The level of copy number alteration (CNA), termed CNA burden, in the tumor genome is associated with recurrence of primary prostate cancer. Whether CNA burden is associated with prostate cancer ...survival or outcomes in other cancers is unknown. We analyzed the CNA landscape of conservatively treated prostate cancer in a biopsy and transurethral resection cohort, reflecting an increasingly common treatment approach. We find that CNA burden is prognostic for cancer-specific death, independent of standard clinical prognosticators. More broadly, we find CNA burden is significantly associated with disease-free and overall survival in primary breast, endometrial, renal clear cell, thyroid, and colorectal cancer in TCGA cohorts. To assess clinical applicability, we validated these findings in an independent pan-cancer cohort of patients whose tumors were sequenced using a clinically-certified next generation sequencing assay (MSK-IMPACT), where prognostic value varied based on cancer type. This prognostic association was affected by incorporating tumor purity in some cohorts. Overall, CNA burden of primary and metastatic tumors is a prognostic factor, potentially modulated by sample purity and measurable by current clinical sequencing.
Prostate-specific membrane antigen (PSMA) or folate hydrolase 1 (FOLH1) is highly expressed on prostate cancer. Its expression correlates inversely with survival and increases with tumor grade. ...However, the biological role of PSMA has not been explored, and its role in prostate cancer remained elusive. Filling this gap, we demonstrate that in prostate cancer, PSMA initiates signaling upstream of PI3K through G protein-coupled receptors, specifically via the metabotropic glutamate receptor (mGluR). PSMA's carboxypeptidase activity releases glutamate from vitamin B9 and other glutamated substrates, which activate mGluR I. Activated mGluR I subsequently induces activation of phosphoinositide 3-kinase (PI3K) through phosphorylation of p110β independent of
loss. The p110β isoform of PI3K plays a particularly important role in the pathogenesis of prostate cancer, but the origin of its activation was so far unknown. PSMA expression correlated with PI3K-Akt signaling in cells, animal models, and patients. We interrogated the activity of the PSMA-PI3K axis through positron emission tomography and magnetic resonance imaging. Inhibition of PSMA in preclinical models inhibited PI3K signaling and promoted tumor regression. Our data present a novel oncogenic signaling role of PSMA that can be exploited for therapy and interrogated with imaging.
Prostate cancer is characterized by its dependence on androgen receptor (AR) and frequent activation of PI3K signaling. We find that AR transcriptional output is decreased in human and murine tumors ...with
PTEN deletion and that PI3K pathway inhibition activates AR signaling by relieving feedback inhibition of HER kinases. Similarly, AR inhibition activates AKT signaling by reducing levels of the AKT phosphatase PHLPP. Thus, these two oncogenic pathways cross-regulate each other by reciprocal feedback. Inhibition of one activates the other, thereby maintaining tumor cell survival. However, combined pharmacologic inhibition of PI3K and AR signaling caused near-complete prostate cancer regressions in a
Pten-deficient murine prostate cancer model and in human prostate cancer xenografts, indicating that both pathways coordinately support survival.
► Inhibition of the PI3K pathway promotes AR activity ► Androgen blockade activates AKT signaling ► Combined PI3K and AR inhibition is superior to single-agent therapy in PTEN-loss prostate cancer
Primary prostate cancer is the most common malignancy in men but has highly variable outcomes, highlighting the need for biomarkers to determine which patients can be managed conservatively. Few ...large prostate oncogenome resources currently exist that combine the molecular and clinical outcome data necessary to discover prognostic biomarkers. Previously, we found an association between relapse and the pattern of DNA copy number alteration (CNA) in 168 primary tumors, raising the possibility of CNA as a prognostic biomarker. Here we examine this question by profiling an additional 104 primary prostate cancers and updating the initial 168 patient cohort with long-term clinical outcome. We find that CNA burden across the genome, defined as the percentage of the tumor genome affected by CNA, was associated with biochemical recurrence and metastasis after surgery in these two cohorts, independent of the prostate-specific antigen biomarker or Gleason grade, a major existing histopathological prognostic variable in prostate cancer. Moreover, CNA burden was associated with biochemical recurrence in intermediate-risk Gleason 7 prostate cancers, independent of prostate-specific antigen or nomogram score. We further demonstrate that CNA burden can be measured in diagnostic needle biopsies using low-input whole-genome sequencing, setting the stage for studies of prognostic impact in conservatively treated cohorts.
Annotation of prostate cancer genomes provides a foundation for discoveries that can impact disease understanding and treatment. Concordant assessment of DNA copy number, mRNA expression, and focused ...exon resequencing in 218 prostate cancer tumors identified the nuclear receptor coactivator
NCOA2 as an oncogene in ∼11% of tumors. Additionally, the androgen-driven
TMPRSS2-ERG fusion was associated with a previously unrecognized, prostate-specific deletion at chromosome 3p14 that implicates
FOXP1,
RYBP, and
SHQ1 as potential cooperative tumor suppressors. DNA copy-number data from primary tumors revealed that copy-number alterations robustly define clusters of low- and high-risk disease beyond that achieved by Gleason score. The genomic and clinical outcome data from these patients are now made available as a public resource.
► Integrated genomic profiling of 218 prostate tumors provides a unique public resource ► Androgen receptor coactivator
NCOA2 is amplified in primary and metastatic disease ►
TMPRSS2-ERG
+
tumors associate with 3p14 loss and candidates
FOXP1,
RYBP, and
SHQ1 ► Degree and pattern of CNAs in primary tumors is associated with risk of relapse
We demonstrate that the androgen receptor (AR) regulates a transcriptional program of DNA repair genes that promotes prostate cancer radioresistance, providing a potential mechanism by which androgen ...deprivation therapy synergizes with ionizing radiation. Using a model of castration-resistant prostate cancer, we show that second-generation antiandrogen therapy results in downregulation of DNA repair genes. Next, we demonstrate that primary prostate cancers display a significant spectrum of AR transcriptional output, which correlates with expression of a set of DNA repair genes. Using RNA-seq and ChIP-seq, we define which of these DNA repair genes are both induced by androgen and represent direct AR targets. We establish that prostate cancer cells treated with ionizing radiation plus androgen demonstrate enhanced DNA repair and decreased DNA damage and furthermore that antiandrogen treatment causes increased DNA damage and decreased clonogenic survival. Finally, we demonstrate that antiandrogen treatment results in decreased classical nonhomologous end-joining.
We demonstrate that the AR regulates a network of DNA repair genes, providing a potential mechanism by which androgen deprivation synergizes with radiotherapy for prostate cancer.
To pursue a systematic approach to the discovery of functional connections among diseases, genetic perturbation, and drug action, we have created the first installment of a reference collection of ...gene-expression profiles from cultured human cells treated with bioactive small molecules, together with pattern-matching software to mine these data. We demonstrate that this "Connectivity Map" resource can be used to find connections among small molecules sharing a mechanism of action, chemicals and physiological processes, and diseases and drugs. These results indicate the feasibility of the approach and suggest the value of a large-scale community Connectivity Map project.
The association of genes with the nuclear pore complex (NPC) and nuclear transport factors has been implicated in transcriptional regulation. We therefore examined the association of components of ...the nuclear transport machinery including karyopherins, nucleoporins, and the Ran guanine-nucleotide exchange factor (RanGEF) with the
Saccharomyces cerevisiae genome. We find that most nucleoporins and karyopherins preferentially associate with a subset of highly transcribed genes and with genes that possess Rap1 binding sites whereas the RanGEF preferentially associates with transcriptionally inactive genes. Consistent with coupling of transcription to the nuclear pore, we show that transcriptional activation of the
GAL genes results in their association with nuclear pore proteins, relocation to the nuclear periphery, and loss of RanGEF association. Taken together, these results indicate that the organization of the genome is coupled via transcriptional state to the nuclear transport machinery.
Abstract BACKGROUND: Recurrent mutations in the Speckle-Type POZ Protein ( SPOP ) gene occur in up to 15% of prostate cancers. However, the frequency and features of cancers with these mutations ...across different populations is unknown. OBJECTIVE: To investigate SPOP mutations across diverse cohorts and validate a series of assays employing high-resolution melting (HRM) analysis and Sanger sequencing for mutational analysis of formalin-fixed paraffin-embedded material. DESIGN, SETTING, AND PARTICIPANTS: 720 prostate cancer samples from six international cohorts spanning Caucasian, African American, and Asian patients, including both prostate-specific antigen-screened and unscreened populations, were screened for their SPOP mutation status. Status of SPOP was correlated to molecular features ( ERG rearrangement, PTEN deletion, and CHD1 deletion) as well as clinical and pathologic features. RESULTS AND LIMITATIONS: Overall frequency of SPOP mutations was 8.1% (4.6% to 14.4%), SPOP mutation was inversely associated with ERG rearrangement ( P < .01), and SPOP mutant ( SPOPmut ) cancers had higher rates of CHD1 deletions ( P < .01). There were no significant differences in biochemical recurrence in SPOPmut cancers. Limitations of this study include missing mutational data due to sample quality and lack of power to identify a difference in clinical outcomes. CONCLUSION: SPOP is mutated in 4.6% to 14.4% of patients with prostate cancer across different ethnic and demographic backgrounds. There was no significant association between SPOP mutations with ethnicity, clinical, or pathologic parameters. Mutual exclusivity of SPOP mutation with ERG rearrangement as well as a high association with CHD1 deletion reinforces SPOP mutation as defining a distinct molecular subclass of prostate cancer.
A multigenic locus at 3p13-14, spanning FOXP1 to SHQ1, is commonly deleted in prostate cancer and lost broadly in a range of cancers but has unknown significance to oncogenesis or prognosis. Here, we ...report that FOXP1-SHQ1 deletion cooperates with PTEN loss to accelerate prostate oncogenesis and that loss of component genes correlates with prostate, breast, and head and neck cancer recurrence. We demonstrate that Foxp1-Shq1 deletion accelerates prostate tumorigenesis in mice in combination with Pten loss, consistent with the association of FOXP1-SHQ1 and PTEN loss observed in human cancers. Tumors with combined Foxp1-Shq1 and Pten deletion show increased proliferation and anaplastic dedifferentiation, as well as mTORC1 hyperactivation with reduced Akt phosphorylation. Foxp1-Shq1 deletion restores expression of AR target genes repressed in tumors with Pten loss, circumventing PI3K-mediated repression of the androgen axis. Moreover, FOXP1-SHQ1 deletion has prognostic relevance, with cancer recurrence associated with combined loss of PTEN and FOXP1-SHQ1 genes.
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