David F Jarrard

University of Wisconsin–Madison, Madison, Wisconsin, United States

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Publications (103)495.32 Total impact

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    ABSTRACT: Genomic imprinting is an epigenetic mechanism that restricts gene expression to one inherited allele. Improper maintenance of imprinting has been implicated in a number of human diseases and developmental syndromes. Assays are needed that can quantify the contribution of each paternal allele to a gene expression profile. We have developed a rapid, sensitive quantitative assay for the measurement of individual allelic ratios termed Pyrosequencing for Imprinted Expression (PIE). Advantages of PIE over other approaches include shorter experimental time, decreased labor, avoiding the need for restriction endonuclease enzymes at polymorphic sites, and prevent heteroduplex formation which is problematic in quantitative PCR-based methods. We demonstrate the improved sensitivity of PIE including the ability to detect differences in allelic expression down to 1%. The assay is capable of measuring genomic heterozygosity as well as imprinting in a single run. PIE is applied to determine the status of Insulin-like Growth Factor-2 (IGF2) imprinting in human and mouse tissues. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of cellular biochemistry. 01/2015;
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    ABSTRACT: There is a major deficit in our ability to detect and predict the clinical behavior of prostate cancer (PCa). Epigenetic changes are associated with PCa development and progression. This review will focus on recent results in the clinical application of diagnostic and prognostic epigenetic markers. The development of high throughput technology has seen an enormous increase in the discovery of new markers that encompass epigenetic changes including those in DNA methylation and histone modifications. Application of these findings to urine and other biofluids, but also cancer and noncancerous prostate tissue, has resulted in new biomarkers. There has been a recent commercial development of a DNA methylation-based assay for identifying PCa risk from normal biopsy tissue. Other biomarkers are currently in the validation phase and encompass combinations of multiple genes. Epigenetic changes improve the specificity and sensitivity of PCa diagnosis and have the potential to help determine clinical prognosis. Additional studies will not only provide new and better biomarker candidates, but also have the potential to inform new therapeutic strategies given the reversibility of these processes.
    Current opinion in urology. 01/2015; 25(1):83-8.
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    ABSTRACT: Abnormal expression and function of chromatin regulators results in the altered chromatin structure seen in cancer. The chromatin regulator CTCF, its cofactor CHD8, and antagonistic paralogue BORIS have wide-ranging effects on gene regulation. Their concurrent expression and regulation was examined in benign, localized, and metastatic prostate cancer (PCa) arrays with extended follow-up using an automated quantitative imaging system, VECTRA. Epithelial staining was quantified and compared against a range of clinicopathologic variables. CHD8 expression was decreased in HGPIN, localized, and metastatic PCa compared to benign (P < .001). CHD8 promoter hypermethylation, assessed by Quantitative Pyrosequencing, occurred in over 45% of primary cancers in this population as well as the TGCA database. Treatment of cell lines with the demethylating agent 5-Aza-2'-deoxycytidine reinduced expression. An interesting dichotomy for CHD8 was observed within primary cancers, with higher nuclear protein expression associated with adverse clinical outcomes including extracapsular extension (P = .007), presence of metastases (P = .025) and worse PSA-recurrence free survival (P = .048). CHD8 outperformed Gleason score and predicted biochemical failure within intermediate grade prostate cancers. The BORIS/CTCF expression ratio increased in localized (P = .03) and metastatic PCa (P = .006) and was associated with higher Gleason score (P = .02), increased tumor volume (P = .02) and positive margins (P = .04). Per cell heterogeneity of expression revealed all protein expression to be more heterogeneous in cancerous tissue (both P < .001), especially high grade (P < .01). In the first detailed analysis in cancer, a marked loss of CHD8 expression and increased BORIS/CTCF ratio indicate frequent disruption of CTCF and its effector genes in PCa. Copyright © 2014 Neoplasia Press, Inc. Published by Elsevier Inc. All rights reserved.
    Neoplasia (New York, N.Y.) 12/2014; 16(12):1018-27. · 5.40 Impact Factor
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    ABSTRACT: Androgen receptor (AR) signaling initiates mouse prostate development by stimulating prostate ductal bud formation and specifying bud patterns. Curiously, however, prostatic bud initiation lags behind the onset of gonadal testosterone synthesis by about three days. This study's objective was to test the hypothesis that DNA methylation controls the timing and scope of prostate ductal development by regulating Ar expression in the urogenital sinus (UGS) from which the prostate derives. We determined that Ar DNA methylation decreases in UGS mesenchyme during prostate bud formation in vivo and that this change correlates with decreased DNA methyltransferase expression in the same cell population during the same time period. To examine the role of DNA methylation in prostate development, fetal UGSs were grown in serum-free medium and 5 alpha dihydrotestosterone (DHT) and the DNA methylation inhibitor 5′-aza-2′-deoxycytidine (5AzadC) were introduced into the medium at specific times. As a measure of prostate development, in situ hybridization was used to visualize and count Nkx3-1 mRNA positive prostatic buds. We determined that inhibiting DNA methylation when prostatic buds are being specified, accelerates the onset of prostatic bud development, increases bud number, and sensitizes the budding response to androgens. Inhibition of DNA methylation also reduces Ar DNA methylation in UGS explants and increases Ar mRNA and protein in UGS mesenchyme and epithelium. Together, these results support a novel mechanism whereby Ar DNA methylation regulates UGS androgen sensitivity to control the rate and number of prostatic buds formed, thereby establishing a developmental checkpoint.
    Developmental Biology 10/2014; · 3.64 Impact Factor
  • David F Jarrard, Michael L Blute, Mark A Ritter
    Journal of Clinical Oncology 10/2014; · 17.88 Impact Factor
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    ABSTRACT: While perioperative blood transfusion (BT) has been associated with adverse outcomes in multiple malignancies, the importance of BT timing has not been established.
    European Urology 09/2014; · 12.48 Impact Factor
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    ABSTRACT: The mechanisms underlying the potential for aggressive behavior of prostate cancer (PCa) remain elusive. In this study, whole genome and/or transcriptome sequencing was performed on 19 specimens of PCa, matched adjacent benign prostate tissues, matched blood specimens, and organ donor prostates. A set of novel fusion transcripts was discovered in PCa. Eight of these fusion transcripts were validated through multiple approaches. The occurrence of these fusion transcripts was then analyzed in 289 prostate samples from three institutes, with clinical follow-up ranging from 1 to 15 years. The analyses indicated that most patients [69 (91%) of 76] positive for any of these fusion transcripts (TRMT11-GRIK2, SLC45A2-AMACR, MTOR-TP53BP1, LRRC59-FLJ60017, TMEM135-CCDC67, KDM4-AC011523.2, MAN2A1-FER, and CCNH-C5orf30) experienced PCa recurrence, metastases, and/or PCa-specific death after radical prostatectomy. These outcomes occurred in only 37% (58/157) of patients without carrying those fusion transcripts. Three fusion transcripts occurred exclusively in PCa samples from patients who experienced recurrence or PCa–related death. The formation of these fusion transcripts may be the result of genome recombination. A combination of these fusion transcripts in PCa with Gleason's grading or with nomogram significantly improves the prediction rate of PCa recurrence. Our analyses suggest that formation of these fusion transcripts may underlie the aggressive behavior of PCa.
    American Journal Of Pathology 09/2014; · 4.60 Impact Factor
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    ABSTRACT: The objective of this study was to compare the predictive ability of potential tissue biomarkers to known prognostic factors that predict RCC recurrence using an automated system of immunohistochemical (IHC) analysis. After IRB approval, a tissue (TMA) microarray was constructed using tissue from patients who had partial or radical nephrectomy for RCC. Patients with metastatic disease were excluded. IHC staining of the TMA for Ki-67, C reactive protein (CRP), carbonic anhydrase 9 (CAIX), HIF1α, HIF2α was analyzed using automated image analysis. Univariable and multivariable analysis was performed to evaluate the association of putative biomarkers and known prognostic factors. Of 216 patients who met entrance criteria, 34 (16%) patients developed metastatic recurrence within a median follow-up interval of 60.9 [IQR 13.9-87.1] months. RCC morphotypes analyzed in this study include clear cell (N=156), papillary (N=38), chromophobe (N=16), and collecting duct/unclassified (N=6). Univariable analysis identified that only increased Ki-67 was predictive of RCC recurrence among the proteins evaluated, in addition to other known clinical and pathologic prognostic factors. After multivariable analysis, Ki-67 was identified as an independently predictive risk factor for RCC recurrence HR 3.73 [CI 1.60-8.68]. Other independent predictors of RCC recurrence included tumor diameter HR 1.20 [1.02-1.41] and perinephric fat invasion HR 4.49 [CI 1.11-18.20]. We conclude that Ki-67 positivity is independently predictive of RCC recurrence after surgery in non-metastatic patients. Automated analysis of tissue protein expression can facilitate more objective and expedient investigation of tissue biomarkers for RCC.
    Human pathology 05/2014; · 2.81 Impact Factor
  • The Journal of Urology 04/2014; 191(4):e426. · 3.75 Impact Factor
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    ABSTRACT: Genomic imprinting is the allele-specific expression of a gene based on parental origin. Loss of imprinting(LOI) of Insulin-like Growth Factor 2 (IGF2) during aging is important in tumorigenesis, yet the regulatory mechanisms driving this event are largely unknown. In this study oxidative stress, measured by increased NF-κB activity, induces LOI in both cancerous and noncancerous human prostate cells. Decreased expression of the enhancer-blocking element CCCTC-binding factor(CTCF) results in reduced binding of CTCF to the H19-ICR (imprint control region), a major factor in the allelic silencing of IGF2. This ICR then develops increased DNA methylation. Assays identify a recruitment of the canonical pathway proteins NF-κB p65 and p50 to the CTCF promoter associated with the co-repressor HDAC1 explaining gene repression. An IκBα super-repressor blocks oxidative stress-induced activation of NF-κB and IGF2 imprinting is maintained. In vivo experiments using IκBα mutant mice with continuous NF-κB activation demonstrate increased IGF2 LOI further confirming a central role for canonical NF-κB signaling. We conclude CTCF plays a central role in mediating the effects of NF-κB activation that result in altered imprinting both in vitro and in vivo. This novel finding connects inflammation found in aging prostate tissues with the altered epigenetic landscape.
    PLoS ONE 02/2014; 9(2):e88052. · 3.53 Impact Factor
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    ABSTRACT: To evaluate the effect of operative time on the risk of symptomatic venous thromboembolic events (VTEs) in patients undergoing robot-assisted radical prostatectomy (RARP).
    JSLS: Journal of the Society of Laparoendoscopic Surgeons / Society of Laparoendoscopic Surgeons 01/2014; 18(2):282-287. · 0.79 Impact Factor
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    ABSTRACT: Many patients with low-risk prostate cancer (PC) who are diagnosed with Gleason score 6 at biopsy are ultimately found to harbor higher grade PC (Gleason ≥ 7) at radical prostatectomy. This finding increases risk of recurrence and cancer-specific mortality. Validated clinical tools that are available preoperatively are needed to improve the ability to recognize likelihood of upgrading in patients with low-risk PC. More than 30 clinicopathologic parameters were assessed in consecutive patients with Gleason 6 PC upon biopsy who underwent radical prostatectomy. A nomogram for predicting upgrading (Gleason ≥ 7) on final pathology was generated using multivariable logistic regression in a development cohort of 431 patients. External validation was performed in 2 separate cohorts consisting of 1151 patients and 392 patients. Nomogram performance was assessed using receiver operating characteristic curves, calibration, and decision analysis. On multivariable analysis, variables predicting upgrading were prostate-specific antigen density using ultrasound (odds ratio [OR] = 1.72 per 0.1 unit increase PSAD, P = .003), obesity (OR = 1.90, P = .05), number of positive cores (OR = 1.23, P = .01), and maximum core involvement (OR = 1.02, P = .01). On internal validation, the bootstrap-corrected predictive accuracy was 0.753. External validation revealed a predictive accuracy of 0.677 and 0.672. The nomogram demonstrated excellent calibration in all 3 cohorts and decision curves demonstrated high net benefit across a wide range of threshold probabilities. The nomogram demonstrated areas under the curve of 0.597 to 0.672 for predicting upgrading in subsets of men with very low-risk PC who meet active surveillance criteria (all P < .001), allowing further risk stratification of these individuals. A nomogram was developed and externally validated that uses preoperative clinical parameters and biopsy findings to predict the risk of pathological upgrading in Gleason 6 patients. This can be used to further inform patients with lower risk PC who are considering treatment or active surveillance. Cancer 2013. © 2013 American Cancer Society.
    Cancer 09/2013; · 5.20 Impact Factor
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    ABSTRACT: Increasing age is a significant risk factor for prostate cancer. The prostate is exposed to environmental and endogenous stress that may underlie this remarkable incidence. DNA methylation, genomic imprinting, and histone modifications are examples of epigenetic factors known to undergo change in the aging and cancerous prostate. In this review we examine the data linking epigenetic alterations in the prostate with aging to cancer development. An online search of current and past peer reviewed literature on epigenetic changes with cancer and aging was performed. Relevant articles were analyzed. Epigenetic changes are responsible for modifying expression of oncogenes and tumor suppressors. Several of these changes may represent a field defect that predisposes to cancer development. Focal hypermethylation occurs at CpG islands in the promoters of certain genes including GSTP1, RARβ2, and RASSF1A with both age and cancer, while global hypomethylation is seen in prostate cancer and known to occur in the colon and other organs. A loss of genomic imprinting is responsible for biallelic expression of the well-known Insulin-like Growth Factor 2 (IGF2) gene. Loss of imprinting (LOI) at IGF2 has been documented in cancer and is also known to occur in benign aging prostate tissue marking the presence of cancer. Histone modifications have the ability to dictate chromatin structure and direct gene expression. Epigenetic changes with aging represent molecular mechanisms to explain the increased susceptibly of the prostate to develop cancer in older men. These changes may provide an opportunity for diagnostic and chemopreventive strategies given the epigenome can be modified. Prostate 9999: 1-10, 2013. © 2013 Wiley Periodicals, Inc.
    The Prostate 09/2013; · 3.57 Impact Factor
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    ABSTRACT: We have developed a rapid and sensitive quantitative assay for the measurement of individual allelic ratios. This assay minimizes time and labor, the need for special restriction endonuclease enzymes for polymorphic sites, and avoids heteroduplex formation seen with traditional quantitative PCR-based methods. It has improved sensitivity compared to other methods and is capable of distinguishing 1% differences in allelic expression. This assay, termed Pyrosequencing for Imprinted Expression (PIE), involves the use of an intron-crossing PCR primer to generate the first PCR product. We applied the assay to analyze Insulin-like Growth Factor-2 (IGF2) imprinting in both human and mouse prostate tissues.
    Epigenetics: official journal of the DNA Methylation Society 08/2013; 8(10). · 5.11 Impact Factor
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    ABSTRACT: Background: Many low risk prostate cancer (PC) patients diagnosed with Gleason score 6 at biopsy are ultimately found to harbor higher grade cancer (Gleason≥7) at radical prostatectomy. This finding increases risk of recurrence and cancer-specific mortality. Validated clinical tools available preoperatively are needed to improve our ability to recognize upgrading in low risk patients. Methods: Over 30 clinicopathologic parameters were assessed in consecutive Gleason 6 biopsy patients who underwent radical prostatectomy. A nomogram for predicting upgrading (Gleason≥7) on final pathology was generated using multivariable logistic regression in a development cohort of 431 patients. External validation was performed in two separate cohorts consisting of 1151 patients and 392 patients. Nomogram performance was assessed using ROC curves, calibration, and decision analysis. Results: On multivariable analysis variables predicting upgrading were PSA density using ultrasound (OR=229, p=0.003), obesity (OR=1.90, p=0.05), number of positive cores (OR=1.23, p=0.01), and maximum core involvement (OR=0.02, p=0.01). On internal validation, the bootstrap-corrected predictive accuracy was 0.753. External validation revealed a predictive accuracy of 0.677 and 0.672. The nomogram demonstrated excellent calibration in all three cohorts and decision curves demonstrated high net benefit across a wide range of threshold probabilities. The nomogram demonstrated AUCs of 0.597-0.672 for predicting upgrading in subsets of very low risk men who meet AS criteria(all p<0.001) allowing further risk stratification of these individuals. Conclusion: We have developed and externally validated a nomogram that uses preoperative clinical parameters and biopsy findings to predict the risk of pathological upgrading in Gleason 6 patients. This can be used to further inform lower risk PC patients considering treatment or AS.
    Cancer 05/2013; · 4.90 Impact Factor
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    ABSTRACT: Background: In vertebrates, DNA methylation occurs primarily at CG dinucleotides but recently, non-CG methylation has been found at appreciable levels in embryonic stem cells. Materials & methods: To assess non-CG methylation in cancer, we compared the extent of non-CG methylation at several biologically important CG islands in prostate cancer and normal cell lines. An assessment of the promoter CG islands EVX1 and FILIP1L demonstrates a fourfold higher rate of non-CG methylation at EVX1 compared with FILIP1L across all cell lines. These loci are densely methylated at CG sites in cancer. Results: No significant difference in non-CG methylation was demonstrated between cancer and normal. Treatment of cancer cell lines with 5-azacytidine significantly reduced methylation within EVX1 at CG and CC sites, preferentially. Conclusion: Non-CG methylation does not correlate with CG methylation at hypermethylated promoter regions in cancer. Furthermore, global inhibition of DNA methyltransferases does not affect all methylated cytosines uniformly.
    Epigenomics 05/2013; · 5.22 Impact Factor
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    ABSTRACT: Prostate cancer (PCa) is typically found as a multifocal disease suggesting the potential for molecular defects within the morphologically normal tissue. The frequency and spatial extent of DNA methylation changes encompassing a potential field defect are unknown. A comparison of non-tumor-associated (NTA) prostate to histologically indistinguishable tumor-associated (TA) prostate tissues detected a distinct profile of DNA methylation alterations (0.2%) using genome-wide DNA arrays based on the Encyclopedia of DNA Elements 18 sequence that tile both gene-rich and poor regions. Hypomethylation (87%) occurred more frequently than hypermethylation (13%). Several of the most significantly altered loci (CAV1, EVX1, MCF2L, and FGF1) were then used as probes to map the extent of these DNA methylation changes in normal tissues from prostates containing cancer. In TA tissues, the extent of methylation was similar both adjacent (2 mm) and at a distance (>1 cm) from tumor foci. These loci were also able to distinguish NTA from TA tissues in a validation set of patient samples. These mapping studies indicate that a spatially widespread epigenetic defect occurs in the peripheral prostate tissues of men who have PCa that may be useful in the detection of this disease.
    Neoplasia (New York, N.Y.) 04/2013; 15(4):399-408. · 5.40 Impact Factor
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    ABSTRACT: BACKGROUND: Aberrant chromatin structure in cancer cells results from altered proteins involved in its packaging. Heterochromatin protein 1 gamma (HP1gamma) is a non-histone heterochromatic protein that functions to maintain chromatin stability and is important in embryonic development. Given an interest in the role developmental genes play in cancer, we investigated HP1gamma expression in prostate cancer (PCa) and its prognostic associations. METHODS: Tissue microarrays consisting of benign (N=96), localized cancer (N=146), metastatic PCa (N=44), and HGPIN (N=50) were immunoflourescently stained for HP1gamma and Ki-67. Using a novel, automated quantitative imaging system, VECTRATM, epithelial staining in both the nucleus and cytoplasm was quantified and compared against clinicopathologic variables. RESULTS: HP1gamma is significantly elevated in HGPIN (80%), localized PCa (76%), and metastatic PCa (98%) compared to benign tissues from both the nuclear and cytoplasmic compartments (P < 0.0001). Increased nuclear and total HP1gamma expression was associated with Gleason score (P = 0.02 and P = 0.04 respectively). Given known binding to the C-terminus of Ki-67, a co-expression analysis was performed that revealed a correlation between nuclear and cytoplasmic HP1gamma and Ki-67 (Pearson Coefficient 0.321 and 0.562 respectively, P < 0.0001). Cox survival analysis demonstrated that cytoplasmic HP1gamma expression was an independent prognostic marker and out-performed pathological Gleason score for predicting PSA-recurrence after radical prostatectomy. CONCLUSIONS: In this first detailed analysis of HP1gamma expression in cancer, VECTRATM demonstrates compartmentalized and total HP1gamma protein expression is increased in PCa and that expression correlates with clinical outcomes better than Gleason score. Given the critical role HP1gamma plays in chromatin organization and gene expression, it represents a novel prognostic and therapeutic target.
    BMC Cancer 03/2013; 13(1):148. · 3.32 Impact Factor
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    ABSTRACT: BACKGROUND: Prostate cancer is the most common malignancy and second leading cause of cancer related deaths in American men supporting the study of prostate cancer chemoprevention. Major risk factors for this disease have been associated with low serum levels of vitamin D. Here, we evaluate the biologic activity of a less calcemic vitamin D analog 1α-hydroxyvitamin D2 [1α-OH-D2] (Bone Care International, Inc.) in patients with prostate cancer and high grade prostatic intraepithelial neoplasia (HG PIN). METHODS: Patients with clinically organ-confined prostate cancer and HG PIN were randomized to 1α-OH-D2 versus placebo for 28 days prior to radical prostatectomy. Intermediate endpoint biomarkers included serum vitamin D metabolites, TGFß 1/2, free/total PSA, IGF-1, IGFBP-3, bFGF, and VEGF. Tissue endpoints included histology, MIB-1 and TUNEL staining, microvessel density and factor VIII staining, androgen receptor and PSA, vitamin D receptor expression and nuclear morphometry. RESULTS: The 1α-OH-D2 vitamin D analog was well tolerated and could be safely administered with good compliance and no evidence of hypercalcemia over 28 days. While serum vitamin D metabolite levels only slightly increased, evidence of biologic activity was observed with significant reductions in serum PTH levels. TGF-ß2 was the only biomarker significantly altered by vitamin D supplementation. Whether reduced TGF-ß2 levels in our study is an early indicator of response to vitamin D remains unclear. CONCLUSIONS: While further investigation of vitamin D may be warranted based on preclinical studies, results of the present trial do not appear to justify evaluation of 1α-OH-D2 in larger clinical prostate cancer prevention studies. Prostate © 2013 Wiley Periodicals, Inc.
    The Prostate 01/2013; · 3.57 Impact Factor
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    ABSTRACT: PURPOSE: Senescence related regulatory pathways serve as barriers to cancer immortalization and progression but they are currently not well defined. FILIP1L is a growth inhibitory gene with multiple isoforms whose expression is increased in senescent prostate and prostate cancer cells, and decreased in many cancers. We investigated whether DNA methylation regulates FILIP1L in senescence and in prostate cancer development. MATERIALS AND METHODS: FILIP1L mRNA expression was assessed in prostate cancer and associated normal prostate tissues using quantitative polymerase chain reaction. A tissue microarray was constructed using 95 prostate cancer specimens and 45 benign prostate specimens. Vectra™ imaging was used to quantitate nuclear and cytoplasmic FILIP1L protein expression. Bisulfite sequencing and Pyrosequencing® were used to assess methylation. Prostate cancer cell lines were treated with 2'-deoxy-5-azacytidine and mRNA expression was assessed. RESULTS: FILIP1L isoform 2 mRNA was increased in replicatively senescent human prostate epithelial cells and decreased in prostate cancer specimens. We verified a reduction in nuclear FILIP1L protein in prostate cancer using tissue microarrays (p = 0.006). A CpG island 5' of the isoform 2 translational start site was identified that showed hypermethylation in prostate cancer cell lines and tumors compared to normal prostate cells and tissues. Pyrosequencing confirmed FILIP1L hypermethylation in all 14 tumors compared to paired normal tissues (p <0.0001). Isoform 2 expression was induced in prostate cancer cell lines using 2'-deoxy-5-azacytidine. CONCLUSIONS: FILIP1L isoform 2 is one of the most commonly hypermethylated genes in prostate cancer. It may serve as an important marker of prostate cancer. Isoform 2 expression is associated with senescence and its down-regulation may represent an early important biological event in prostate cancer development.
    The Journal of urology 11/2012; · 3.75 Impact Factor

Publication Stats

3k Citations
495.32 Total Impact Points

Institutions

  • 1999–2014
    • University of Wisconsin–Madison
      • • Department of Urology
      • • Department of Surgery
      Madison, Wisconsin, United States
  • 2012
    • Comprehensive Cancer Centers of Nevada
      Las Vegas, Nevada, United States
  • 1997–2005
    • Johns Hopkins University
      • Department of Pathology
      Baltimore, MD, United States
  • 1996–1997
    • Johns Hopkins Medicine
      • Department of Urology
      Baltimore, Maryland, United States
  • 1995
    • University of Maryland, Baltimore
      Baltimore, Maryland, United States