Gene signatures in prostate cancer linked to the Gleason score
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE32571 | GEO | 2012/10/19
SECONDARY ACCESSION(S): PRJNA147105
REPOSITORIES: GEO
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Project description:The identification of novel oncogenic and druggable targets in patient subgroups with poor prognosis may help to develop corresponding targeted therapy approaches. Microarray data analyses of 59 prostate cancer and 39 benign tissue samples revealed major transcriptional differences. More than 5.000 genes were identified to be differentially expressed between matched tumor and benign samples. In the prostate cancer samples we identified 144 differentially expressed associated with Gleason pattern. Illumina microarray experiments were done from of 59 prostate cancer and 39 matched benign tissue samples. We analyzed for differentially expressed genes between tumor and benign tissues, and between tumors with higher Gleason patter (4+3 and higher) against lower Gleason patter (3+4 and lower).
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Project description:In this dataset, we report the gene expression of adjacent Gleason 3 and Gleason 4 foci microdissected from the same prostate cancer sample. We found a striking similarity between adjacent G3 and G4 tumors, consistent with their clonal origin, but very few recurrently up- or down- regulated genes across patients.
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Project description:PSA screening has led to enormous overtreatment of prostate cancer, due to the inability to distinguish potentially lethal disease at diagnosis. We reasoned that by identifying an mRNA signature of Gleason grade, the best predictor of prognosis, we could improve prediction of lethal disease among men with moderate Gleason 7 tumors, the most common grade, and most indeterminate in terms of prognosis. Using the complementary DNA (cDNA)–mediated annealing, selection, extension, and ligation assay, we measured the mRNA expression of 6,100 genes in prostate tumor tissue in the Swedish Watchful Waiting cohort (N=358) and Physicians’ Health Study (PHS; N=109). We developed an mRNA signature of Gleason comparing individuals with Gleason ≤6 to those with Gleason ≥8 tumors, and applied the model among Gleason 7 cases to discriminate lethal cases. We built a157-gene signature using the Swedish data that predicted Gleason with low misclassification (AUC=0.91); when this signature was tested in the PHS validation set, the discriminatory ability remained high (AUC=0.94). In men with Gleason 7 tumors, who were excluded from the model building, the signature significantly improved the prediction of lethal disease beyond knowing whether the Gleason score was 4+3 or 3+4 (p=0.006). Our expression signature and the genes identified may improve our understanding of the de-differentiation process of prostate tumors. Additionally, the signature may have clinical applications among men with Gleason 7, by further estimating their risk of lethal prostate cancer and thereby guiding therapy decisions to improve outcomes and reduce overtreatment.
2012-05-01 | GSE37663 | GEO
Project description:PSA screening has led to enormous overtreatment of prostate cancer, due to the inability to distinguish potentially lethal disease at diagnosis. We reasoned that by identifying an mRNA signature of Gleason grade, the best predictor of prognosis, we could improve prediction of lethal disease among men with moderate Gleason 7 tumors, the most common grade, and most indeterminate in terms of prognosis. Using the complementary DNA (cDNA)M-bM-^@M-^Smediated annealing, selection, extension, and ligation assay, we measured the mRNA expression of 6,100 genes in prostate tumor tissue in the Swedish Watchful Waiting cohort (N=358) and PhysiciansM-bM-^@M-^Y Health Study (PHS; N=109). We developed an mRNA signature of Gleason comparing individuals with Gleason M-bM-^IM-$6 to those with Gleason M-bM-^IM-%8 tumors, and applied the model among Gleason 7 cases to discriminate lethal cases. We built a157-gene signature using the Swedish data that predicted Gleason with low misclassification (AUC=0.91); when this signature was tested in the PHS validation set, the discriminatory ability remained high (AUC=0.94). In men with Gleason 7 tumors, who were excluded from the model building, the signature significantly improved the prediction of lethal disease beyond knowing whether the Gleason score was 4+3 or 3+4 (p=0.006). Our expression signature and the genes identified may improve our understanding of the de-differentiation process of prostate tumors. Additionally, the signature may have clinical applications among men with Gleason 7, by further estimating their risk of lethal prostate cancer and thereby guiding therapy decisions to improve outcomes and reduce overtreatment. 198 cases from the population-based Swedish-Watchful Waiting cohort. The cohort consists of men with localized prostate cancer (clinical stage T1-T2, Mx, N0); expression profiles from tumors with Gleason M-bM-^IM-%8 (N=89) were compared to those from tumors with Gleason M-bM-^IM-$6 (N=109)
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Project description:Androgens are a prequisite for the development of human prostate and prostate cancer. Androgen action is mediated via androgen receptor. Androgen ablation therapy is used for the treatment of metastasized prostate cancer. The aim of the study was to identify genes differentially expressed in benign human prostate, prostate cancer and in prostate tissue three days after castration. These genes are potential diagnostic and therapeutic targets for prostate cancer and benign prostatic hyperplasia. We used microarrays to examine the gene expression profiles in benign prostate adjacent to prostate cancer and prostate cancer in radical prostatectomy specimens and in prostate tissue samples taken 3 days after surgical castration performed for treatment of prostate cancer. Human prostate tissue was obtained from radical prostatectomy samples and from prostate biopsy samples (castrated samples). Benign and malignant tissues samples were microdissected from prostatectomy samples. Tissues were used for RNA isolation and were further processed as samples for microarray. Three prostatectomy samples were used as replicates (benign and malignant prostate). All prostate cancers were Gleason 3+3 pattern. Castrated tissue samples were taken from patients three days after surgical castration for the treatment of advanced or metastasized prostate cancer. Six biopsies were taken from each subject and individual subject samples were used as three replicates in microarray.
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Project description:A major challenge in the clinical management of prostate cancer is the inability to definitively diagnose indolent versus aggressive cases. Contributing to this challenge is a lack of basic science understanding of the molecular basis behind aggressiveness subtypes in prostate cancer. DNA methylation is the epigenetic addition of a methyl group to the DNA base cytosine and has been found to regulate cell proliferation and environmental adaptation. We hypothesized that DNA methylation changes are a mechanism by which an aggressive cancer attains phenotypes that distinguish it from indolent cases via disruption of regulatory networks. This hypothesis was tested by comparing DNA methylation between benign prostate and both low grade (Gleason score 6) and high grade (Gleason score 8 to 10) groups. Methylome-wide next generation sequencing was performed on formalin-fixed paraffin embedded (FFPE) samples from radical prostatectomy cases using MBD-isolated genome sequencing (MiGS). This technique uses a DNA methylation binding protein (MBD) to purify fragments from a genomic library with a high level of CpG DNA methylation. These fragments were then sequenced via next generation sequencing, the reads were aligned to a reference genome, and then the reads were counted within non-overlapping 50bp windows genome wide. Statistical analysis was then performed on these windowed counts to produce differentially methylated regions (DMRs). MBD-isolated Genome Sequencing (MiGS) for groups of benign prostate (from cystoprostatectomy), low grade prostate cancer (from radical prostatectomy with Gleason Score 6), and high grade prostate cancer (from radical prostatectomy with Gleason Scores 8 to 10) in both European Americans and African Americans
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