Applications of Genetic Prostate Cancer Screening in Clinic
Applications of Genetic Prostate Cancer Screening in Clinic
Biomolecular markers of outcome prediction in prostate cancer include PCA3, TMPSS2, MMP-9, ANXA3, GSTP1, BRCA1, BRCA2, Mismatch Re pair Genes, HOXB13, and HPC.
Recent efforts have identified promising protein-based, metabolite-based, and nucleic acid-based urine biomarkers for prostate cancer detection. These biomarkers are under further study to determine potential clinical utility (see Table 1). The sensitivity of urine tests for prostate cancer is unacceptably low to date (Li-Wan-Po et al., 2010).
Urologic clinicians can benefit from an awareness of the multiple genome-wide association studies (GWAS) in recent years. Studies have identified a number of germline single nucleotide polymorphisms (SNPs), which are associated with a risk of prostate cancer (Eeles et al., 2008; Gudmundsson et al., 2008; Thomas et al., 2008). The measurement of the fusion of TMPRSS2 to ERG helps to identify prostate cancer aggressiveness and also the personalization of treatment options (Park et al., 2010; Yu et al., 2010). In 2012, Ventana Medical Systems, Inc. developed a probe for the measurement of ERG protein in patients with prostate cancer. The ERG gene is commonly repressed in prostate cells in the absence of an oncogenic fusion to the TMPRSS2 gene and is one of the most commonly methylated genes.
Hypermethylation (which is an increase in the epigenetic methylation of cytosine and adenosine residues in DNA) of GSTP1 and APC is expressed more commonly in prostate tumor tissue than benign tissue. The analysis of the GSTPI and APC genes on the remaining prostate tissue from a previously negative biopsy helps reduce unnecessary repeat biopsies, and also identifies high-risk patients (Trock et al., 2012; Truong et al., 2013; van Neste et al., 2012). The prognostic evaluation by testing DNA methylation remains in the development phase, but still can serve as a tool to distinguish between aggressive and nonaggressive tumors. Five reference genes and 12 cancer genes represent pathways in prostate tumorigenesis in OncotypeDX Prostate Cancer Assay, which includes AZGP1, KLK2, SRD5A2, FAM13C, FLNC, GSN, TPM2, GSTM2, TPX2, BGN, COL1A1, and SFRP4. Reference gene normalization is used to control analytical sensitivity, which in cludes assessment for ARF1, ATP5E, CLTC, GPS1, and PGK1 (Knezevic et al., 2013). Reference-normalized expression of the 12 cancer-related genes is used to evaluate the Genomic Prostate Score (GPS), which is being utilized to refine and individualize the risk assessment and treatment decision for men with localized prostate cancer (Cooperberg, Simko, Falzarano et al., 2013).
Besides the diagnostic markers that have been evaluated in the clinical settings, some prognostic markers are also selected for monitoring. Recent literature has demonstrated that the Prolaris diagnostic test is the single most prognostic parameter of meaningful outcomes for prostatic cancer diagnosis (Cooperberg, Simko, Cowan et al., 2013; Cuzick et al., 2011, 2012; Freedland et al., 2013). The cell cycle progression (CCP) score is clinically approved as the strongest independent predictor of prostatic cancer mortality and the most valuable prognostic information to improve accuracy of risk stratification for men with localized prostate cancer (Crawford et al., 2014; Cuzick, 2014). Mutations in the PTEN gene result in an altered protein that has lost its tumor suppressor function. In some cases, the presence of PTEN gene mutations is associated with more advanced stages of prostate tumor growth (Barbieri et al., 2013; Phin, Moore, & Cotter, 2013; Vesprini, Liu, & Nam, 2013). Metastatic tumors have a significantly in creased level of PTEN. However, PTEN is not a specific marker for prostate cancer (Vesprini et al., 2013). While genetic testing for prostate cancer is not yet standard clinical practice, research from selected cohorts has reported increased prostate cancer risk in men with mutations in BRCA1 and BRCA2 (Agalliu, Gern, Leanza, & Burk, 2009; Edwards et al., 2010; Gallagher et al., 2010; Kote-Jarai et al., 2011; Leongamornlert et al., 2012; Narod et al., 2008; Ostrander & Udler, 2008; Vesprini et al., 2013). Increased risk has also been noted on a smaller scale in the mismatch repair (MMR) genes (Grindedal et al., 2009; Langeberg, Kwon, Koopmeiners, Ostrander, & Stanford, 2010). Clinical genetic testing has been available for these genes for years. Several studies indicate the risk may be greater among men with the BRCA2 founder mutation than among those with one of the BRCA1 founder mutations (Agalliau et al., 2009; Gallagher et al., 2010). Some data suggest that BRCA-related pro state cancer has a significantly worse prognosis than prostate cancer that occurs among non-carriers (Gallagher et al., 2010). Other data suggest that BRCA2 mutation carriers have a poorer survival rate than do BRCA1 mutation carriers (Narod et al., 2008). A populationbased case-control study, which examined three MMR genes (MLH1, MSH2 and PMS2) provides some evidence supporting the contribution of genetic variation in MLH1 and the overall risk of prostate cancer (Langeberg et al., 2010).
Many studies focus on the biomarkers associated with prostate cancer (Ateeq et al., 2011; Dhani et al., 2012; Hoogland et al., 2014; Palanisamy et al., 2010; Ren et al., 2012; Rodrigues, Butler, Estelles, & de Bono, 2014). More population-based case-control research must be conducted before test kits are developed. As of today, no single test can fulfill the diagnostic and prognostic requirement for prostate cancer in every patient. Researchers have suggested that future genetic tests for prostate cancer combine screenings for multiple biomarkers by using protein analysis and gene microarrays (Velonas, Woo, Remedios, & Assinder, 2013).
Genetic Susceptibility to Prostate Cancer
Biomolecular markers of outcome prediction in prostate cancer include PCA3, TMPSS2, MMP-9, ANXA3, GSTP1, BRCA1, BRCA2, Mismatch Re pair Genes, HOXB13, and HPC.
Recent efforts have identified promising protein-based, metabolite-based, and nucleic acid-based urine biomarkers for prostate cancer detection. These biomarkers are under further study to determine potential clinical utility (see Table 1). The sensitivity of urine tests for prostate cancer is unacceptably low to date (Li-Wan-Po et al., 2010).
Urologic clinicians can benefit from an awareness of the multiple genome-wide association studies (GWAS) in recent years. Studies have identified a number of germline single nucleotide polymorphisms (SNPs), which are associated with a risk of prostate cancer (Eeles et al., 2008; Gudmundsson et al., 2008; Thomas et al., 2008). The measurement of the fusion of TMPRSS2 to ERG helps to identify prostate cancer aggressiveness and also the personalization of treatment options (Park et al., 2010; Yu et al., 2010). In 2012, Ventana Medical Systems, Inc. developed a probe for the measurement of ERG protein in patients with prostate cancer. The ERG gene is commonly repressed in prostate cells in the absence of an oncogenic fusion to the TMPRSS2 gene and is one of the most commonly methylated genes.
Hypermethylation (which is an increase in the epigenetic methylation of cytosine and adenosine residues in DNA) of GSTP1 and APC is expressed more commonly in prostate tumor tissue than benign tissue. The analysis of the GSTPI and APC genes on the remaining prostate tissue from a previously negative biopsy helps reduce unnecessary repeat biopsies, and also identifies high-risk patients (Trock et al., 2012; Truong et al., 2013; van Neste et al., 2012). The prognostic evaluation by testing DNA methylation remains in the development phase, but still can serve as a tool to distinguish between aggressive and nonaggressive tumors. Five reference genes and 12 cancer genes represent pathways in prostate tumorigenesis in OncotypeDX Prostate Cancer Assay, which includes AZGP1, KLK2, SRD5A2, FAM13C, FLNC, GSN, TPM2, GSTM2, TPX2, BGN, COL1A1, and SFRP4. Reference gene normalization is used to control analytical sensitivity, which in cludes assessment for ARF1, ATP5E, CLTC, GPS1, and PGK1 (Knezevic et al., 2013). Reference-normalized expression of the 12 cancer-related genes is used to evaluate the Genomic Prostate Score (GPS), which is being utilized to refine and individualize the risk assessment and treatment decision for men with localized prostate cancer (Cooperberg, Simko, Falzarano et al., 2013).
Besides the diagnostic markers that have been evaluated in the clinical settings, some prognostic markers are also selected for monitoring. Recent literature has demonstrated that the Prolaris diagnostic test is the single most prognostic parameter of meaningful outcomes for prostatic cancer diagnosis (Cooperberg, Simko, Cowan et al., 2013; Cuzick et al., 2011, 2012; Freedland et al., 2013). The cell cycle progression (CCP) score is clinically approved as the strongest independent predictor of prostatic cancer mortality and the most valuable prognostic information to improve accuracy of risk stratification for men with localized prostate cancer (Crawford et al., 2014; Cuzick, 2014). Mutations in the PTEN gene result in an altered protein that has lost its tumor suppressor function. In some cases, the presence of PTEN gene mutations is associated with more advanced stages of prostate tumor growth (Barbieri et al., 2013; Phin, Moore, & Cotter, 2013; Vesprini, Liu, & Nam, 2013). Metastatic tumors have a significantly in creased level of PTEN. However, PTEN is not a specific marker for prostate cancer (Vesprini et al., 2013). While genetic testing for prostate cancer is not yet standard clinical practice, research from selected cohorts has reported increased prostate cancer risk in men with mutations in BRCA1 and BRCA2 (Agalliu, Gern, Leanza, & Burk, 2009; Edwards et al., 2010; Gallagher et al., 2010; Kote-Jarai et al., 2011; Leongamornlert et al., 2012; Narod et al., 2008; Ostrander & Udler, 2008; Vesprini et al., 2013). Increased risk has also been noted on a smaller scale in the mismatch repair (MMR) genes (Grindedal et al., 2009; Langeberg, Kwon, Koopmeiners, Ostrander, & Stanford, 2010). Clinical genetic testing has been available for these genes for years. Several studies indicate the risk may be greater among men with the BRCA2 founder mutation than among those with one of the BRCA1 founder mutations (Agalliau et al., 2009; Gallagher et al., 2010). Some data suggest that BRCA-related pro state cancer has a significantly worse prognosis than prostate cancer that occurs among non-carriers (Gallagher et al., 2010). Other data suggest that BRCA2 mutation carriers have a poorer survival rate than do BRCA1 mutation carriers (Narod et al., 2008). A populationbased case-control study, which examined three MMR genes (MLH1, MSH2 and PMS2) provides some evidence supporting the contribution of genetic variation in MLH1 and the overall risk of prostate cancer (Langeberg et al., 2010).
Many studies focus on the biomarkers associated with prostate cancer (Ateeq et al., 2011; Dhani et al., 2012; Hoogland et al., 2014; Palanisamy et al., 2010; Ren et al., 2012; Rodrigues, Butler, Estelles, & de Bono, 2014). More population-based case-control research must be conducted before test kits are developed. As of today, no single test can fulfill the diagnostic and prognostic requirement for prostate cancer in every patient. Researchers have suggested that future genetic tests for prostate cancer combine screenings for multiple biomarkers by using protein analysis and gene microarrays (Velonas, Woo, Remedios, & Assinder, 2013).
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