovarian cancer precursor cell types, and evidence of tissues specific regulatory signatures to non-gynecological cell types. We found significant enrichment for risk-associated SNPs intersecting regulatory biofeatures at 17 known HGSOC susceptibility loci in FTSECs (P=3.8x10-30) OSECs (P=2.4x10-23) and HMECs (P=6.7x10-15) but not for EECs (P=0.45) or LNCaP cells (P=0.88). Hierarchical clustering of risk SNPs conditioned on the six different cell types indicates FTSECs and OSECs are highly related (96% of samples using multi-scale bootstrapping) indicating both cell types may be precursors of HGSOC. These data represent the first description of regulatory catalogues of normal precursor cells for different ovarian cancer subtypes, and provide unique insights into the tissue specific regulatory variation with respect to the likely functional targets germline genetic susceptibility variants for ovarian cancer
2015-04-22 | GSE68104 | GEO
Project description:Premature ovarian insufficiency (POI) is a heterogeneous female disorder characterized by the loss of ovarian function before the age of 40. It represents a significant detriment to female fertility. However, the known POI-causative genes currently account for only a fraction of cases. To elucidate the genetic factors underlying POI, we conducted whole-exome sequencing on a family with three fertile POI patients and identified a deleterious missense variant in RNF111. In a subsequent replication study involving 1030 POI patients, this variant was not only confirmed but also accompanied by the discovery of three additional predicted deleterious RNF111 variants. These variants collectively account for eight cases, representing 0.78% of the study cohort. A further study involving 500 patients with diminished ovarian reserves also identified two additional RNF111 variants. Notably, RNF111 encodes an E3-ubiquitin ligase with a regulatory role in the TGF-β/BMP signaling pathway. Our analysis revealed that RNF111/RNF111 is predominantly expressed in the oocytes of mice, monkeys, and humans. To further investigate the functional implications of RNF111 variants, we generated two mouse models: one with a heterozygous missense mutation (Rnf111+/M) and another with a heterozygous null mutation (Rnf111+/−). Both mouse models exhibited impaired female fertility, characterized by reduced litter sizes and small ovarian reserve. Additionally, RNA-seq and quantitative proteomics analysis unveiled that Rnf111 haploinsufficiency led to dysregulation in female gonad development and negative regulation of the BMP signaling pathway within mouse ovaries. In conclusion, our findings strongly suggest that monoallelic deleterious variants in RNF111 can impair female fertility and induce POI in both humans and mice.
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Project description:We identified pathogenic and likely pathogenic variants in 17.8% of the patients within a wide range of cancer types. In particular, mesothelioma, ovarian cancer, cervical cancer, urothelial cancer, and cancer of unknown primary origin displayed high frequencies of pathogenic variants. In total, 22 BRCA1 and BRCA2 germline variant were identified in 12 different cancer types, of which 10 (45%) variants were not previously identified in these patients. Pathogenic germline variants were predominantly found in DNA repair pathways; approximately half of the variants were within genes involved in homologous recombination repair. Loss of heterozygosity and somatic second hits were identified in several of these genes, supporting possible causality for cancer development. A potential treatment target based on pathogenic germline variant could be suggested in 25 patients (4%).
2019-05-11 | GSE131027 | GEO
Project description:Genome sequencing has uncovered numerous pathogenic missense variants; however, their functional consequences remain largely unexplored, limiting our understanding of their precise roles in diseases. These variants may disrupt post-translational modifications (PTMs), which are crucial for cellular signaling and disease pathogenesis. Here, we present DeepVEP, a computational framework that uses deep learning-based PTM site prediction models to assess the impact of missense variants on six key PTMs. Our PTM site prediction models, trained on 397,524 PTM sites curated in PTMAtlas through systematic reanalysis of 241 PTM-enriched mass spectrometry datasets, significantly outperform existing models. DeepVEP’s variant effect predictions align closely with experimental results, as validated against literature-derived PTM-altering variants and two proteogenomic datasets. Its application to both pathogenic germline and somatic cancer variants creates a comprehensive landscape of PTM-altering disease variants. Furthermore, DeepVEP's interpretability facilitates connecting altered PTMs to potential modifying enzymes, opening new avenues for therapeutic interventions.
2025-09-29 | PXD059468 | Pride
Project description:Nuclear deubiquitinase BAP1 (BRCA1-Associated Protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor gene whose germline loss-of-function variants predispose to cancer. To our knowledge, there are very rare examples of different germline variants in the same gene causing either a NDD or a tumor predisposition syndrome. Here, we report a series of 11 de novo germline heterozygous missense BAP1 variants associated with a rare syndromic neurodevelopmental disorder (NDD). Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired in matching peripheral blood mononuclear cells, histone H3 K27 acetylation ChIP-seq indicated that these BAP1 variants induced genome-wide chromatin state alterations, with enrichment for regulatory regions surrounding genes of the ubiquitin-proteasome system (UPS). Altogether, these results define a clinical syndrome caused by rare germline missense BAP1 variants that alter chromatin remodeling through abnormal histone ubiquitination and lead to transcriptional dysregulation of developmental genes.
2021-12-10 | GSE190394 | GEO
Project description:Objectives. Ovarian cancer (OC) is the eighth most common cancer and the eighth most common cause of cancer-related death in women. Identification of pathogenic variants in OC tissues is important to predict treatment response. This study aim to evaluate the mutational profile of a patient cohort, negative for BRCA1/2 germinal mutations and Mismatch Repair (MMR) defects, using next generation sequencing approach on DNA from formalin-fixed paraffin-embedded (FFPE) samples. We used a custom NGS panel, targeting 34 cancer related-genes, and analyzed NGS data to identify somatic and germline mutations in Italian patients affected by primary epithelia ovarian cancer.
2022-12-15 | E-MTAB-11133 | biostudies-arrayexpress
Project description:Germline BRCA2 loss-of function (LOF) variants identified by clinical genetic testing predispose to breast, ovarian, prostate and pancreatic cancer. However, variants of uncertain significance (VUS) (n>5000) limit the clinical use of testing results. Thus, there is an urgent need for functional characterization and clinical classification of all BRCA2 variants. Here we report on comprehensive saturation genome editing-based functional characterization of 99% of all possible single nucleotide variants (SNVs) in the BRCA2 DNA Binding Domain hotspot for pathogenic missense variants that is encoded by exons 15 to 26. The assay was based on deep sequence analysis of HAP1 haploid cells endogenously targeted using a CRISPR/cas9 knockin approach. A total of 6959 SNVs were characterized for effects on cell survival. The assay was validated relative to nonsense and synonymous variants, ClinVar pathogenic/likely pathogenic and benign/likely benign variants and homology directed repair cell based DNA repair assay results, all of which showed >94% sensitivity and specificity. Variants were assigned posterior probabilities of pathogenicity using a VarCall two component Bayesian mixture model and were further grouped according to ACMG strength of evidence under the PS3/BS3 rule resulting in Benign Strong (n=5430), Benign Moderate (n=190), Benign Supporting (n=61), VUS (122), Pathogenic Strong (n=1021), Pathogenic Moderate (n=88), and Pathogenic Supporting (n=47). Breast cancer case-control association studies showed that pooled SNVs encoding functionally pathogenic missense variants were associated with increased risks of breast (odds ratio (OR)3.81, 95%CI: 2.88-5.07) and ovarian cancer (OR 5.93, 95%CI: 4.12-8.52). The functional data were also combined with other sources of information in the ClinGen BRCA1/2 VCEP ACMG/AMP-classification model. A total of 785 SNVs, including 261 missense SNVs, were classified as pathogenic or likely pathogenic, while 5566 SNVs, including 3786 missense SNVs, were classified as benign or likely benign. These classified variants can now be used for risk assessment and clinical care of variant carriers.
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Project description:Inactivating germline monoallelic mutations in the tumor suppressor BRCA2 predispose to breast and ovarian cancer. BRCA2 is essential in DNA repair via homologous recombination (HR). Tumorigenesis in this setting is thought to require the inactivation of the second allele; however, this event is not always observed suggesting haploinsufficiency. We investigated this question recreating two BRCA2 pathogenic truncating variants in heterozygosis in breast epithelial cells. One prompted sensitivity to PARP inhibitors (PARPi) and reduced HR capacity unlike the other. The other resulted in transcriptomic and epigenetic changes including histone H4 acetylation levels and NF-kB activation that we link to PCAF acetyl transferase. These changes impacted on cell migration and proliferation in 2D and 3D, processes that were also deregulated in tumors. Our work demonstrates that distinct truncating variants of BRCA2 are not phenotypically equivalent. It also identifies PCAF as shaping BRCA2-related gene expression. These findings may have implications in cancer prevention.
2024-11-21 | GSE272335 | GEO