The Proteogenomic Landscape of Curable Prostate Cancer
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
Dr. Thomas Kislinger
PROVIDER: MSV000081552 | MassIVE |
REPOSITORIES: MassIVE
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Project description:DNA sequencing studies have identified specific recurrent somatic mutations that drive the aggressiveness of localized prostate cancers. Surprisingly, though, it is poorly understood how the prostate cancer proteome is shaped by genomic, epigenomic and transcriptomic dysregulation. To fill this gap, we profiled the whole genomes, methylomes, epigenomes, transcriptomes and proteomes of 55 localized, intermediate-risk, prostate cancers. This multi-modal dataset revealed that the genomic subtypes of prostate cancer converge on four proteomic subtypes, which are associated with distinct clinical trajectories. ETS fusion genes, the most common mutation in prostate tumours, perturb the proteome and transcriptome in divergent ways – with different genes and pathways affected at each level. Indeed, mRNA abundance changes explain only ~10% of variability in protein levels. Perhaps as a direct result, prognostic biomarkers that combine genomic or epigenomic features with proteomic ones significantly outperform those comprised of either molecular feature alone. These data suggest that the proteome of prostate cancer is shaped by a complex interplay of genomic, epigenomic, transcriptomic and post-transcriptional dysregulation.
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Project description:The Proteogenomic Landscape of Curable Prostate Cancer [microarray]
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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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