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Integrinated Omic analysis of lung cancer reveals metabolism proteome signatures with prognostic impact

ABSTRACT: Cancer results from processes prone to selective pressure and dysregulation acting along the sequence-to-phenotype continuum DNA→RNA→Protein→Disease. However, the extent to which cancer is a manifestation of the proteome is unknown. Here we present an integrated omic map representing non-small cell lung carcinoma. Dysregulated proteins not previously implicated as cancer drivers are encoded throughout the genome including but not limited to regions of recurrent DNA amplification/deletion. Clustering reveals signatures composed of metabolism proteins particularly highly recapitulated between patient-matched primary and xenograft tumours. Interrogation of The Cancer Genome Atlas reveals cohorts of patients with lung and other cancers that have DNA alterations in genes encoding the signatures, and this was accompanied by differences in survival. The recognition of genome and proteome alterations as related products of selective pressure driving the disease phenotype may be a general approach to uncover and group together cryptic, polygenic disease drivers. Total RNAs from xenografts, primary tumor, and normal adjacent tissues were amplified by DASL kit and hybridized to Illumina HT12v4 chip

ORGANISM(S): Homo sapiens

SUBMITTER: Ming Tsao

PROVIDER: E-GEOD-62113 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Integrinated Omic analysis of lung cancer reveals metabolism proteome signatures with prognostic impact

Project description:Cancer results from processes prone to selective pressure and dysregulation acting along the sequence-to-phenotype continuum DNA→RNA→Protein→Disease. However, the extent to which cancer is a manifestation of the proteome is unknown. Here we present an integrated omic map representing non-small cell lung carcinoma. Dysregulated proteins not previously implicated as cancer drivers are encoded throughout the genome including but not limited to regions of recurrent DNA amplification/deletion. Clustering reveals signatures composed of metabolism proteins particularly highly recapitulated between patient-matched primary and xenograft tumours. Interrogation of The Cancer Genome Atlas reveals cohorts of patients with lung and other cancers that have DNA alterations in genes encoding the signatures, and this was accompanied by differences in survival. The recognition of genome and proteome alterations as related products of selective pressure driving the disease phenotype may be a general approach to uncover and group together cryptic, polygenic disease drivers.

2014-10-09 | GSE62113 | GEO

Homo sapiens

Project description:Integrinated Omic analysis of lung cancer reveals metabolism proteome signatures with prognostic impact

| PRJNA263446 | ENA

A Blood-based Multi-omic Landscape for the molecular characterization of Kidney Stone Disease

Project description:Kidney stone disease (KSD, also named renal calculi, nephrolithiasis, or urolithiasis) is a common urological disease entailing the formation of minerals and salts that form inside the urinary tract, frequently caused by diabetes and high blood pressure, hypertension, and monogenetic components in most patients. 10% of adults worldwide are affected by KSD, which incidence continues to be highly prevalent and increasing. For the identification of novel therapeutic targets in KSD to deal with this situation, we adopted high-throughput sequencing and mass spectrometry (MS) techniques in this study and carried out an integrative analysis of exosome proteome and DNA methylation data from blood samples of normal and KSD patients. Our study described the profiling of serum exosome and DNA methylation in blood from both normal individuals and those with Kidney Stone Disease (KSD), finding the overexpressed proteins and the demethylated DNA genes in KSD samples are related to immune reactions. The consistency of the results in proteomics and epigenetics supports the feasibility of the comprehensive strategy. Our understanding of the molecular landscape of KSD provides an opportunity for more information on the pathogenic mechanism, precise diagnosis, and treatment for KSD.

2024-01-01 | GSE240640 | GEO

Selective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers

Project description:Chromatin regulators have become highly attractive targets for cancer therapy, yet many of these regulators are expressed in a broad range of healthy cells and contribute generally to gene expression. An important conundrum has thus emerged: how can inhibition of a general regulator of gene expression produce selective effects at specific oncogenes? Here we investigate how inhibition of the transcriptional coactivator BRD4 (Bromodomain containing 4) leads to selective inhibition of disease-critical oncogenes in a highly malignant blood cancer, multiple myeloma (MM). We found that BRD4 generally occupies the promoter elements of active genes together with the Mediator coactivator, but remarkably high levels of these two coactivator proteins were associated with a small set of exceptionally large enhancers. These super-enhancers are associated with genes that feature prominently in MM biology, including the MYC oncogene. Treatment of MM tumor cells with the BET-bromodomain inhibitor JQ1 led to preferential loss of BRD4 at super-enhancers and consequent transcription elongation defects that preferentially impact genes with super-enhancers, including the c-MYC oncogene. Super-enhancers were found at key oncogenic drivers in many other tumor cells. Thus, super-enhancers can regulate oncogenic drivers in tumor cells, which in some cells can be preferentially disrupted by BRD4 inhibition, which in turn contributes to the selective transcriptional effects observed at these oncogenes. These observations have implications for the discovery of novel cancer therapeutics directed at components of super-enhancers in diverse tumor types. ChIP-Seq for chromatin regulators and RNA Polymerase II in multiple myeloma, glioblastoma multiforme, and small cell lung cancer

2013-01-02 | E-GEOD-42355 | biostudies-arrayexpress

Selective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers [Affymetrix]

Project description:Chromatin regulators have become highly attractive targets for cancer therapy, yet many of these regulators are expressed in a broad range of healthy cells and contribute generally to gene expression. An important conundrum has thus emerged: how can inhibition of a general regulator of gene expression produce selective effects at specific oncogenes? Here we investigate how inhibition of the transcriptional coactivator BRD4 (Bromodomain containing 4) leads to selective inhibition of disease-critical oncogenes in a highly malignant blood cancer, multiple myeloma (MM). We found that BRD4 generally occupies the promoter elements of active genes together with the Mediator coactivator, but remarkably high levels of these two coactivator proteins were associated with a small set of exceptionally large enhancers. These super-enhancers are associated with genes that feature prominently in MM biology, including the MYC oncogene. Treatment of MM tumor cells with the BET-bromodomain inhibitor JQ1 led to preferential loss of BRD4 at super-enhancers and consequent transcription elongation defects that preferentially impact genes with super-enhancers, including the c-MYC oncogene. Super-enhancers were found at key oncogenic drivers in many other tumor cells. Thus, super-enhancers can regulate oncogenic drivers in tumor cells, which in some cells can be preferentially disrupted by BRD4 inhibition, which in turn contributes to the selective transcriptional effects observed at these oncogenes. These observations have implications for the discovery of novel cancer therapeutics directed at components of super-enhancers in diverse tumor types. Gene expression profiling in multiple myeloma cells after BET-Bromodomain inhibition with JQ1

2013-03-07 | E-GEOD-44929 | biostudies-arrayexpress

Homo sapiens

Project description:Molecular Signatures Underlying Selective Regional Vulnerability to Alzheimer's Disease

| PRJNA329139 | ENA

A Time-resolved Multi-omic Atlas of the Developing Mouse Stomach

Project description:The mouse stomach secrets digestive enzymes and stomach acid, and plays a key role in food digestion. While there are a few studies on the morphological changes during the stomach development, a comprehensive, systematic omics study is still missing. Here, we present a comprehensive, temporal proteome atlas of the mouse stomach by sequential mapping stomach tissues at multiple developmental stages. The quantitative analysis of 12,108 gene products provides coverage sufficient to observe the protein dynamics of the developing stomach. The whole process of stomach development can be roughly divided into three phases according to changes of RNAs or proteins. The molecular functions of protein modules pinpoint the gain of stomach functions at the longitudinal scale. Dissection of 8 key signaling pathways identified master regulators in governing stomach development and gastric cancer. Remarkably, many proteins differentially expressed in stomach development are also significantly overexpressed in diffuse-type gastric cancer, suggesting a close correlation between development and tumorigenesis. The transcriptome of the developing stomach reveals functionally important isoforms relevant to development. When combined with the proteomes, several functionally unannotated novel splicing junction transcripts were identified and validated at the peptide level. Overall, our study provides a valuable resource to understand stomach development and its connection to gastric cancer.

2018-08-04 | GSE118083 | GEO

Knock-in of PIK3CA-H1047R into MCF-10A

Project description:We have compared the proteome, transcriptome and metabolome of two isogenic cell lines: MCF-10A, derived from human breast epithelium, and the mutant MCF-10A-H1047R. These cell lines differ by a single amino acid substitution (H1047R) caused by single nucleotide change in one allele of the PIK3CA gene which encodes the catalytic subunit p110Î± of phosphatidylinositol 3-kinase (PI3K). The H1047R mutation of PIK3CA is one of the most frequently encountered somatic cancer-specific mutations. In MCF-10A, this mutation induces an extensive cellular reorganization that far exceeds the known signaling activities of PI3K. The changes are highly diverse; with examples in structural protein levels, the DNA repair machinery and sterol synthesis. Gene set enrichment analysis reveals a highly significant concordance of the genes differentially expressed in MCF-10A-H1047R cells and the established protein and RNA signatures of basal breast cancer. No such concordance was found with the specific gene signatures of other histological types of breast cancer. Our data document the power of a single base mutation, inducing an extensive remodeling of the cell toward the phenotype of a specific cancer. 2 cell lines (H1047R and WT), 4 time points (0, 6, 12, 24 hours), 3 replicates

2015-01-19 | E-GEOD-63452 | biostudies-arrayexpress

Defining the Relationship Between Cellular and Extracellular Vesicle (EV) Content in Breast Cancer via an Integrative Multi-Omic Analysis

Project description:Much recent work has been dedicated to exploring the utility of extracellular vesicles (EVs) as circulating cancer biomarkers. This is driven by the understanding that the molecular cargo of EVs reflects their originating cell, meaning EVs may enable non-invasive tumour surveillance. Few attempts have been made, however, to empirically validate this assumption on the -omic level and define the relationship between the molecular phenotype of cells and EVs. To this end, we present an integrative multi-omic analysis of a panel of breast cancer cell lines and corresponding EVs. Transcriptomic analysis of the cells was first used to confirm that expression of disease-related transcripts remained stable following transition to a low serum EV production medium. Proteomic analysis of the EVs indicated that neither the ER nor PR protein could be directly detected in EVs, but cellular expression of ER could be indirectly inferred from the EV proteome. Transcriptomic analyses generally suggested a direct positive correlation between transcript levels in cells and EVs. Integrative analysis suggested that the EV proteome and transcriptome captured select hallmarks of aberrant pathway activity in the originating cells, supporting the potential use of EVs to non-invasively monitor molecular evolution in breast cancers.

2023-11-03 | GSE188385 | GEO

Epigenetic signatures of alcohol abuse and hepatitis infection during hepatocarcinogenesis

Project description:Hepatocellular carcinoma (HCC) is the second most common cause of cancer deaths worldwide. Altered DNA methylation landscapes are ubiquitous features of cancer. Interpretation of epigenetic aberrations in HCC is confounded by effects of multiple etiologic drivers and underlying cirrhosis in most cases. We globally profiled the DNA methylome of 34 normal livers and 122 primary liver disease tissues arising in the setting of chronic hepatitis B (HBV) or C (HCV) viral infection, alcoholism (EtOH), and other causes to examine how these environmental agents impact DNA methylation in a manner that contributes to liver disease. Our results demonstrate that each etiologic factor leaves unique and overlapping signatures on the DNA methylome. CpGs aberrantly methylated in cirrhosis-HCV and conserved in HCC were enriched for cancer driver genes, suggesting a pathogenic role for HCV-induced methylation changes. Additionally, large genomic regions displaying stepwise hypermethylation or hypomethylation during disease progression were identified. HCC-HCV/EtOH methylomes overlap highly with cryptogenic HCC, suggesting shared epigenetically deregulated pathways for hepatic carcinogenesis. Finally, overlapping methylation abnormalities between primary and cultured tumors unveil highly conserved epigenetic signatures in HCC. Taken together, this study characterizes progressive liver DNA methylome changes under exposure to detrimental environmental agents and illuminates possible biomarkers for early detection of HCC. 156 primary tissues and 25 cultured normal and HCC cell lines

2014-09-16 | E-GEOD-60753 | biostudies-arrayexpress

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