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Integrative Clinical Sequencing Analysis of Metastatic Castration Resistant Prostate Cancer Reveals a High Frequency of Clinical Actionability

ABSTRACT: Integrative Clinical Sequencing Analysis of Metastatic Castration Resistant Prostate Cancer Reveals a High Frequency of Clinical Actionability

PROVIDER: PRJNA283922 | ENA |

REPOSITORIES: ENA

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Integrative Clinical Sequencing Analysis of Metastatic Castration Resistant Prostate Cancer Reveals a High Frequency of Clinical Actionability

Project description:<p>Most prostate cancer deaths are caused by metastatic, castration resistant disease (mCRPC). To develop a precision medicine framework for mCRPC, we established a multi-institutional, international clinical sequencing infrastructure to enroll and carry out prospective whole exome and transcriptome sequencing of tumors from a cohort of mCRPC patients. We obtained high quality DNA and RNA sequence data from 150 bone or soft tissue biopsies. Central pathology revealed high-grade adenocarcinoma with only four cases (3.6%) showing neuroendocrine differentiation. Aberrations of AR, ETS genes, TP53 and PTEN were frequent (40-60% of cases), with TP53 and AR alterations being the most enriched in mCRPC compared to primary prostate cancer. We identified novel genomic alterations in PIK3CA/B (fusions and mutations); R-spondin, BRAF and RAF1 (fusions); APC (inactivating mutations); delta-catenin (missense mutations); and ZBTB16/PLZF (homozygous deletions). Aberrations of BRCA2, BRCA1 and ATM were observed at substantially higher frequencies (19.3% overall) than seen in primary prostate cancers, with 56% of these being exclusively somatic. Putative driver gene alterations were identified in nearly all patients, and over half also harbored driver gene fusions, homozygous deletions and/or amplifications. Moreover, 89% of patients harbored a clinically actionable aberration including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with actionable pathogenic germline alterations. Overall, integrative clinical sequencing analysis can be safely and efficiently performed in mCRPC, yields findings that may be actionable for enrolling patients in clinical trials of targeted therapies, and may inform the basis of individual clinical responses.</p>

| phs000915 | dbGaP

Whole Transcriptomic Sequencing of Metastatic Castration Resistant Prostate Cancer Samples

Project description:We report the gene expression profile of 8 metastatic castration resisistant prostate cancer samples analyzed by paired-end RNA-seq. We found evidence of extensive abnormal splicing as well as several novel fusion genes. Finally, we also observed several recurrent high-confidence somatic mutations. Paired-end RNA-seq by rRNA depletion

2014-09-06 | E-GEOD-50630 | biostudies-arrayexpress

Genomic Characterization of Metastatic Castration Resistant Prostate Cancer

Project description:Genomic Characterization of Metastatic Castration Resistant Prostate Cancer

| PRJNA479543 | ENA

Genomic Characterization of Metastatic Castration Resistant Prostate Cancer

Project description:Genomic Characterization of Metastatic Castration Resistant Prostate Cancer

| PRJNA479544 | ENA

Homo sapiens

Project description:Integrative Clinical Sequencing Analysis of Metastatic Castration Resistant Prostate Cancer Reveals a High Frequency of Clinical Actionability

| PRJNA283923 | ENA

Whole Genome Methylation Analysis of Metastatic Castration Resistant Prostate Cancer

Project description:Relatively little is known about how changes in gene copy number (CN) and gene CpG methylation interact to affect specific pathways in metastatic castration-resistant prostate cancer (CRPC). Oligonucleotide array comparative genomic hybridization (aCGH) was performed on DNA isolated from 15 metastatic CRPC samples. Commonly aberrant genes were evaluated in a confirmatory fashion using PCR, aCGH data from primary tumors, and existing CRPC expression data. Array-based comprehensive CpG methylation was assessed on the same sample set. A total of 495 genes (79 gained, 416 deleted) were CN aberrant in ?66% of the samples by aCGH, and 77 (9 amplified, 68 deleted) had statistically concordant expression including gain of AR and loss of PTEN and RB1. Significant CN differences were seen between the genomes of patients with AR-amplified and AR-unamplified tumors, including common loss of AR repressors in AR-unamplified tumors. The majority of CRPC samples were hypermethylated compared to benign prostate tissue. Simultaneous methylation and heterozygous gene deletion occurred in the tumor suppressor RB1 and in HSD17B2, responsible for testosterone metabolism. Establishment of a comprehensive methylation signature and coupling of epigenomic and structural analyses sheds light on the alterations that allow CRPC to circumvent hormonal therapy and may provide new drug targets for what is currently an incurable disease state. 15 tumor samples taken from 14 men with metastatic castration resistant prostate cancer were analyzed, including two samples from the same patient. No control samples were used for this experiment.

2011-12-06 | E-GEOD-34174 | biostudies-arrayexpress

Whole Transcriptomic Sequencing of Metastatic Castration Resistant Prostate Cancer Samples

2014-09-06 | GSE50630 | GEO

Molecular profiling of peripheral blood is associated with circulating tumor cells content and poor survival in metastatic castration-resistant prostate cancer

Project description:The enumeration of circulating tumor cells (CTCs) in peripheral blood correlates with clinical outcome in castration-resistant prostate cancer (CRPC). We analyzed the molecular profiling of peripheral blood from 43 metastatic CRPC patients with known CTC content in order to identify genes that may be related to prostate cancer progression. Global gene expression analysis identified the differential expression of 282 genes between samples with ?5 CTCs vs <5 CTCs, 58.6% of which were previously described as over-expressed in prostate cancer (18.9% in primary tumors and 56.1% in metastasis). Those genes were involved in survival functions such as metabolism, signal transduction, gene expression, and cell growth, death, and movement. The expression of selected genes was evaluated by quantitative RT-PCR. This analysis revealed a two-gene model (SELENBP1 and MMP9) with a high significant prognostic ability (HR 6; 95% CI 2.61 - 13.79; P<0.0001). The combination of the two-gene signature plus the CTCs count showed a higher prognostic ability than neither CTCs enumeration nor gene expression alone (P<0.05). This study shows a gene expression profile in PBMNC is associated with CTCs count and clinical outcome in metastatic CRPC, describing genes and pathways potentially associated with CRPC progression. The complete database comprised the expression measurements of 43 metastatic castration-resistant prostate cancer (CRPC) samples and their asociation with the number of circulating tumor cells (CTCs). Twenty of them have a number circulating tumor cells (CTCs) greater than 5.

2015-04-30 | E-GEOD-66532 | biostudies-arrayexpress

Integrative Genomic and Proteomic Analysis of Prostate Cancer Reveals Signatures of Metastatic Progression

Project description:An integrative analysis of this compendium of proteomic alterations and transcriptomic data was performed revealing only 48-64% concordance between protein and transcript levels. Importantly, differential proteomic alterations between metastatic and clinically localized prostate cancer that mapped concordantly to gene transcripts served as predictors of clinical outcome in prostate cancer as well as other solid tumors. Keywords: prostate cancer progression

2005-09-20 | GSE3325 | GEO

Dysregulated expression of genes in regulatory T cells from metastatic castration-resistant prostate cancer patients

Project description:We analyzed the global gene expression pattern of Tregs between healthy donors and prostate cancer patients. We found that genes related to cell cycle, cellular proliferation, immune responses, hematological system development and function were differentially expressed in Tregs from prostate cancer patients. Total RNA samples of Tregs, isolated from peripheral blood, were obtained from three separate healthy donors and three metastatic castration-resistant prostate cancer patients. Global gene expression pattern was examined by performing GeneChip microarray hybridization. Genes differentially expressed between the two groups of donors were sorted and categorized based on their biological functions.

2013-03-05 | E-GEOD-38043 | biostudies-arrayexpress

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