Person: Berkowitz, Ross
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Berkowitz
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Ross
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Berkowitz, Ross
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Publication Gene Expression Signature of Normal Cell-of-Origin Predicts Ovarian Tumor Outcomes(Public Library of Science, 2013) Merritt, Melissa A.; Bentink, Stefan; Schwede, Matthew; Iwanicki, Marcin; Quackenbush, John; Woo, Terri; Agoston, Elin S.; Reinhardt, Ferenc; Crum, Christopher; Berkowitz, Ross; Mok, Samuel C.; Witt, Abigail E.; Jones, Michelle A.; Wang, Bin; Ince, Tan A.The potential role of the cell-of-origin in determining the tumor phenotype has been raised, but not adequately examined. We hypothesized that distinct cells-of-origin may play a role in determining ovarian tumor phenotype and outcome. Here we describe a new cell culture medium for in vitro culture of paired normal human ovarian (OV) and fallopian tube (FT) epithelial cells from donors without cancer. While these cells have been cultured individually for short periods of time, to our knowledge this is the first long-term culture of both cell types from the same donors. Through analysis of the gene expression profiles of the cultured OV/FT cells we identified a normal cell-of-origin gene signature that classified primary ovarian cancers into OV-like and FT-like subgroups; this classification correlated with significant differences in clinical outcomes. The identification of a prognostically significant gene expression signature derived solely from normal untransformed cells is consistent with the hypothesis that the normal cell-of-origin may be a source of ovarian tumor heterogeneity and the associated differences in tumor outcome.Publication Etiology and Pathogenesis of Epithelial Ovarian Cancer(IOS Press, 2007) Mok, Samuel C.; Kwong, Joseph; Welch, William; Samimi, Goli; Ozbun, Laurent; Bonome, Tomas; Birrer, Michael J.; Berkowitz, Ross; Wong, Kwong-KwokOvarian cancer is complex disease composed of different histological grades and types. However, the underlying molecular mechanisms involved in the development of different phenotypes remain largely unknown. Epidemiological studies identified multiple exogenous and endogenous risk factors for ovarian cancer development. Among them, an inflammatory stromal microenvironment seems to play a critical role in the initiation of the disease. The interaction between such a microenvironment, genetic polymorphisms, and different epithelial components such as endosalpingiosis, endometriosis, and ovarian inclusion cyst in the ovarian cortex may induce different genetic changes identified in the epithelial component of different histological types of ovarian tumors. Genetic studies on different histological grades and types provide insight into the pathogenetic pathways for the development of different disease phenotypes. However, the link between all these genetic changes and the etiological factors remains to be established.Publication Profiles of Genomic Instability in High-Grade Serous Ovarian Cancer Predict Treatment Outcome(American Association for Cancer Research (AACR), 2012) Wang, Z. C.; Birkbak, N; Culhane, Aedin; Drapkin, Ronny; Fatima, Aquila; Tian, R; Schwede, M.; Alsop, K.; Daniels, K. E.; Piao, H.; Liu, Joy; Etemadmoghadam, D.; Miron, A; Salvesen, H. B.; Mitchell, G.; DeFazio, A.; Quackenbush, John; Berkowitz, Ross; Iglehart, James; Bowtell, D. D. L.; Matulonis, UrsulaPurpose—High-grade serous cancer (HGSC) is the most common cancer of the ovary and is characterized by chromosomal instability. Defects in homologous recombination repair (HRR) are associated with genomic instability in HGSC, and are exploited by therapy targeting DNA repair. Defective HRR causes uniparental deletions and loss of heterozygosity (LOH). Our purpose is to profile LOH in HGSC and correlate our findings to clinical outcome, and compare HGSC and high-grade breast cancers. Experimental Design—We examined LOH and copy number changes using single nucleotide polymorphism array data from three HGSC cohorts and compared results to a cohort of high-grade breast cancers. The LOH profiles in HGSC were matched to chemotherapy resistance and progression-free survival (PFS). Results—LOH-based clustering divided HGSC into two clusters. The major group displayed extensive LOH and was further divided into two subgroups. The second group contained remarkably less LOH. BRCA1 promoter methylation was associated with the major group. LOH clusters were reproducible when validated in two independent HGSC datasets. LOH burden in the major cluster of HGSC was similar to triple-negative, and distinct from other high-grade breast cancers. Our analysis revealed an LOH cluster with lower treatment resistance and a significant correlation between LOH burden and PFS. Conclusions—Separating HGSC by LOH-based clustering produces remarkably stable subgroups in three different cohorts. Patients in the various LOH clusters differed with respect to chemotherapy resistance, and the extent of LOH correlated with PFS. LOH burden may indicate vulnerability to treatment targeting DNA repair, such as PARP1 inhibitors.Publication Correlates of the preoperative level of CA125 at presentation of ovarian cancer(Elsevier BV, 2010) Cramer, Daniel; Vitonis, Allison F.; Welch, William; Terry, Kathryn; Goodman, Annekathryn; Rueda, Bo; Berkowitz, RossObjective CA125 at presentation of ovarian cancer carries important prognostic significance; but, other than tumor characteristics, little is known about factors that influence CA125 levels. We examined the effect of epidemiologic variables and tumor features on CA125 at diagnosis and their effects on survival. Methods CA125 levels before treatment, tumor features, and questionnaire data were recorded on 805 women with ovarian cancer receiving care at Partners Hospitals. CA125 values were log-normalized and generalized linear, logistic, or Cox proportional hazards models used to identify predictors of CA125 and influence on survival in the subset of women with invasive, non-mucinous tumors. Results The importance of histology, grade, stage, laterality, and presence of ascites on CA125 level was confirmed. For non-mucinous invasive cancers, Jewish ethnicity, parity, prior breast cancer, and family history of breast or ovarian cancer predicted higher CA125 and greater body mass index (BMI), recurrent yeast infections, colitis, and appendectomy predicted lower CA125. A quadratic model best described the relationship between CA125 and age with lower levels in youngest and oldest women. In multivariate modeling, stage, ascites, and prior breast cancer were the strongest predictors of high CA125 and appendectomy and yeast infections strongest predictors of low CA125. A model with these variables plus CA125 revealed high CA125 remains a predictor of poorer survival. Conclusions Ovarian tumor features and presence of ascites are key determinants of CA125 at diagnosis, but epidemiologic features such as BMI, parity, prior breast cancer, and history of inflammatory conditions of the genitourinary or gastrointestinal tracts may also play a role.Publication Pinin interacts with C-terminal binding proteins for RNA alternative splicing and epithelial cell identity of human ovarian cancer cells(Impact Journals LLC, 2016) Zhang, Yanli; Kwok, Jamie Sui-Lam; Choi, Pui-Wah; Liu, Minghua; Yang, Junzheng; Singh, Margit; Ng, Shu-Kay; Welch, William; Muto, Michael; Tsui, Stephen KW; Sugrue, Stephen P.; Berkowitz, Ross; Ng, Shu-WingUnlike many other human solid tumors, ovarian tumors express many epithelial markers at a high level for cell growth and local invasion. The phosphoprotein Pinin plays a key role in epithelial cell identity. We showed that clinical ovarian tumors and ovarian cancer cell lines express a high level of Pinin when compared with normal ovarian tissues and immortalized normal ovarian surface epithelial cell lines. Pinin co-localized and physically interacted with transcriptional corepressor C-terminal binding proteins, CtBP1 and CtBP2, in the nuclei of cancer cells. Knockdown of Pinin in ovarian cancer cells resulted in specific reduction of CtBP1 protein expression, cell adhesion, anchorage-independent growth, and increased drug sensitivity. Whole transcriptomic comparison of next-generation RNA sequencing data between control ovarian cancer cell lines and cancer cell lines with respective knockdown of Pinin, CtBP1, and CtBP2 expression also showed reduced expression of CtBP1 mRNA in the Pinin knockdown cell lines. The Pinin knockdown cell lines shared significant overlap of differentially expressed genes and RNA splicing aberrations with CtBP1 knockdown and in a lesser degree with CtBP2 knockdown cancer cells. Hence, Pinin and CtBP are oncotargets that closely interact with each other to regulate transcription and pre-mRNA alternative splicing and promote cell adhesion and other epithelial characteristics of ovarian cancer cells.Publication Diagnostic potential for a serum miRNA neural network for detection of ovarian cancer(eLife Sciences Publications, Ltd, 2017) Elias, Kevin; Fendler, Wojciech; Stawiski, Konrad; Fiascone, Stephen; Vitonis, Allison F; Berkowitz, Ross; Frendl, Gyorgy; Konstantinopoulos, Panagiotis; Crum, Christopher; Kedzierska, Magdalena; Cramer, Daniel; Chowdhury, DipanjanRecent studies posit a role for non-coding RNAs in epithelial ovarian cancer (EOC). Combining small RNA sequencing from 179 human serum samples with a neural network analysis produced a miRNA algorithm for diagnosis of EOC (AUC 0.90; 95% CI: 0.81–0.99). The model significantly outperformed CA125 and functioned well regardless of patient age, histology, or stage. Among 454 patients with various diagnoses, the miRNA neural network had 100% specificity for ovarian cancer. After using 325 samples to adapt the neural network to qPCR measurements, the model was validated using 51 independent clinical samples, with a positive predictive value of 91.3% (95% CI: 73.3–97.6%) and negative predictive value of 78.6% (95% CI: 64.2–88.2%). Finally, biologic relevance was tested using in situ hybridization on 30 pre-metastatic lesions, showing intratumoral concentration of relevant miRNAs. These data suggest circulating miRNAs have potential to develop a non-invasive diagnostic test for ovarian cancer.Publication Autoantibody profiling to identify biomarkers of key pathogenic pathways in mucinous ovarian cancer(Elsevier BV, 2010) Tang, Liangdan; Yang, Junzheng; Ng, Shu-Kay; Rodriguez, Noah; Choi, Pui-Wah; Vitonis, Allison; Wang, Kui; McLachlan, Geoffrey J.; Caiazzo, Robert J.; Liu, Brian C.-S.; Welch, William; Cramer, Daniel; Berkowitz, Ross; Ng, Shu-WingMucinous epithelial ovarian cancers are clinically and morphologically distinct from the other histopathologic subtypes of ovarian cancer. Unlike other ovarian subtypes, epidemiologic studies have indicated that tobacco exposure is a significant risk factor for developing mucinous ovarian cancer. Detection of autoantibody reactivity is useful in biomarker discovery and for explaining the role of important pathophysiologic pathways in disease. In order to study if there are specific antibody biomarkers in the plasma samples of mucinous ovarian cancer patients, we have initiated a screen by employing a “reverse capture antibody microarray” platform that uses native host antigens derived from mucinous ovarian tissues as “baits” for the capture of differentially labeled patient and control autoantibodies. 35 autoantibodies that were significantly elevated in the cancer plasma samples compared with healthy controls, and six autoantibodies that segregated smoking and nonsmoking patients were identified. Functional annotation of the antibody targets has identified nine target antigens involved in integrin and Wnt signaling pathways. Immunohistochemistry of archived ovarian specimens showed significant overexpression of eight of the nine target antigens in mucinous ovarian tumor tissues, suggesting that plasma autoantibodies from mucinous ovarian cancer patients might have heightened reactivities with epitopes presented by these overexpressed antigens. Autoantibody profiling may have an unexpected utility in uncovering key signaling pathways that are dysregulated in the system of interest.Publication Endometriosis-Associated Ovarian Cancer: A Review of Pathogenesis(Molecular Diversity Preservation International (MDPI), 2013) Worley, Michael; Welch, William; Berkowitz, Ross; Ng, Shu-WingEndometriosis is classically defined as the presence of endometrial glands and stroma outside of the endometrial lining and uterine musculature. With an estimated frequency of 5%–10% among women of reproductive age, endometriosis is a common gynecologic disorder. While in itself a benign lesion, endometriosis shares several characteristics with invasive cancer, has been shown to undergo malignant transformation, and has been associated with an increased risk of epithelial ovarian carcinoma (EOC). Numerous epidemiologic studies have shown an increased risk of EOC among women with endometriosis. This is particularly true for women with endometrioid and clear cell ovarian carcinoma. However, the carcinogenic pathways by which endometriosis associated ovarian carcinoma (EAOC) develops remain poorly understood. Current molecular studies have sought to link endometriosis with EAOC through pathways related to oxidative stress, inflammation and hyperestrogenism. In addition, numerous studies have sought to identify an intermediary lesion between endometriosis and EAOC that may allow for the identification of endometriosis at greatest risk for malignant transformation or for the prevention of malignant transformation of this common gynecologic disorder. The objective of the current article is to review the current data regarding the molecular events associated with EAOC development from endometriosis, with a primary focus on malignancies of the endometrioid and clear cell histologic sub-types.Publication Direct Identification of an HPV-16 Tumor Antigen from Cervical Cancer Biopsy Specimens(Frontiers Research Foundation, 2011) Keskin, Derin Benerci; Reinhold, Bruce; Lee, Sun Young; Zhang, Guanglan; Lank, Simon; O’Connor, David H.; Berkowitz, Ross; Brusic, Vladimir; Kim, Seung Jo; Reinherz, EllisPersistent infection with high-risk human papilloma viruses (HPV) is the worldwide cause of many cancers, including cervical, anal, vulval, vaginal, penile, and oropharyngeal. Since T cells naturally eliminate the majority of chronic HPV infections by recognizing epitopes displayed on virally altered epithelium, we exploited Poisson detection mass spectrometry (MS\(^3\)) to identify those epitopes and inform future T cell-based vaccine design. Nine cervical cancer biopsies from HPV-16 positive HLA-A*02 patients were obtained, histopathology determined, and E7 oncogene PCR-amplified from tumor DNA and sequenced. Conservation of E7 oncogene coding segments was found in all tumors. MS\(^3\) analysis of HLA-A*02 immunoprecipitates detected E7\(_{11–19}\) peptide (YMLDLQPET) in seven of the nine tumor biopsies. The remaining two samples were E7\(_{11–19}\) negative and lacked the HLA-A*02 binding GILT thioreductase peptide despite possessing binding-competent HLA-A*02 alleles. Thus, the conserved E7\(_{11–19}\) peptide is a dominant HLA-A*02 binding tumor antigen in HPV-16 transformed cervical squamous and adenocarcinomas. Findings that a minority of HLA-A*02:01 tumors lack expression of both E7\(_{11–19}\) and a peptide from a thioreductase important in processing of cysteine-rich proteins like E7 underscore the value of physical detection, define a potential additional tumor escape mechanism and have implications for therapeutic cancer vaccine development.Publication Differential hRad17 Expression by Histologic Subtype of Ovarian Cancer(BioMed Central, 2011) Young, Jennifer L; Koon, E Colin; Kwong, Joseph; Welch, William; Muto, Michael; Berkowitz, Ross; Mok, Samuel CBackground: In the search for unique ovarian cancer biomarkers, ovarian specific cDNA microarray analysis identified hRad17, a cell cycle checkpoint protein, as over-expressed in ovarian cancer. The aim of this study was to validate this expression. Methods: Immunohistochemistry was performed on 72 serous, 19 endometrioid, 10 clear cell, and 6 mucinous ovarian cancers, 9 benign ovarian tumors, and 6 normal ovarian tissue sections using an anti-hRad17 antibody. Western blot analysis and quantitative PCR were performed using cell lysates and total RNA prepared from 17 ovarian cancer cell lines and 6 normal ovarian epithelial cell cultures (HOSE). Results: Antibody staining confirmed upregulation of hRad17 in 49.5% of ovarian cancer cases. Immunohistochemistry demonstrated that only 42% of serous and 47% of endometrioid subtypes showed overexpression compared to 80% of clear cell and 100% of mucinous cancers. Western blot confirmed overexpression of hRad17 in cancer cell lines compared to HOSE. Quantitative PCR demonstrated an upregulation of hRad17 RNA by 1.5-7 fold. hRad17 RNA expression differed by subtype. Conclusions: hRad17 is over-expressed in ovarian cancer. This over-expression varies by subtype suggesting a role in the pathogenesis of these types. Functional studies are needed to determine the potential role of this protein in ovarian cancer.