Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA177194 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The Mutational Landscape of Lethal Castrate Resistant Prostate Cancer
| PRJNA151651 | ENA
Project description:Mutational Landscape of Lethal Castrate Resistant Prostate Cancer
| PRJNA177193 | ENA
Project description:Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains/losses, including ETS gene fusions, PTEN loss and androgen receptor (AR) amplification, that drive prostate cancer development and progression to lethal, metastatic castrate resistant prostate cancer (CRPC)1. As less is known about the role of mutations2-4, here we sequenced the exomes of 50 lethal, heavily-pretreated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment naïve, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPC (2.00/Mb) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy number analysis identified disruptions of CHD1, which define a subtype of ETS? prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in ~1/3 of CRPCs (commonly through TMPRSS2:ERG fusions), is a prostate cancer tumor suppressor that can also be deregulated through mutation. Further, we identified recurrent mutations in multiple chromatin/histone modifying genes, including MLL2 (mutated in 8.6% of prostate cancers), and demonstrate interaction of the MLL complex with AR, which is required for AR mediated signaling. We also identified novel recurrent mutations in the AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC) , and showed that mutated FOXA1 represses androgen signaling and increases tumor growth in vitro and in vivo. Proteins that physically interact with AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX, and ASXL1 were found to be mutated in CRPC, suggesting novel drivers of prostate cancer progression and potential resistance mechanisms to anti-androgen therapies. In summary, we describe the mutational landscape of a heavily treated metastatic cancer, identify novel mechanisms of AR signaling deregulated in prostate cancer, and prioritize candidates for future study. Gene expression profiling and array CGH (aCGH) was performed on matched benign prostate tissues (n=28), localized prostate cancer (n=59), and metastatic castrate resistant prostate cancer (CRPC, n=35). For gene expression profiling, frozen prostate tissue samples (channel 2), were hybridized against a commercial pool of benign prostate tissue (Clontech, channel 1). For aCGH, frozen prostate tissue samples (channel 2) were hybridized against a commerical sample of Human Male Genomic DNA (Promega, channel 1).
2012-05-22 | E-GEOD-35988 | biostudies-arrayexpress
Project description:Prostate cancer translational research has been hampered by the lack of comprehensive and tractable models that represent the genomic landscape of clinical disease. Metastatic castrate-resistant prostate cancer (mCRPC) patient derived xenografts (PDXs) recapitulate the genetic and phenotypic diversity of the disease. We sought to establish a representative, preclinical platform of PDX-derived organoids that is experimentally facile for high throughput and mechanistic analysis.
2018-05-10 | GSE113709 | GEO
Project description:Prostate gland is a highly androgen dependent gland. The first line of treatment for metastatic prostate cancer therefore, is androgen ablation. This can be achieved by multiple non-surgical methods. However, most of these cancers although respond well initially, become resistant to androgen ablation sooner or later. These cancers then become extremely aggressive and difficult to treat, thereby drastically affect the patient prognosis. A gene expression signature for castrate resistant prostate cancer would be useful in identification of mechanisms responsible for castrate resistance, as well as to predict the progression of the cancer into castrate resistance. For this, our group has done a RNA-seq analysis of a. Control group (C); b. Castrate Sensitive group (B) and c. Castrate Resistant group (A). Gene expression profiling was performed on these samples using RNA-seq. Differentially expressed genes between control and castrate sensitive as well as control and castrate resistant groups were identified.
2024-09-11 | GSE262940 | GEO
Project description:Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains/losses, including ETS gene fusions, PTEN loss and androgen receptor (AR) amplification, that drive prostate cancer development and progression to lethal, metastatic castrate resistant prostate cancer (CRPC)1. As less is known about the role of mutations2-4, here we sequenced the exomes of 50 lethal, heavily-pretreated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment naïve, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPC (2.00/Mb) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy number analysis identified disruptions of CHD1, which define a subtype of ETS‑ prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in ~1/3 of CRPCs (commonly through TMPRSS2:ERG fusions), is a prostate cancer tumor suppressor that can also be deregulated through mutation. Further, we identified recurrent mutations in multiple chromatin/histone modifying genes, including MLL2 (mutated in 8.6% of prostate cancers), and demonstrate interaction of the MLL complex with AR, which is required for AR mediated signaling. We also identified novel recurrent mutations in the AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC) , and showed that mutated FOXA1 represses androgen signaling and increases tumor growth in vitro and in vivo. Proteins that physically interact with AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX, and ASXL1 were found to be mutated in CRPC, suggesting novel drivers of prostate cancer progression and potential resistance mechanisms to anti-androgen therapies. In summary, we describe the mutational landscape of a heavily treated metastatic cancer, identify novel mechanisms of AR signaling deregulated in prostate cancer, and prioritize candidates for future study.
2012-05-23 | GSE35988 | GEO
Project description:To identify changes at multiple omic levels between hormone naive and castration resistant prostate cancer. Using orthograft murine tumour models of human cell lines injected into the prostate of CD-1 Nude mice grown under castration resistant (castrate) or hormone naive (non-castrate) conditions.
2021-05-03 | E-MTAB-9831 | biostudies-arrayexpress
Project description:Prostate cancer translational research has been hampered by the lack of comprehensive and tractable models that represent the genomic landscape of clinical disease. Metastatic castrate-resistant prostate cancer (mCRPC) patient derived xenografts (PDXs) recapitulate the genetic and phenotypic diversity of the disease. We sought to establish a representative, preclinical platform of PDX-derived organoids that is experimentally facile for high throughput and mechanistic analysis.
2018-05-10 | GSE113741 | GEO
Project description:Patient Derived Xenograft for Delivery of Precision Medicine in Castrate Resistant Prostate Cancer
| PRJNA288475 | ENA
Project description:Benign prostate tissue and prostate cancer tissue (untreated, androgen deprivation therapy responding, or castrate-resistant) was collected from patients at the time of transurethral resection of the prostate surgery.
2012-12-01 | GSE28680 | GEO