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A Molecular Portrait of Potentially Curable Prostate Cancer

ABSTRACT: Herein we describe a molecular portrait of potentially curable, Gleason 7 and intermediate risk prostate cancer based on genome-wide CNV profiles of 96 patients, and subsequent whole-genome sequencing of 28 tumours from 10 patients, using DNA quantities that are achievable in diagnostic biopsies (50 ng). We show that Gleason 7 cancer is highly heterogeneous at the SNV, CNV, and intra-chromosomal translocation levels, and is characterized by a very low number of recurrent SNVs but significant structural variation. We identified a novel recurrent MYCL1 amplification, which was strongly associated with TP53 deletion and prognostic for biochemical recurrence in this cohort. Moreover, we identified clear evidence of divergent tumour evolution in multi focal cancer and, in 2/5 cases evaluated, multiple tumours of independent clonal origin. Taken together, these data represent the first systematic evaluation of the differential genomics of potentially curable prostate cancer, and strongly suggest that a more robust understanding of the relationship between genetic heterogeneity and clinical outcomes is required to effectively develop biomarkers of prognosis based on tumour genomics.

ORGANISM(S): Homo sapiens

PROVIDER: GSE64619 | GEO | 2015/04/20

SECONDARY ACCESSION(S): PRJNA271469

REPOSITORIES: GEO

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A Molecular Portrait of Potentially Curable Prostate Cancer

Project description:Herein we describe a molecular portrait of potentially curable, Gleason 7 and intermediate risk prostate cancer based on genome-wide CNV profiles of 96 patients, and subsequent whole-genome sequencing of 28 tumours from 10 patients, using DNA quantities that are achievable in diagnostic biopsies (50 ng). We show that Gleason 7 cancer is highly heterogeneous at the SNV, CNV, and intra-chromosomal translocation levels, and is characterized by a very low number of recurrent SNVs but significant structural variation. We identified a novel recurrent MYCL1 amplification, which was strongly associated with TP53 deletion and prognostic for biochemical recurrence in this cohort. Moreover, we identified clear evidence of divergent tumour evolution in multi focal cancer and, in 2/5 cases evaluated, multiple tumours of independent clonal origin. Taken together, these data represent the first systematic evaluation of the differential genomics of potentially curable prostate cancer, and strongly suggest that a more robust understanding of the relationship between genetic heterogeneity and clinical outcomes is required to effectively develop biomarkers of prognosis based on tumour genomics. Six samples were analyzed in duplicate. Samples included untreated cells, cells transfected with vector only, and cells transfected with 4 different MYCL transcript variants. Expression constructs and vector were purchased from GeneCopoeia

2015-04-20 | E-GEOD-64619 | biostudies-arrayexpress

CPC-GENE Prostate Cancer Heterogeneity Study

| EGAS00001000549 | EGA

Integrative tissue analysis of men with prostate cancer III

Project description:Prostate cancer is readily curable if detected early. The overall goal of this study is to conduct integrative profiling of tumor and blood genomics and transcriptomics.

2021-09-30 | GSE162868 | GEO

Integrative tissue analysis of men with prostate cancer VI

Project description:Prostate cancer is readily curable if detected early. The overall goal of this study is to conduct integrative profiling of tumor and blood genomics and transcriptomics.

2022-04-27 | GSE201284 | GEO

Integrative tissue analysis of men with prostate cancer V

Project description:Prostate cancer is readily curable if detected early. The overall goal of this study is to conduct integrative profiling of tumor and blood genomics and transcriptomics.

2021-09-30 | GSE183019 | GEO

Integrative tissue analysis of men with prostate cancer IV

Project description:Prostate cancer is readily curable if detected early. The overall goal of this study is to conduct integrative profiling of tumor and blood genomics and transcriptomics.

2021-09-30 | GSE183015 | GEO

Neurogenesis in Prostate Cancer is driven by Neural Precursors from the Central Nervous System

Project description:The development of autonomic nerve fibres in the tumour microenvironment is a pivotal event that regulates prostate cancer initiation and dissemination, but how nerves emerge in tumours is presently unknown. Here we show that Doublecortine-expressing (DCX+) neural precursors from the central nervous system (CNS) infiltrate prostate tumours and differentiate into neo-neurons that contribute to tumour development. In human primary prostate tumours and transgenic mouse cancer tissues, the density of DCX+ neural progenitors is strongly associated with tumour aggressiveness, invasion and recurrence. We found that DCX+ neural precursors egress from the subventricular zone, a neurogenic area of the CNS, and circulate in the blood to reach the tumour where they initiate neurogenesis. Hence, the DCX+ cells in prostate tumour can differentiate into neurons ex vivo and build up a tumour-associated neural network in vivo. Selective genetic depletion of DCX+ cells in mice significantly inhibits the early phases of prostate cancer development, whereas orthotopic transplantation of DCX+ cells purified from prostate tumour or brain tissues promotes tumour growth and cancer cell dissemination. These results unveil a unique crosstalk between the CNS and the tumour that drives a process of neurogenesis necessary for prostate cancer development, and indicate a novel neural element of the tumour microenvironment as a potential target for cancer treatment.

2019-05-16 | E-MTAB-7727 | biostudies-arrayexpress

Homo sapiens

Project description:Prostate Cancer Gleason Score

| PRJNA115927 | ENA

Human Prostate Cancer Illumina Infinium Human Methylation450 (HM450K bead array) BeadChip samples (benign vs tumor)

Project description:In order to examine the impact our probe filtering efforts might have on the analysis of real-world primary data, we analyzed clinical prostate cancer specimens. This included profiling of four prostate tumour tissue samples and four benign prostate tissues using the Illumina Infinium Human Methylation450 (HM450K bead array) BeadChip. These samples were used to explore the effects on analysis with and without a probe filtering. Four tumour samples containing Gleason 6 cancer and four benign samples from other prostate glands containing Gleason 6 cancer were selected for study. Tissue samples were cryosectioned for histopathological assessment. Genomic DNA was extracted from the homogenized samples using the Allprep Micro Kit (Qiagen, CA, USA) following manufacturer’s instructions and bisulfite converted using the Zymo EZ DNA Methylation kit (Zymo Research Corporation, CA, USA). The resulting libraries were hybridized onto the Illumina HumanMethylation450 (HM450K bead array) BeadChip. Raw intensity data was generated using an iScan microarray reader (Illumina).

2014-12-23 | E-GEOD-47915 | biostudies-arrayexpress

Proteomic-based computational stratification of intermediate-risk prostate cancer patients.

Project description:Gleason grading is an important prognostic indicator for prostate adenocarcinoma and is crucial for patient treatment decisions. However, intermediate-risk patients diagnosed in Gleason Grade Groups (GG) 2 and GG3 can harbour either aggressive or non-aggressive disease, resulting in under- or over-treatment of a significant number of patients. Here, we performed proteomic, differential expression, machine learning, and survival analyses for 1,348 matched tumour and benign samples from 278 patients. Three proteins (F5, TMEM126B and EARS2) were identified as candidate biomarkers in patients with biochemical recurrence. Multivariate Cox regression yielded 18 proteins, from which a risk score was constructed to dichotomise prostate cancer patients into low- and high-risk groups. This 18-protein signature is prognostic for the risk of biochemical recurrence and completely independent of the intermediate GG. Our results suggest that markers generated by computational proteomic profiling have the potential for clinical applications including integration into prostate cancer management.

2023-11-30 | PXD041005 | Pride

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