A comprehensive genomic meta-analysis identifies confirmatory role of OBSCN gene in breast tumorigenesis.
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ABSTRACT:
SUBMITTER: Rajendran BK
PROVIDER: S-EPMC5731952 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeGenomic profiling studies suggest that triple-negative breast cancer (TNBC) is a heterogeneous disease. In this study, we sought to define TNBC subtypes and identify subtype-specific markers and targets.Experimental designRNA and DNA profiling analyses were conducted on 198 TNBC tumors [estrogen receptor (ER) negativity defined as Allred scale value ≤ 2] with >50% cellularity (discovery set: n = 84; validation set: n = 114) collected at Baylor College of Medicine (Houston, TX). An external dataset of seven publically accessible TNBC studies was used to confirm results. DNA copy number, disease-free survival (DFS), and disease-specific survival (DSS) were analyzed independently using these datasets.ResultsWe identified and confirmed four distinct TNBC subtypes: (i) luminal androgen receptor (AR; LAR), (ii) mesenchymal (MES), (iii) basal-like immunosuppressed (BLIS), and (iv) basal-like immune-activated (BLIA). Of these, prognosis is worst for BLIS tumors and best for BLIA tumors for both DFS (log-rank test: P = 0.042 and 0.041, respectively) and DSS (log-rank test: P = 0.039 and 0.029, respectively). DNA copy number analysis produced two major groups (LAR and MES/BLIS/BLIA) and suggested that gene amplification drives gene expression in some cases [FGFR2 (BLIS)]. Putative subtype-specific targets were identified: (i) LAR: androgen receptor and the cell surface mucin MUC1, (ii) MES: growth factor receptors [platelet-derived growth factor (PDGF) receptor A; c-Kit], (iii) BLIS: an immunosuppressing molecule (VTCN1), and (iv) BLIA: Stat signal transduction molecules and cytokines.ConclusionThere are four stable TNBC subtypes characterized by the expression of distinct molecular profiles that have distinct prognoses. These studies identify novel subtype-specific targets that can be targeted in the future for the effective treatment of TNBCs.
| S-EPMC4362882 | biostudies-literature
Project description:Background and Aims: Gastric adenocarcinoma (gastric cancer, GC) is a major cause of global cancer mortality. Identifying molecular programs contributing to GC patient survival may improve our understanding of GC pathogenesis, highlight new prognostic factors, and reveal novel therapeutic targets. We aimed to produce a comprehensive inventory of gene expression programs expressed in primary GCs, and to identify those expression programs significantly associated with patient survival. Methods: Using a network modeling approach, we performed a large scale meta-analysis of GC transcriptome data integrating 940 gastric transcriptomes from multiple independent patient cohorts. We analyzed a training set of 428 GCs and 163 non neoplastic gastric mucosa (‘non-malignants’), and a validation set of 288 GCs and 61 non-malignants. Results: We identified 178 gene expression programs (modules) expressed in primary GCs, which were associated with distinct biological processes, chromosomal location patterns, cis-regulatory motifs, and clinicopathological parameters. Amongst these modules, expression of a TGF-B-signaling associated “super-module” of stroma-related genes consistently predicted patient survival in multiple GC validation cohorts. Analysis of histopathological tissue sections from gastrectomy specimens revealed that expression of this stromal module was associated with the proportion of intra-tumoral stroma (ITS). Further supporting the stromal module expression/ITS association, we found that the ITS proportion, measured directly from tissue sections, also predicted GC patient survival. Conclusion: Stromal gene expression predicts GC patient survival in multiple independent cohorts and may be closely related to the ITS proportion, a specific morphological GC phenotype. These findings suggest that therapeutic approaches targeting pathways associated with the GC stroma may merit evaluation.
2012-07-05 | GSE37023 | GEO
Project description:HER2 is a transmembrane receptor tyrosine kinase, which plays a key role in breast cancer due to a common genomic amplification. It is used as a marker to stratify patients in the clinic and is targeted by a number of drugs including Trastuzumab and Lapatinib. HER2 has previously been shown to translocate to the nucleus. In this study, we have explored the properties of nuclear HER2 by analysing the binding of this protein to the chromatin in two breast cancer cell lines. We find genome-wide re-programming of HER2 binding after treatment with the growth factor EGF and have identified a de novo motif at HER2 binding sites. Over 2,000 HER2 binding sites are found in both breast cancer cell lines after EGF treatment, and according to pathway analysis, these binding sites were enriched near genes involved in protein kinase activity and signal transduction. HER2 was shown to co-localise at a small subset of regions demarcated by H3K4me1, a hallmark of functional enhancer elements and HER2/H3K4me1 co-bound regions were enriched near EGF regulated genes providing evidence for their functional role as regulatory elements. A chromatin bound role for HER2 was verified by independent methods, including Proximity Ligation Assay (PLA), which confirmed a close association between HER2 and H3K4me1. Mass spectrometry analysis of the chromatin bound HER2 complex identified EGFR and STAT3 as interacting partners in the nucleus. These findings reveal a global role for HER2 as a chromatin-associated factor that binds to enhancer elements to elicit direct gene expression events in breast cancer cells.
| S-EPMC6867699 | biostudies-literature
Project description:Somatic mutations are one of the most important factors in tumorigenesis and are the focus of most cancer-sequencing efforts. The co-occurrence of multiple mutations in one tumor has gained increasing attention as a means of identifying cooperating mutations or pathways that contribute to cancer. Using multi-omics, phenotypical, and clinical data from 29,559 cancer subjects and 1747 cancer cell lines covering 78 distinct cancer types, we show that co-mutations are associated with prognosis, drug sensitivity, and disparities in sex, age, and race. Some co-mutation combinations displayed stronger effects than their corresponding single mutations. For example, co-mutation TP53:KRAS in pancreatic adenocarcinoma is significantly associated with disease specific survival (hazard ratio = 2.87, adjusted p-value = 0.0003) and its prognostic predictive power is greater than either TP53 or KRAS as individually mutated genes. Functional analyses revealed that co-mutations with higher prognostic values have higher potential impact and cause greater dysregulation of gene expression. Furthermore, many of the prognostically significant co-mutations caused gains or losses of binding sequences of RNA binding proteins or micro RNAs with known cancer associations. Thus, detailed analyses of co-mutations can identify mechanisms that cooperate in tumorigenesis.
| S-EPMC8774165 | biostudies-literature
Project description:HER2 is a transmembrane receptor tyrosine kinase, which plays a key role in breast cancer due to a common genomic amplification. It is used as a marker to stratify patients in the clinic and is targeted by a number of drugs including Trastuzumab and Lapatinib. HER2 has previously been shown to translocate to the nucleus. In this study, we have explored the properties of nuclear HER2 by analysing the binding of this protein to the chromatin in three breast cancer cell lines. We find genome-wide re-programming of HER2 binding after treatment with the growth factor EGF. Over 4,000 HER2 binding sites are found in all three breast cancer cell lines, and these occur near genes involved in protein kinase activity and signal transduction. HER2 was shown to co-localise at a subset of regions demarcated by H3K4me1, a hallmark of functional enhancer elements and HER2/H3K4me1 co-bound regions were enriched near EGF regulated genes providing evidence for their functional role as regulatory elements. A chromatin bound role for HER2 was verified by independent methods, including Proximity Ligation Assay (PLA), which confirmed a close association between HER2 and H3K4me1. Interestingly, HER2 bound to the ErbB2 gene itself indicating a potential self-regulatory mechanism for HER2. Mass spectrometry analysis of the chromatin bound HER2 complex identified EGFR and STAT3 as interacting partners. These findings reveal a global role for HER2 as a chromatin-associated factor that binds to enhancer elements to elicit direct gene expression events in breast cancer cells.
2020-05-26 | PXD003915 | Pride
Project description:BackgroundAurora kinases (AURKs) family plays a vital role not only in cell division but also in tumorigenesis. However, there are still rare systematic analyses of the diverse expression patterns and prognostic value of the AURKs family in breast cancer (BC). Systematic bioinformatics analysis was conducted to explore the biological role, prognostic value, and immunologic function of AURKs family in BC.MethodsThe expression, prognostic value, and clinical functions of AURKs family in BC were evaluated with several bioinformatics web portals: ONCOMINE Gene Expression Profiling Interactive Analysis, Kaplan-Meier plotter, cBioPortal, Metascape, GeneMANIA, and LinkedOmics; and the result was verified using human tissues.ResultsThe expression of AURKA and AURKB were upregulated in BC in subgroup analyses based on tumor stage (all P < 0.05). BC patients with high AURKA and AURKB expression had a worse overall survival, relapse-free survival, and distant metastasis-free survival (all P < 0.05). Verification experiment revealed that AURKA and AURKB were upregulated in BC ( P < 0.05). AURKA and AURKB were specifically associated with several tumor-associated kinases (polo-like kinase 1 and cyclin-dependent kinase 1), miRNAs (miR-507 and miR-381), and E2F transcription factor 1. Moreover, AURKA and AURKB were correlated with immune cell infiltration. Functional enrichment analysis revealed that AURKA and AURKB were involved in the cell cycle signaling pathway, platinum drug resistance signaling pathway, ErbB signaling pathway, Hippo signaling pathway, and nucleotide-binding and oligomerization domain-like receptor signaling pathway.ConclusionsAurora kinases AURKA and AURKB could be employed as novel prognostic biomarkers or promising therapeutic targets for BC.
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Project description:Small-cell lung cancer (SCLC) is an exceptionally aggressive disease with poor prognosis. Here, we obtained exome, transcriptome and copy-number alteration data from approximately 53 samples consisting of 36 primary human SCLC and normal tissue pairs and 17 matched SCLC and lymphoblastoid cell lines. We also obtained data for 4 primary tumors and 23 SCLC cell lines. We identified 22 significantly mutated genes in SCLC, including genes encoding kinases, G protein-coupled receptors and chromatin-modifying proteins. We found that several members of the SOX family of genes were mutated in SCLC. We also found SOX2 amplification in ?27% of the samples. Suppression of SOX2 using shRNAs blocked proliferation of SOX2-amplified SCLC lines. RNA sequencing identified multiple fusion transcripts and a recurrent RLF-MYCL1 fusion. Silencing of MYCL1 in SCLC cell lines that had the RLF-MYCL1 fusion decreased cell proliferation. These data provide an in-depth view of the spectrum of genomic alterations in SCLC and identify several potential targets for therapeutic intervention.
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Project description:Rheumatoid arthritis (RA), a symmetric polyarticular arthritis, has long been feared as one of the most disabling forms of arthritis. Identification of gene signatures associated with RA onset and progression would lead toward development of novel diagnostics and therapeutic interventions. This study was undertaken to identify unique gene signatures of RA patients through large-scale meta-profiling of a diverse collection of gene expression data sets. We carried out a meta-analysis of 8 publicly available RA patients' (107 RA patients and 76 healthy controls) gene expression data sets and further validated a few meta-signatures in RA patients through quantitative real-time PCR (RT-qPCR). We identified a robust meta-profile comprising 33 differentially expressed genes, which were consistently and significantly expressed across all the data sets. Our meta-analysis unearthed upregulation of a few novel gene signatures including PLCG2, HLA-DOB, HLA-F, EIF4E2, and CYFIP2, which were validated in peripheral blood mononuclear cell samples of RA patients. Further, functional and pathway enrichment analysis reveals perturbation of several meta-genes involved in signaling pathways pertaining to inflammation, antigen presentation, hypoxia, and apoptosis during RA. Additionally, PLCG2 (phospholipase Cγ2) popped out as a novel meta-gene involved in most of the pathways relevant to RA including inflammasome activation, platelet aggregation, and activation, thereby suggesting PLCG2 as a potential therapeutic target for controlling excessive inflammation during RA. In conclusion, these findings highlight the utility of meta-analysis approach in identifying novel gene signatures that might provide mechanistic insights into disease onset, progression and possibly lead toward the development of better diagnostic and therapeutic interventions against RA.
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Project description:Cancer stem cells (CSCs) are a small subpopulation of cancer cells that have increased resistance to conventional therapies and are capable of establishing metastasis. However, only a few biomarkers of CSCs have been identified. Here, we report that ganglioside GD2 (a glycosphingolipid) identifies a small fraction of cells in human breast cancer cell lines and patient samples that are capable of forming mammospheres and initiating tumors with as few as 10 GD2+ cells. In addition, the majority of GD2+ cells are also CD44hiCD24lo, the previously established CSC-associated cell surface phenotype. Gene expression analysis revealed that GD3 synthase (GD3S) is highly expressed in GD2+ as well as in CD44hiCD24lo cells and that interference with GD3S expression, either by shRNA or using a pharmacological inhibitor, reduced the CSC population and CSC-associated properties. GD3S knockdown completely abrogated tumor formation in vivo. Also, induction of epithelial-mesenchymal transition (EMT) in transformed human mammary epithelial cells (HMLER cells) dramatically increased GD2 as well as GD3S expression in these cells, suggesting a role of EMT in the origin of GD2+ breast CSCs. In summary, we identified GD2 as a new CSC-specific cell surface marker and GD3S as a potential therapeutic target for CSCs, with the possibility of improving survival and cure rates in patients with breast cancer.
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Project description:Oncocytomas are predominantly benign neoplasms possessing pathogenic mitochondrial mutations and accumulation of respiration-defective mitochondria, characteristics of unknown significance. Using exome and transcriptome sequencing, we identified two main subtypes of renal oncocytoma. Type 1 is diploid with CCND1 rearrangements, whereas type 2 is aneuploid with recurrent loss of chromosome 1, X or Y, and/or 14 and 21, which may proceed to more aggressive eosinophilic chromophobe renal cell carcinoma (ChRCC). Oncocytomas activate 5' adenosine monophosphate-activated protein kinase (AMPK) and Tp53 (p53) and display disruption of Golgi and autophagy/lysosome trafficking, events attributed to defective mitochondrial function. This suggests that the genetic defects in mitochondria activate a metabolic checkpoint, producing autophagy impairment and mitochondrial accumulation that limit tumor progression, revealing a novel tumor-suppressive mechanism for mitochondrial inhibition with metformin. Alleviation of this metabolic checkpoint in type 2 by p53 mutations may allow progression to eosinophilic ChRCC, indicating that they represent higher risk.
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