Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA312246 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Prostate cancers exhibit a spectrum of molecular aberrations of which a substantial subset are amenable to targeted therapeutics. To determine the diversity of somatic alterations present in metastasis within and between individuals we characterized the genomic landscapes of 176 tumors acquired from 63 men. In contrast to the considerable variation across individuals, the molecular diversity of tumors within an individual was substantially less: alterations in putative drivers of cancer growth and cell cycle progression status were highly concordant. While androgen receptor activity was inversely related to proliferation, the expression of Fanconi Anemia complex genes was strongly associated with increased cell cycle progression. Inhibition of FANCA, FANCC, FANCD2 and BRCA2 expression reduced prostate cancer growth. The limited molecular diversity across metastases may result from bottlenecks imposed by the dissemination process, limited evolutionary time between metastatic seeding and tumor sampling, intermixing of tumor clones, and selection resulting from treatment pressures. Though exceptions exist, evaluating a single metastasis provides a reasonable assessment of the key molecular processes that occur throughout the spectrum of disseminated tumors within an individual, and may be used for selecting treatments based on predicted molecular vulnerabilities. Custom Agilent 44K whole human genome expression oligonucleotide microarrays were used to profile 171 CRPC tumors from 63 patients. RNA was amplified prior to hybridization against a common reference pool of prostate tumor cell lines.
2015-12-18 | E-GEOD-74685 | biostudies-arrayexpress
Project description:Intraindividual tumor heterogeneity may reduce the efficacy of molecularly guided systemic therapy for cancers that have metastasized. To determine whether the genomic alterations in a single metastasis provide a reasonable assessment of the major oncogenic drivers of other dispersed metastases in an individual, we analyzed multiple tumors from men with disseminated prostate cancer through whole-exome sequencing, array comparative genomic hybridization (CGH) and RNA transcript profiling [GSE74685], and we compared the genomic diversity within and between individuals. Custom Agilent 44K whole human genome expression oligonucleotide microarrays were used to profile 171 CRPC tumors from 63 patients. RNA was amplified prior to hybridization against a common reference pool of prostate tumor cell lines. Custom Agilent 415K whole human CGH microarrays were used to profile 149 CRPC tumors from 60 patients. Genomic DNA from tumors was hybridized against a pool of reference normal male DNA.
2016-02-16 | E-GEOD-77930 | biostudies-arrayexpress
Project description:Tumor heterogeneity may reduce the efficacy of molecularly guided systemic therapy for cancers that have metastasized. To determine whether the genomic alterations in a single metastasis provide a reasonable assessment of the major oncogenic drivers of other dispersed metastases in an individual, we analyzed multiple tumors from men with disseminated prostate cancer through whole-exome sequencing, array comparative genomic hybridization (CGH) and RNA transcript profiling, and we compared the genomic diversity within and between individuals.
2016-02-16 | GSE77930 | GEO
Project description:Current prostate cancer prognostic models are based on pre-treatment prostate-specific antigen (PSA) levels, biopsy Gleason score, and clinical staging but in practice are inadequate to accurately predict clinical disease progression. Hence, we sought to develop a molecular panel for prostate cancer progression by reasoning that molecular profiles might further improve current clinical models. We analyzed a Swedish Watchful Waiting cohort (1977â1999) with up to 30 years of clinical follow up using a novel method for gene expression profiling. This cDNA-mediated annealing, selection, ligation, and extension (DASL) method enabled the use of formalin-fixed paraffin-embedded transurethral resection of prostate (TURP) samples taken at the time of the initial diagnosis. We determined the expression profiles of 6100 genes for 281 men divided in two extreme groups: men who died of prostate cancer or developed metastases and men who survived more than 10 years without metastases (lethals and indolents, respectively). Several models using clinical and molecular features were evaluated for their ability to distinguish lethal from indolent cases. Surprisingly, none of the predictive models using molecular profiles significantly improved over models using clinical variables only. We reasoned that tumor sampling might preclude the identification of the dominant metastatic nodule. Additional computational analysis confirmed that molecular heterogeneity within both the lethal and indolent classes is widespread in prostate cancer as compared to other types of tumors. Thus the determination of the molecularly dominant tumor nodule may be limited by sampling at time of initial diagnosis, may not be present at time of initial diagnosis, or may occur as the disease progresses preventing the development of molecular biomarkers for prostate cancer progression. 281 cases from the population-based Swedish-Watchful Waiting cohort. The cohort consists of men with localized prostate cancer (clinical stage T1-T2, Mx, N0); Training set: first 186 samples; Validation cohort: remaining 95 cases from the same population.
2010-05-07 | E-GEOD-16560 | biostudies-arrayexpress
Project description:Comprehensive molecular cancer studies have extensively characterized most primary and some metastatic tumor types over the last decade. In prostate cancer, the most common tumor type in men, genomic studies have been most notably conducted for primary and metastatic tumors that had progressed under androgen deprivation therapies (ADT) to castration-resistant disease (CRPC). More recent studies have also looked at genetic alterations in a smaller number of prostate cancers frequently associated with neuroendocrine trans-differentiation. For this tumor type, it’s becoming clear that the complexity of genomic alterations does not allow an accurate assessment of the transformed phenotype. To overcome these hurdles, we show in patient-derived xenograft models how disease progression emerges at single-cell resolution and how pharmacologic perturbation can revert this process. Given this approach, we were able to investigate disease progression and androgen independence at single cell level: in our xenograft models, we show how tumor cell subpopulation progress along the trajectory from androgen-sensitive to insensitive disease.
2021-10-08 | E-MTAB-9903 | biostudies-arrayexpress
Project description:Androgen deprivation is the mainstay of therapy for progressive prostate cancer. Despite initial and dramatic tumor inhibition, most men eventually fail therapy and die of metastatic castration-resistant (CR) disease. Here, we characterize the profound degree of genomic alteration found in CR tumors using array CGH, gene expression arrays, and FISH. By cluster analysis, we show that the similarity of the genomic profiles from primary and metastatic tumors is driven by the patient. Using data adjusted for this similarity, we identify numerous high-frequency alterations in the CR tumors, such as 8p loss and chromosome 7 and 8q gain. By integrating array CGH and expression array data, we reveal genes whose correlated values suggest they are relevant to prostate cancer biology. We find alterations that are significantly associated with the metastases of specific organ sites, and others with CR tumors versus the tumors of patients with localized prostate cancer, not treated with androgen deprivation. Within the high-frequency sites of loss in CR metastases, we find an over-representation of genes involved in cellular lipid metabolism, including PTEN. Finally, using FISH we verify the presence of a gene fusion between TMPRSS2 and ERG suggested by chromosome-21 deletions detected by array CGH. We find the fusion in 54% of our CR tumors, and 81% of the fusion-positive tumors contain cells with multiple copies of the fusion. Our investigation lays the foundation for a better understanding of and possible therapeutic targets for CR disease, the poorly responsive and final stage of prostate cancer. The aim of this study was to characterize the genomic changes identified in a set of matched castrate-resistant primary and metastatic prostate cancers. Tumor cells were isolated by laser-capture microdissection from 14 patients, a total of 54 tumor samples. LCM capture samples were isolated from multiple metastastases from all but one patient from whom a single metastasis was available. Primary prostate tumor samples were collected from 12 patients. DNA was amplified by either ligation-mediated PCR (LMP) or WGA (Sigma-Aldrich, St. Louis, MO, USA). Reference DNA was isolated from peripheral blood from a single female individual.
2010-05-22 | E-GEOD-18259 | biostudies-arrayexpress
Project description:Purpose: Prostate cancer is the most frequently diagnosed cancer in men and the third leading cause of cancer related deaths among men living in developed countries. Biomarkers that predict disease outcome at the time of initial diagnosis would aid management of the disease. Experimental design: Proteins extracted from formalin-fixed paraffin-embeddded sections were identified either using LC-MALDI MS/MS of tryptic digests or after separation by one- or two-dimensional electrophoresis. A list of potential biomarker candidates, based on proposed associations with prostate cancer, was derived from the 320 identified proteins. Results: Four of the candidates: annexin A2, peroxiredoxin-1, prostate-specific antigen and zinc-alpha-2-glycoprotein, were examined by Western blotting of extracts of biopsies from men whom there was 10-year disease outcome data. Multiplexed Western blotting using cocktails of antibodies and fluor-labeled detection reagents showed that annexin A2 provided the best prediction of risk of metastatic disease. Conclusions and clinical relevance: This pilot study indicates that tumour expression of ANXA2 in diagnostic biopsies of a prostate cancer is predictive for the metastatic potential of that cancer. The potential of protein profiling of each cancer is to lead to an overall reduction in mortality from metastatic prostate cancer as well as reduced treatment associated morbidity.
2015-09-14 | PXD000963 | Pride
Project description:Prostate cancer incidence and related mortality are disproportionately higher in African American (AA) men than European American (EA) men, but the molecular mechanisms contributing to racial disparities are not fully elucidated. To identify molecular factors that can contribute to disease biology in prostate cancer from AA and EA men, we utilized a multi-omics approach to measure and integrate DNA methylation with gene expression changes. We compared and contrasted results from adjacent non-tumor and tumor tissues from AA and EA men. We found that hypermethylated regions are enriched for PRC2 and H3K27me3 pathways and EZH2/SUZ12 cofactors in a race-independent manner. On the other hand, hypomethylated regions in prostate tumors from AA men were enriched for olfactory/ribosomal pathways as well as distinct cofactors such as CTCF and KMT2A. DNA methylation at transcription start sites and 5’-UTR at GATA3, an androgen receptor (AR) coregulator, is associated with decreased gene expression in prostate tumors of AA men. Our analysis also showed an inverse correlation between DNA methylation and RNA expression of AR transcriptional targets, such as TRIM63, in prostate tumors of AA men. Our observations suggest a dysregulation of the AR signaling pathway in prostate cancer from AA men. To determine whether targeting AR results in race-specific gene expression changes, we utilized a prostate-cancer-specific Boolean network. Our simulation revealed that prolonged AR inhibition results in significant dysregulation in TGF-β, IDH1, and cell cycle pathways in prostate cancer of AA men. We expanded our observation of gene expression changes in the Boolean network and investigated RNA-sequencing data to better understand overall transcriptional alterations occurring in prostate tumors from AA and EA men. We found that gene expression changes related to microtubules, a subset of immune-related, and TMPRSS2-fusion pathways were dysregulated in prostate tumors of AA men and corresponded with progression-free survival of AA men. Altogether, the current study dissects complex signaling networks that are clinically actionable in prostate cancer from AA and EA men.
2023-12-21 | GSE237995 | GEO
Project description:Prostate cancer incidence and related mortality are disproportionately higher in African American (AA) men than European American (EA) men, but the molecular mechanisms contributing to racial disparities are not fully elucidated. To identify molecular factors that can contribute to disease biology in prostate cancer from AA and EA men, we utilized a multi-omics approach to measure and integrate DNA methylation with gene expression changes. We compared and contrasted results from adjacent non-tumor and tumor tissues from AA and EA men. We found that hypermethylated regions are enriched for PRC2 and H3K27me3 pathways and EZH2/SUZ12 cofactors in a race-independent manner. On the other hand, hypomethylated regions in prostate tumors from AA men were enriched for olfactory/ribosomal pathways as well as distinct cofactors such as CTCF and KMT2A. DNA methylation at transcription start sites and 5’-UTR at GATA3, an androgen receptor (AR) coregulator, is associated with decreased gene expression in prostate tumors of AA men. Our analysis also showed an inverse correlation between DNA methylation and RNA expression of AR transcriptional targets, such as TRIM63, in prostate tumors of AA men. Our observations suggest a dysregulation of the AR signaling pathway in prostate cancer from AA men. To determine whether targeting AR results in race-specific gene expression changes, we utilized a prostate-cancer-specific Boolean network. Our simulation revealed that prolonged AR inhibition results in significant dysregulation in TGF-β, IDH1, and cell cycle pathways in prostate cancer of AA men. We expanded our observation of gene expression changes in the Boolean network and investigated RNA-sequencing data to better understand overall transcriptional alterations occurring in prostate tumors from AA and EA men. We found that gene expression changes related to microtubules, a subset of immune-related, and TMPRSS2-fusion pathways were dysregulated in prostate tumors of AA men and corresponded with progression-free survival of AA men. Altogether, the current study dissects complex signaling networks that are clinically actionable in prostate cancer from AA and EA men.
2024-03-27 | GSE262524 | GEO
Project description:Prostate cancer incidence and related mortality are disproportionately higher in African American (AA) men than European American (EA) men, but the molecular mechanisms contributing to racial disparities are not fully elucidated. To identify molecular factors that can contribute to disease biology in prostate cancer from AA and EA men, we utilized a multi-omics approach to measure and integrate DNA methylation with gene expression changes. We compared and contrasted results from adjacent non-tumor and tumor tissues from AA and EA men. We found that hypermethylated regions are enriched for PRC2 and H3K27me3 pathways and EZH2/SUZ12 cofactors in a race-independent manner. On the other hand, hypomethylated regions in prostate tumors from AA men were enriched for olfactory/ribosomal pathways as well as distinct cofactors such as CTCF and KMT2A. DNA methylation at transcription start sites and 5’-UTR at GATA3, an androgen receptor (AR) coregulator, is associated with decreased gene expression in prostate tumors of AA men. Our analysis also showed an inverse correlation between DNA methylation and RNA expression of AR transcriptional targets, such as TRIM63, in prostate tumors of AA men. Our observations suggest a dysregulation of the AR signaling pathway in prostate cancer from AA men. To determine whether targeting AR results in race-specific gene expression changes, we utilized a prostate-cancer-specific Boolean network. Our simulation revealed that prolonged AR inhibition results in significant dysregulation in TGF-β, IDH1, and cell cycle pathways in prostate cancer of AA men. We expanded our observation of gene expression changes in the Boolean network and investigated RNA-sequencing data to better understand overall transcriptional alterations occurring in prostate tumors from AA and EA men. We found that gene expression changes related to microtubules, a subset of immune-related, and TMPRSS2-fusion pathways were dysregulated in prostate tumors of AA men and corresponded with progression-free survival of AA men. Altogether, the current study dissects complex signaling networks that are clinically actionable in prostate cancer from AA and EA men.
2024-03-27 | GSE262522 | GEO