523 results on '"Karnezis, Anthony"'
Search Results
152. L1CAM further stratifies endometrial carcinoma patients with no specific molecular risk profile.
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Kommoss, Felix Kf, Karnezis, Anthony N, Kommoss, Friedrich, Talhouk, Aline, Taran, Florin-Andrei, Staebler, Annette, Gilks, C Blake, Huntsman, David G, Krämer, Bernhard, Brucker, Sara Y, McAlpine, Jessica N, and Kommoss, Stefan
- Abstract
Background: The newly developed Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) has consistently been shown to be prognostically significant in endometrial carcinomas (EC). Recently, we and others have demonstrated L1 cell-adhesion molecule (L1CAM) to be a significant indicator of high-risk disease in EC. In the current study, it was our aim to determine the prognostic significance of aberrant L1CAM expression in ProMisE subgroups in a large, single centre, population-based EC cohort.Methods: ProMisE (POLE; MMR-D; p53 wt/NSMP; p53 abn) classification results from a cohort of 452 EC were available for analysis. L1CAM expression was studied by immunohistochemistry on whole slides. Correlations between clinicopathological data and survival were calculated.Results: Expression of L1CAM was most frequent in p53 abnormal tumours (80%). L1CAM status was predictive of worse outcome among tumours with no specific molecular profile (p53 wt/NSMP) (p < 0.0001). Among p53 wt/NSMP EC, L1CAM remained a significant prognosticator for disease-specific survival after multivariate analysis (p = 0.035).Conclusion: L1CAM status was able to significantly stratify risk among tumours of the large p53 wt/NSMP ProMisE subgroup of EC. Furthermore, our study confirms a highly significant correlation between mutation-type p53 immunostaining and abnormal L1CAM expression in EC. [ABSTRACT FROM AUTHOR]- Published
- 2018
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153. Preclinical Models of Ovarian Cancer: Pathogenesis, Problems, and Implications for Prevention.
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KARNEZIS, ANTHONY N. and CHO, KATHLEEN R.
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BIOLOGICAL models , *FALLOPIAN tubes , *MICE , *ORAL contraceptives , *OVARIAN tumors , *POULTRY , *TRANSGENIC animals , *TUBAL sterilization , *SALPINGECTOMY , *PREVENTION - Abstract
Preclinical models are relatively underutilized and underfunded resources for modeling the pathogenesis and prevention of ovarian cancers. Several reviews have detailed the numerous published models of ovarian cancer. In this review, we will provide an overview of experimental model systems, their strengths and limitations, and use selected models to illustrate how they can be used to address specific issues about ovarian cancer pathogenesis. We will then highlight some of the preclinical prevention studies performed to date and discuss experiments needed to address important unanswered questions about ovarian cancer prevention strategies. [ABSTRACT FROM AUTHOR]
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- 2017
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154. Evaluation of endometrial carcinoma prognostic immunohistochemistry markers in the context of molecular classification.
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Karnezis, Anthony N, Leung, Samuel, Magrill, Jamie, McConechy, Melissa K, Yang, Winnie, Chow, Christine, Kobel, Martin, Lee, Cheng-Han, Huntsman, David G, Talhouk, Aline, Kommoss, Friederich, Gilks, C Blake, and McAlpine, Jessica N
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- 2017
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155. DICER1and FOXL2Mutation Status Correlates With Clinicopathologic Features in Ovarian Sertoli-Leydig Cell Tumors
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Karnezis, Anthony N., Wang, Yemin, Keul, Jacqueline, Tessier-Cloutier, Basile, Magrill, Jamie, Kommoss, Stefan, Senz, Janine, Yang, Winnie, Proctor, Lily, Schmidt, Dietmar, Clement, Philip B., Gilks, C. Blake, Huntsman, David G., and Kommoss, Friedrich
- Abstract
Supplemental Digital Content is available in the text.Sertoli-Leydig cell tumors (SLCTs) are rare ovarian sex cord-stromal neoplasms. The only known recurrent genetic abnormality is DICER1mutation, with rare mutations reported in FOXL2. We set out to establish a molecular classifier using DICER1and FOXL2somatic mutation status and clinicopathologic features in 42 SLCTs. Five tumors (12%) were well differentiated, 31 (74%) moderately differentiated, and 6 (14%) poorly differentiated. Eight (19%) had heterologous elements, and 2 (5%) showed retiform differentiation; all 10 were moderately differentiated. DICER1RNase IIIb domain mutations were identified in 18/41 (44%; 17 moderately, 1 poorly differentiated), including all cases with retiform or heterologous elements. FOXL2c.402C>G(p.C134W) mutation was identified in 8/42 (19%) tumors (5 moderately, 3 poorly differentiated). DICER1and FOXL2mutations were mutually exclusive. Median age for the cohort was 47 years (range, 15 to 90 y). Patients with DICER1mutations were younger (median, 24.5 y; range, 15 to 62 y) than patients with FOXL2mutation (median, 79.5 y; range, 51 to 90 y) (P<0.0001). Nine of 10 tumors with retiform or heterologous elements occurred in premenopausal patients (median, 26.5 y; range, 15 to 57 y). Patients with tumors that were wild type for DICER1and FOXL2(15/42, 37%) had an intermediate age (median, 51 y; range, 17 to 74 y). All tumors were FOXL2 positive by immunohistochemistry. Patients with FOXL2mutation trended toward presenting more often with abnormal bleeding (P=0.13); DICER1-mutant patients trended toward having more androgenic symptoms (P=0.22). Our data suggest at least 3 molecular subtypes of SLCT with distinct clinicopathologic features: DICER1mutant (younger, more androgenic symptoms, moderately/poorly differentiated, retiform or heterologous elements), FOXL2mutant (postmenopausal, abnormal bleeding, moderately/poorly differentiated, no retiform or heterologous elements), and DICER1/FOXL2wild type (intermediate age, no retiform or heterologous elements, including all well-differentiated tumors).
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- 2019
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156. Classification of Vulvar Squamous Cell Carcinoma and Precursor Lesions by p16 and p53 Immunohistochemistry: Considerations, Caveats, and an Algorithmic Approach.
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Yang, Hang, Almadani, Noorah, Thompson, Emily F., Tessier-Cloutier, Basile, Chen, Julia, Ho, Julie, Senz, Janine, McConechy, Melissa K., Chow, Christine, Ta, Monica, Cheng, Angela, Karnezis, Anthony, Huvila, Jutta, McAlpine, Jessica N., Gilks, Blake, Jamieson, Amy, and Hoang, Lynn N.
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- 2023
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157. Abstract POSTER-BIOL-1327: Small cell carcinoma of the ovary, hypercalcemic type displays frequent inactivating germline and somatic mutations in SMARCA4
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Ramos, Pilar, primary, Karnezis, Anthony N., additional, Craig, David W., additional, Sekulic, Aleksandar, additional, Russell, Megan L., additional, Hendricks, William P.D., additional, Corneveaux, Jason J., additional, Barrett, Michael T., additional, Shumansky, Karey, additional, Yang, Yidong, additional, Shah, Sohrab P., additional, Prentice, Leah M., additional, Marra, Marco A., additional, Kiefer, Jeffrey, additional, Zismann, Victoria L., additional, McEachron, Troy A., additional, Salhia, Bodour, additional, Prat, Jaime, additional, Clarke, Blaise A., additional, Pressey, Joseph G., additional, Farley, John H., additional, Anthony, Stephen P., additional, Roden, Richard B.S., additional, Cunliffe, Heather E., additional, Huntsman, David G., additional, and Trent, Jeffrey M., additional
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- 2015
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158. Abstract 5381: Therapeutic potential of HDAC inhibitors in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT)
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Wang, Yemin, primary, Ramos, Pilar, additional, Karnezis, Anthony N., additional, Trent, Jeffrey M., additional, and Huntsman, David G., additional
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- 2015
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159. Comprehensive genomic profiles of small cell lung cancer
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George, Julie, primary, Lim, Jing Shan, additional, Jang, Se Jin, additional, Cun, Yupeng, additional, Ozretić, Luka, additional, Kong, Gu, additional, Leenders, Frauke, additional, Lu, Xin, additional, Fernández-Cuesta, Lynnette, additional, Bosco, Graziella, additional, Müller, Christian, additional, Dahmen, Ilona, additional, Jahchan, Nadine S., additional, Park, Kwon-Sik, additional, Yang, Dian, additional, Karnezis, Anthony N., additional, Vaka, Dedeepya, additional, Torres, Angela, additional, Wang, Maia Segura, additional, Korbel, Jan O., additional, Menon, Roopika, additional, Chun, Sung-Min, additional, Kim, Deokhoon, additional, Wilkerson, Matt, additional, Hayes, Neil, additional, Engelmann, David, additional, Pützer, Brigitte, additional, Bos, Marc, additional, Michels, Sebastian, additional, Vlasic, Ignacija, additional, Seidel, Danila, additional, Pinther, Berit, additional, Schaub, Philipp, additional, Becker, Christian, additional, Altmüller, Janine, additional, Yokota, Jun, additional, Kohno, Takashi, additional, Iwakawa, Reika, additional, Tsuta, Koji, additional, Noguchi, Masayuki, additional, Muley, Thomas, additional, Hoffmann, Hans, additional, Schnabel, Philipp A., additional, Petersen, Iver, additional, Chen, Yuan, additional, Soltermann, Alex, additional, Tischler, Verena, additional, Choi, Chang-min, additional, Kim, Yong-Hee, additional, Massion, Pierre P., additional, Zou, Yong, additional, Jovanovic, Dragana, additional, Kontic, Milica, additional, Wright, Gavin M., additional, Russell, Prudence A., additional, Solomon, Benjamin, additional, Koch, Ina, additional, Lindner, Michael, additional, Muscarella, Lucia A., additional, la Torre, Annamaria, additional, Field, John K., additional, Jakopovic, Marko, additional, Knezevic, Jelena, additional, Castaños-Vélez, Esmeralda, additional, Roz, Luca, additional, Pastorino, Ugo, additional, Brustugun, Odd-Terje, additional, Lund-Iversen, Marius, additional, Thunnissen, Erik, additional, Köhler, Jens, additional, Schuler, Martin, additional, Botling, Johan, additional, Sandelin, Martin, additional, Sanchez-Cespedes, Montserrat, additional, Salvesen, Helga B., additional, Achter, Viktor, additional, Lang, Ulrich, additional, Bogus, Magdalena, additional, Schneider, Peter M., additional, Zander, Thomas, additional, Ansén, Sascha, additional, Hallek, Michael, additional, Wolf, Jürgen, additional, Vingron, Martin, additional, Yatabe, Yasushi, additional, Travis, William D., additional, Nürnberg, Peter, additional, Reinhardt, Christian, additional, Perner, Sven, additional, Heukamp, Lukas, additional, Büttner, Reinhard, additional, Haas, Stefan A., additional, Brambilla, Elisabeth, additional, Peifer, Martin, additional, Sage, Julien, additional, and Thomas, Roman K., additional
- Published
- 2015
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160. Synchronous Endometrial and Ovarian Carcinomas: Evidence of Clonality
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Anglesio, Michael S., primary, Wang, Yi Kan, additional, Maassen, Madlen, additional, Horlings, Hugo M., additional, Bashashati, Ali, additional, Senz, Janine, additional, Mackenzie, Robertson, additional, Grewal, Diljot S., additional, Li-Chang, Hector, additional, Karnezis, Anthony N., additional, Sheffield, Brandon S., additional, McConechy, Melissa K., additional, Kommoss, Friedrich, additional, Taran, Florin A., additional, Staebler, Annette, additional, Shah, Sohrab P., additional, Wallwiener, Diethelm, additional, Brucker, Sara, additional, Gilks, C. Blake, additional, Kommoss, Stefan, additional, and Huntsman, David G., additional
- Published
- 2015
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161. Targeted deep sequencing of mucinous ovarian tumors reveals multiple overlapping RAS-pathway activating mutations in borderline and cancerous neoplasms
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Mackenzie, Robertson, primary, Kommoss, Stefan, additional, Winterhoff, Boris J., additional, Kipp, Benjamin R., additional, Garcia, Joaquin J., additional, Voss, Jesse, additional, Halling, Kevin, additional, Karnezis, Anthony, additional, Senz, Janine, additional, Yang, Winnie, additional, Prigge, Elena-Sophie, additional, Reuschenbach, Miriam, additional, Doeberitz, Magnus Von Knebel, additional, Gilks, Blake C., additional, Huntsman, David G., additional, Bakkum-Gamez, Jamie, additional, McAlpine, Jessica N., additional, and Anglesio, Michael S., additional
- Published
- 2015
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162. Multifocal endometriotic lesions associated with cancer are clonal and carry a high mutation burden
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Anglesio, Michael S, primary, Bashashati, Ali, additional, Wang, Yi Kan, additional, Senz, Janine, additional, Ha, Gavin, additional, Yang, Winnie, additional, Aniba, Mohamed R, additional, Prentice, Leah M, additional, Farahani, Hossein, additional, Li Chang, Hector, additional, Karnezis, Anthony N, additional, Marra, Marco A, additional, Yong, Paul J, additional, Hirst, Martin, additional, Gilks, Blake, additional, Shah, Sohrab P, additional, and Huntsman, David G, additional
- Published
- 2015
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163. Abstract LB-202: The rare, highly malignant small cell carcinoma of the ovary displays common inactivating germline and somatic mutations in the tumor suppressor SMARCA4
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Ramos, Pilar, primary, Karnezis, Anthony, additional, Craig, David, additional, Sekulic, Aleksandar, additional, Russell, Megan, additional, Hendricks, William, additional, Barrett, Michael, additional, Shumansky, Karey, additional, Yang, Yidong, additional, Shah, Sohrab, additional, Prentice, Leah, additional, Marra, Marco, additional, Kiefer, Jeffrey, additional, Zismann, Victoria, additional, McEachron, Troy, additional, Salhia, Bodour, additional, Pressey, Joseph, additional, Farley, John, additional, Anthony, Stephen, additional, Roden, Richard, additional, Cunliffe, Heather, additional, Huntsman, David, additional, and Trent, Jeffrey, additional
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- 2014
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164. Abstract LB-312: The somatic mutational landscape of ovarian clear cell carcinoma and its precursor lesions
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Bashashati, Ali, primary, Anglesio, Michael, additional, Wang, Yikan, additional, Ha, Gavin, additional, Senz, Janine, additional, Yang, Winnie, additional, Kalloger, Steve, additional, Prentice, Leah, additional, Yanagida, Satoshi, additional, Salamanca, Clara, additional, Soukhatcheva, Galina, additional, Karnezis, Anthony, additional, Chang, Hector, additional, Hirst, Martin, additional, Mes-Mason, Anne-Marie, additional, Okamoto, Aikou, additional, Marra, Marco, additional, Gilks, Blake, additional, Shah, Sohrab, additional, and Huntsman, David, additional
- Published
- 2014
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165. The histone methyltransferase EZH2 is a therapeutic target in small cell carcinoma of the ovary, hypercalcaemic type.
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Wang, Yemin, Chen, Shary Yuting, Karnezis, Anthony N, Colborne, Shane, Santos, Nancy Dos, Lang, Jessica D, Hendricks, William PD, Orlando, Krystal A, Yap, Damian, Kommoss, Friedrich, Bally, Marcel B, Morin, Gregg B, Trent, Jeffrey M, Weissman, Bernard E, and Huntsman, David G
- Abstract
Small cell carcinoma of the ovary, hypercalcaemic type ( SCCOHT) is a rare but aggressive and untreatable malignancy affecting young women. We and others recently discovered that SMARCA4, a gene encoding the ATPase of the SWI/ SNF chromatin-remodelling complex, is the only gene recurrently mutated in the majority of SCCOHT. The low somatic complexity of SCCOHT genomes and the prominent role of the SWI/ SNF chromatin-remodelling complex in transcriptional control of genes suggest that SCCOHT cells may rely on epigenetic rewiring for oncogenic transformation. Herein, we report that approximately 80% (19/24) of SCCOHT tumour samples have strong expression of the histone methyltransferase EZH2 by immunohistochemistry, with the rest expressing variable amounts of EZH2. Re-expression of SMARCA4 suppressed the expression of EZH2 in SCCOHT cells. In comparison to other ovarian cell lines, SCCOHT cells displayed hypersensitivity to EZH2 shRNAs and two selective EZH2 inhibitors, GSK126 and EPZ-6438. EZH2 inhibitors induced cell cycle arrest, apoptosis, and cell differentiation in SCCOHT cells, along with the induction of genes involved in cell cycle regulation, apoptosis, and neuron-like differentiation. EZH2 inhibitors suppressed tumour growth and improved the survival of mice bearing SCCOHT xenografts. Therefore, our data suggest that loss of SMARCA4 creates a dependency on the catalytic activity of EZH2 in SCCOHT cells and that pharmacological inhibition of EZH2 is a promising therapeutic strategy for treating this disease. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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166. Impact of oviductal versus ovarian epithelial cell of origin on ovarian endometrioid carcinoma phenotype in the mouse.
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Wu, Rong, Zhai, Yali, Kuick, Rork, Karnezis, Anthony N, Garcia, Paloma, Naseem, Anum, Hu, Tom C, Fearon, Eric R, and Cho, Kathleen R
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Endometrioid carcinoma ( EC) is a relatively indolent ovarian carcinoma subtype that is nonetheless deadly if detected late. Existing genetically engineered mouse models ( GEMMs) of the disease, based on transformation of the ovarian surface epithelium ( OSE), take advantage of known ovarian EC driver gene lesions, but do not fully recapitulate the disease features seen in patients. An EC model in which the Apc and Pten tumour suppressor genes are conditionally deleted in murine OSE yields tumours that are biologically more aggressive and significantly less differentiated than human ECs. Importantly, OSE is not currently thought to be the tissue of origin of most ovarian cancers, including ECs, suggesting that tumour initiation in Müllerian epithelium may produce tumours that more closely resemble their human tumour counterparts. We have developed Ovgp1- iCreER
T2 mice in which the Ovgp1 promoter controls expression of tamoxifen ( TAM)-regulated Cre recombinase in oviductal epithelium - the murine equivalent of human Fallopian tube epithelium. Ovgp1- iCreERT2 ;Apcfl/fl ;Ptenfl/fl mice treated with TAM or injected with adenovirus expressing Cre into the ovarian bursa uniformly develop oviductal or ovarian ECs, respectively. On the basis of their morphology and global gene expression profiles, the oviduct-derived tumours more closely resemble human ovarian ECs than do OSE-derived tumours. Furthermore, mice with oviductal tumours survive much longer than their counterparts with ovarian tumours. The slow progression and late metastasis of oviductal tumours resembles the relatively indolent behaviour characteristic of so-called Type I ovarian carcinomas in humans, for which EC is a prototype. Our studies demonstrate the utility of Ovgp1- iCreERT2 mice for manipulating genes of interest specifically in the oviductal epithelium, and establish that the cell of origin is an important consideration in mouse ovarian cancer GEMMs. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]- Published
- 2016
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167. Immunophenotypic features of dedifferentiated endometrial carcinoma - insights from BRG1/ INI1-deficient tumours.
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Hoang, Lien N, Lee, Yow‐Shan, Karnezis, Anthony N, Tessier‐Cloutier, Basile, Almandani, Noorah, Coatham, Mackenzie, Gilks, C Blake, Soslow, Robert A, Stewart, Colin J R, Köbel, Martin, and Lee, Cheng‐Han
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TREATMENT of endometrial cancer ,ENDOMETRIAL cancer ,IMMUNOPHENOTYPING ,ESTROGEN receptors ,GENETIC mutation ,IMMUNOSTAINING ,GENETICS - Abstract
Aims Dedifferentiated endometrial carcinoma ( DDEC) is defined by the presence of an undifferentiated carcinoma together with an endometrioid carcinoma. Inactivation of SMARCA4 ( BRG1) and inactivation of SMARCB1 ( INI1) were recently described as potential mechanisms underlying the histological dedifferentiation. The aim of this study was to characterize the immunophenotypic features of DDECs, particularly in cases with prototypical histological and molecular features ( BRG1/ INI1 deficiency). Methods and results We evaluated PAX8, oestrogen receptor ( ER) and p53 immunostaining in the endometrioid and the undifferentiated components of 20 BRG1/ INI1-deficient DDECs and 15 BRG1/ INI1-intact DDECs, and compared the results with those of 23 grade 3 endometrioid carcinomas. The differentiated endometrioid component was positive for PAX8 and/or ER in 19 of 20 BRG1/ INI1-deficient DDECs, whereas the corresponding undifferentiated component of all 20 tumours showed a complete absence of PAX8 and ER staining. All except one of the BRG1/ INI1-deficient tumours showed a wild-type p53 staining pattern. PAX8 and ER expression in the undifferentiated component was absent in 67% and 80% of BRG1/ INI1-intact DDECs, respectively, whereas 47% of the BRG1/ INI1-intact DDECs showed a mutated p53 staining pattern. In comparison, absent PAX8 expression and absent ER expression were each observed in the more solid area of 48% and 48% of grade 3 endometrioid carcinomas. Conclusions The consistent absence of PAX8 and ER expression in molecularly defined ( BRG1/ INI1-deficient) DDECs suggests that the loss of PAX8 and ER expression is a fundamental feature of dedifferentiation. The frequent findings of a mutated p53 staining pattern in BRG1/ INI1-intact DDECs indicate that BRG1/ INI1-intact DDECs may be biologically different from BRG1/ INI1-deficient tumours. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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168. Association of Tumor Morphology With Mismatch-repair Protein Status in Older Endometrial Cancer Patients
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Rabban, Joseph T., primary, Calkins, Sarah M., additional, Karnezis, Anthony N., additional, Grenert, James P., additional, Blanco, Amie, additional, Crawford, Beth, additional, and Chen, Lee-may, additional
- Published
- 2014
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169. Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4
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Ramos, Pilar, primary, Karnezis, Anthony N, additional, Craig, David W, additional, Sekulic, Aleksandar, additional, Russell, Megan L, additional, Hendricks, William P D, additional, Corneveaux, Jason J, additional, Barrett, Michael T, additional, Shumansky, Karey, additional, Yang, Yidong, additional, Shah, Sohrab P, additional, Prentice, Leah M, additional, Marra, Marco A, additional, Kiefer, Jeffrey, additional, Zismann, Victoria L, additional, McEachron, Troy A, additional, Salhia, Bodour, additional, Prat, Jaime, additional, D'Angelo, Emanuela, additional, Clarke, Blaise A, additional, Pressey, Joseph G, additional, Farley, John H, additional, Anthony, Stephen P, additional, Roden, Richard B S, additional, Cunliffe, Heather E, additional, Huntsman, David G, additional, and Trent, Jeffrey M, additional
- Published
- 2014
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170. RAS Transformation Requires CUX1-Dependent Repair of Oxidative DNA Damage
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Ramdzan, Zubaidah M., primary, Vadnais, Charles, additional, Pal, Ranjana, additional, Vandal, Guillaume, additional, Cadieux, Chantal, additional, Leduy, Lam, additional, Davoudi, Sayeh, additional, Hulea, Laura, additional, Yao, Lu, additional, Karnezis, Anthony N., additional, Paquet, Marilène, additional, Dankort, David, additional, and Nepveu, Alain, additional
- Published
- 2014
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171. Loss of the tumor suppressor SMARCA4 in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT)
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Ramos, Pilar, primary, Karnezis, Anthony N, additional, Hendricks, William P D, additional, Wang, Yemin, additional, Tembe, Waibhav, additional, Zismann, Victoria L, additional, Legendre, Christophe, additional, Liang, Winnie S, additional, Russell, Megan L, additional, Craig, David W, additional, Farley, John H, additional, Monk, Bradley J, additional, Anthony, Stephen P, additional, Sekulic, Aleksandar, additional, Cunliffe, Heather E, additional, Huntsman, David G, additional, and Trent, Jeffrey M, additional
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- 2014
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172. Inhibition of Myc family proteins eradicates KRas-driven lung cancer in mice
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Soucek, Laura, primary, Whitfield, Jonathan R., additional, Sodir, Nicole M., additional, Massó-Vallés, Daniel, additional, Serrano, Erika, additional, Karnezis, Anthony N., additional, Swigart, Lamorna Brown, additional, and Evan, Gerard I., additional
- Published
- 2013
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173. Transitional Cell-like Morphology in Ovarian Endometrioid Carcinoma
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Karnezis, Anthony N., primary, Aysal, Anil, additional, Zaloudek, Charles J., additional, and Rabban, Joseph T., additional
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- 2013
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174. Synchronous Endometrial and Ovarian Carcinomas: Evidence of Clonality.
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Anglesio, Michael S., Yi Kan Wang, Maassen, Madlen, Horlings, Hugo M., Bashashati, Ali, Senz, Janine, Mackenzie, Robertson, Grewal, Diljot S., Li-Chang, Hector, Karnezis, Anthony N., Sheffield, Brandon S., McConechy, Melissa K., Kommoss, Friedrich, Taran, Florin A., Staebler, Annette, Shah, Sohrab P., Wallwiener, Diethelm, Brucker, Sara, Gilks, C. Blake, and Kommoss, Stefan
- Subjects
DNA analysis ,CELLS ,EPITHELIAL cell tumors ,GENOMES ,MULTIPLE tumors ,OVARIAN tumors ,TUMOR classification ,ENDOMETRIAL tumors ,SAMPLE size (Statistics) ,SEQUENCE analysis ,TUMOR grading - Abstract
Many women with ovarian endometrioid carcinoma present with concurrent endometrial carcinoma. Organ-confined and low-grade synchronous endometrial and ovarian tumors (SEOs) clinically behave as independent primary tumors rather than a single advanced-stage carcinoma. We used 18 SEOs to investigate the ancestral relationship between the endometrial and ovarian components. Based on both targeted and exome sequencing, 17 of 18 patient cases of simultaneous cancer of the endometrium and ovary from our series showed evidence of a clonal relationship, ie, primary tumor and metastasis. Eleven patient cases fulfilled clinicopathological criteria that would lead to classification as independent endometrial and ovarian primary carcinomas, including being of FIGO stage T1a/1A, with organ-restricted growth and without surface involvement; 10 of 11 of these cases showed evidence of clonality. Our observations suggest that the disseminating cells amongst SEOs are restricted to physically accessible and microenvironment-compatible sites yet remain indolent, without the capacity for further dissemination. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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175. Dual loss of the SWI/ SNF complex ATPases SMARCA4/ BRG1 and SMARCA2/ BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcaemic type.
- Author
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Karnezis, Anthony N, Wang, Yemin, Ramos, Pilar, Hendricks, William PD, Oliva, Esther, D'Angelo, Emanuela, Prat, Jaime, Nucci, Marisa R, Nielsen, Torsten O, Chow, Christine, Leung, Samuel, Kommoss, Friedrich, Kommoss, Stefan, Silva, Annacarolina, Ronnett, Brigitte M, Rabban, Joseph T, Bowtell, David D, Weissman, Bernard E, Trent, Jeffrey M, and Gilks, C Blake
- Abstract
Small cell carcinoma of the ovary, hypercalcaemic type ( SCCOHT) is a lethal and sometimes familial ovarian tumour of young women and children. We and others recently discovered that over 90% of SCCOHTs harbour inactivating mutations in the chromatin remodelling gene SMARCA4 with concomitant loss of its encoded protein SMARCA4 ( BRG1), one of two mutually exclusive ATPases of the SWI/ SNF chromatin remodelling complex. To determine the specificity of SMARCA4 loss for SCCOHT, we examined the expression of SMARCA4 by immunohistochemistry in more than 3000 primary gynaecological tumours. Among ovarian tumours, it was only absent in clear cell carcinoma (15 of 360, 4%). In the uterus, it was absent in endometrial stromal sarcomas (4 of 52, 8%) and high-grade endometrioid carcinomas (2 of 338, 1%). Recent studies have shown that SMARCA2 ( BRM), the other mutually exclusive ATPase of the SWI/ SNF complex, is necessary for survival of tumour cells lacking SMARCA4. Therefore, we examined SMARCA2 expression and discovered that all SMARCA4-negative SCCOHTs also lacked SMARCA2 protein by IHC, including the SCCOHT cell lines BIN67 and SCCOHT1. Among ovarian tumours, the SMARCA4/ SMARCA2 dual loss phenotype appears completely specific for SCCOHT. SMARCA2 loss was not due to mutation but rather from an absence of mRNA expression, which was restored by treatment with the histone deacetylase inhibitor trichostatin A. Re-expression of SMARCA4 or SMARCA2 inhibited the growth of BIN67 and SCCOHT1 cell lines. Our results indicate that SMARCA4 loss, either alone or with SMARCA2, is highly sensitive and specific for SCCOHT and that restoration of either SWI/ SNF ATPase can inhibit the growth of SCCOHT cell lines. © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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176. Correction: Polygenic risk modeling for prediction of epithelial ovarian cancer risk
- Author
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Dareng, Eileen O., Tyrer, Jonathan P., Barnes, Daniel R., Jones, Michelle R., Yang, Xin, Aben, Katja K. H., Adank, Muriel A., Agata, Simona, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Arun, Banu K., Augustinsson, Annelie, Balmaña, Judith, Bandera, Elisa V., Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia V., Bonanni, Bernardo, Borg, Ake, Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S., Cai, Hui, Caligo, Maria A., Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K., Claes, Kathleen B. M., Colonna, Sarah, Cook, Linda S., Couch, Fergus J., Daly, Mary B., Dao, Fanny, Davies, Eleanor, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A., Domchek, Susan M., Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana M., Eliassen, Heather A., Engel, Christoph, Evans, Gareth D., Fasching, Peter A., Flanagan, James M., Fortner, Renée T., Machackova, Eva, Friedman, Eitan, Ganz, Patricia A., Garber, Judy, Gensini, Francesca, Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hamann, Ute, Hansen, Thomas V. O., Harris, Holly R., Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle A. T., Høgdall, Estrid, Høgdall, Claus K., Hopper, John L., Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J., Huntsman, David G., Imyanitov, Evgeny N., Isaacs, Claudine, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th., John, Esther M., Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony, Kelemen, Linda E., Khusnutdinova, Elza, Kiemeney, Lambertus A., Kim, Byoung-Gie, Kjaer, Susanne K., Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W., Kwong, Ava, Lambrechts, Diether, Larson, Melissa C., Lazaro, Conxi, Le, Nhu D., Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Levine, Douglas A., Li, Lian, Li, Jingmei, Loud, Jennifer T., Lu, Karen H., Lubiński, Jan, Mai, Phuong L., Manoukian, Siranoush, Marks, Jeffrey R., Matsuno, Rayna Kim, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R., McNeish, Iain A., Mebirouk, Noura, Menon, Usha, Miller, Austin, Milne, Roger L., Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Munro, Elizabeth, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nielsen, Henriette Roed, Nielsen, Finn C., Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo I., Olson, Sara H., Olsson, Håkan, Osorio, Ana, Papi, Laura, Park, Sue K., Parsons, Michael T., Pathak, Harsha, Pedersen, Inge Sokilde, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B., Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J., Risch, Harvey A., Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P., Santamariña, Marta, Soucy, Penny, Schmutzler, Rita K., Setiawan, V. Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sokolenko, Anna P., Song, Honglin, Southey, Melissa C., Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J., Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Terry, Kathryn L., Terry, Mary Beth, Thomassen, Mads, Thompson, Pamela J., Thomsen, Liv Cecilie Vestrheim, Thull, Darcy L., Tischkowitz, Marc, Titus, Linda, Toland, Amanda E., Torres, Diana, Trabert, Britton, Travis, Ruth, Tung, Nadine, Tworoger, Shelley S., Valen, Ellen, van Altena, Anne M., van der Hout, Annemieke H., Van Nieuwenhuysen, Els, van Rensburg, Elizabeth J., Vega, Ana, Edwards, Digna Velez, Vierkant, Robert A., Wang, Frances, Wappenschmidt, Barbara, Webb, Penelope M., Weinberg, Clarice R., Weitzel, Jeffrey N., Wentzensen, Nicolas, White, Emily, Whittemore, Alice S., Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zavaglia, Katia M., Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Kleibl, Zdenek, Easton, Douglas, Lawrenson, Kate, DeFazio, Anna, Sellers, Thomas A., Ramus, Susan J., Pearce, Celeste L., Monteiro, Alvaro N., Cunningham, Julie, Goode, Ellen L., Schildkraut, Joellen M., Berchuck, Andrew, Chenevix-Trench, Georgia, Gayther, Simon A., Antoniou, Antonis C., and Pharoah, Paul D. P.
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- 2022
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177. Ovarian Endometrioid Adenocarcinoma
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Aysal, Anil, primary, Karnezis, Anthony, additional, Medhi, Irum, additional, Grenert, James P., additional, Zaloudek, Charles J., additional, and Rabban, Joseph T., additional
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- 2012
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178. The disparate origins of ovarian cancers: pathogenesis and prevention strategies
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Karnezis, Anthony N., Cho, Kathleen R., Gilks, C. Blake, Pearce, Celeste Leigh, and Huntsman, David G.
- Abstract
Ovarian cancer is the fifth cause of cancer-related death in women and comprises a histologically and genetically broad range of tumours, including those of epithelial, sex cord-stromal and germ cell origin. Recent evidence indicates that high-grade serous ovarian carcinoma, clear cell carcinoma and endometrioid carcinoma primarily arise from tissues that are not normally present in the ovary. These histogenetic pathways are informing risk-reduction strategies for the prevention of ovarian and ovary-associated cancers and have highlighted the importance of the seemingly unique ovarian microenvironment.
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- 2017
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179. Distinct p53 Transcriptional Programs Dictate Acute DNA-Damage Responses and Tumor Suppression
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Brady, Colleen A., primary, Jiang, Dadi, additional, Mello, Stephano S., additional, Johnson, Thomas M., additional, Jarvis, Lesley A., additional, Kozak, Margaret M., additional, Broz, Daniela Kenzelmann, additional, Basak, Shashwati, additional, Park, Eunice J., additional, McLaughlin, Margaret E., additional, Karnezis, Anthony N., additional, and Attardi, Laura D., additional
- Published
- 2011
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180. Endogenous Myc maintains the tumor microenvironment
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Sodir, Nicole M., primary, Swigart, Lamorna Brown, additional, Karnezis, Anthony N., additional, Hanahan, Douglas, additional, Evan, Gerard I., additional, and Soucek, Laura, additional
- Published
- 2011
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181. Junctional Epithelial Zones of the Fallopian Tube
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Rabban, Joseph T., primary, Karnezis, Anthony N., additional, and Zaloudek, Charles J., additional
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- 2011
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182. Neural stem cells and their role in the pathology and classification of central nervous system tumors
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Tihan, Tarik, primary, Pekmezci, Melike, additional, and Karnezis, Anthony, additional
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- 2011
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183. Loss of p130 Accelerates Tumor Development in a Mouse Model for Human Small-Cell Lung Carcinoma
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Schaffer, Bethany E., primary, Park, Kwon-Sik, additional, Yiu, Gloria, additional, Conklin, Jamie F., additional, Lin, Chenwei, additional, Burkhart, Deborah L., additional, Karnezis, Anthony N., additional, Sweet-Cordero, E. Alejandro, additional, and Sage, Julien, additional
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- 2010
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184. Kras regulatory elements and exon 4A determine mutation specificity in lung cancer
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To, Minh D, primary, Wong, Christine E, additional, Karnezis, Anthony N, additional, Del Rosario, Reyno, additional, Di Lauro, Roberto, additional, and Balmain, Allan, additional
- Published
- 2008
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185. p27Kip1 as a Target to Improve Hepatocyte Transplantation Success
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Karnezis, Anthony N., additional and Zhu, Liang, additional
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- 2002
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186. Role of thyroid hormone in stimulating liver repopulation in the rat by transplanted hepatocytes
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Oren, Ran, primary, Dabeva, Mariana D., additional, Karnezis, Anthony N., additional, Petkov, Petko M., additional, Rosencrantz, Richard, additional, Sandhu, Jaswinder P., additional, Moss, Steven F., additional, Wang, Shaobai, additional, Hurston, Ethel, additional, Laconi, Ezio, additional, Holt, Peter R., additional, Thung, Swan N., additional, Zhu, Liang, additional, and Shafritz, David A., additional
- Published
- 1999
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187. Reciprocal Regulation of Neu Tyrosine Kinase Activity and Caveolin-1 Protein Expression in Vitro and in Vivo
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Engelman, Jeffrey A., primary, Lee, Richard J., additional, Karnezis, Anthony, additional, Bearss, David J., additional, Webster, Marc, additional, Siegel, Peter, additional, Muller, William J., additional, Windle, Jolene J., additional, Pestell, Richard G., additional, and Lisanti, Michael P., additional
- Published
- 1998
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188. Cloning and Subcellular Localization of Human Mitochondrial hsp70
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Bhattacharyya, Timothy, primary, Karnezis, Anthony N., additional, Murphy, Shawn P., additional, Hoang, Thuc, additional, Freeman, Brian C., additional, Phillips, Benette, additional, and Morimoto, Richard I., additional
- Published
- 1995
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189. Neural Stem Cells and their Role in the Pathology and Classification of Central Nervous System Tumors.
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Tıhan, Tarık, Pekmezcı, Melike, and Karnezis, Anthony
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NEURAL stem cells ,BRAIN tumors ,TUMOR growth ,CENTRAL nervous system tumors ,PATHOLOGY ,MEDICAL research - Abstract
Copyright of Turkish Journal of Pathology is the property of Turkish Journal of Pathology and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2011
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190. BrafV600E cooperates with Pten loss to induce metastatic melanoma.
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Dankort, David, Curley, David P., Cartlidge, Robert A., Nelson, Betsy, Karnezis, Anthony N., Damsky Jr, William E., Mingjian J. You, DePinho, Ronald A., McMahon, Martin, and Bosenberg, Marcus
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MELANOMA ,TUMOR suppressor genes ,GENE expression ,GENE silencing ,HYPERPLASIA ,GENETIC regulation ,METASTASIS ,GENETIC research - Abstract
Mutational activation of BRAF is the earliest and most common genetic alteration in human melanoma. To build a model of human melanoma, we generated mice with conditional melanocyte-specific expression of BRaf
V600E . Upon induction of BRafV600E expression, mice developed benign melanocytic hyperplasias that failed to progress to melanoma over 15–20 months. By contrast, expression of BRafV600E combined with Pten tumor suppressor gene silencing elicited development of melanoma with 100% penetrance, short latency and with metastases observed in lymph nodes and lungs. Melanoma was prevented by inhibitors of mTorc1 (rapamycin) or MEK1/2 (PD325901) but, upon cessation of drug administration, mice developed melanoma, indicating the presence of long-lived melanoma-initiating cells in this system. Notably, combined treatment with rapamycin and PD325901 led to shrinkage of established melanomas. These mice, engineered with a common genetic profile to human melanoma, provide a system to study melanoma's cardinal feature of metastasis and for preclinical evaluation of agents designed to prevent or treat metastatic disease. [ABSTRACT FROM AUTHOR]- Published
- 2009
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191. Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcaemic type
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Karnezis, Anthony N, Wang, Yemin, Ramos, Pilar, Hendricks, William PD, Oliva, Esther, D'Angelo, Emanuela, Prat, Jaime, Nucci, Marisa R, Nielsen, Torsten O, Chow, Christine, Leung, Samuel, Kommoss, Friedrich, Kommoss, Stefan, Silva, Annacarolina, Ronnett, Brigitte M, Rabban, Joseph T, Bowtell, David D, Weissman, Bernard E, Trent, Jeffrey M, Gilks, C Blake, and Huntsman, David G
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Original Paper ,small cell carcinoma ,hypercalcaemic type ,rhabdoid tumour ,trichostatin A ,epigenetic silencing - Abstract
Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) is a lethal and sometimes familial ovarian tumour of young women and children. We and others recently discovered that over 90% of SCCOHTs harbour inactivating mutations in the chromatin remodelling gene SMARCA4 with concomitant loss of its encoded protein SMARCA4 (BRG1), one of two mutually exclusive ATPases of the SWI/SNF chromatin remodelling complex. To determine the specificity of SMARCA4 loss for SCCOHT, we examined the expression of SMARCA4 by immunohistochemistry in more than 3000 primary gynaecological tumours. Among ovarian tumours, it was only absent in clear cell carcinoma (15 of 360, 4%). In the uterus, it was absent in endometrial stromal sarcomas (4 of 52, 8%) and high‐grade endometrioid carcinomas (2 of 338, 1%). Recent studies have shown that SMARCA2 (BRM), the other mutually exclusive ATPase of the SWI/SNF complex, is necessary for survival of tumour cells lacking SMARCA4. Therefore, we examined SMARCA2 expression and discovered that all SMARCA4‐negative SCCOHTs also lacked SMARCA2 protein by IHC, including the SCCOHT cell lines BIN67 and SCCOHT1. Among ovarian tumours, the SMARCA4/SMARCA2 dual loss phenotype appears completely specific for SCCOHT. SMARCA2 loss was not due to mutation but rather from an absence of mRNA expression, which was restored by treatment with the histone deacetylase inhibitor trichostatin A. Re‐expression of SMARCA4 or SMARCA2 inhibited the growth of BIN67 and SCCOHT1 cell lines. Our results indicate that SMARCA4 loss, either alone or with SMARCA2, is highly sensitive and specific for SCCOHT and that restoration of either SWI/SNF ATPase can inhibit the growth of SCCOHT cell lines. © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
- Published
- 2015
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192. The P72R Polymorphism in R248Q/W p53 Mutants Modifies the Mutant Effect on Epithelial to Mesenchymal Transition Phenotype and Cell Invasion via CXCL1 Expression.
- Author
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De Souza, Cristabelle, Madden, Jill A., Minn, Dennis, Kumar, Vigneshwari Easwar, Montoya, Dennis J., Nambiar, Roshni, Zhu, Zheng, Xiao, Wen-Wu, Tahmassebi, Neeki, Kathi, Harikumara, Nelson, Nina, Karnezis, Anthony N., and Chien, Jeremy
- Subjects
EPITHELIAL-mesenchymal transition ,P53 antioncogene ,OVARIAN epithelial cancer ,MISSENSE mutation ,RNA sequencing ,PHENOTYPES - Abstract
High-grade serous carcinoma (HGSC), the most lethal subtype of epithelial ovarian cancer (EOC), is characterized by widespread TP53 mutations (>90%), most of which are missense mutations (>70%). The objective of this study was to investigate differential transcriptional targets affected by a common germline P72R SNP (rs1042522) in two p53 hotspot mutants, R248Q and R248W, and identify the mechanism through which the P72R SNP affects the neomorphic properties of these mutants. Using isogenic cell line models, transcriptomic analysis, xenografts, and patient data, we found that the P72R SNP modifies the effect of p53 hotspot mutants on cellular morphology and invasion properties. Most importantly, RNA sequencing studies identified CXCL1 a critical factor that is differentially affected by P72R SNP in R248Q and R248W mutants and is responsible for differences in cellular morphology and functional properties observed in these p53 mutants. We show that the mutants with the P72 SNP promote a reversion of the EMT phenotype to epithelial characteristics, whereas its R72 counterpart promotes a mesenchymal transition via the chemokine CXCL1. These studies reveal a new role of the P72R SNP in modulating the neomorphic properties of p53 mutants via CXCL1, which has significant implications for tumor invasion and metastasis. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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193. Reciprocal Regulation of Neu Tyrosine Kinase Activity and Caveolin-1 Protein Expression in Vitroand in Vivo
- Author
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Engelman, Jeffrey A., Lee, Richard J., Karnezis, Anthony, Bearss, David J., Webster, Marc, Siegel, Peter, Muller, William J., Windle, Jolene J., Pestell, Richard G., and Lisanti, Michael P.
- Abstract
Neu(c-erbB2) is a proto-oncogene product that encodes an epidermal growth factor-like receptor tyrosine kinase. Amplification of wild-type c-Neuand mutational activation of Neu(Neu T) have been implicated in oncogenic transformation of cultured fibroblasts and mammary tumorigenesis in vivo. Here, we examine the relationship between Neu tyrosine kinase activity and caveolin-1 protein expression in vitroand in vivo.Recent studies have suggested that caveolins may function as negative regulators of signal transduction. Our current results show that mutational activation of c-Neu down-regulates caveolin-1 protein expression, but not caveolin-2, in cultured NIH 3T3 and Rat 1 cells. Conversely, recombinant overexpression of caveolin-1 blocks Neu-mediated signal transduction in vivo. These results suggest a reciprocal relationship between c-Neu tyrosine kinase activity and caveolin-1 protein expression. We next analyzed a variety of caveolin-1 deletion mutants to map this caveolin-1-dependent inhibitory activity to a given region of the caveolin-1 molecule. Results from this mutational analysis show that this functional in vivoinhibitory activity is contained within caveolin-1 residues 32–95. In accordance with thesein vivostudies, a 20-amino acid peptide derived from this region (the caveolin-1 scaffolding domain) was sufficient to inhibit Neu autophosphorylation in an in vitrokinase assay. To further confirm or refute the relevance of our findings in vivo, we next examined the expression levels of caveolin-1 in mammary tumors derived from c-Neu transgenic mice. Our results indicate that dramatic reduction of caveolin-1 expression occurs in mammary tumors derived from c-Neu-expressing transgenic mice and other transgenic mice expressing downstream effectors of Neu-mediated signal transduction, such as Src and Ras. Taken together, our data suggest that a novel form of reciprocal negative regulation exists between c-Neu and caveolin-1.
- Published
- 1998
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194. Endogenous Myc maintains the tumor microenvironment
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Sodir, Nicole M., Swigart, Lamorna Brown, Karnezis, Anthony N., Hanahan, Douglas, Evan, Gerard I., and Soucek, Laura
- Subjects
tumor ,Induced Apoptosis ,Promoter ,Expression ,Pancreatic-Islet Tumors ,microenvironment ,Matrix-Metalloproteinase Inhibitors ,Transgenic Mice ,Myc inhibition ,T-Antigen ,therapeutics ,C-Myc ,pancreas ,Angiogenic Switch ,Cancer-Therapy - Abstract
The ubiquitous deregulation of Myc in human cancers makes it an intriguing therapeutic target, a notion supported by recent studies in Ras-driven lung tumors showing that inhibiting endogenous Myc triggers ubiquitous tumor regression. However, neither the therapeutic mechanism nor the applicability of Myc inhibition to other tumor types driven by other oncogenic mechanisms is established. Here, we show that inhibition of endogenous Myc also triggers ubiquitous regression of tumors in a simian virus 40 (SV40)-driven pancreatic islet tumor model. Such regression is presaged by collapse of the tumor microenvironment and involution of tumor vasculature. Hence, in addition to its diverse intracellular roles, endogenous Myc serves an essential and nonredundant role in coupling diverse intracellular oncogenic pathways to the tumor microenvironment, further bolstering its credentials as a pharmacological target.
195. Polygenic Risk Modelling for Prediction of Epithelial Ovarian Cancer Risk
- Author
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Dareng, Eileen O, Tyrer, Jonathan, Barnes, Daniel, Jones, Michelle R, Yang, Xin, Aben, Katja KH, Adank, Muriel A, Agata, Simona, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Aravantinos, Gerasimos, Arun, Banu K, Augustinsson, Annelie, Balma��a, Judith, Bandera, Elisa V, Barkardottir, Rosa B, Barrowdale, Daniel, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q, Bjorge, Line, Black, Amanda, Bogdanova, Natalia V, Bonanni, Bernardo, Borg, Ake, Brenton, James, Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S, Cai, Hui, Caligo, Maria A, Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K, Claes, Kathleen BM, Colanna, Sarah, Cook, Linda S, Couch, Fergus J, Daly, Mary B, Dao, Fanny, Davies, Eleanor, De La Hoya, Miguel, Putter, Robin De, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A, Domchek, Susan M, D��rk, Thilo, Bois, Andreas Du, D��rst, Matthias, Eccles, Diana M, Eliassen, Heather A, Engel, Christoph, Evans, D Gareth, Fasching, Peter A, Flanagan, James M, Foretova, Lenka, Fortner, Ren��e T, Friedman, Eitan, Ganz, Patricia A, Garber, Judy, Gensini, Francesca, Giles, Graham G, Glendon, Gord, Godwin, Andrew K, Goodman, Marc T, Greene, Mark H, Gronwald, Jacek, Hahnen, Eric, Haiman, Christopher A, H��kansson, Niclas, Hamann, Ute, Hansen, Thomas VO, Harris, Holly R, Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle AT, H��gdall, Estrid, H��gdall, Claus K, Hopper, John L, Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J, Huntsman, David G, Imyanitov, Evgeny N, Isaacs, Claudine, Jakubowska, Anna, James, Paul A, Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th, John, Esther M, Jones, Michael E, Kang, Daehee, Karlan, Beth Y, Karnezis, Anthony, Kelemen, Linda E, Khusnutdinova, Elza, Kiemeney, Lambertus A, Kim, Byoung-Gie, Kjaer, Susanne K, Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W, Kwong, Ava, Lambrechts, Diether, Larson, Melissa C, Lazaro, Conxi, Le, Nhu D, Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Levine, Douglas A, Li, Lian, Li, Jingmei, Loud, Jennifer T, Lu, Karen H, Lubi��ski, Jan, Machackova, Eva, Mai, Phuong L, Manoukian, Siranoush, Marks, Jeffrey R, Matsuno, Rayna Kim, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R, McNeish, Iain A, Mebirouk, Noura, Menon, Usha, Miller, Austin, Milne, Roger L, Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B, Munro, Elizabeth, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nielsen, Henriette Roed, Nielsen, Finn C, Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo I, Olson, Sara H, Olsson, H��kan, Osorio, Ana, Papi, Laura, Park, Sue K, Parsons, Michael T, Pathak, Harsha, Pedersen, Inge Sokilde, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B, Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J, Risch, Harvey A, Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P, Santamari��a, Marta, Soucy, Penny, Schmutzler, Rita K, Setiawan, V Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F, Sokolenko, Anna P, Song, Honglin, Southey, Melissa C, Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J, Tan, Yen Yen, Teixeira, Manuel R, Teo, Soo Hwang, Terry, Kathryn L, Terry, Mary Beth, Thomassen, Mads, Thompson, Pamela J, Vestrheim Thomsen, Liv Cecilie, Thull, Darcy L, Tischkowitz, Marc, Titus, Linda, Toland, Amanda E, Torres, Diana, Trabert, Britton, Travis, Ruth, Tung, Nadine, Tworoger, Shelley S, Valen, Ellen, Van Altena, Anne M, Van Der Hout, Annemieke H, Van Nieuwenhuysen, Els, Van Rensburg, Elizabeth J, Vega, Ana, Edwards, Digna Velez, Vierkant, Robert A, Wang, Frances, Wappenschmidt, Barbara, Webb, Penelope M, Weinberg, Clarice R, Weitzel, Jeffrey N, Wentzensen, Nicolas, White, Emily, Whittemore, Alice S, Winham, Stacey J, Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H, Yan, Li, Yannoukakos, Drakoulis, Zavaglia, Katia M, Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K, Easton, Douglas, Lawrenson, Kate, DeFazio, Anna, Sellers, Thomas A, Ramus, Susan J, Pearce, Celeste L, Monteiro, Alvaro N, Cunningham, Julie, Goode, Ellen L, Schildkraut, Joellen M, Berchuck, Andrew, Chenevix-Trench, Georgia, Gayther, Simon A, Antoniou, Antonis C, and Pharoah, Paul DP
- Subjects
3. Good health - Abstract
Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally-efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, ���select and shrink for summary statistics��� (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestry; 7,669 women of East Asian ancestry; 1,072 women of African ancestry, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestry. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38(95%CI:1.28���1.48,AUC:0.588) per unit standard deviation, in women of European ancestry; 1.14(95%CI:1.08���1.19,AUC:0.538) in women of East Asian ancestry; 1.38(95%CI:1.21-1.58,AUC:0.593) in women of African ancestry; hazard ratios of 1.37(95%CI:1.30���1.44,AUC:0.592) in BRCA1 pathogenic variant carriers and 1.51(95%CI:1.36-1.67,AUC:0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
196. Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcaemic type
- Author
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Nucci, Marisa R., D'Angelo, Emanuela, Prat, Jaime, Huntsman, David G., Nielsen, Torsten O., Oliva, Esther, Ronnett, Brigitte M., Kommoss, Friedrich, Gilks, C Blake, Bowtell, David D., Chow, Christine, Wang, Yemin, Rabban, Joseph T., Trent, Jeffrey M., Hendricks, William P.D., Karnezis, Anthony N., Leung, Samuel, Silva, Annacarolina, Weissman, Bernard E., Ramos, Pilar, and Kommoss, Stefan
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3. Good health - Abstract
Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) is a lethal and sometimes familial ovarian tumour of young women and children. We and others recently discovered that over 90% of SCCOHTs harbour inactivating mutations in the chromatin remodelling gene SMARCA4 with concomitant loss of its encoded protein SMARCA4 (BRG1), one of two mutually exclusive ATPases of the SWI/SNF chromatin remodelling complex. To determine the specificity of SMARCA4 loss for SCCOHT, we examined the expression of SMARCA4 by immunohistochemistry in more than 3000 primary gynaecological tumours. Among ovarian tumours, it was only absent in clear cell carcinoma (15 of 360, 4%). In the uterus, it was absent in endometrial stromal sarcomas (4 of 52, 8%) and high‐grade endometrioid carcinomas (2 of 338, 1%). Recent studies have shown that SMARCA2 (BRM), the other mutually exclusive ATPase of the SWI/SNF complex, is necessary for survival of tumour cells lacking SMARCA4. Therefore, we examined SMARCA2 expression and discovered that all SMARCA4‐negative SCCOHTs also lacked SMARCA2 protein by IHC, including the SCCOHT cell lines BIN67 and SCCOHT1. Among ovarian tumours, the SMARCA4/SMARCA2 dual loss phenotype appears completely specific for SCCOHT. SMARCA2 loss was not due to mutation but rather from an absence of mRNA expression, which was restored by treatment with the histone deacetylase inhibitor trichostatin A. Re‐expression of SMARCA4 or SMARCA2 inhibited the growth of BIN67 and SCCOHT1 cell lines. Our results indicate that SMARCA4 loss, either alone or with SMARCA2, is highly sensitive and specific for SCCOHT and that restoration of either SWI/SNF ATPase can inhibit the growth of SCCOHT cell lines. © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
197. Quantitative Profiling of Single Formalin Fixed Tumour Sections: proteomics for translational research.
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Hughes, Christopher S., McConechy, Melissa K., Cochrane, Dawn R., Nazeran, Tayyebeh, Karnezis, Anthony N., Huntsman, David G., and Morin, Gregg B.
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- 2016
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198. Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium.
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Martins, Filipe Correia, Couturier, Dominique-Laurent, Paterson, Anna, Karnezis, Anthony N., Chow, Christine, Nazeran, Tayyebeh M., Odunsi, Adekunle, Gentry-Maharaj, Aleksandra, Vrvilo, Aleksandra, Hein, Alexander, Talhouk, Aline, Osorio, Ana, Hartkopf, Andreas D., Brooks-Wilson, Angela, DeFazio, Anna, Fischer, Anna, Hartmann, Arndt, Hernandez, Brenda Y., McCauley, Bryan M., and Karpinskyj, Chloe
- Abstract
Background: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study.Methods: Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests.Results: Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016).Conclusions: PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes. [ABSTRACT FROM AUTHOR]- Published
- 2020
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199. Short-term organoid culture for drug sensitivity testing of high-grade serous carcinoma.
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Chen, Hui, Gotimer, Kristin, De Souza, Cristabelle, Tepper, Clifford G., Karnezis, Anthony N., Leiserowitz, Gary S., Chien, Jeremy, and Smith, Lloyd H.
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CLINICAL drug trials , *EPITHELIAL-mesenchymal transition , *CARCINOMA , *CELL proliferation , *PLEURAL effusions - Abstract
Cancer patient-derived organoids (PDOs) grow as three dimensional (3D) structures in the presence of extracellular matrix and have been found to represent the original tumor's genetic complexity. In addition, PDOs can be grown and subjected to drug sensitivity testing in a shorter time course and with lesser expense than patient-derived xenograft models. Many patients with recurrent ovarian cancer develop malignant effusions that become refractory to chemotherapy. Since these same patients often present for palliative aspiration of ascites or pleural effusions, there is a potential opportunity to obtain tumor specimens in the form of multicellular spheroids (MCS) present in malignant effusion fluids. Our objective was to develop a short duration culture of MCS from ovarian cancer malignant effusions in conditions selected to support organoid growth and use them as a platform for empirical drug sensitivity testing. In this study, malignant effusion specimens were collected from patients with high-grade serous ovarian carcinoma (HGSOC). MCS were recovered and subjected to culture conditions designed to support organoid growth. In a subset of specimens, RNA-sequencing was performed at two time points during the short-term culture to determine changes in transcriptome in response to culture conditions. Organoid induction was also characterized in these specimens using Ki67 staining and histologic analysis. Drug sensitivity testing was performed on all specimens. Our model describes organoids formed within days of primary culture, which can recapitulate the histological features of malignant ascites fluid and can be expanded for at least 6 days. RNA-seq analysis of four patient specimens showed that within 6 days of culture, there was significant up-regulation of genes related to cellular proliferation, epithelial-mesenchymal transition, and KRAS signaling pathways. Drug sensitivity testing identified several agents with therapeutic potential. Short duration organoid culture of MCS from HGSOC malignant effusions can be used as a platform for empiric drug sensitivity testing. These ex vivo models may be helpful in screening new or existing therapeutic agents prior to individualized treatment options. • Patient-derived organoids (PDOs) can be derived from malignant ascites and pleural effusions. • PDOs can be used for empirical drug testing of novel therapeutics. • RNA-sequencing analysis indicates gene signature associated with proliferation upon organoid induction. • PDOs represent an efficient model that recapitulates histological features of malignant ascites and pleural effusions. [ABSTRACT FROM AUTHOR]
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- 2020
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200. Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions.
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Dareng EO, Coetzee SG, Tyrer JP, Peng PC, Rosenow W, Chen S, Davis BD, Dezem FS, Seo JH, Nameki R, Reyes AL, Aben KKH, Anton-Culver H, Antonenkova NN, Aravantinos G, Bandera EV, Beane Freeman LE, Beckmann MW, Beeghly-Fadiel A, Benitez J, Bernardini MQ, Bjorge L, Black A, Bogdanova NV, Bolton KL, Brenton JD, Budzilowska A, Butzow R, Cai H, Campbell I, Cannioto R, Chang-Claude J, Chanock SJ, Chen K, Chenevix-Trench G, Chiew YE, Cook LS, DeFazio A, Dennis J, Doherty JA, Dörk T, du Bois A, Dürst M, Eccles DM, Ene G, Fasching PA, Flanagan JM, Fortner RT, Fostira F, Gentry-Maharaj A, Giles GG, Goodman MT, Gronwald J, Haiman CA, Håkansson N, Heitz F, Hildebrandt MAT, Høgdall E, Høgdall CK, Huang RY, Jensen A, Jones ME, Kang D, Karlan BY, Karnezis AN, Kelemen LE, Kennedy CJ, Khusnutdinova EK, Kiemeney LA, Kjaer SK, Kupryjanczyk J, Labrie M, Lambrechts D, Larson MC, Le ND, Lester J, Li L, Lubiński J, Lush M, Marks JR, Matsuo K, May T, McLaughlin JR, McNeish IA, Menon U, Missmer S, Modugno F, Moffitt M, Monteiro AN, Moysich KB, Narod SA, Nguyen-Dumont T, Odunsi K, Olsson H, Onland-Moret NC, Park SK, Pejovic T, Permuth JB, Piskorz A, Prokofyeva D, Riggan MJ, Risch HA, Rodríguez-Antona C, Rossing MA, Sandler DP, Setiawan VW, Shan K, Song H, Southey MC, Steed H, Sutphen R, Swerdlow AJ, Teo SH, Terry KL, Thompson PJ, Vestrheim Thomsen LC, Titus L, Trabert B, Travis R, Tworoger SS, Valen E, Van Nieuwenhuysen E, Edwards DV, Vierkant RA, Webb PM, Weinberg CR, Weise RM, Wentzensen N, White E, Winham SJ, Wolk A, Woo YL, Wu AH, Yan L, Yannoukakos D, Zeinomar N, Zheng W, Ziogas A, Berchuck A, Goode EL, Huntsman DG, Pearce CL, Ramus SJ, Sellers TA, Freedman ML, Lawrenson K, Schildkraut JM, Hazelett D, Plummer JT, Kar S, Jones MR, Pharoah PDP, and Gayther SA
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- Humans, Female, Carcinoma, Ovarian Epithelial genetics, Transcriptome, Risk Factors, Genomics methods, Case-Control Studies, Multiomics, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Genetic Predisposition to Disease
- Abstract
To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10
-8 ) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10-5 ). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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