Proteomic-based computational stratification of intermediate-risk prostate cancer patients.
Ontology highlight
ABSTRACT:
INSTRUMENT(S): TripleTOF 6600
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Prostate Gland
DISEASE(S): Prostate Adenocarcinoma
SUBMITTER: 
Zainab Noor
LAB HEAD: Qing Zhong
PROVIDER: PXD041005 | Pride | 2023-11-30
REPOSITORIES: Pride
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Project description:Prostate cancer is the most common malignancy in men. Yet, the modest benefit of treatment highlights the unmet need for prognostic biomarkers in prostate cancer (1). Few large prostate oncogenome resources currently exist that combine the molecular and clinical outcome data necessary for prognostic discovery. To determine the extent to which genomic aberrations reflect the risk of prostate cancer-specific outcomes, we profiled more than 100 primary prostate cancers with long-term follow-up for genome-wide copy number alterations (CNA). We also updated the long-term clinical outcome (median 8 years) of an additional independent cohort of 181 primary prostate cancers that we previously profiled for CNA and expression changes (2). Together, we found that CNA burden across the genome, defined as the percent of the tumor genome affected by CNA, is prognostic for recurrence and metastasis in these two cohorts. This prognostic significance of CNA is independent of Gleason grade, a major existing histopathological prognostic variable in prostate cancer. Moreover, in intermediate-risk Gleason 7 prostate cancers that show a wide range of outcomes, CNA burden is also prognostic for biochemical recurrence, independent of prostate-specific antigen or nomogram score. CNA burden therefore has the potential to stratify patients by their risk of recurrence in an otherwise intermediate risk subpopulation. We further demonstrate that CNA burden can be established in diagnostic FFPE needle biopsies using low-input whole genome sequencing. Together, this work highlights the potential of oncogenomics to identify useful and clinically amenable prognostic factors that may inform prostate cancer outcome and treatment. Human prostate samples were profiled on Agilent 1M aCGH arrays per manufacturer's instructions. A pooled reference normal DNA was used as the reference.
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Project description:Prostate cancer is the most common malignancy in men. Yet, the modest benefit of treatment highlights the unmet need for prognostic biomarkers in prostate cancer (1). Few large prostate oncogenome resources currently exist that combine the molecular and clinical outcome data necessary for prognostic discovery. To determine the extent to which genomic aberrations reflect the risk of prostate cancer-specific outcomes, we profiled more than 100 primary prostate cancers with long-term follow-up for genome-wide copy number alterations (CNA). We also updated the long-term clinical outcome (median 8 years) of an additional independent cohort of 181 primary prostate cancers that we previously profiled for CNA and expression changes (2). Together, we found that CNA burden across the genome, defined as the percent of the tumor genome affected by CNA, is prognostic for recurrence and metastasis in these two cohorts. This prognostic significance of CNA is independent of Gleason grade, a major existing histopathological prognostic variable in prostate cancer. Moreover, in intermediate-risk Gleason 7 prostate cancers that show a wide range of outcomes, CNA burden is also prognostic for biochemical recurrence, independent of prostate-specific antigen or nomogram score. CNA burden therefore has the potential to stratify patients by their risk of recurrence in an otherwise intermediate risk subpopulation. We further demonstrate that CNA burden can be established in diagnostic FFPE needle biopsies using low-input whole genome sequencing. Together, this work highlights the potential of oncogenomics to identify useful and clinically amenable prognostic factors that may inform prostate cancer outcome and treatment.
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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
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Project description:To identify biomarkers predictive of biochemical recurrence, we isolated the RNA from 70 formalin-fixed paraffin-embedded (FFPE) radical prostatectomy specimens with known long term outcome to perform DASL expression profiling with a custom-designed panel of 522 prostate cancer relevant genes that we designed. We identified a panel of ten protein-coding genes and two miRNA genes that could be used to separate patients with and without biochemical recurrence (p < 0.001), as well as for the subset of 42 Gleason score 7 patients (p < 0.001). We performed an independent validation analysis on 40 samples and found that the biomarker panel was also significant at prediction of recurrence for all cases (p = 0.013) and for a subset of 19 Gleason score 7 cases (p = 0.010), both of which were adjusted for relevant clinical information including T-stage, PSA and Gleason score. Importantly, these biomarkers could significantly predict clinical recurrence for Gleason 7 patients. These biomarkers may increase the accuracy of prognostication following radical prostatectomy using formalin-fixed specimens. Total RNA prepared from FFPE cores from prostatectomy samples of 70 patients were used for the training phase (29 with biochemical recurrence and 41 controls). All samples were analyzed by both custom Prostate DASL of 522 genes and by Illumina miRNA microarray. Subsequently in the validation phase, samples from 40 patients were used on the same platforms (13 with biochemical recurrence and 27 controls). For the training set, 45 cases were from Sunnybrook Health Science Center (Toronto, ON), and 25 patients from Emory University. For the validation set, all samples were from Emory University. Relevant clinical metadata included are PSA, T-stage, and Gleason Score.
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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.
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Project description:To identify biomarkers predictive of biochemical recurrence, we isolated the RNA from 70 formalin-fixed paraffin-embedded (FFPE) radical prostatectomy specimens with known long term outcome to perform DASL expression profiling with a custom-designed panel of 522 prostate cancer relevant genes that we designed. We identified a panel of ten protein-coding genes and two miRNA genes that could be used to separate patients with and without biochemical recurrence (p < 0.001), as well as for the subset of 42 Gleason score 7 patients (p < 0.001). We performed an independent validation analysis on 40 samples and found that the biomarker panel was also significant at prediction of recurrence for all cases (p = 0.013) and for a subset of 19 Gleason score 7 cases (p = 0.010), both of which were adjusted for relevant clinical information including T-stage, PSA and Gleason score. Importantly, these biomarkers could significantly predict clinical recurrence for Gleason 7 patients. These biomarkers may increase the accuracy of prognostication following radical prostatectomy using formalin-fixed specimens. Total RNA prepared from FFPE cores from prostatectomy samples of 70 patients were used for the training phase (29 with biochemical recurrence and 41 controls). All samples were analyzed by both custom Prostate DASL of 522 genes and by Illumina miRNA microarray. Subsequently in the validation phase, samples from 40 patients were used on the same platforms (13 with biochemical recurrence and 27 controls). For the training set, 45 cases were from Sunnybrook Health Science Center (Toronto, ON), and 25 patients from Emory University. For the validation set, all samples were from Emory University. Relevant clinical metadata included are PSA, T-stage, and Gleason Score. ***This submission represents the mRNA component of the study
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