Genomic Markers in GRID Tumor RNA Expression Profile
Standard Research-Use-Only (RUO) Tumor RNA Expression Profiles for Decipher GRID include expression status of the following list of markers representing the genes currently evaluated for their prognostic and predictive power in prostate cancer. Click here to see a sample GRID profile.
Androgen signaling, via interaction with its intracellular receptor (AR), is a key axis in primary prostate tumor driven proliferation. AR can also regulate cellular events such invasion, differentiation and apoptosis.24 Prostate cancer initiation and progression is uniquely dependent on AR. Dysregulation of the AR-axis may play a role in castrate resistant prostate cancer (CRPC) progression.25 Perturbation of the AR pathway through AR deprivation or other AR-targeted therapies are currently used to treat prostate cancer.26,27 Studies have shown that patients with low AR activity tend to be more responsive to the chemotherapy docetaxel.27 AR gene expression or AR-signaling activity through Decipher GRID may provide additional insight into a patient’s response to hormonal treatments such as abirateron, biclatumide or enzalutamide.
Lower expression of AR is correlated to poor response to hormonal therapy and associated with development of neuroendocrine prostate cancer.1,18,33
High expression of AR is associated with increased proliferation and response to AR antagonists or blockade.15
Lower expression of KLK2 in prostate tumors is correlated to poor response to hormonal therapy and associated with neuroendocrine prostate cancer.1
High expression of KLK2 is associated with increased proliferation, markers of aggressive prostate cancer and response to AR antagonists or blockade.15
Lower expression of tissue PSA (KLK3) in prostate tumors is correlated to poor response to hormonal therapy and associated with neuroendocrine prostate cancer.2,33
High expression of tissue PSA (KLK3) is associated with increased proliferation and response to AR antagonists or blockade.2,15
PCA3 over-expression is associated with advanced pathologic stage.1,2,7 PCA3 is a long non-coding RNA that is only expressed in prostate tissues. In the early stages of prostate cancer, PCA3 is highly abundant making it a robust diagnostic tumor biomarker.49 However, patients with advanced-stage prostate cancer and poor outcomes typically have low PCA3 expression [Alshalalfa et al, manuscript in preparation].
NKX3-1 (8p21) is an androgen-responsive transcription factor that functions as a tumor suppressor gene. It’s expression is absent or at low-levels in many high-grade prostate cancers and completely lost in the majority of metastatic prostate cancer.1,36
SRD5A1 catalyzes the conversion of testosterone into dihydrotestosterone (DHT) that leads to AR synthesis. SRD5A1 is upregulated in castrate-resistant prostate cancer and may be associated with poor response to hormonal therapy. Combined inhibition of SRD5A1 and AR pathways may overcome castration resistance.20
Small cell neuroendocrine prostate carcinomas are a rare subtype of prostate cancer (PCa) which exhibit aggressive behavior, rapid growth, early spread to distant sites and innate resistance to androgen deprivation therapy (ADT).28 Small cell PCa tumors present a unique expression profile with high expression of CHGA, AURKA, MYCN and loss of RB1.27,29,30 Localized tumors with small cell-like genomic profile are at higher risk of becoming metastatic and often fail ADT.30 Genomic expression of small cell markers may be used as a tool to aid oncologist with appropriate treatment decision and guide avoidance of ADT or AR-targeted therapy.
Loss of pRB (RB1) by deletion is a common event in prostatic small cell carcinoma. Under-expression in prostatic adenocarcinoma may be associated with development of a neuroendocrine phenotype and resistance to hormonal therapy.1,10
Cyclin D1 (CCND1) loss is common in small cell carcinoma, which are resistant to hormone blockade. In men with prostate adenocarcinoma who were treated with hormonal therapy, lower cyclin D1 gene expression was associated with more rapid onset of metastasis and death.9,33
Chromogranin A (CHGA) is a marker of neurendocrine prostate cancer. Tumors with higher chromogranin A expression may be less sensitive to hormonal therapy.2,33
AURKA is significantly overexpressed and amplified in neuroendocrine (NE) prostate cancer compared to prostate adenocarcinoma. AURKA overexpression may act as a potential prognostic biomarker that may help to identify patients with prostate cancer who are at high risk for developing castrate-resistant disease with clinical features of small cell carcinoma. In preclinical models, AURKA inhibition results in dramatic and preferential anti-tumor activity in NEPC.18,19,33
High NEAT1 expression is associated with prostate cancer progression and resistance to AR antagonists.8
High MYCN is highly associated with aggressive localized prostate cancer. MYCN is significantly overexpressed and amplified in neuroendocrine prostate cancer compared to prostate adenocarcinoma.18,19,33
Cell proliferation is the process of cell growth and replication. Proliferation occurs through a controlled mechanism called “the cell cycle” where cells must pass specific checkpoint to divide. Cancer cells can bypass checkpoints by sustaining proliferative signals via overexpression of cell surface receptors, invasion of growth suppressors and resistance of cell death.1 Patients with high expression of proliferative genes, such as TOP2A and MKi67, have been associated with poor prostate cancer specific progression and metastatic outcome.2 The activity of multiple growth factor mediated proliferation signals in tumor cells nominates proliferative and growth factor genes for therapeutic targeting. Providing oncologist with transcriptomic activity of cell proliferation and growth factor biomarkers via Decipher GRID may refine stratification of patient risk and may aid in the selection of optimal therapies for patients with urological cancers.
ki-67 (MKI67) is a cell proliferation marker. Overexpression has been shown to be associated with increased risk of metastasis and prostate cancer death.1,2
TOP2A is a cell proliferation marker and high expression is correlated to poor outcome in prostate cancer. Patients with TOP2A over-expression may be sensitive to etoposide chemotherapy.1,2
EGFR signaling plays a critical role in tumor growth and cell proliferation via AR signaling. EGFR (ERBB1) is over-expressed in the majority of metastatic castration-resistant prostate cancers (mCRPC). EGFR expression increases during the natural history of prostate cancer and correlation with disease progression, Gleason grade and hormone-refractory disease. EGFR inhibition induces apoptosis and might improve the outcome of patients with mCRPC.24,25
HER2 (ERBB2) is a member of the epidermal growth factor receptor family mediating cell growth and cancer development and associated with poor clinical outcome in several cancers. High expression of HER2 induces key cancer signalling pathways like PI3K/AKT and MAPK mediating the activation of RAS oncogene that have been implicated in cell survival and cancer metastasis. Inhibiting HER2 inhibited prostate cancer tumors growth. HER2 is a prominent player in mediating the AR-dependent and independent PCa progression and survival making it a potential therapeutic target for dual inhibition of AR pathways and HER2.26,32
ERBB3 plays a pivotal in the development of castrate-resistant prostate cancer (CRPC). High expression of ERBB3 in CRPC leads to androgen receptor stabilization and activation of PI-3K/Akt signaling. ERBB3 interacts with HER2 or EGFR to mediate ERBB3 signaling thus making dual inhibition of ERBB3 and HER2 or EGFR a potential therapy to overcome CRPC.30,31
MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to VEGF signaling, a key player in angiogenesis. MET signaling play important roles in prostate cancer progression and bone metastasis. Increased MET expression in prostate cancer cells correlate with disease recurrence and disease progression, with highest levels in bone metastases. Dual Inhibition of VEGFR2 and MET with cabozantinib which inhibit tumor angiogenesis and metastasis has shown clinical benefit in men with mCRPC.23,34
A hallmark of cancer cells is genomic instability due to defects in the mechanisms involved in repair of DNA damage. Genomic instability here refers to a high frequency of alterations within the genome due to deficiency of DNA repair, recombination or replication. DNA damage is considered one of the most frequent events contributing to development of prostate cancer. DNA damage response (DDR) includes the activation of numerous cellular activities that prevent duplication of DNA lesions and maintain genomic integrity, which is critical for the survival of normal and cancer cells. Tumors with high activity of DNA damage and repair (DDR) pathway is associated with worse prognosis in patients with prostate cancer after prostatectomy. Deficient DNA repair processes may be a major determinant of radiosensitivity and high DDR activity may be associated with higher proliferation and radioresistsnce. Tumors with defects in DNA repair activity may be sensitive to PARP and/or ATM inhibitors. Recent studies provide evidence supporting the role for AR in DDR activation and repair of DNA damage in prostate cancer cell survival through regulation of relevant genetic activities and pathways. Given a potential for AR to regulate genetic activities and pathways that influence DDR gene, particularly those related to ATM signaling, combination therapy with ADT plus a PARP inhibitor or ADT plus ATR and/or Chk1 inhibitors represents a rational therapeutic strategy. Combination of a DDR-targeted agent with a cytotoxic DNA-damaging agent (e.g. platinum agents) is another approach to be considered.31,32
ATM is DNA damage response kinase. When DNA damage occurs during cell division, ATM causes the cells to delay dividing and signals DNA damage response pathways. If DNA damage occurs in cells with aberrant ATM expression, mutations can accumulate due to ineffective DNA damage response signalling. Inhibition of ATM may be particularly effective if combined with ionising radiation, as ATM-deficient tumors are particularly sensitive to this cancer therapy.40
ATR is very closely related to ATM. Like ATM, this gene is involved in DNA damage signalling and is an attractive target for therapeutic intervention.40
RAD21 is part of the cohesin complex and is involved in the repair of DNA double-strand breaks. Aberrant RAD21 expression has been reported in multiple cancers, including breast, lung, bladder, brain and ovarian. 41
DNAPK is a key component of the DNA damage response pathway and helps to maintain genome stability. It functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis in prostate cancer nominating it as a therapeutic target for advanced malignancies. PRKDC plays a role in the cross-talk between DNA repair and AR signaling as it is induced by AR activity and function as AR-co activator thus overexpression of PRKDC enhance the repair capacity and promote radioresistance of prostate cancer and bypass anti-androgen therapy. 42,43 DNA-PKcs inhibitors are effective as single agents against ATM-defective tumors.44
NBN is involved in detecting and triggering the repair of double-stranded DNA breaks. In prostate cancer, copy number gain and over-expression of NBN was found to be predictive of a weak response to image-guided radiotherapy, suggesting surgery may be a more appropriate therapy in these cases. 45
PARP is a key enzyme in DNA damage response and repair pathways. Certain cancers, including ovarian and breast cancer, can become highly dependent on PARP activity making this an attractive therapeutic target.46,47 In a promising study, sporadic cases of metastatic, castration-resistant prostate cancer with aberrant expression of PARP were found to benefit from PARP inhibition therapy. 48
Tumor metastasis is a complex process involving migration and invasion of cancer cells to other tissues and organs. The metastatic cascade is dependent on the loss of adhesion between cancer cells as well as between cells and their extracellular matrix. This adhesive loss results in the dissociation of cells from the primary tumor and invasion into the surrounding stroma.3 Once tumor cells acquire the motile ability to penetrate surrounding tissues, they pass through the basement membrane and the extracellular matrix to enter the lymphatic or vascular circulation.4,5 Motile tumor cells then attach to new tissues and proliferate to produce secondary tumors. Upon invasion, tumor cells switch on angiogenesis to fuel their growth and sustain nutritional sources. Prostate cancer cells induce cell proliferation and microvessel density via production and release of angiogenic factors.6,7 Targeting angiogenic pathways such as VEGF or HGF has been a key area of interest for pharmaceutical research. Various strategies have been employed to disrupt or block new blood vessel growth to developing tumors.8,9 Genes involved in angiogenesis have been ideal therapeutic targets for patients with prostate cancer. Research has shown that patients with low expression of genes involved in cell adhesion and cytoskeletal organization, or high activity of angiogenic factors, have been associated with poorer prognosis and increased likelihood of metastasis.10–12 Decipher GRID provides the genomic profile of cell adhesion genes and angiogenic pathways to gain a greater understanding of the potential metastatic risk of prostate tumors.
SChLAP1 is a regulator of cell migration and invasion. Overexpression is associated with more aggressive prostate cancer, especially in the subset of ERG positive tumors.3,4
High expression of EZH2 is associated with invasion, metastatic progression and castrate-resistant prostate cancer (CRPC).13,14,35
SPARCL1 is a regulator of cell migration/invasion. Its loss is independently associated with prostate cancer recurrence. 5
Low GSTP1 expression is associated with an increased risk of recurrence.21
High GSTP1 expression may demarcate a basal cell tumor.21
The immune system is able to recognize and destroy the most immunologically vulnerable cancer cells through the recognition of tumor antigens.13 Tumor cells have developed mechanisms to invade immune surveillance, making immune evasion a major stumbling block in designing effective anticancer therapeutic strategies.14 One mechanism developed by tumor cells involves expression of ligands that interact with immune cells to bypass immune checkpoints, preventing their elimination by the immune system.15,16 Prostate cancer patients with compromised immune system may have increased incidence of cancer specific mortality. Immunologic checkpoint blockade with antibodies that target checkpoint inhibitors, such as CTLA-4, PD1/PDL1/PDL2 pathways have demonstrated promise in a variety of malignancies.17 Providing the expression of these immune checkpoint inhibitors through the GRID may provide oncologists with clinical information to aid in the selection of patients for immunotherapy.
PD-L1/PD-1-mediated T cell coinhibition is involved in immune evasion in prostate cancer. Over-expression of PD1 (PDCD1) by cancer cells may enable tumors to evade T cell immune responses. Over-expression of PD1 is correlated to greater responses to anti-PD1 therapy.12
B7H3 (CD276) is highly expressed in many solid tumors and not in normal tissue. In prostate cancer, over-expression of B7H3 is associated with the development of aggressive prostate cancer and metastatic disease. B7H3 expression increases in response to hormone therapy and inhibition of B7H3 may be useful for treating hormone resistant prostate cancer.2,11
CTLA4 is a key negative regulator of T cell activation. Low CTLA4 expression allows T cell repertoire evolution and diversification, which promotes anti-tumor T cell immunity and a clinical response.50 Conversely, high levels of CTLA4 results in the down regulation of these same immune responses. Tumors may leverage this feature by over-expressing CTLA4 to evade T cell-mediated immunity, as demonstrated in a number of pre-clincal and clinical studies.51
IDO1 expression mediates the degradation of the essential amino acid tryptophan. Over-expression of IDO results in a depletion of tryptophan in the cancer microenvironment resulting in immunosuppression, as T-cells are sensitive to low levels of tryptophan.52 In addition, IDO1 is linked to oncogenic signaling pathways making it a promising target for therapeutic intervention.53 The development of IDO inhibitors may improve responses to cancer immunotherapy by allowing appropriate T-cell responses.54
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- Hurley, et al., Secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) is down regulated in aggressive prostate cancers and is prognostic for poor clinical outcome, PNAS, 2012, 109(37):14977-82.
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- Maldonado et al, GSTP1 promoter methylation is associated with recurrence in early stage prostate cancer, J Urol, 2014 Nov;192(5):1542-8.
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