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Ahmad Jalili,
Christine Wagner,
Mikhail Pashenkov,
Gaurav Pathria, Kirsten D Mertz,
Hans R Widlund,
Mathieu Lupien,
Jean-Philippe Brunet,
Todd R Golub,
Georg Stingl,
David E Fisher,
Sridhar Ramaswamy,
Stephan N Wagner
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ABSTRACT: Resistance to BRAF(V600E) inhibitors is associated with reactivation of mitogen-activated protein kinase (MAPK) signaling at different levels in melanoma. To identify downstream effectors of MAPK signaling that could be used as potential additional therapeutic targets for BRAF(V600E) inhibitors, we used hTERT/CDK4R24C/p53DD-immortalized primary human melanocytes genetically modified to ectopically express BRAF ( V600E ) or NRAS ( G12D ) and observed induction of the AP-1 transcription factor family member c-Jun. Using a dominant negative approach, in vitro cell proliferation assays, western blots, and flow cytometry showed that MAPK signaling via BRAF(V600E) promotes melanoma cell proliferation at G1 through AP-1-mediated negative regulation of the INK4 family member, cyclin-dependent kinase inhibitor 2C (CDKN2C), and the CIP/KIP family member, cyclin-dependent kinase inhibitor 1A (CDKN1A). These effects were antagonized by pharmacological inhibition of CDKN2C and CDKN1A targets CDK2 and CDK4 in vitro. In contrast to BRAF ( V600E ) or NRAS ( G12D )-expressing melanocytes, melanoma cells have an inherent resistance to suppression of AP-1 activity by BRAF(V600E)- or MEK-inhibitors. Here, CDK2/4 inhibition statistically significantly augmented the effects of BRAF(V600E)- or MEK-inhibitors on melanoma cell viability in vitro and growth in athymic nude Foxn1 ( nu ) mice (P = .03 when mean tumor volume at day 13 was compared for BRAF(V600E) inhibitor vs BRAF(V600E) inhibitor plus CDK2/4 inhibition; P = .02 when mean tumor volume was compared for MEK inhibitor vs MEK inhibitor plus CDK2/4 inhibition; P values were calculated by a two-sided Welch t test; n = 4-8 mice per group).
CancerSpectrum Knowledge Environment 09/2012; · 14.07 Impact Factor
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ABSTRACT: About 10% of patients with Merkel cell carcinoma (MCC) suffer from an associated squamous cell carcinoma (SCC). In European patients, Merkel cell polyomavirus (MCPyV) is detectable in 60%-88% of the MCC tumors. In combined lesions, MCPyV was not detectable so far.
We investigated 2 combined tumors of MCC and SCC for the presence of MCPyV and human papillomavirus (HPV) by polymerase chain reaction and immunohistochemistry.
In both lesions, MCPyV DNA was found, and in 1 case, HPV DNA was also detected. This is the first report of a coinfection with HPV and MCPyV in combined MCC-SCC tumors.
The results underline the hypothesis of co-cancerogenesis of 2 oncogenic viruses in nonmelanoma skin cancer. Technical reasons and a low viral copy number of MCPyV hampering immunohistochemical detection may be responsible for the negative results in the literature.
The American Journal of dermatopathology 04/2012; 34(5):506-10. · 1.30 Impact Factor
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ABSTRACT: Organ transplant recipients (OTR) are at significantly increased risk to develop a wide variety of skin cancers, particularly epithelial skin cancer, Merkel cell carcinoma and Kaposi's sarcoma. In addition, melanoma, skin adnexal neoplasm and cutaneous lymphomas are more common in OTR and may differ in their clinicopathological presentation from tumors in immunocompetent patients. The accuracy of clinical diagnosis of suspected premalignant and malignant skin lesions in OTR is modest. Therefore, histopathological diagnosis is an essential element for the diagnostic workup of skin cancers, and additionally provides important information on prognosis. This review discusses the histopathological aspects of skin cancers in OTR, the impact of dermatopathological analysis on prognosis and understanding of the pathogenesis of these neoplasms.
Current problems in dermatology 01/2012; 43:18-35.
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ABSTRACT: Renal cell carcinomas (RCCs) with an Xp11.2 translocation predominantly affect young patients, and can present at an advanced stage. However, more cases in older patients and incidentally detected cancers at earlier stages are also being identified. As the histology of Xp11.2 RCCs overlaps with clear cell and papillary RCCs, it is not infrequent that Xp11.2 RCCs are overlooked and misdiagnosed. The objective of this study was to validate the use of fluorescence in-situ hybridization (FISH) for identifying Xp11.2 RCCs. One hundred fifty-eight consecutive, unselected renal tumors were evaluated in tissue microarrays, including 109 clear cell RCCs, 20 papillary RCCs, 3 RCCs with mixed papillary and clear cell features, 1 Xp11.2 translocation RCC, 8 chromophobe RCCs, 10 oncocytomas, and 7 angiomyolipomas. FISH evaluation was performed blinded to karyotype data, available in about two-thirds of cases. Furthermore, conventional sections of 4 Xp11.2 RCCs, 4 RCCs with mixed papillary and clear cell features, and 4 cases of alveolar soft part sarcoma (the latter for control purposes) were also assessed by FISH. Break-apart signals were homogeneously identified throughout tumor cells in 2 cases from the tissue microarrays including 1 known Xp11.2 RCC and 1 misdiagnosed Xp11.2 RCC. All conventional sections from the Xp11.2 RCC and alveolar soft part sarcoma cases were positive for the TFE3 rearrangement by FISH. All remaining cases were negative. Our study shows the clinical application of FISH in formalin-fixed, paraffin-embedded tissue for detection of Xp11.2 translocation RCCs and other tumors with this genetic aberration.
Diagnostic molecular pathology: the American journal of surgical pathology, part B 09/2011; 20(3):129-37. · 1.58 Impact Factor
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David S Rickman,
Ying-Bei Chen,
Samprit Banerjee,
Yihang Pan,
Jindan Yu,
Terry Vuong,
Sven Perner,
Christopher J Lafargue, Kirsten D Mertz,
Sunita R Setlur,
Kanishka Sircar,
Arul M Chinnaiyan,
Tarek A Bismar,
Mark A Rubin,
Francesca Demichelis
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ABSTRACT: To elucidate the role of ETS gene fusions in castration-resistant prostate cancer (CRPC), we characterized the transcriptome of 54 CRPC tumor samples from men with locally advanced or metastatic disease. Trefoil factor 3 (TFF3) emerged as the most highly differentially regulated gene with respect to ERG rearrangement status and resistance to hormone ablation therapy. Conventional chromatin immunoprecipitation (ChIP)-polymerase chain reaction and ChIP followed by DNA sequencing (ChIP-seq) revealed direct binding of ERG to ETS binding sites in the TFF3 promoter in ERG-rearranged prostate cancer cell lines. These results were confirmed in ERG-rearranged hormone-naive prostate cancer (HNPC) and CRPC tissue samples. Functional studies demonstrated that ERG has an inhibitory effect on TFF3 expression in hormone-naive cancer but not in the castration-resistant state. In addition, we provide evidence suggesting an effect of androgen receptor signaling on ERG-regulated TFF3 expression. Furthermore, TFF3 overexpression enhances ERG-mediated cell invasion in CRPC prostate cancer cells. Taken together, our findings reveal a novel mechanism for enhanced tumor cell aggressiveness resulting from ERG rearrangement in the castration-resistant setting through TFF3 gene expression.
Neoplasia (New York, N.Y.) 12/2010; 12(12):1031-40. · 5.48 Impact Factor
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ABSTRACT: Polyomaviruses have been linked to diseases of immunosuppressed patients. We sought to determine the prevalence of Merkel cell polyomavirus in benign epithelial skin neoplasms and nonmelanoma skin cancer of immunosuppressed renal transplant recipients and long-term dialysis patients. Merkel cell polyomavirus DNA was detected by polymerase chain reaction (PCR) in 2 (10%) of 20 patients, in carcinomas in situ (Bowen's disease). In one of our patients with Merkel cell polyomavirus-positive carcinoma in situ, 9 (39.1%) of 23 skin lesions at various anatomical locations tested positive for Merkel cell polyomavirus sequences by PCR, including all of his common warts (4/4), half of his carcinoma in situ lesions (3/6), and 2 of his 3 seborrheic keratoses. In a second cohort of immunosuppressed renal transplant recipients, Merkel cell polyomavirus DNA was found in 1 (6.3%) of 16 common warts and in 2 (9.5%) of 21 carcinomas in situ. In immunocompetent individuals, Merkel cell polyomavirus DNA was found in 2 (6.7%) of 30 common warts and in 2 (8.3%) of 24 carcinomas in situ. DNA of other human polyomaviruses was not detected in any of the investigated skin neoplasms. We conclude that common warts and carcinomas in situ can be positive for Merkel cell polyomavirus in immunosuppressed as well as immunocompetent individuals. Remarkably, some of the Merkel cell polyomavirus-positive common warts did not contain human papillomavirus. Furthermore, Merkel cell polyomavirus can be found in various skin neoplasms of the same individual.
Human pathology 10/2010; 41(10):1369-79. · 3.03 Impact Factor
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ABSTRACT: Basal cell carcinoma (BCC) is the most common malignancy among Caucasians worldwide. The risk of BCC is 10-16 times higher among immunosuppressed transplant recipients compared with the general population.
To analyze the incidence, clinical presentation, histologic features, treatment and recurrence rate of BCC in a cohort of 69 renal transplant recipients (RTRs; 53 male).
Retrospective population-based cohort study of immunosuppressed RTRs.
Ten of 69 patients (14.5%, five male) developed a total of 17 BCCs, mostly on the head. Mean age at first diagnosis of BCC was 65.5 +/- 8.5 years, and latency between kidney transplantation and diagnosis of the first BCC was 11.1 +/- 6.3 years (mean +/- SD). The risk of female RTRs to develop BCCs appeared to be three times higher than the risk of male RTRs, and female RTRs developed BCCs earlier after transplantation. Nodular BCC was the most common histologic subtype. Most BCCs in these RTRs were treated by complete surgical excision. Recurrence after surgical excision was observed in one of the 10 patients (10%).
Our results suggest female RTRs to be at higher risk to develop cutaneous BCCs than male RTRs. There are no differences in localization and clinicopathologic presentation of BCCs developing in RTRs compared with immunocompetent patients. Therefore, BCCs in RTRs do not require different treatment than in other patient groups. As patients tend to develop a second BCC, close follow-up is mandatory.
International journal of dermatology 04/2010; 49(4):385-9. · 1.18 Impact Factor
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ABSTRACT: Morphea, granuloma annulare (GA) and lichen sclerosus et atrophicans (LSA) have also been suggested to be linked to Borrelia infection. Previous studies based on serologic data or detection of Borrelia by immunohistochemistry and polymerase chain reaction (PCR) reported contradictory results. Thus, we examined skin biopsies of morphea, GA and LSA by PCR to assess the prevalence of Borrelia DNA in an endemic area and to compare our results with data in the literature.
Amplification of DNA sequences of Borrelia burgdorferi sensu lato by nested PCR from formalin-fixed and paraffin-embedded skin biopsies of morphea, GA and LSA, followed by automated sequencing of amplification products. PCR-based studies on Borrelia species in these disorders published until July 2009 were retrieved by a literature search.
Borrelia DNA was detected in 3 of 112 skin biopsies (2.7%) including one of 49 morphea biopsies (2.0%), one of 48 GA biopsies (2.1%) and one of 15 LSA biopsies (6.6%). Amplification products belonged to B. burgdorferi sensu stricto in two cases available for sequence analysis.
The results of our and most of other PCR-based studies do not argue for a significant association of B. burgdorferi sensu lato with morphea, GA, LSA.
Journal of Cutaneous Pathology 12/2009; 37(5):571-7. · 1.56 Impact Factor
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ABSTRACT: Merkel cell polyomavirus (MCPyV) is a recently discovered virus that is implicated in the oncogenesis of Merkel cell carcinoma (MCC). The route of dissemination and the reservoir(s) of MCPyV within the human body have not yet been identified. In this study we describe two patients with multiple MCPyV-positive inflammatory and neoplastic skin lesions at different anatomic sites. Patient 1 was suffering from psoriasis for many years and was diagnosed with MCC 7 years before this study. Patient 2 had developed numerous non-melanoma skin cancer lesions under post-transplant immunosuppression. In both patients, MCPyV DNA was detected in whole blood and in urine using PCR and direct sequencing of PCR products. When we analyzed different blood compartments, we found MCPyV exclusively in cell-free serum and in blood monocytes, but not in lymphocytes or granulocytes. Upon separate analysis of resident (CD14(lo)CD16(+)) and inflammatory (CD14(+)CD16(-)) monocytes, we detected MCPyV exclusively in inflammatory, but not in resident monocytes. Our findings raise the possibility that MCPyV persists in inflammatory monocytes and spreads along the migration routes of inflammatory monocytes. This points to intervention strategies to contain MCPyV. Moreover, blood or urine tests may serve as ancillary tests to confirm MCPyV infection in a clinical setting.
Journal of Investigative Dermatology 12/2009; 130(4):1146-51. · 6.31 Impact Factor
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Rameen Beroukhim,
Jean-Philippe Brunet,
Arianna Di Napoli, Kirsten D Mertz,
Apryle Seeley,
Maira M Pires,
David Linhart,
Robert A Worrell,
Holger Moch,
Mark A Rubin,
William R Sellers,
Matthew Meyerson,
W Marston Linehan,
William G Kaelin,
Sabina Signoretti
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ABSTRACT: Recent insights into the role of the von-Hippel Lindau (VHL) tumor suppressor gene in hereditary and sporadic clear-cell renal cell carcinoma (ccRCC) have led to new treatments for patients with metastatic ccRCC, although virtually all patients eventually succumb to the disease. We performed an integrated, genome-wide analysis of copy-number changes and gene expression profiles in 90 tumors, including both sporadic and VHL disease-associated tumors, in hopes of identifying new therapeutic targets in ccRCC. We identified 14 regions of nonrandom copy-number change, including 7 regions of amplification (1q, 2q, 5q, 7q, 8q, 12p, and 20q) and 7 regions of deletion (1p, 3p, 4q, 6q, 8p, 9p, and 14q). An analysis aimed at identifying the relevant genes revealed VHL as one of three genes in the 3p deletion peak, CDKN2A and CDKN2B as the only genes in the 9p deletion peak, and MYC as the only gene in the 8q amplification peak. An integrated analysis to identify genes in amplification peaks that are consistently overexpressed among amplified samples confirmed MYC as a potential target of 8q amplification and identified candidate oncogenes in the other regions. A comparison of genomic profiles revealed that VHL disease-associated tumors are similar to a subgroup of sporadic tumors and thus more homogeneous overall. Sporadic tumors without evidence of biallelic VHL inactivation fell into two groups: one group with genomic profiles highly dissimilar to the majority of ccRCC and a second group with genomic profiles that are much more similar to tumors with biallelic inactivation of VHL.
Cancer Research 07/2009; 69(11):4674-81. · 7.86 Impact Factor
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BJU International 06/2009; 103(9):1293; author reply 1293. · 2.84 Impact Factor
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ABSTRACT: Cellular neurothekeoma is a benign dermal lesion of uncertain differentiation. The atypical variant of cellular neurothekeoma, characterized by features such as large size, deep penetration, diffusely infiltrative borders, vascular invasion, high mitotic rate and marked cytologic pleomorphism, has been very rarely reported in the literature. We present the clinical, histopathological and immunohistochemical profile of a new case of atypical cellular neurothekeoma in a 68-year-old female patient who was diagnosed with ductal breast carcinoma in situ before. An erythematous painless papule arose in her right breast, and tentative clinical diagnosis was orientated toward skin metastasis of breast cancer or fibroma. Upon histological examination, the lesion showed the histological and immunohistochemical features of atypical variant of cellular neurothekeoma with high mitotic rate, marked cellular pleomorphism and penetration into subcutaneous fat. A further unusual feature in our patient was her age, because she is the oldest patient reported in the literature with diagnosis of atypical cellular neurothekeoma so far. Prognosis remains uncertain because only few cases of atypical cellular neurothekeoma have been reported in the literature, with a very limited follow-up time. Our report contributes to a better characterization of the clinical and morphologic features of atypical cellular neurothekeoma.
Journal of Cutaneous Pathology 04/2009; 36(11):1210-4. · 1.56 Impact Factor
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Kirsten D Mertz,
Francesca Demichelis,
Andrea Sboner,
Michelle S Hirsch,
Paola Dal Cin,
Kirsten Struckmann,
Martina Storz,
Simone Scherrer,
Daniel M Schmid,
Räto T Strebel,
Nicole M Probst-Hensch,
Mark Gerstein,
Holger Moch,
Mark A Rubin
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ABSTRACT: The purpose of our study was to demonstrate that distinct cytogenetic alterations in the most common subtype of renal cell cancer, clear cell renal cell carcinoma (ccRCC), are reflected in protein expression profiles. We performed conventional cytogenetics and immunohistochemical analysis for cytokeratins (CKs) on 126 ccRCCs. Protein expression was evaluated in situ using a semiautomated quantitative system. The results were validated using an independent cohort of 209 ccRCCs with long-term follow-up. Cytogenetic alterations were identified in 96 of 126 ccRCCs, most of them involving chromosome 3 through loss, deletion or translocation. Expression of CKs and E-cadherin in ccRCC was associated with lack of cytogenetic alterations and low nuclear grade. In the validation set, CK7 and CK19 protein expression was associated with better clinical outcome. At the multivariate level, the best model included metastatic status and CK19 expression. Expression microarray analysis on 21 primary ccRCCs and 14 ccRCC metastases identified genes significantly associated with CK7 and CK19 expressing ccRCCs. Two novel ccRCC biomarkers associated with the CK7 positive ccRCC phenotype, PMS2 and MT1-MMP (MMP14), were further validated. We conclude that the variability observed for CK expression in ccRCC can be explained by genetic heterogeneity. Distinct molecular subtypes of ccRCC with prognostic relevance were identified, and the CK7/CK19 expressing subtype is associated with better outcome.
International Journal of Cancer 09/2008; 123(3):569-76. · 5.44 Impact Factor
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Sunita R Setlur, Kirsten D Mertz,
Yujin Hoshida,
Francesca Demichelis,
Mathieu Lupien,
Sven Perner,
Andrea Sboner,
Yudi Pawitan,
Ove Andrén,
Laura A Johnson, [......],
Katja Fall,
Lorelei A Mucci,
Philip W Kantoff,
Meir J Stampfer,
Swen-Olof Andersson,
Eberhard Varenhorst,
Jan-Erik Johansson,
Myles Brown,
Todd R Golub,
Mark A Rubin
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ABSTRACT: The majority of prostate cancers harbor gene fusions of the 5'-untranslated region of the androgen-regulated transmembrane protease serine 2 (TMPRSS2) promoter with erythroblast transformation-specific transcription factor family members. The common fusion between TMPRESS2 and v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) is associated with a more aggressive clinical phenotype, implying the existence of a distinct subclass of prostate cancer defined by this fusion.
We used complementary DNA-mediated annealing, selection, ligation, and extension to determine the expression profiles of 6144 transcriptionally informative genes in archived biopsy samples from 455 prostate cancer patients in the Swedish Watchful Waiting cohort (1987-1999) and the United States-based Physicians(') Health Study cohort (1983-2003). A gene expression signature for prostate cancers with the TMPRSS2-ERG fusion was determined using partitioning and classification models and used in computational functional analysis. Cell proliferation and TMPRSS2-ERG expression in androgen receptor-negative (NCI-H660) prostate cancer cells after treatment with vehicle or estrogenic compounds were assessed by viability assays and quantitative polymerase chain reaction, respectively. All statistical tests were two-sided.
We identified an 87-gene expression signature that distinguishes TMPRSS2-ERG fusion prostate cancer as a discrete molecular entity (area under the curve = 0.80, 95% confidence interval [CI] = 0.792 to 0.81; P < .001). Computational analysis suggested that this fusion signature was associated with estrogen receptor (ER) signaling. Viability of NCI-H660 cells decreased after treatment with estrogen (viability normalized to day 0, estrogen vs vehicle at day 8, mean = 2.04 vs 3.40, difference = 1.36, 95% CI = 1.12 to 1.62) or ERbeta agonist (ERbeta agonist vs vehicle at day 8, mean = 1.86 vs 3.40, difference = 1.54, 95% CI = 1.39 to 1.69) but increased after ERalpha agonist treatment (ERalpha agonist vs vehicle at day 8, mean = 4.36 vs 3.40, difference = 0.96, 95% CI = 0.68 to 1.23). Similarly, expression of TMPRSS2-ERG decreased after ERbeta agonist treatment (fold change over internal control, ERbeta agonist vs vehicle at 24 hours, NCI-H660, mean = 0.57- vs 1.0-fold, difference = 0.43-fold, 95% CI = 0.29- to 0.57-fold) and increased after ERalpha agonist treatment (ERalpha agonist vs vehicle at 24 hours, mean = 5.63- vs 1.0-fold, difference = 4.63-fold, 95% CI = 4.34- to 4.92-fold).
TMPRSS2-ERG fusion prostate cancer is a distinct molecular subclass. TMPRSS2-ERG expression is regulated by a novel ER-dependent mechanism.
CancerSpectrum Knowledge Environment 06/2008; 100(11):815-25. · 14.07 Impact Factor
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Juan-Miguel Mosquera,
Sven Perner,
Elizabeth M Genega,
Martin Sanda,
Matthias D Hofer, Kirsten D Mertz,
Pamela L Paris,
Jeff Simko,
Tarek A Bismar,
Gustavo Ayala,
Rajal B Shah,
Massimo Loda,
Mark A Rubin
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ABSTRACT: More than 1,300,000 prostate needle biopsies are done annually in the United States with up to 16% incidence of isolated high-grade prostatic intraepithelial neoplasia (HGPIN). HGPIN has low predictive value for identifying prostate cancer on subsequent needle biopsies in prostate-specific antigen-screened populations. In contemporary series, prostate cancer is detected in approximately 20% of repeat biopsies following a diagnosis of HGPIN. Further, discrete histologic subtypes of HGPIN with clinical implication in management have not been characterized. The TMPRSS2-ERG gene fusion that has recently been described in prostate cancer has also been shown to occur in a subset of HGPIN. This may have significant clinical implications given that TMPRSS2-ERG fusion prostate cancer is associated with a more aggressive clinical course.
In this study, we assessed a series of HGPIN lesions and paired prostate cancer for the presence of TMPRSS2-ERG gene fusion.
Fusion-positive HGPIN was observed in 16% of the 143 number of lesions, and in all instances, the matching cancer shared the same fusion pattern. Sixty percent of TMPRSS2-ERG fusion prostate cancer had fusion-negative HGPIN.
Given the more aggressive nature of TMPRSS2-ERG prostate cancer, the findings of this study raise the possibility that gene fusion-positive HGPIN lesions are harbingers of more aggressive disease. To date, pathologic, molecular, and clinical variables do not help stratify which men with HGPIN are at increased risk for a cancer diagnosis. Our results suggest that the detection of isolated TMPRSS2-ERG fusion HGPIN would improve the positive predictive value of finding TMPRSS2-ERG fusion prostate cancer in subsequent biopsies.
Clinical Cancer Research 06/2008; 14(11):3380-5. · 7.74 Impact Factor
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ABSTRACT: Microarrays have been used to identify genes involved in cancer progression. We have now developed an algorithm that identifies dysregulated pathways from multiple expression array data sets without a priori definition of gene expression thresholds. Integrative microarray analysis of pathways (IMAP) was done using existing expression array data from localized and metastatic prostate cancer. Comparison of metastatic cancer and localized disease in multiple expression array profiling studies using the IMAP approach yielded a list of about 100 pathways that were significantly dysregulated (P < 0.05) in prostate cancer metastasis. The pathway that showed the most significant dysregulation, HIV-I NEF, was validated at both the transcript level and the protein level by quantitative PCR and immunohistochemical analysis, respectively. Validation by unsupervised analysis on an independent data set using the gene expression signature from the HIV-I NEF pathway verified the accuracy of our method. Our results indicate that this pathway is especially dysregulated in hormone-refractory prostate cancer.
Cancer Research 11/2007; 67(21):10296-303. · 7.86 Impact Factor
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ABSTRACT: Microvessel density (MVD) has been reported to have prognostic relevance for clear cell renal cell carcinoma (ccRCC). However, this finding is controversial because of the difficulty of MVD evaluation in this complex vascularized tumor type. The present study evaluates the use of an automated quantitative analysis (AQUA) system for objective and reproducible determination of tumor vascularization in clear cell renal cell carcinoma (ccRCC). The AQUA system was applied to tissue microarrays with 284 primary ccRCC tumors. To determine angiogenesis in ccRCC, we created an epithelial/stromal mask consisting of CD10, epithelial membrane antigen, and vimentin to distinguish epithelial tumor cells from CD34-positive endothelial cells. Using immunofluorescence and computer-aided quantification of CD34 expression, we measured the relative microvessel area (MVA) and compared the MVA to the manually counted MVD. The MVA determined by AQUA in a test set with 209 ccRCCs ranged from 0% to 30.3% (mean +/- SD, 10.1% +/- 6.3%). The manually determined MVD ranged from 6 to 987 vessels/mm(2) (416.8 +/- 252.8 vessels/mm(2)). MVA and MVD were significantly correlated (P < .001). A larger MVA was associated with histologic grade (P < .001), tumor stage (P =.008), presence of metastasis (P = .005), presence of sarcomatoid areas (P < .001), and tumor-specific survival (P < .001). Using MVA as defined in the test set, all associations with clinical and pathologic parameters were confirmed in a second independent validation set. MVA determination by AQUA is an objective and reliable method to quantify tumor vascularization in ccRCC. A large MVA correlates with a high MVD and is associated with better patient prognosis.
Human Pathlogy 10/2007; 38(10):1454-62. · 2.88 Impact Factor
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Kirsten D Mertz,
Sunita R Setlur,
Saravana M Dhanasekaran,
Francesca Demichelis,
Sven Perner,
Scott Tomlins,
Joëlle Tchinda,
Bharathi Laxman,
Robert L Vessella,
Rameen Beroukhim,
Charles Lee,
Arul M Chinnaiyan,
Mark A Rubin
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ABSTRACT: Recent studies have established that a significant fraction of prostate cancers harbor a signature gene fusion between the 5' region of androgen-regulated TMPRSS2 and an ETS family transcription factor, most commonly ERG. Studies on the molecular mechanisms and functional consequences of this important chromosomal rearrangement are currently limited to the VCaP cell line derived from a vertebral bone metastasis of a hormone-refractory prostate tumor. Here we report on the NCI-H660 cell line, derived from a metastatic site of an extrapulmonary small cell carcinoma arising from the prostate. NCI-H660 harbors TMPRSS2-ERG fusion with a homozygous intronic deletion between TMPRSS2 and ERG. We demonstrate this by real-time quantitative polymerase chain reaction, a two-stage dual-color interphase fluorescence in situ hybridization (FISH) assay testing for TMPRSS2 and ERG break-aparts, and single-nucleotide polymorphism oligonucleotide arrays. The deletion is consistent with the common intronic deletion found on chromosome 21q22.2-3 in human prostate cancer samples. We demonstrate the physical juxtaposition of TMPRSS2 and ERG on the DNA level by fiber FISH. The androgen receptor-negative NCI-H660 cell line expresses ERG in an androgen-independent fashion. This in vitro model system has the potential to provide important pathobiologic insights into TMPRSS2-ERG fusion prostate cancer.
Neoplasia (New York, N.Y.) 03/2007; 9(3):200-6. · 5.48 Impact Factor
