Prostatic adenocarcinoma is the most common noncutaneous malignancy in men and the second leading... more Prostatic adenocarcinoma is the most common noncutaneous malignancy in men and the second leading cause of cancer death in Western populations. Despite its prevalence, an understanding of the molecular alterations affecting the development, progression, and treatment of the disease was largely lacking until recently. Rapid advances in molecular techniques in the past decade have seen a dramatic increase in our understanding of the role molecular alterations play in prostate cancer. Though still early, these developments have provided insight into distinct subsets of prostate cancer that promise to change how the disease is both diagnosed and managed. The molecular alterations discovered have shown that prostate cancer development involves multiple genetic abnormalities and that detection or targeting of a single genetic event is unlikely to impact all cases of prostate cancer. Of the ones that have shown the most promise to changing diagnostic and treatment paradigms are the gene fusion of TMPRSS2 and members of the ETS family of transcription factors, primarily ERG, as well as the inactivation of the tumor suppressor PTEN. A greater understanding of the molecular alterations present in prostate cancer will lead to further improvements in diagnosis, prediction of prognosis, stratification for specific therapies, and ultimately better outcomes for patients.
Purpose: Analytically validated assays to interrogate biomarker status in clinical samples are cr... more Purpose: Analytically validated assays to interrogate biomarker status in clinical samples are crucial for personalized medicine. PTEN is a tumor suppressor commonly inactivated in prostate cancer that has been mechanistically linked to disease aggressiveness. Though deletion of PTEN, as detected by cumbersome FISH spot counting assays, is associated with poor prognosis, few studies have validated immunohistochemistry (IHC) assays to determine whether loss of PTEN protein is associated with unfavorable disease.Experimental Design: PTEN IHC was validated by employing formalin fixed and paraffin-embedded isogenic human cell lines containing or lacking intact PTEN alleles. PTEN IHC was 100% sensitive and 97.8% specific for detecting genomic alterations in 58 additional cell lines. PTEN protein loss was then assessed on 376 prostate tumor samples, and PTEN FISH or high resolution single nucleotide polymorphism microarray analysis was done on a subset of these cases.Results: PTEN protein...
43 Background: Loss of the PTEN tumor suppressor and subsequent activation of the PI3K pathway is... more 43 Background: Loss of the PTEN tumor suppressor and subsequent activation of the PI3K pathway is common and has potential clinical and therapeutic value in CaP. We examined the PTEN status of primary tumors in pts who underwent adjuvant docetaxel tx in a prospective clinical trial. Methods: Of the 77 pts enrolled in a prospective multi-institutional adjuvant docetaxel trial (TAX 2501, J Urol 2007), we prospectively collected 56 primary tumor pathology specimens suitable for analysis of PTEN status by immunoreactivity (IHC) and/or fluorescence in situ hybridisation (FISH) assay. Protocol defined progression included a PSA of ≥ 0.4 ng/mL, radiological/pathological evidence of recurrent disease or death from any cause. Univariate and multivariable analyses based on the Cox proportional hazards regression model were used to analyze the independent association of PTEN and other known prognostic factors with progression free survival (PFS). Results: PTEN loss was observed in 37/56 pts (6...
BackgroundTherapies targeting the androgen receptor (AR) have improved the outcome for patients w... more BackgroundTherapies targeting the androgen receptor (AR) have improved the outcome for patients with castration-sensitive prostate cancer (CSPC). Expression of the constitutively active AR splice variant-7 (AR-V7) has shown clinical utility as a predictive biomarker of AR-targeted therapy resistance in castration-resistant prostate cancer (CRPC), but its importance as predictive biomarker in CSPC remains understudied.MethodsWe explored multiple approaches to quantify AR-V7 mRNA and protein in prostate cancer cell lines and patient-derived xenograft (PDX) models, in both publicly available and independent institutional clinical cohorts, to identify reliable approaches for detecting AR-V7 mRNA and protein, and its association with clinical outcome.ResultsIn publicly available benign prostate, CSPC and CRPC cohorts, AR-V7 mRNA was much less abundant when detected using reads across splice boundaries than when considering isoform-specific exonic reads. The RM7 AR-V7 antibody had increas...
Background: PARP inhibitors (PARPi) are approved for the treatment of metastatic prostate cancer ... more Background: PARP inhibitors (PARPi) are approved for the treatment of metastatic prostate cancer (mPC) associated to various DNA damage repair (DDR) gene mutations; but clinical benefit differs among patients. Biomarkers of homologous recombination repair (HRR) deficiency may help refine patient stratification for a more precise therapy selection. We report an exploratory analysis from the TOPARP-B phase II clinical trial of olaparib in mPC (NCT01682772), investigating the predictive value of an HRR function assay detecting RAD51 foci by immunofluorescence in tumor biopsies. Design: We analyzed formalin-fixed paraffin-embedded (FFPE) primary or metastatic biopsies from mPC patients treated with olaparib in the clinical trial. We evaluated baseline HRR function based on detection of RAD51 and γH2AX foci in geminin-positive tumor cells by immunofluorescence (IF). All samples were scored by two trained readers blinded to genomic and clinical data. Samples were considered HRR deficient ...
Background: CD38, an ecto-enzyme involved in adenosine synthesis, is implicated in tumor immune e... more Background: CD38, an ecto-enzyme involved in adenosine synthesis, is implicated in tumor immune evasion. Its expression and role in the prostate tumor microenvironment (TME) has not been fully elucidated. Main objectives: To determine whether CD38 is associated with prostate cancer (PC) immune evasion, to characterize CD38 expression on PC epithelial cells and tumor infiltrating immune cells (TIICs) as tumors progress from castration-sensitive PC (CSPC) to metastatic castration-resistant PC (mCRPC), and to determine the association between CD38+ TIICs and survival. Methods: Data from 159 mCRPC transcriptomes from the Stand Up To Cancer/Prostate Cancer Foundation cohort were analyzed for associations between CD38 and 200 cell signaling pathways, an adenosine signature and T cell exhaustion signatures. CD38 protein expression on tumor epithelial cells and TIICs was scored using validated immunohistochemistry (IHC) assays on 51 treatment-naïve CSPC biopsies and matching, same-patient m...
Prostate cancer is a major cause of cancer morbidity and mortality. Intra-prostatic inflammation ... more Prostate cancer is a major cause of cancer morbidity and mortality. Intra-prostatic inflammation is a risk factor for prostate carcinogenesis, with diet, chemical injury and an altered microbiome being causally implicated. Intra-prostatic inflammatory cell recruitment and expansion can ultimately promote DNA double-strand breaks and androgen receptor activation in prostate epithelial cells. The activation of the senescence-associated secretory phenotype fuels further ‘inflammatory storms’, with free radicals leading to further DNA damage. This drives the overexpression of DNA repair and tumour suppressor genes, rendering these genes susceptible to mutagenic insults, with carcinogenesis accelerated by germline DNA repair gene defects. We provide updates on recent advances in elucidating prostate carcinogenesis and explore novel therapeutic and prevention strategies harnessing these discoveries. This Review discusses intra-prostatic inflammatory processes and how they are induced and perpetuated, thereby driving prostate cancer development and progression. By discussing external inflammatory cues in connection to cancer cell-intrinsic factors in prostate tumorigenesis, the authors provide insight into potential preventative and therapeutic strategies.
5002 Background: Prostate-specific membrane antigen (PSMA) is a promising target for theranostics... more 5002 Background: Prostate-specific membrane antigen (PSMA) is a promising target for theranostics in metastatic castration resistant prostate cancer (mCRPC). Methods: Membranous PSMA (mPSMA) expression was immunohistochemically evaluated in castration sensitive (CSPC) (n = 38) and mCRPC (n = 60) tissue biopsies, and associations with molecular aberrations (next-generation sequencing; NGS) and clinical outcome were determined. Results: mPSMA expression was significantly higher (p = 0.005) in mCRPC biopsies (median H-score [interquartile range]; 55.0 [2.8-117.5]) compared to CSPC biopsies (17.5 [0.0-60.0]). Furthermore, patients with higher mPSMA expression ( > median H-score) at diagnosis had higher Gleason Grade (p = 0.04) and shorter OS (p = 0.006). Critically, 42% (16/38) of CSPC biopsies and 27% (16/60) of mCRPC biopsies were completely negative for mPSMA expression. In addition, CSPC and mCRPC biopsies expressing mPSMA demonstrated marked intra-tumor heterogeneity in expressi...
Archives of Pathology & Laboratory Medicine, 2018
Context.— Phosphatase and tensin homolog (PTEN) is a promising prognostic and potentially predict... more Context.— Phosphatase and tensin homolog (PTEN) is a promising prognostic and potentially predictive biomarker in prostate cancer. Objective.— To assess the effects of preanalytic variables on an analytically validated and fully automated PTEN immunohistochemistry assay. Design.— PTEN immunohistochemistry was performed on Ventana immunostaining systems. In benign prostate tissues, immunostaining intensity across variable conditions was assessed by digital image analysis. In prostate tumor tissues, immunostaining was scored visually. Results.— Delay of fixation for 4 hours or longer at room temperature or 48 hours or longer at 4°C and duration of formalin fixation did not significantly alter immunostaining intensity. Intensity of staining was highest in 10% formalin compared with other fixatives. Tumor tissues with PTEN loss processed using protocols from 11 academic institutions were all evaluable and scored identically. PTEN immunostaining of needle biopsies where tissue blocks had...
Cancer prevention research (Philadelphia, Pa.), Jan 29, 2015
Inflammation may play an etiologic role in prostate cancer. Several dietary factors influence inf... more Inflammation may play an etiologic role in prostate cancer. Several dietary factors influence inflammation; studies have shown that long-chain n-3 polyunsaturated fatty acids are anti-inflammatory, while n-6 and trans fatty acids are pro-inflammatory. We evaluated whether serum phospholipid n-3, n-6, and trans fatty acids were associated with intraprostatic inflammation, separately in 191 prostate cancer cases and 247 controls from the placebo arm of the in the Prostate Cancer Prevention Trial (PCPT). Men without a prostate cancer diagnosis underwent prostate biopsy at trial end, and benign prostate tissue inflammation was evaluated in approximately three biopsy cores per man; this was expressed as no, some, or all cores with inflammation. In controls, serum eicosapentaenoic acid (OR of all cores with inflammation versus none (95%CI): 0.35 (0.14, 0.89)), and docosahexaenoic acid (OR (95%CI): 0.42 (0.17, 1.02)) were inversely associated with, while linoleic acid (OR (95%CI): 3.85 (1....
Proceedings of the National Academy of Sciences, 2012
Prostate cancer is the second leading cause of cancer death among United States men. However, dis... more Prostate cancer is the second leading cause of cancer death among United States men. However, disease aggressiveness is varied, with low-grade disease often being indolent and high-grade cancer accounting for the greatest density of deaths. Outcomes are also disparate among men with high-grade prostate cancer, with upwards of 65% having disease recurrence even after primary treatment. Identification of men at risk for recurrence and elucidation of the molecular processes that drive their disease is paramount, as these men are the most likely to benefit from multimodal therapy. We previously showed that androgen-induced expression profiles in prostate development are reactivated in aggressive prostate cancers. Herein, we report the down-regulation of one such gene, Sparcl1 , a secreted protein, acidic and rich in cysteine (SPARC) family matricellular protein, during invasive phases of prostate development and regeneration. We further demonstrate a parallel process in prostate cancer,...
Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Background: Chronic... more Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Background: Chronic inflammation may be crucial for the etiology of prostatic adenocarcinoma (CaP). If inflammation is part of the pathogenesis of this disease then it might be expected that prostates with adenocarcinoma would harbor more inflammation than prostates without adenocarcinoma. Design: Cases (biopsy detected and centrally reviewed) and age frequency-matched controls, defined as negative for adenocarcinoma on an end-of-study biopsy, were selected using a nested case-control design from among participants in placebo arm of the Prostate Cancer Prevention Trial (PCPT). The PCPT (n= 18,000 men) determined whether finasteride, a 5-alpha reductase inhibitor, could reduce the period prevalence of adenocarcinoma over 7 years. All men were screened annually by PSA and DRE, and all men not diagnosed with adenocarcinoma during the study were offered an end-of-study biopsy. Cases consisted of 191 men, and controls were from 209 men. Microscope slides (1- 5 core biopsies for each man) were digitized and evaluated online after masking of adenocarcinoma and random benign areas to ensure blinding of the pathologist to case/control status. Inflammation was assessed using a modified National Institutes of Health (NIH) grading system and data were analyzed using logistic regression. Result: Men who had at least one biopsy core positive for chronic inflammation (CI) (majority was chronic) had 1.79 (95% CI 1.06-3.04) times the risk of prostate cancer compared with no cores positive. The association was stronger for higher-grade (Gleason score 7-10; OR=2.41, 95% CI 1.17-4.95) disease than for lower-grade (Gleason score 6; OR=1.45, 95% CI 0.79-2.68) disease. Risk of prostate cancer (p-trend=0.05) and higher-grade disease (p-trend=0.02) increased with increasing percent of cores positive. Conclusion: The presence of any chronic inflammation in benign prostate tissue was positively and statistically significantly associated with adenocarcinoma, especially higher grade lesions (Gleason score 7-10). Additional studies to further examine a potential role for inflammation as a cofactor in overall and high-grade prostate cancer should help determine whether chronic inflammation present in benign tissue is a reaction to the presence of cancer, or, is related to the pathogenesis of prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4366.
Prostatic adenocarcinoma is the most common noncutaneous malignancy in men and the second leading... more Prostatic adenocarcinoma is the most common noncutaneous malignancy in men and the second leading cause of cancer death in Western populations. Despite its prevalence, an understanding of the molecular alterations affecting the development, progression, and treatment of the disease was largely lacking until recently. Rapid advances in molecular techniques in the past decade have seen a dramatic increase in our understanding of the role molecular alterations play in prostate cancer. Though still early, these developments have provided insight into distinct subsets of prostate cancer that promise to change how the disease is both diagnosed and managed. The molecular alterations discovered have shown that prostate cancer development involves multiple genetic abnormalities and that detection or targeting of a single genetic event is unlikely to impact all cases of prostate cancer. Of the ones that have shown the most promise to changing diagnostic and treatment paradigms are the gene fusion of TMPRSS2 and members of the ETS family of transcription factors, primarily ERG, as well as the inactivation of the tumor suppressor PTEN. A greater understanding of the molecular alterations present in prostate cancer will lead to further improvements in diagnosis, prediction of prognosis, stratification for specific therapies, and ultimately better outcomes for patients.
Purpose: Analytically validated assays to interrogate biomarker status in clinical samples are cr... more Purpose: Analytically validated assays to interrogate biomarker status in clinical samples are crucial for personalized medicine. PTEN is a tumor suppressor commonly inactivated in prostate cancer that has been mechanistically linked to disease aggressiveness. Though deletion of PTEN, as detected by cumbersome FISH spot counting assays, is associated with poor prognosis, few studies have validated immunohistochemistry (IHC) assays to determine whether loss of PTEN protein is associated with unfavorable disease.Experimental Design: PTEN IHC was validated by employing formalin fixed and paraffin-embedded isogenic human cell lines containing or lacking intact PTEN alleles. PTEN IHC was 100% sensitive and 97.8% specific for detecting genomic alterations in 58 additional cell lines. PTEN protein loss was then assessed on 376 prostate tumor samples, and PTEN FISH or high resolution single nucleotide polymorphism microarray analysis was done on a subset of these cases.Results: PTEN protein...
43 Background: Loss of the PTEN tumor suppressor and subsequent activation of the PI3K pathway is... more 43 Background: Loss of the PTEN tumor suppressor and subsequent activation of the PI3K pathway is common and has potential clinical and therapeutic value in CaP. We examined the PTEN status of primary tumors in pts who underwent adjuvant docetaxel tx in a prospective clinical trial. Methods: Of the 77 pts enrolled in a prospective multi-institutional adjuvant docetaxel trial (TAX 2501, J Urol 2007), we prospectively collected 56 primary tumor pathology specimens suitable for analysis of PTEN status by immunoreactivity (IHC) and/or fluorescence in situ hybridisation (FISH) assay. Protocol defined progression included a PSA of ≥ 0.4 ng/mL, radiological/pathological evidence of recurrent disease or death from any cause. Univariate and multivariable analyses based on the Cox proportional hazards regression model were used to analyze the independent association of PTEN and other known prognostic factors with progression free survival (PFS). Results: PTEN loss was observed in 37/56 pts (6...
BackgroundTherapies targeting the androgen receptor (AR) have improved the outcome for patients w... more BackgroundTherapies targeting the androgen receptor (AR) have improved the outcome for patients with castration-sensitive prostate cancer (CSPC). Expression of the constitutively active AR splice variant-7 (AR-V7) has shown clinical utility as a predictive biomarker of AR-targeted therapy resistance in castration-resistant prostate cancer (CRPC), but its importance as predictive biomarker in CSPC remains understudied.MethodsWe explored multiple approaches to quantify AR-V7 mRNA and protein in prostate cancer cell lines and patient-derived xenograft (PDX) models, in both publicly available and independent institutional clinical cohorts, to identify reliable approaches for detecting AR-V7 mRNA and protein, and its association with clinical outcome.ResultsIn publicly available benign prostate, CSPC and CRPC cohorts, AR-V7 mRNA was much less abundant when detected using reads across splice boundaries than when considering isoform-specific exonic reads. The RM7 AR-V7 antibody had increas...
Background: PARP inhibitors (PARPi) are approved for the treatment of metastatic prostate cancer ... more Background: PARP inhibitors (PARPi) are approved for the treatment of metastatic prostate cancer (mPC) associated to various DNA damage repair (DDR) gene mutations; but clinical benefit differs among patients. Biomarkers of homologous recombination repair (HRR) deficiency may help refine patient stratification for a more precise therapy selection. We report an exploratory analysis from the TOPARP-B phase II clinical trial of olaparib in mPC (NCT01682772), investigating the predictive value of an HRR function assay detecting RAD51 foci by immunofluorescence in tumor biopsies. Design: We analyzed formalin-fixed paraffin-embedded (FFPE) primary or metastatic biopsies from mPC patients treated with olaparib in the clinical trial. We evaluated baseline HRR function based on detection of RAD51 and γH2AX foci in geminin-positive tumor cells by immunofluorescence (IF). All samples were scored by two trained readers blinded to genomic and clinical data. Samples were considered HRR deficient ...
Background: CD38, an ecto-enzyme involved in adenosine synthesis, is implicated in tumor immune e... more Background: CD38, an ecto-enzyme involved in adenosine synthesis, is implicated in tumor immune evasion. Its expression and role in the prostate tumor microenvironment (TME) has not been fully elucidated. Main objectives: To determine whether CD38 is associated with prostate cancer (PC) immune evasion, to characterize CD38 expression on PC epithelial cells and tumor infiltrating immune cells (TIICs) as tumors progress from castration-sensitive PC (CSPC) to metastatic castration-resistant PC (mCRPC), and to determine the association between CD38+ TIICs and survival. Methods: Data from 159 mCRPC transcriptomes from the Stand Up To Cancer/Prostate Cancer Foundation cohort were analyzed for associations between CD38 and 200 cell signaling pathways, an adenosine signature and T cell exhaustion signatures. CD38 protein expression on tumor epithelial cells and TIICs was scored using validated immunohistochemistry (IHC) assays on 51 treatment-naïve CSPC biopsies and matching, same-patient m...
Prostate cancer is a major cause of cancer morbidity and mortality. Intra-prostatic inflammation ... more Prostate cancer is a major cause of cancer morbidity and mortality. Intra-prostatic inflammation is a risk factor for prostate carcinogenesis, with diet, chemical injury and an altered microbiome being causally implicated. Intra-prostatic inflammatory cell recruitment and expansion can ultimately promote DNA double-strand breaks and androgen receptor activation in prostate epithelial cells. The activation of the senescence-associated secretory phenotype fuels further ‘inflammatory storms’, with free radicals leading to further DNA damage. This drives the overexpression of DNA repair and tumour suppressor genes, rendering these genes susceptible to mutagenic insults, with carcinogenesis accelerated by germline DNA repair gene defects. We provide updates on recent advances in elucidating prostate carcinogenesis and explore novel therapeutic and prevention strategies harnessing these discoveries. This Review discusses intra-prostatic inflammatory processes and how they are induced and perpetuated, thereby driving prostate cancer development and progression. By discussing external inflammatory cues in connection to cancer cell-intrinsic factors in prostate tumorigenesis, the authors provide insight into potential preventative and therapeutic strategies.
5002 Background: Prostate-specific membrane antigen (PSMA) is a promising target for theranostics... more 5002 Background: Prostate-specific membrane antigen (PSMA) is a promising target for theranostics in metastatic castration resistant prostate cancer (mCRPC). Methods: Membranous PSMA (mPSMA) expression was immunohistochemically evaluated in castration sensitive (CSPC) (n = 38) and mCRPC (n = 60) tissue biopsies, and associations with molecular aberrations (next-generation sequencing; NGS) and clinical outcome were determined. Results: mPSMA expression was significantly higher (p = 0.005) in mCRPC biopsies (median H-score [interquartile range]; 55.0 [2.8-117.5]) compared to CSPC biopsies (17.5 [0.0-60.0]). Furthermore, patients with higher mPSMA expression ( > median H-score) at diagnosis had higher Gleason Grade (p = 0.04) and shorter OS (p = 0.006). Critically, 42% (16/38) of CSPC biopsies and 27% (16/60) of mCRPC biopsies were completely negative for mPSMA expression. In addition, CSPC and mCRPC biopsies expressing mPSMA demonstrated marked intra-tumor heterogeneity in expressi...
Archives of Pathology & Laboratory Medicine, 2018
Context.— Phosphatase and tensin homolog (PTEN) is a promising prognostic and potentially predict... more Context.— Phosphatase and tensin homolog (PTEN) is a promising prognostic and potentially predictive biomarker in prostate cancer. Objective.— To assess the effects of preanalytic variables on an analytically validated and fully automated PTEN immunohistochemistry assay. Design.— PTEN immunohistochemistry was performed on Ventana immunostaining systems. In benign prostate tissues, immunostaining intensity across variable conditions was assessed by digital image analysis. In prostate tumor tissues, immunostaining was scored visually. Results.— Delay of fixation for 4 hours or longer at room temperature or 48 hours or longer at 4°C and duration of formalin fixation did not significantly alter immunostaining intensity. Intensity of staining was highest in 10% formalin compared with other fixatives. Tumor tissues with PTEN loss processed using protocols from 11 academic institutions were all evaluable and scored identically. PTEN immunostaining of needle biopsies where tissue blocks had...
Cancer prevention research (Philadelphia, Pa.), Jan 29, 2015
Inflammation may play an etiologic role in prostate cancer. Several dietary factors influence inf... more Inflammation may play an etiologic role in prostate cancer. Several dietary factors influence inflammation; studies have shown that long-chain n-3 polyunsaturated fatty acids are anti-inflammatory, while n-6 and trans fatty acids are pro-inflammatory. We evaluated whether serum phospholipid n-3, n-6, and trans fatty acids were associated with intraprostatic inflammation, separately in 191 prostate cancer cases and 247 controls from the placebo arm of the in the Prostate Cancer Prevention Trial (PCPT). Men without a prostate cancer diagnosis underwent prostate biopsy at trial end, and benign prostate tissue inflammation was evaluated in approximately three biopsy cores per man; this was expressed as no, some, or all cores with inflammation. In controls, serum eicosapentaenoic acid (OR of all cores with inflammation versus none (95%CI): 0.35 (0.14, 0.89)), and docosahexaenoic acid (OR (95%CI): 0.42 (0.17, 1.02)) were inversely associated with, while linoleic acid (OR (95%CI): 3.85 (1....
Proceedings of the National Academy of Sciences, 2012
Prostate cancer is the second leading cause of cancer death among United States men. However, dis... more Prostate cancer is the second leading cause of cancer death among United States men. However, disease aggressiveness is varied, with low-grade disease often being indolent and high-grade cancer accounting for the greatest density of deaths. Outcomes are also disparate among men with high-grade prostate cancer, with upwards of 65% having disease recurrence even after primary treatment. Identification of men at risk for recurrence and elucidation of the molecular processes that drive their disease is paramount, as these men are the most likely to benefit from multimodal therapy. We previously showed that androgen-induced expression profiles in prostate development are reactivated in aggressive prostate cancers. Herein, we report the down-regulation of one such gene, Sparcl1 , a secreted protein, acidic and rich in cysteine (SPARC) family matricellular protein, during invasive phases of prostate development and regeneration. We further demonstrate a parallel process in prostate cancer,...
Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Background: Chronic... more Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Background: Chronic inflammation may be crucial for the etiology of prostatic adenocarcinoma (CaP). If inflammation is part of the pathogenesis of this disease then it might be expected that prostates with adenocarcinoma would harbor more inflammation than prostates without adenocarcinoma. Design: Cases (biopsy detected and centrally reviewed) and age frequency-matched controls, defined as negative for adenocarcinoma on an end-of-study biopsy, were selected using a nested case-control design from among participants in placebo arm of the Prostate Cancer Prevention Trial (PCPT). The PCPT (n= 18,000 men) determined whether finasteride, a 5-alpha reductase inhibitor, could reduce the period prevalence of adenocarcinoma over 7 years. All men were screened annually by PSA and DRE, and all men not diagnosed with adenocarcinoma during the study were offered an end-of-study biopsy. Cases consisted of 191 men, and controls were from 209 men. Microscope slides (1- 5 core biopsies for each man) were digitized and evaluated online after masking of adenocarcinoma and random benign areas to ensure blinding of the pathologist to case/control status. Inflammation was assessed using a modified National Institutes of Health (NIH) grading system and data were analyzed using logistic regression. Result: Men who had at least one biopsy core positive for chronic inflammation (CI) (majority was chronic) had 1.79 (95% CI 1.06-3.04) times the risk of prostate cancer compared with no cores positive. The association was stronger for higher-grade (Gleason score 7-10; OR=2.41, 95% CI 1.17-4.95) disease than for lower-grade (Gleason score 6; OR=1.45, 95% CI 0.79-2.68) disease. Risk of prostate cancer (p-trend=0.05) and higher-grade disease (p-trend=0.02) increased with increasing percent of cores positive. Conclusion: The presence of any chronic inflammation in benign prostate tissue was positively and statistically significantly associated with adenocarcinoma, especially higher grade lesions (Gleason score 7-10). Additional studies to further examine a potential role for inflammation as a cofactor in overall and high-grade prostate cancer should help determine whether chronic inflammation present in benign tissue is a reaction to the presence of cancer, or, is related to the pathogenesis of prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4366.
Hypomethylation of CpG dinucleotides in genomic DNA was one of the first somatic epigenetic alter... more Hypomethylation of CpG dinucleotides in genomic DNA was one of the first somatic epigenetic alterations discovered in human cancers. DNA hypomethylation is postulated to occur very early in almost all human cancers, perhaps facilitating genetic instability and cancer initiation and progression. We therefore examined the nature, extent, and timing of DNA hypomethylation changes in human prostate cancer. Contrary to the prevailing view that global DNA hypomethylation changes occur extremely early in all human cancers, we show that reductions in 5meC content in the genome occur very late in prostate cancer progression, appearing at a significant extent only at the stage of metastatic disease. Furthermore, we found that, whereas some LINE1 promoter hypomethylation does occur in primary prostate cancers compared with normal tissues, this LINE1 hypomethylation is significantly more pronounced in metastatic prostate cancer. Next, we carried out a tiered gene expression microarray and bisul...
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