A Molecular Portrait of Potentially Curable Prostate Cancer
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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. 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
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.
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.
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.
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.
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.
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.
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.
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).