ABSTRACT: Integrative Clinical Sequencing Analysis of Metastatic Castration Resistant Prostate Cancer Reveals a High Frequency of Clinical Actionability
Project description:Integrative Clinical Sequencing Analysis of Metastatic Castration Resistant Prostate Cancer Reveals a High Frequency of Clinical Actionability
Project description:Supporting ChIP-Seq data for the article "The genomic landscape of metastatic castration-resistant prostate cancers" by Dessel et al. (Nat. Comm. 2019) reveals multiple distinct genotypes with potential clinical impact
Project description:Prostate cancer is one of the major cancers that seriously affect men's health. It has high morbidity and high mortality, but there is still no ideal molecular markers for the diagnosis and prognosis of prostate cancer. Castration-resistant prostate cancer is associated with wide variations in survival. To determine whether differentially expressed circRNAs in plasma exosomes can be used as a novel biomarker for castration-resistant prostate cancer prognosis, we performed high-throughput circRNA sequencing on 15 pairs of plasma exosomes from 30 metastatic castration-resistant prostate cancer patients, with or without early progression, to screen differentially expressed circRNAs.
Project description:Prostate cancer is the most common cancer in men and AR downstream signalings promote prostate cancer cell proliferation. Androgen-deprivation therapy is the first-line treatment strategy for advanced prostate cancer. However, many tumors develop to castration-resistant prostate cancer (CRPC) and relapse. Thus, analyzing key factors for development of CRPC is important. We found PSF functions as RNA binding protein and transcription factor to promote castration-resistant tumor growth. High expression of PSF in metastatic prostate cancer tissue indicates the clinical relevance. In order to investigate the PSF function in CRPC cells, we performed gene expression in CRPC model cells derived from AR-positive prostate cancer cell lines after siPSF treatment.
Project description:EZH2 is frequently over-expressed in aggressive and metastatic solid tumors, including castration resistant prostate cancer (CRPC). We sought to determine EZH2-dependent gene expression programmes in prostate cancer progression, and found an intriguing functional switch of EZH2 from a repressor to an activator during CRPC development. We used microarrays to detail the global profiling of gene expression that are differentially regulated upon EZH2 depletion in two different prostate cancer cell lines. The androgen-dependent prostate cancer cell line LNCaP and the LNCaP-derived androgen-independent cell line LNCaP-abl (abl) were used for this study, as their transcription profiles strongly resemble that of clinical androgen-dependent and castration resistant prostate tumors, respectively. EZH2 was silenced by specific siRNAs in both cell lines, and total RNA was extracted and hybridized on Affymetrix microarrays.
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.
Project description:Docetaxel-based chemotherapy is the standard first-line therapy in metastatic castration-resistant prostate cancer. However, most patients eventually develop resistance to this treatment. The aim of the study was to identify key molecular genes and networks associated with docetaxel resistance in 2 models of docetaxel-resistant castration-resistant prostate cancer cell lines.
Project description:Current knowledge of prostate cancer genomes is largely based on relatively small patient cohorts using single modality analysis platforms. Here we report concordant assessment of DNA copy number, mRNA and microRNA expression and focused exon resequencing in prostate tumors from 218 patients with primary or metastatic prostate cancer with a median of 5 years clinical follow-up, now made available as a public resource. Mutations in known, commonly mutated oncogenes and tumor suppressor genes such as PIK3CA, KRAS, BRAF and TP53 are present but generally rare. However, integrative analysis of mutations with copy number alterations (CNAs) and expression changes reveal alterations in the PI3K, RAS/RAF and androgen receptor (AR) pathways in nearly all metastatic samples and in a higher frequency of primary samples than previously suspected based on single-gene studies. Other new findings include evidence that the nuclear receptor coactivator NCOA2 functions as a driver oncogene in ~20 percent of primaries. Tumors with the androgen-driven TMPRSS2-ERG fusion were significantly associated with a small, previously unrecognized, prostate-specific 3p14 deletion that, through mRNA expression and resequencing analysis, implicates FOXP1, RYBP and SHQ1 as candidate cooperative tumor suppressors. Comparison of transcriptome and DNA copy number data from primary tumors for prognostic impact revealed that CNAs robustly define clusters of low- and high-risk disease beyond that achieved by Gleason score. In sum, this integrative genomic analysis of a substantial cohort of tumors clarifies the role of several known cancer pathways in prostate cancer, implicates several new ones, reveals a previously unappreciated role for CNAs in prognosis and provides a blueprint for clinical development of pathway inhibitors. Human prostate samples were profiled on Agilent microRNA V2 arrays per manufacturer's instructions.
Project description:Bulk RNA sequencing of peripheral blood neutrophils from prostate cancer at different stages of disease progression, including localized disease, hormone-sensitive- and castration-resistant metastatic prostate cancer
Project description:Docetaxel-based chemotherapy is the standard first-line therapy in metastatic castration-resistant prostate cancer. However, most patients eventually develop resistance to this treatment. The aim of the study was to identify key molecular genes and networks associated with docetaxel resistance in 2 models of docetaxel-resistant castration-resistant prostate cancer cell lines. DU-145 and PC-3 cells were converted to docetaxel-resistant cells, DU-145R and PC-3R, respectively. Whole-genome arrays were used to compare global gene expression between these 4 cell lines. Arrays were performed by triplicate for each cell line.