523 results on '"Karnezis, Anthony"'
Search Results
2. Primary clear cell carcinoma of the vulva: A case report.
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Pomerantz, Tali, Rubin, Nicole, Karnezis, Anthony, Zhao, Xiao, and Brooks, Rebecca
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Clear cell carcinoma of vulva ,Endometriosis ,Episiotomy ,Vulvar carcinoma - Abstract
Clear cell carcinoma (CCC) of the vulva is extremely rare. We report a case of a 54-year-old woman who presented with a 5 cm mass of the mons pubis. She underwent needle biopsy demonstrating CCC. She then underwent radical vulvectomy with bilateral inguinofemoral lymph node dissection. Surgical pathology revealed CCC of the vulva with lymphovascular space invasion (LVSI) and metastatic carcinoma in 1/7 inguinal lymph nodes. The patient has a history of endometriosis, raising suspicion that her CCC could have arisen from endometriosis in the mons. She completed adjuvant treatment with cisplatin and concurrent external beam radiation therapy with radiographic evidence of complete response. However, short-interval imaging demonstrated multi-focal recurrence, which was confirmed with supraclavicular lymph node biopsy. She then completed 8 cycles carboplatin, paclitaxel, and biosimilar bevacizumab-bvzr with favorable response on imaging. She was continued on bevacizumab maintenance. She was later started on pembroluzimab for disease progression based on new mediastinal adenopathy and worsening retroperitoneal lymphadenopathy. She received eight cycles of pembrolizumab with ongoing disease progression before enrolling in hospice and discontinuing cancer-directed treatment. As described in the related literature which we summarize here, the majority of reported cases of vulvar CCC arise from endometriosis implants at the site of prior episiotomy or from the Bartholins gland. This patient had clinical history of endometriosis; prior tissue sampling was not performed to support the diagnosis. Given the absence of data regarding this rare type of primary vulvar cancer, treatment of this patients disease was based on existing data specific to squamous cell carcinoma of the vulva and extrapolated from treatment guidelines for CCC of the ovary and endometrium. Continued research is needed on this rare form of vulvar carcinoma to determine the risk factors, prognostic factors, and treatment recommendations specific to this disease.
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- 2023
3. The Prognostic Effect of Immune Cell Infiltration Depends on Molecular Subtype in Endometrioid Ovarian Carcinomas.
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Heinze, Karolin, Cairns, Evan, Thornton, Shelby, Harris, Bronwyn, Milne, Katy, Grube, Marcel, Meyer, Charlotte, Fereday, Sian, Garsed, Dale, Leung, Samuel, Chiu, Derek, Moubarak, Malak, Harter, Philipp, Heitz, Florian, McAlpine, Jessica, DeFazio, Anna, Bowtell, David, Goode, Ellen, Pike, Malcolm, Ramus, Susan, Pearce, C, Staebler, Annette, Köbel, Martin, Kommoss, Stefan, Talhouk, Aline, Nelson, Brad, Anglesio, Michael, and Karnezis, Anthony
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Female ,Humans ,Prognosis ,Biomarkers ,Tumor ,Carcinoma ,Endometrioid ,Ovarian Neoplasms ,Endometrial Neoplasms ,Carcinoma ,Ovarian Epithelial ,Tumor Microenvironment - Abstract
PURPOSE: Endometrioid ovarian carcinoma (ENOC) is the second most-common type of ovarian carcinoma, comprising 10%-20% of cases. Recently, the study of ENOC has benefitted from comparisons to endometrial carcinomas including defining ENOC with four prognostic molecular subtypes. Each subtype suggests differential mechanisms of progression, although tumor-initiating events remain elusive. There is evidence that the ovarian microenvironment may be critical to early lesion establishment and progression. However, while immune infiltrates have been well studied in high-grade serous ovarian carcinoma, studies in ENOC are limited. EXPERIMENTAL DESIGN: We report on 210 ENOC, with clinical follow-up and molecular subtype annotation. Using multiplex IHC and immunofluorescence, we examine the prevalence of T-cell lineage, B-cell lineage, macrophages, and populations with programmed cell death protein 1 or programmed death-ligand 1 across subtypes of ENOC. RESULTS: Immune cell infiltrates in tumor epithelium and stroma showed higher densities in ENOC subtypes with known high mutation burden (POLEmut and MMRd). While molecular subtypes were prognostically significant, immune infiltrates were not (overall survival P > 0.2). Analysis by molecular subtype revealed that immune cell density was prognostically significant in only the no specific molecular profile (NSMP) subtype, where immune infiltrates lacking B cells (TILB minus) had inferior outcome (disease-specific survival: HR, 4.0; 95% confidence interval, 1.1-14.7; P < 0.05). Similar to endometrial carcinomas, molecular subtype stratification was generally superior to immune response in predicting outcomes. CONCLUSIONS: Subtype stratification is critical for better understanding of ENOC, in particular the distribution and prognostic significance of immune cell infiltrates. The role of B cells in the immune response within NSMP tumors warrants further study.
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- 2023
4. The Genomic Landscape of Vulvar Squamous Cell Carcinoma.
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Corey, Logan, Wallbillich, John, Wu, Sharon, Farrell, Alex, Hodges, Kurt, Xiu, Joanne, Nabhan, Chadi, Guastella, Anthony, Kheil, Mira, Gogoi, Radhika, Winer, Ira, Bandyopadhyay, Sudeshna, Huang, Marilyn, Jones, Nathaniel, Wilhite, Annelise, Thaker, Premal, Herzog, Thomas, Oberley, Matthew, Korn, William, Vezina, Alex, Morris, Robert, Ali-Fehmi, Rouba, and Karnezis, Anthony
- Abstract
Vulvar squamous cell cancer (VSC) accounts for 90% of vulvar cancers. Next-generation sequencing studies of VSC imply human papillomavirus (HPV) and p53 status play separate roles in carcinogenesis and prognosis. We sought to describe the genomic landscape and analyze the immunologic profiles of VSC with respect to HPV and p53 status. A total of 443 VSC tumors underwent tumor profiling. Next-generation sequencing was performed on genomic DNA isolated from formalin-fixed paraffin-embedded tumor samples. PD-L1, microsatellite instability were tested by fragment analysis, IHC, and next-generation sequencing. Tumor mutational burden-high was defined as >10 mutations per MB. HPV 16/18 positive (HPV+) status was determined using whole exome sequencing on 105 samples. Three cohorts were identified from 105 samples with known HPV: HPV+, HPV-/p53wt, and HPV-/p53mt. Where HPV and p53 status were examined, TP53 mutations were exclusive of HPV+ tumors. In all, 37% of samples were HPV+. Among the 66 HPV- tumors, 52 (78.8%) were HPV-/p53mt and 14 (21.2%) were HPV-/p53wt. The HPV-/p53wt cohort had a higher rate of mutations in the PI3KCA gene (42.9% HPV-/p53wt vs 26.3% HPV+ vs. 5.8% HPV-/p53mt, q =0.028) and alterations in the PI3K/AkT/mTOR pathway (57.1% HPV-/p53wt vs. 34.2% HPV+ vs. 7.7% HPV-/p53mt, q =0.0386) than the other 2 cohorts. Ninety-eight VSC tumors with HPV16/18 information underwent transcriptomic analysis and immune deconvolution method. No differences were observed in immune profiles. The HPV-/p53wt VSC tumors had significantly higher rates of mutations in the PI3KCA gene and alterations in the PI3K/AkT/mTOR pathway, a potential target that merits further investigation in this subgroup.
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- 2023
5. Profiling the immune landscape in mucinous ovarian carcinoma.
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Meagher, Nicola, Hamilton, Phineas, Milne, Katy, Thornton, Shelby, Harris, Bronwyn, Weir, Ashley, Alsop, Jennifer, Bisinoto, Christiani, Brenton, James, Brooks-Wilson, Angela, Chiu, Derek, Cushing-Haugen, Kara, Fereday, Sian, Garsed, Dale, Gayther, Simon, Gentry-Maharaj, Aleksandra, Gilks, Blake, Jimenez-Linan, Mercedes, Kennedy, Catherine, Le, Nhu, Piskorz, Anna, Riggan, Marjorie, Shah, Mitul, Singh, Naveena, Talhouk, Aline, Widschwendter, Martin, Bowtell, David, Candido Dos Reis, Francisco, Cook, Linda, Fortner, Renée, García, María, Harris, Holly, Huntsman, David, Köbel, Martin, Menon, Usha, Pharoah, Paul, Doherty, Jennifer, Anglesio, Michael, Pike, Malcolm, Pearce, Celeste, Friedlander, Michael, DeFazio, Anna, Nelson, Brad, Ramus, Susan, and Karnezis, Anthony
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Immune infiltrate ,Mucinous ovarian carcinoma ,Rare histotype ,Humans ,Female ,B7-H1 Antigen ,Carcinoma ,Ovarian Epithelial ,Ovarian Neoplasms ,CD8-Positive T-Lymphocytes ,Forkhead Transcription Factors ,Lymphocytes ,Tumor-Infiltrating ,Tumor Microenvironment - Abstract
OBJECTIVE: Mucinous ovarian carcinoma (MOC) is a rare histotype of ovarian cancer, with low response rates to standard chemotherapy, and very poor survival for patients diagnosed at advanced stage. There is a limited understanding of the MOC immune landscape, and consequently whether immune checkpoint inhibitors could be considered for a subset of patients. METHODS: We performed multicolor immunohistochemistry (IHC) and immunofluorescence (IF) on tissue microarrays in a cohort of 126 MOC patients. Cell densities were calculated in the epithelial and stromal components for tumor-associated macrophages (CD68+/PD-L1+, CD68+/PD-L1-), T cells (CD3+/CD8-, CD3+/CD8+), putative T-regulatory cells (Tregs, FOXP3+), B cells (CD20+/CD79A+), plasma cells (CD20-/CD79a+), and PD-L1+ and PD-1+ cells, and compared these values with clinical factors. Univariate and multivariable Cox Proportional Hazards assessed overall survival. Unsupervised k-means clustering identified patient subsets with common patterns of immune cell infiltration. RESULTS: Mean densities of PD1+ cells, PD-L1- macrophages, CD4+ and CD8+ T cells, and FOXP3+ Tregs were higher in the stroma compared to the epithelium. Tumors from advanced (Stage III/IV) MOC had greater epithelial infiltration of PD-L1- macrophages, and fewer PD-L1+ macrophages compared with Stage I/II cancers (p = 0.004 and p = 0.014 respectively). Patients with high epithelial density of FOXP3+ cells, CD8+/FOXP3+ cells, or PD-L1- macrophages, had poorer survival, and high epithelial CD79a + plasma cells conferred better survival, all upon univariate analysis only. Clustering showed that most MOC (86%) had an immune depleted (cold) phenotype, with only a small proportion (11/76,14%) considered immune inflamed (hot) based on T cell and PD-L1 infiltrates. CONCLUSION: In summary, MOCs are mostly immunogenically cold, suggesting they may have limited response to current immunotherapies.
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- 2023
6. The impact of whole genome and transcriptome analysis (WGTA) on predictive biomarker discovery and diagnostic accuracy of advanced malignancies
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Tessier‐Cloutier, Basile, Grewal, Jasleen K, Jones, Martin R, Pleasance, Erin, Shen, Yaoqing, Cai, Ellen, Dunham, Chris, Hoang, Lynn, Horst, Basil, Huntsman, David G, Ionescu, Diana, Karnezis, Anthony N, Lee, Anna F, Lee, Cheng Han, Lee, Tae Hoon, Twa, David DW, Mungall, Andrew J, Mungall, Karen, Naso, Julia R, Ng, Tony, Schaeffer, David F, Sheffield, Brandon S, Skinnider, Brian, Smith, Tyler, Williamson, Laura, Zhong, Ellia, Regier, Dean A, Laskin, Janessa, Marra, Marco A, Gilks, C Blake, Jones, Steven JM, and Yip, Stephen
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Genetics ,Cancer ,Rare Diseases ,Human Genome ,4.2 Evaluation of markers and technologies ,Detection ,screening and diagnosis ,Algorithms ,Biomarkers ,Tumor ,Gene Expression Profiling ,Humans ,Neoplasms ,biomarker ,diagnostic ,WGTA ,pathology ,precision medicine ,oncology ,cancer of unknown primary ,machine learning ,Clinical sciences - Abstract
In this study, we evaluate the impact of whole genome and transcriptome analysis (WGTA) on predictive molecular profiling and histologic diagnosis in a cohort of advanced malignancies. WGTA was used to generate reports including molecular alterations and site/tissue of origin prediction. Two reviewers analyzed genomic reports, clinical history, and tumor pathology. We used National Comprehensive Cancer Network (NCCN) consensus guidelines, Food and Drug Administration (FDA) approvals, and provincially reimbursed treatments to define genomic biomarkers associated with approved targeted therapeutic options (TTOs). Tumor tissue/site of origin was reassessed for most cases using genomic analysis, including a machine learning algorithm (Supervised Cancer Origin Prediction Using Expression [SCOPE]) trained on The Cancer Genome Atlas data. WGTA was performed on 652 cases, including a range of primary tumor types/tumor sites and 15 malignant tumors of uncertain histogenesis (MTUH). At the time WGTA was performed, alterations associated with an approved TTO were identified in 39 (6%) cases; 3 of these were not identified through routine pathology workup. In seven (1%) cases, the pathology workup either failed, was not performed, or gave a different result from the WGTA. Approved TTOs identified by WGTA increased to 103 (16%) when applying 2021 guidelines. The histopathologic diagnosis was reviewed in 389 cases and agreed with the diagnostic consensus after WGTA in 94% of non-MTUH cases (n = 374). The remainder included situations where the morphologic diagnosis was changed based on WGTA and clinical data (0.5%), or where the WGTA was non-contributory (5%). The 15 MTUH were all diagnosed as specific tumor types by WGTA. Tumor board reviews including WGTA agreed with almost all initial predictive molecular profile and histopathologic diagnoses. WGTA was a powerful tool to assign site/tissue of origin in MTUH. Current efforts focus on improving therapeutic predictive power and decreasing cost to enhance use of WGTA data as a routine clinical test.
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- 2022
7. Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions
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Dareng, Eileen O., Coetzee, Simon G., Tyrer, Jonathan P., Peng, Pei-Chen, Rosenow, Will, Chen, Stephanie, Davis, Brian D., Dezem, Felipe Segato, Seo, Ji-Heui, Nameki, Robbin, Reyes, Alberto L., Aben, Katja K.H., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Bandera, Elisa V., Beane Freeman, Laura E., Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia V., Bolton, Kelly L., Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Cai, Hui, Campbell, Ian, Cannioto, Rikki, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chenevix-Trench, Georgia, Chiew, Yoke-Eng, Cook, Linda S., DeFazio, Anna, Dennis, Joe, Doherty, Jennifer A., Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana M., Ene, Gabrielle, Fasching, Peter A., Flanagan, James M., Fortner, Renée T., Fostira, Florentia, Gentry-Maharaj, Aleksandra, Giles, Graham G., Goodman, Marc T., Gronwald, Jacek, Haiman, Christopher A., Håkansson, Niclas, Heitz, Florian, Hildebrandt, Michelle A.T., Høgdall, Estrid, Høgdall, Claus K., Huang, Ruea-Yea, Jensen, Allan, Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony N., Kelemen, Linda E., Kennedy, Catherine J., Khusnutdinova, Elza K., Kiemeney, Lambertus A., Kjaer, Susanne K., Kupryjanczyk, Jolanta, Labrie, Marilyne, Lambrechts, Diether, Larson, Melissa C., Le, Nhu D., Lester, Jenny, Li, Lian, Lubiński, Jan, Lush, Michael, Marks, Jeffrey R., Matsuo, Keitaro, May, Taymaa, McLaughlin, John R., McNeish, Iain A., Menon, Usha, Missmer, Stacey, Modugno, Francesmary, Moffitt, Melissa, Monteiro, Alvaro N., Moysich, Kirsten B., Narod, Steven A., Nguyen-Dumont, Tu, Odunsi, Kunle, Olsson, Håkan, Onland-Moret, N. Charlotte, Park, Sue K., Pejovic, Tanja, Permuth, Jennifer B., Piskorz, Anna, Prokofyeva, Darya, Riggan, Marjorie J., Risch, Harvey A., Rodríguez-Antona, Cristina, Rossing, Mary Anne, Sandler, Dale P., Setiawan, V. Wendy, Shan, Kang, Song, Honglin, Southey, Melissa C., Steed, Helen, Sutphen, Rebecca, Swerdlow, Anthony J., Teo, Soo Hwang, Terry, Kathryn L., Thompson, Pamela J., Vestrheim Thomsen, Liv Cecilie, Titus, Linda, Trabert, Britton, Travis, Ruth, Tworoger, Shelley S., Valen, Ellen, Van Nieuwenhuysen, Els, Edwards, Digna Velez, Vierkant, Robert A., Webb, Penelope M., Weinberg, Clarice R., Weise, Rayna Matsuno, Wentzensen, Nicolas, White, Emily, Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zeinomar, Nur, Zheng, Wei, Ziogas, Argyrios, Berchuck, Andrew, Goode, Ellen L., Huntsman, David G., Pearce, Celeste L., Ramus, Susan J., Sellers, Thomas A., Freedman, Matthew L., Lawrenson, Kate, Schildkraut, Joellen M., Hazelett, Dennis, Plummer, Jasmine T., Kar, Siddhartha, Jones, Michelle R., Pharoah, Paul D.P., and Gayther, Simon A.
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- 2024
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8. SMARCA4 biology in alveolar rhabdomyosarcoma
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Bharathy, Narendra, Cleary, Megan M, Kim, Jin-Ah, Nagamori, Kiyo, Crawford, Kenneth A, Wang, Eric, Saha, Debarya, Settelmeyer, Teagan P, Purohit, Reshma, Skopelitis, Damianos, Chang, Kenneth, Doran, Jessica A, Kirschbaum, C Ward, Bharathy, Suriya, Crews, Davis W, Randolph, Matthew E, Karnezis, Anthony N, Hudson-Price, Lisa, Dhawan, Jyotsna, Michalek, Joel E, Ciulli, Alessio, Vakoc, Christopher R, and Keller, Charles
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Rare Diseases ,Pediatric Research Initiative ,Genetics ,Pediatric Cancer ,Orphan Drug ,Pediatric ,Aetiology ,2.1 Biological and endogenous factors ,Biology ,Child ,DNA Helicases ,Humans ,Neoplasms ,Nuclear Proteins ,Rhabdomyosarcoma ,Alveolar ,Rhabdomyosarcoma ,Embryonal ,Transcription Factors ,Clinical Sciences ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and phenocopies a muscle precursor that fails to undergo terminal differentiation. The alveolar subtype (ARMS) has the poorest prognosis and represents the greatest unmet medical need for RMS. Emerging evidence supports the role of epigenetic dysregulation in RMS. Here we show that SMARCA4/BRG1, an ATP-dependent chromatin remodeling enzyme of the SWI/SNF complex, is prominently expressed in primary tumors from ARMS patients and cell cultures. Our validation studies for a CRISPR screen of 400 epigenetic targets identified SMARCA4 as a unique factor for long-term (but not short-term) tumor cell survival in ARMS. A SMARCA4/SMARCA2 protein degrader (ACBI-1) demonstrated similar long-term tumor cell dependence in vitro and in vivo. These results credential SMARCA4 as a tumor cell dependency factor and a therapeutic target in ARMS.
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- 2022
9. STING pathway expression in low‐grade serous carcinoma of the ovary: an unexpected therapeutic opportunity?
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Huvila, Jutta, Cochrane, Dawn R, Ta, Monica, Chow, Christine, Greening, Kendall, Leung, Samuel, Karnezis, Anthony N, DiFeo, Analisa, and Huntsman, David G
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Ovarian Cancer ,Rare Diseases ,Cancer ,Good Health and Well Being ,Biomarkers ,Tumor ,Female ,Humans ,Immunity ,Innate ,Immunotherapy ,Membrane Proteins ,Neoplasm Grading ,Neoplasms ,Cystic ,Mucinous ,and Serous ,Ovarian Neoplasms ,Signal Transduction ,STING ,innate immunity ,low-grade serous ovarian carcinoma - Abstract
Ovarian carcinoma histotypes are distinct diseases with variable clinical outcomes and response to treatment. There is a need for new subtype-specific treatment modalities, especially for women with widespread and chemo-resistant disease. Stimulator of interferon genes (STING) is a part of the cGAS-STING pathway that mediates innate immune defence against infectious DNA-containing pathogens and also detects tumour-derived DNA and generates intrinsic antitumour immunity. The STING signalling pathway is suppressed by several mechanisms in a variety of malignant diseases and, in some cancers that may be a requirement for cellular transformation. The aim of this study was to use immunohistochemistry to evaluate STING protein expression across normal tissue, paratubal and ovarian cysts, and ovarian tumour histotypes including ovarian carcinomas. Herein, we show that the fallopian tube ciliated cells express STING protein, whereas the secretory cells are negative. STING expression differs among ovarian cancer histotypes; low-grade serous ovarian carcinomas and serous borderline tumours have uniform high STING expression, while high-grade serous and endometrioid carcinomas have heterogeneous expression, and clear cell and mucinous carcinomas show low expression. As low-grade serous carcinomas are known to be genomically stable and typically lack a prominent host immune response, the consistently high STING expression is unexpected. High STING expression may reflect pathway activation or histogenesis and the mechanisms may be different in different ovarian carcinoma histotypes. Further studies are needed to determine whether the STING signalling pathway is active and whether these tumours would be candidates for therapeutic interventions that trigger innate immunity activation.
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- 2021
10. Effect of the p53 P72R Polymorphism on Mutant TP53 Allele Selection in Human Cancer
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De Souza, Cristabelle, Madden, Jill, Koestler, Devin C, Minn, Dennis, Montoya, Dennis J, Minn, Kay, Raetz, Alan G, Zhu, Zheng, Xiao, Wen-Wu, Tahmassebi, Neeki, Kathi, Harikumara R, Nelson, Nina, Karnezis, Anthony N, and Chien, Jeremy
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Genetics ,Cancer ,Cancer Genomics ,Human Genome ,Women's Health ,Rare Diseases ,Ovarian Cancer ,2.1 Biological and endogenous factors ,Alleles ,Female ,Genes ,p53 ,Humans ,Ovarian Neoplasms ,Polymorphism ,Single Nucleotide ,Tumor Suppressor Protein p53 ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundTP53 mutations occur in more than 50% of cancers. We sought to determine the effect of the intragenic P72R single nucleotide polymorphism (SNP; rs1042522) on the oncogenic properties of mutant p53.MethodsP72R allelic selection in tumors was determined from genotype calls and a Gaussian distributed mixture model. The SNP effect on mutant p53 was determined in p53-negative cancer cell lines. RNA-sequencing, chromatin immunoprecipitation, and survival analysis were performed to describe the SNP effect. All statistical tests were 2-sided.ResultsAmong 409 patients with germline heterozygous P72R SNP who harbored somatic mutations in TP53, we observed a selection bias against missense TP53 mutants encoding the P72 SNP (P = 1.64 x 10-13). Exogenously expressed hotspot p53 mutants with the P72 SNP were negatively selected in cancer cells. Gene expression analyses showed the enrichment of p53 pathway genes and inflammatory genes in cancer cells transduced with mutants encoding P72 SNP. Immune gene signature is enriched in patients harboring missense TP53 mutations with homozygous P72 SNP. These patients have improved overall survival as compared with those with the R72 SNP (P = .04).ConclusionThis is the largest study demonstrating a selection against the P72 SNP. Missense p53 mutants with the P72 SNP retain partial wild-type tumor-suppressive functions, which may explain the selection bias against P72 SNP across cancer types. Ovarian cancer patients with the P72 SNP have a better prognosis than with the R72 SNP. Our study describes a previously unknown role through which the rs1042522 SNP modifies tumor suppressor activities of mutant p53 in patients.
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- 2021
11. Quantitative imaging of RAD51 expression as a marker of platinum resistance in ovarian cancer
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Hoppe, Michal M, Jaynes, Patrick, Wardyn, Joanna D, Upadhyayula, Sai Srinivas, Tan, Tuan Zea, Lie, Stefanus, Lim, Diana GZ, Pang, Brendan NK, Lim, Sherlly, Yeong, Joe PS, Karnezis, Anthony, Chiu, Derek S, Leung, Samuel, Huntsman, David G, Sedukhina, Anna S, Sato, Ko, Topp, Monique D, Scott, Clare L, Choi, Hyungwon, Patel, Naina R, Brown, Robert, Kaye, Stan B, Pitt, Jason J, Tan, David SP, and Jeyasekharan, Anand D
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Rare Diseases ,Cancer ,Genetics ,Ovarian Cancer ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Carcinoma ,Ovarian Epithelial ,Female ,Humans ,Neoplasm Recurrence ,Local ,Ovarian Neoplasms ,Paclitaxel ,Platinum ,Rad51 Recombinase ,HRD ,immune exclusion ,multiplexed IHC ,ovarian cancer ,RAD51 ,Biological Sciences ,Medical and Health Sciences - Abstract
Early relapse after platinum chemotherapy in epithelial ovarian cancer (EOC) portends poor survival. A-priori identification of platinum resistance is therefore crucial to improve on standard first-line carboplatin-paclitaxel treatment. The DNA repair pathway homologous recombination (HR) repairs platinum-induced damage, and the HR recombinase RAD51 is overexpressed in cancer. We therefore designed a REMARK-compliant study of pre-treatment RAD51 expression in EOC, using fluorescent quantitative immunohistochemistry (qIHC) to overcome challenges in quantitation of protein expression in situ. In a discovery cohort (n = 284), RAD51-High tumours had shorter progression-free and overall survival compared to RAD51-Low cases in univariate and multivariate analyses. The association of RAD51 with relapse/survival was validated in a carboplatin monotherapy SCOTROC4 clinical trial cohort (n = 264) and was predominantly noted in HR-proficient cancers (Myriad HRDscore
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- 2021
12. Re-assigning the histologic identities of COV434 and TOV-112D ovarian cancer cell lines
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Karnezis, Anthony N, Chen, Shary Yuting, Chow, Christine, Yang, Winnie, Hendricks, William PD, Ramos, Pilar, Briones, Natalia, Mes-Masson, Anne-Marie, Bosse, Tjalling, Gilks, C Blake, Trent, Jeffrey M, Weissman, Bernard, Huntsman, David G, and Wang, Yemin
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Rare Diseases ,Ovarian Cancer ,Genetics ,Cancer ,Aetiology ,2.1 Biological and endogenous factors ,Animals ,Carcinoma ,Ovarian Epithelial ,Carcinoma ,Small Cell ,Cell Dedifferentiation ,Cell Line ,Tumor ,DNA Helicases ,Enhancer of Zeste Homolog 2 Protein ,Female ,Gene Expression Profiling ,Humans ,Mice ,Nuclear Proteins ,Ovarian Neoplasms ,Transcription Factors ,Exome Sequencing ,Xenograft Model Antitumor Assays ,COV434 ,TOV-112D ,SCCOHT ,Granulosa cell tumour ,Dedifferentiated carcinoma ,SMARCA4 ,Oncology and Carcinogenesis ,Paediatrics and Reproductive Medicine ,Oncology & Carcinogenesis - Abstract
ObjectiveThe development of effective cancer treatments depends on the availability of cell lines that faithfully recapitulate the cancer in question. This study definitively re-assigns the histologic identities of two ovarian cancer cell lines, COV434 (originally described as a granulosa cell tumour) and TOV-112D (originally described as grade 3 endometrioid carcinoma), both of which were recently suggested to represent small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), based on their shared gene expression profiles and sensitivity to EZH2 inhibitors.MethodsFor COV434 and TOV-112D, we re-reviewed the original pathology slides and obtained clinical follow-up on the patients, when available, and performed immunohistochemistry for SMARCA4, SMARCA2 and additional diagnostic markers on the original formalin-fixed, paraffin-embedded (FFPE) clinical material, when available. For COV434, we further performed whole exome sequencing and validated SMARCA4 mutations by Sanger sequencing. We studied the growth of the cell lines at baseline and upon re-expression of SMARCA4 in vitro for both cell lines and evaluated the serum calcium levels in vivo upon injection into immunodeficient mice for COV434 cells.ResultsThe available morphological, immunohistochemical, genetic, and clinical features indicate COV434 is derived from SCCOHT, and TOV-112D is a dedifferentiated carcinoma. Transplantation of COV434 into mice leads to increased serum calcium level. Re-expression of SMARCA4 in either COV434 and TOV-112D cells suppressed their growth dramatically.ConclusionsCOV434 represents a bona fide SCCOHT cell line. TOV-112D is a dedifferentiated ovarian carcinoma cell line.
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- 2021
13. Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers
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Glubb, Dylan M, Thompson, Deborah J, Aben, Katja KH, Alsulimani, Ahmad, Amant, Frederic, Annibali, Daniela, Attia, John, Barricarte, Aurelio, Beckmann, Matthias W, Berchuck, Andrew, Bermisheva, Marina, Bernardini, Marcus Q, Bischof, Katharina, Bjorge, Line, Bodelon, Clara, Brand, Alison H, Brenton, James D, Brinton, Louise A, Bruinsma, Fiona, Buchanan, Daniel D, Burghaus, Stefanie, Butzow, Ralf, Cai, Hui, Carney, Michael E, Chanock, Stephen J, Chen, Chu, Chen, Xiao Qing, Chen, Zhihua, Cook, Linda S, Cunningham, Julie M, De Vivo, Immaculata, deFazio, Anna, Doherty, Jennifer A, Dörk, Thilo, du Bois, Andreas, Dunning, Alison M, Dürst, Matthias, Edwards, Todd, Edwards, Robert P, Ekici, Arif B, Ewing, Ailith, Fasching, Peter A, Ferguson, Sarah, Flanagan, James M, Fostira, Florentia, Fountzilas, George, Friedenreich, Christine M, Gao, Bo, Gaudet, Mia M, Gawełko, Jan, Gentry-Maharaj, Aleksandra, Giles, Graham G, Glasspool, Rosalind, Goodman, Marc T, Gronwald, Jacek, Harris, Holly R, Harter, Philipp, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Høgdall, Estrid, Høgdall, Claus K, Holliday, Elizabeth G, Huntsman, David G, Huzarski, Tomasz, Jakubowska, Anna, Jensen, Allan, Jones, Michael E, Karlan, Beth Y, Karnezis, Anthony, Kelley, Joseph L, Khusnutdinova, Elza, Killeen, Jeffrey L, Kjaer, Susanne K, Klapdor, Rüdiger, Köbel, Martin, Konopka, Bozena, Konstantopoulou, Irene, Kopperud, Reidun K, Koti, Madhuri, Kraft, Peter, Kupryjanczyk, Jolanta, Lambrechts, Diether, Larson, Melissa C, Le Marchand, Loic, Lele, Shashikant, Lester, Jenny, Li, Andrew J, Liang, Dong, Liebrich, Clemens, Lipworth, Loren, Lissowska, Jolanta, Lu, Lingeng, Lu, Karen H, Macciotta, Alessandra, Mattiello, Amalia, May, Taymaa, McAlpine, Jessica N, and McGuire, Valerie
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Epidemiology ,Biomedical and Clinical Sciences ,Health Sciences ,Oncology and Carcinogenesis ,Human Genome ,Uterine Cancer ,Genetics ,Biotechnology ,Ovarian Cancer ,Prevention ,Cancer ,Rare Diseases ,2.1 Biological and endogenous factors ,Aetiology ,Carcinoma ,Ovarian Epithelial ,Endometrial Neoplasms ,Female ,Genome-Wide Association Study ,Humans ,Ovarian Neoplasms ,Quantitative Trait Loci ,Risk Factors ,OPAL Study Group ,AOCS Group ,Medical and Health Sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
BackgroundAccumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers.MethodsUsing LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data.ResultsGenetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10-5). We found seven loci associated with risk for both cancers (P Bonferroni < 2.4 × 10-9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified (P < 5 × 10-7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation.ConclusionsUsing cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis.ImpactOur research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.
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- 2021
14. The P72R Polymorphism in R248Q/W p53 Mutants Modifies the Mutant Effect on Epithelial to Mesenchymal Transition Phenotype and Cell Invasion via CXCL1 Expression.
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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
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Tumor Cells ,Cultured ,Animals ,Humans ,Mice ,Ovarian Neoplasms ,Neoplasm Invasiveness ,Xenograft Model Antitumor Assays ,Apoptosis ,Cell Proliferation ,Gene Expression Regulation ,Neoplastic ,Phenotype ,Mutation ,Polymorphism ,Genetic ,Female ,Tumor Suppressor Protein p53 ,Chemokine CXCL1 ,Epithelial-Mesenchymal Transition ,Biomarkers ,Tumor ,CXCL1 ,P72R polymorphism ,mutant p53 ,ovarian cancer ,tumor invasion ,Genetics ,Ovarian Cancer ,Biotechnology ,Cancer ,Rare Diseases ,2.1 Biological and endogenous factors ,Other Chemical Sciences ,Other Biological Sciences ,Chemical Physics - 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.
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- 2020
15. 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, Karpinskyj, Chloe, de Sousa, Christiani B, Høgdall, Claus, Tiezzi, Daniel G, Herpel, Esther, Taran, Florin Andrei, Modugno, Francesmary, Keeney, Gary, Nelson, Gregg, Steed, Helen, Song, Honglin, Luk, Hugh, Benitez, Javier, Alsop, Jennifer, Koziak, Jennifer M, Lester, Jenny, Rothstein, Joseph H, de Andrade, Jurandyr M, Lundvall, Lene, Paz-Ares, Luis, Robles-Díaz, Luis, Wilkens, Lynne R, Garcia, Maria J, Intermaggio, Maria P, Alcaraz, Marie-Lyne, Brett, Mary A, Beckmann, Matthias W, Jimenez-Linan, Mercedes, Anglesio, Michael, Carney, Michael E, Schneider, Michael, Traficante, Nadia, Pejovic, Nadja, Singh, Naveena, Le, Nhu, Sinn, Peter, Ghatage, Prafull, Erber, Ramona, Edwards, Robert, Vierkant, Robert, Ness, Roberta B, Leung, Samuel, Orsulic, Sandra, Brucker, Sara Y, Kaufmann, Scott H, Fereday, Sian, Gayther, Simon, Winham, Stacey J, Kommoss, Stefan, Pejovic, Tanja, Longacre, Teri A, McGuire, Valerie, Rhenius, Valerie, Sieh, Weiva, Shvetsov, Yurii B, Whittemore, Alice S, Staebler, Annette, Karlan, Beth Y, Rodriguez-Antona, Cristina, Bowtell, David D, Goode, Ellen L, Høgdall, Estrid, Candido Dos Reis, Francisco J, Gronwald, Jacek, Chang-Claude, Jenny, Moysich, Kirsten B, Kelemen, Linda E, Cook, Linda S, Goodman, Marc T, Fasching, Peter A, Crawford, Robin, Deen, Suha, Menon, Usha, Huntsman, David G, Köbel, Martin, Ramus, Susan J, Pharoah, Paul DP, and Brenton, James D
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Oncology & Carcinogenesis ,Oncology and Carcinogenesis ,Public Health and Health Services - Abstract
BackgroundPTEN 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.MethodsTumours 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.ResultsDownregulation 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
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- 2020
16. Arginine Depletion Therapy with ADI-PEG20 Limits Tumor Growth in Argininosuccinate Synthase–Deficient Ovarian Cancer, Including Small-Cell Carcinoma of the Ovary, Hypercalcemic Type
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Ji, Jennifer X, Cochrane, Dawn R, Tessier-Cloutier, Basile, Chen, Shary Yutin, Ho, Germain, Pathak, Khyatiben V, Alcazar, Isabel N, Farnell, David, Leung, Samuel, Cheng, Angela, Chow, Christine, Colborne, Shane, Negri, Gian Luca, Kommoss, Friedrich, Karnezis, Anthony, Morin, Gregg B, McAlpine, Jessica N, Gilks, C Blake, Weissman, Bernard E, Trent, Jeffrey M, Hoang, Lynn, Pirrotte, Patrick, Wang, Yemin, and Huntsman, David G
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Biotechnology ,Ovarian Cancer ,Cancer ,Rare Diseases ,Orphan Drug ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,Arginine ,Argininosuccinate Synthase ,Carcinoma ,Small Cell ,Cell Line ,Tumor ,Cell Proliferation ,Female ,Humans ,Hydrolases ,Mice ,Ovarian Neoplasms ,Ovary ,Parathyroid Hormone-Related Protein ,Polyethylene Glycols ,Proteomics ,Xenograft Model Antitumor Assays ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
PurposeMany rare ovarian cancer subtypes, such as small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT), have poor prognosis due to their aggressive nature and resistance to standard platinum- and taxane-based chemotherapy. The development of effective therapeutics has been hindered by the rarity of such tumors. We sought to identify targetable vulnerabilities in rare ovarian cancer subtypes.Experimental designWe compared the global proteomic landscape of six cases each of endometrioid ovarian cancer (ENOC), clear cell ovarian cancer (CCOC), and SCCOHT to the most common subtype, high-grade serous ovarian cancer (HGSC), to identify potential therapeutic targets. IHC of tissue microarrays was used as validation of arginosuccinate synthase (ASS1) deficiency. The efficacy of arginine-depriving therapeutic ADI-PEG20 was assessed in vitro using cell lines and patient-derived xenograft mouse models representing SCCOHT.ResultsGlobal proteomic analysis identified low ASS1 expression in ENOC, CCOC, and SCCOHT compared with HGSC. Low ASS1 levels were validated through IHC in large patient cohorts. The lowest levels of ASS1 were observed in SCCOHT, where ASS1 was absent in 12 of 31 cases, and expressed in less than 5% of the tumor cells in 9 of 31 cases. ASS1-deficient ovarian cancer cells were sensitive to ADI-PEG20 treatment regardless of subtype in vitro. Furthermore, in two cell line mouse xenograft models and one patient-derived mouse xenograft model of SCCOHT, once-a-week treatment with ADI-PEG20 (30 mg/kg and 15 mg/kg) inhibited tumor growth in vivo.ConclusionsPreclinical in vitro and in vivo studies identified ADI-PEG20 as a potential therapy for patients with rare ovarian cancers, including SCCOHT.
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- 2020
17. 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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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Ovarian Cancer ,Biotechnology ,Cancer ,Orphan Drug ,Rare Diseases ,Good Health and Well Being ,Aged ,Cystadenoma ,Serous ,Female ,Humans ,Middle Aged ,Neoplasm Grading ,Organ Culture Techniques ,Organoids ,Ovarian Neoplasms ,Ovarian cancer ,Patient-derived organoid models ,Multicellular spheroids ,Targeted experimental therapeutics ,Paediatrics and Reproductive Medicine ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis ,Reproductive medicine - Abstract
ObjectiveCancer 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.MethodsIn 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.ResultsOur 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.ConclusionsShort 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.
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- 2020
18. Cross-cancer genome-wide association study of endometrial cancer and epithelial ovarian cancer identifies genetic risk regions associated with risk of both cancers
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Glubb, Dylan M, Thompson, Deborah J, Aben, Katja KH, Alsulimani, Ahmad, Amant, Frederic, Annibali, Daniela, Attia, John, Barricarte, Aurelio, Beckmann, Matthias W, Berchuck, Andrew, Bermisheva, Marina, Bernardini, Marcus Q, Bischof, Katharina, Bjorge, Line, Bodelon, Clara, Brand, Alison H, Brenton, James D, Brinton, Louise, Bruinsma, Fiona, Buchanan, Daniel D, Burghaus, Stefanie, Butzow, Ralf, Cai, Hui, Carney, Michael E, Chanock, Stephen J, Chen, Chu, Chen, Xiao Qing, Chen, Zhihua, Cook, Linda S, Cunningham, Julie M, De Vivo, Immaculata, deFazio, Anna, Doherty, Jennifer A, Dörk, Thilo, du Bois, Andreas, Dunning, Alison M, Dürst, Matthias, Edwards, Todd, Edwards, Robert P, Ekici, Arif B, Ewing, Ailith, Fasching, Peter A, Ferguson, Sarah, Flanagan, James M, Fostira, Florentia, Fountzilas, George, Friedenreich, Christine M, Gao, Bo, Gaudet, Mia M, Gawełko, Jan, Gentry-Maharaj, Aleksandra, Giles, Graham G, Glasspool, Rosalind, Goodman, Marc T, Gronwald, Jacek, Group, OPAL Study, Group, AOCS, Harris, Holly R, Harter, Philipp, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Høgdall, Estrid, Høgdall, Claus K, Holliday, Elizabeth G, Huntsman, David G, Huzarski, Tomasz, Jakubowska, Anna, Jensen, Allan, Jones, Michael E, Karlan, Beth Y, Karnezis, Anthony, Kelley, Joseph L, Khusnutdinova, Elza, Killeen, Jeffrey L, Kjaer, Susanne K, Klapdor, Rüdiger, Köbel, Martin, Konopka, Bozena, Konstantopoulou, Irene, Kopperud, Reidun K, Koti, Madhuri, Kraft, Peter, Kupryjanczyk, Jolanta, Lambrechts, Diether, Larson, Melissa C, Le Marchand, Loic, Lele, Shashikant B, Lester, Jenny, Li, Andrew J, Liang, Dong, Liebrich, Clemens, Lipworth, Loren, Lissowska, Jolanta, Lu, Lingeng, Lu, Karen H, Macciotta, Alessandra, Mattiello, Amalia, and May, Taymaa
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Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Epidemiology ,Health Sciences ,Statistics ,Mathematical Sciences ,Oncology and Carcinogenesis ,Aging ,Rare Diseases ,Human Genome ,Cancer ,Uterine Cancer ,Ovarian Cancer ,Prevention ,Biotechnology ,Aetiology ,2.1 Biological and endogenous factors - Abstract
Abstract: Accumulating evidence suggests a relationship between endometrial cancer and epithelial ovarian cancer. For example, endometrial cancer and epithelial ovarian cancer share epidemiological risk factors and molecular features observed across histotypes are held in common (e.g. serous, endometrioid and clear cell). Independent genome-wide association studies (GWAS) for endometrial cancer and epithelial ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. Using GWAS summary statistics, we explored the shared genetic etiology between endometrial cancer and epithelial ovarian cancer. Genetic correlation analysis using LD Score regression revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10−5). To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e. inverse-variance meta-analysis, co-localization, and M-values), and performed analyses by stratified by subtype. We found seven loci associated with risk for both cancers (PBonferroni < 2.4 × 10−9). In addition, four novel regions at 7p22.2, 7q22.1, 9p12 and 11q13.3 were identified at a sub-genome wide threshold (P < 5 × 10−7). Integration with promoter-associated HiChIP chromatin loops from immortalized endometrium and epithelial ovarian cell lines, and expression quantitative trait loci (eQTL) data highlighted candidate target genes for further investigation.
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- 2020
19. Tubo-Ovarian Transitional Cell Carcinoma and High-grade Serous Carcinoma Show Subtly Different Immunohistochemistry Profiles
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Magrill, Jamie, Karnezis, Anthony N, Tessier-Cloutier, Basile, Talhouk, Aline, Kommoss, Stefan, Cochrane, Dawn, Chow, Christine, Cheng, Angela, Soslow, Robert, Hauptmann, Steffen, du Bois, Andreas, Pfisterer, Jacobus, Gilks, C Blake, Huntsman, David G, and Kommoss, Friedrich
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Biomedical and Clinical Sciences ,Clinical Sciences ,Rare Diseases ,Genetics ,Cancer ,Biomarkers ,Tumor ,Carcinoma ,Transitional Cell ,Cohort Studies ,Female ,Humans ,Immunohistochemistry ,Neoplasm Proteins ,Ovarian Neoplasms ,Proteomics ,Tissue Array Analysis ,Ovarian cancer ,Transitional cell carcinoma ,High-grade serous carcinoma ,Biomarkers ,Paediatrics and Reproductive Medicine ,Pathology ,Reproductive medicine - Abstract
Tubo-ovarian transitional cell carcinoma (TCC) is grouped with high-grade serous carcinoma (HGSC) in the current World Health Organization classification. TCC is associated with BRCA mutations and a better prognosis compared with HGSC. Previous papers examining the immunohistochemical features of TCC have studied limited numbers of samples. No marker reflecting the biological difference between TCC and HGSC is known. We collected a large cohort of TCC to determine whether TCC and HGSC could be distinguished by immunohistochemistry. A tissue microarray was built from 89 TCC and a control cohort of 232 conventional HGSC. Immunohistochemistry was performed, scored, and statistically analyzed for routine markers of HGSC and urothelial tumors: PAX8, WT1, p53, p16, ER, p63, and GATA3. Using scoring cutoffs commonly employed in clinical practice, the immunohistochemical profile of TCC was indistinguishable from HGSC for all markers. However, more detailed scoring criteria revealed statistically significant differences between the 2 groups of tumors with respect to ER, PAX8, and WT1. HGSC showed more diffuse and intense staining for PAX8 (P=0.004 and 0.001, respectively) and WT1 (P=0.002 and 0.002, respectively); conversely, TCC showed more intense staining for ER (P=0.007). TCC and HGSC therefore show subtle differences in their immunohistochemical profiles which might reflect underlying (epi)genetic differences. Further studies using proteomic analysis will focus on the identification of differentially expressed proteins that might serve as markers of TCC-like differentiation, which could help explain biologic differences between TCC and HGSC and might identify other cases of HGSC with a better prognosis.
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- 2019
20. 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, T, 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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21. Characterizing FOLR1 expression in low-grade serous ovarian carcinoma.
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Rushton, Tullia, primary, Krause, Harris Benjamin, additional, Elliott, Andrew, additional, Karnezis, Anthony, additional, Toboni, Michael Driscoll, additional, Thaker, Premal H., additional, Braxton, David R., additional, Oberley, Matthew James, additional, Gershenson, David Marc, additional, and Armstrong, Deborah Kay, additional
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- 2024
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22. Molecular and immune characterization of squamous cell ovarian cancers for identification of therapeutic targets.
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Hollingsworth, Jessie, primary, Wu, Sharon, additional, Adkoli, Anusha, additional, Farrell, Alex Patrick, additional, Hodges, Kurt, additional, Oberley, Matthew James, additional, Karnezis, Anthony, additional, Thaker, Premal H., additional, and Girda, Eugenia, additional
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- 2024
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23. Histone deacetylase inhibitors synergizes with catalytic inhibitors of EZH2 to exhibit anti-tumor activity in small cell carcinoma of the ovary, hypercalcemic type
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Wang, Yemin, Chen, Shary Yuting, Colborne, Shane, Lambert, Galen, Shin, Chae Young, Santos, Nancy Dos, Orlando, Krystal A, Lang, Jessica D, Hendricks, William PD, Bally, Marcel B, Karnezis, Anthony N, Hass, Ralf, Underhill, T Michael, Morin, Gregg B, Trent, Jeffrey M, Weissman, Bernard E, and Huntsman, David G
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Biological Sciences ,Stem Cell Research ,Genetics ,Cancer ,Rare Diseases ,Orphan Drug ,Ovarian Cancer ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Animals ,Antineoplastic Agents ,Apoptosis ,Biocatalysis ,Carcinoma ,Small Cell ,Cell Cycle Checkpoints ,Cell Differentiation ,Cell Line ,Tumor ,Cell Lineage ,DNA Helicases ,Drug Synergism ,Enhancer of Zeste Homolog 2 Protein ,Epigenesis ,Genetic ,Female ,Gene Expression Regulation ,Neoplastic ,Histone Deacetylase Inhibitors ,Humans ,Hydroxamic Acids ,Hypercalcemia ,Mice ,Nuclear Proteins ,Ovarian Neoplasms ,Proteome ,Transcription Factors ,Xenograft Model Antitumor Assays ,Pharmacology and Pharmaceutical Sciences ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but extremely lethal malignancy that mainly impacts young women. SCCOHT is characterized by a diploid genome with loss of SMARCA4 and lack of SMARCA2 expression, two mutually exclusive ATPases of the SWI/SNF chromatin-remodeling complex. We and others have identified the histone methyltransferase EZH2 as a promising therapeutic target for SCCOHT, suggesting that SCCOHT cells depend on the alternation of epigenetic pathways for survival. In this study, we found that SCCOHT cells were more sensitive to pan-HDAC inhibitors compared with other ovarian cancer lines or immortalized cell lines tested. Pan-HDAC inhibitors, such as quisinostat, reversed the expression of a group of proteins that were deregulated in SCCOHT cells due to SMARCA4 loss, leading to growth arrest, apoptosis, and differentiation in vitro and suppressed tumor growth of xenografted tumors of SCCOHT cells. Moreover, combined treatment of HDAC inhibitors and EZH2 inhibitors at sublethal doses synergistically induced histone H3K27 acetylation and target gene expression, leading to rapid induction of apoptosis and growth suppression of SCCOHT cells and xenografted tumors. Therefore, our preclinical study highlighted the therapeutic potential of combined treatment of HDAC inhibitors with EZH2 catalytic inhibitors to treat SCCOHT.
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- 2018
24. Polygenic risk modeling for prediction of epithelial ovarian cancer risk
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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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25. EWSR1-WT1 gene fusions in neoplasms other than desmoplastic small round cell tumor: a report of three unusual tumors involving the female genital tract and review of the literature
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Schoolmeester, J. Kenneth, Folpe, Andrew L., Nair, Asha A., Halling, Kevin, Sutton, Bobbie Collett, Landers, Emily, Karnezis, Anthony N., Dickson, Brendan C., Nucci, Marisa R., and Kolin, David L.
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- 2021
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26. 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
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Cancer ,2.1 Biological and endogenous factors ,Aetiology ,Aged ,Aged ,80 and over ,Cohort Studies ,Endometrial Neoplasms ,Female ,Gene Expression Regulation ,Neoplastic ,Humans ,Middle Aged ,Neoplasm Staging ,Neural Cell Adhesion Molecule L1 ,Prognosis ,Survival Analysis ,Tumor Suppressor Protein p53 ,Up-Regulation ,Oncology and Carcinogenesis ,Public Health and Health Services ,Oncology & Carcinogenesis - Abstract
BackgroundThe 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.MethodsProMisE (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.ResultsExpression 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
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- 2018
27. Ponatinib Shows Potent Antitumor Activity in Small Cell Carcinoma of the Ovary Hypercalcemic Type (SCCOHT) through Multikinase Inhibition
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Lang, Jessica D, Hendricks, William PD, Orlando, Krystal A, Yin, Hongwei, Kiefer, Jeffrey, Ramos, Pilar, Sharma, Ritin, Pirrotte, Patrick, Raupach, Elizabeth A, Sereduk, Chris, Tang, Nanyun, Liang, Winnie S, Washington, Megan, Facista, Salvatore J, Zismann, Victoria L, Cousins, Emily M, Major, Michael B, Wang, Yemin, Karnezis, Anthony N, Sekulic, Aleksandar, Hass, Ralf, Vanderhyden, Barbara C, Nair, Praveen, Weissman, Bernard E, Huntsman, David G, and Trent, Jeffrey M
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Ovarian Cancer ,Orphan Drug ,Cancer ,Rare Diseases ,Biotechnology ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Good Health and Well Being ,Animals ,Antineoplastic Agents ,Carcinoma ,Small Cell ,Cell Line ,Tumor ,Computational Biology ,Disease Models ,Animal ,Female ,Humans ,Imidazoles ,Mice ,Ovarian Neoplasms ,Protein Interaction Mapping ,Protein Interaction Maps ,Protein Kinase Inhibitors ,Pyridazines ,RNA ,Small Interfering ,Receptor Protein-Tyrosine Kinases ,Xenograft Model Antitumor Assays ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Purpose: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive ovarian cancer in young women that is universally driven by loss of the SWI/SNF ATPase subunits SMARCA4 and SMARCA2. A great need exists for effective targeted therapies for SCCOHT.Experimental Design: To identify underlying therapeutic vulnerabilities in SCCOHT, we conducted high-throughput siRNA and drug screens. Complementary proteomics approaches profiled kinases inhibited by ponatinib. Ponatinib was tested for efficacy in two patient-derived xenograft (PDX) models and one cell-line xenograft model of SCCOHT.Results: The receptor tyrosine kinase (RTK) family was enriched in siRNA screen hits, with FGFRs and PDGFRs being overlapping hits between drug and siRNA screens. Of multiple potent drug classes in SCCOHT cell lines, RTK inhibitors were only one of two classes with selectivity in SCCOHT relative to three SWI/SNF wild-type ovarian cancer cell lines. We further identified ponatinib as the most effective clinically approved RTK inhibitor. Reexpression of SMARCA4 was shown to confer a 1.7-fold increase in resistance to ponatinib. Subsequent proteomic assessment of ponatinib target modulation in SCCOHT cell models confirmed inhibition of nine known ponatinib target kinases alongside 77 noncanonical ponatinib targets in SCCOHT. Finally, ponatinib delayed tumor doubling time 4-fold in SCCOHT-1 xenografts while reducing final tumor volumes in SCCOHT PDX models by 58.6% and 42.5%.Conclusions: Ponatinib is an effective agent for SMARCA4-mutant SCCOHT in both in vitro and in vivo preclinical models through its inhibition of multiple kinases. Clinical investigation of this FDA-approved oncology drug in SCCOHT is warranted. Clin Cancer Res; 24(8); 1932-43. ©2018 AACR.
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- 2018
28. Preclinical Models of Ovarian Cancer
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Karnezis, Anthony N and Cho, Kathleen R
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Ovarian Cancer ,Prevention ,Rare Diseases ,Animals ,Carcinoma ,Chemoprevention ,Chickens ,Disease Models ,Animal ,Female ,Humans ,Mice ,Ovarian Neoplasms ,Ovariectomy ,Prophylactic Surgical Procedures ,Salpingectomy ,ovarian cancer ,ovary ,fallopian tube ,mouse model ,laying hen ,prevention ,Paediatrics and Reproductive Medicine ,Obstetrics & Reproductive Medicine ,Reproductive medicine - 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.
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- 2017
29. Detection and genomic characterization of a mammary-like adenocarcinoma
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Grewal, Jasleen K, Eirew, Peter, Jones, Martin, Chiu, Kenrry, Tessier-Cloutier, Basile, Karnezis, Anthony N, Karsan, Aly, Mungall, Andy, Zhou, Chen, Yip, Stephen, Tinker, Anna V, Laskin, Janessa, Marra, Marco, and Jones, Steven JM
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Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Oncology and Carcinogenesis ,Biotechnology ,Cancer ,Human Genome ,Breast Cancer ,Prevention ,Rare Diseases ,Good Health and Well Being ,Adenocarcinoma ,Breast ,Breast Neoplasms ,Diagnosis ,Differential ,Female ,Gene Expression Profiling ,Genomics ,Humans ,Immunohistochemistry ,Middle Aged ,Receptor ,ErbB-2 ,Transcriptome ,Vulva ,Vulvar Neoplasms ,Whole Genome Sequencing ,Receptor ,erbB-2 ,neoplasm of the breast ,neoplasm of the genitourinary tract ,Pharmacology and pharmaceutical sciences - Abstract
Whole-genome and transcriptome sequencing were performed to identify potential therapeutic strategies in the absence of viable treatment options for a patient initially diagnosed with vulvar adenocarcinoma. Genomic events were prioritized by comparison against variant distributions in the TCGA pan-cancer data set and complemented with detailed transcriptome sequencing and copy-number analysis. These findings were considered against published scientific literature in order to evaluate the functional effects of potentially relevant genomic events. Analysis of the transcriptome against a background of 27 TCGA cancer types led to reclassification of the tumor as a primary HER2+ mammary-like adenocarcinoma of the vulva. This revised diagnosis was subsequently confirmed by follow-up immunohistochemistry for a mammary-like adenocarcinoma. The patient was treated with chemotherapy and targeted therapies for HER2+ breast cancer. The detailed pathology and genomic findings of this case are presented herein.
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- 2017
30. 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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Genetics ,Cancer ,endometrial cancer ,prognosis ,biomarker ,TCGA ,ProMisE ,L1CAM ,progesterone receptor ,estrogen receptor - Abstract
Molecular subclassification of endometrial carcinoma (EC) with Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) identifies four subtypes [DNA polymerase epsilon (POLE) mutant, mismatch repair-deficient, p53 wild-type (wt), and p53 abnormal]. The aim of this study was to evaluate additional EC biomarkers in the context of these subtypes. Tissue microarrays encompassing 460 previously characterized ECs were assessed for L1-cell adhesion molecule (L1CAM), progesterone receptor (PR), estrogen receptor (ER) alpha, stathmin, and phosphatase and tensin homolog (PTEN), by immunohistochemistry (IHC). Associations with clinicopathological parameters, molecular subtype, and outcomes were determined. About 413 ECs (75% endometrioid, >15% serous) had complete data. L1CAM overexpression was found in 16%, associated with older age, lower body mass index (BMI), advanced stage, grade 3 (97%), non-endometrioid histology (84%), deep myometrial invasion, lymphovascular space invasion (LVSI), and ER-negative, PR-negative status. Tumours overexpressing L1CAM were associated with poor outcomes {hazard ratio (HR) [95% confidence interval (CI)] 3.35 [2.10-5.23] for disease-specific survival [DSS], p
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- 2017
31. Characterization of natural killer and cytotoxic T‐cell immune infiltrates in pancreatic ductal adenocarcinoma
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Persky, Julia, primary, Cruz, Sylvia M., additional, Darrow, Morgan A., additional, Judge, Sean J., additional, Li, Yueju, additional, Bold, Richard J., additional, Karnezis, Anthony N., additional, Matsukuma, Karen E., additional, Qi, Lihong, additional, and Canter, Robert J., additional
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- 2024
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32. 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, Dos Santos, Nancy, 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
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Ovarian Cancer ,Orphan Drug ,Biotechnology ,Rare Diseases ,Stem Cell Research ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,Apoptosis ,Carcinoma ,Ovarian Epithelial ,Carcinoma ,Small Cell ,Cell Cycle Checkpoints ,Cell Line ,Tumor ,Cell Transformation ,Neoplastic ,DNA Helicases ,Down-Regulation ,Enhancer of Zeste Homolog 2 Protein ,Female ,Histone Methyltransferases ,Histone-Lysine N-Methyltransferase ,Humans ,Hypercalcemia ,Neoplasm Transplantation ,Neoplasms ,Glandular and Epithelial ,Nuclear Proteins ,Ovarian Neoplasms ,Transcription Factors ,Transplantation ,Heterologous ,Tumor Cells ,Cultured ,Up-Regulation ,SCCOHT ,SWI/SNF ,chromatin remodelling complex ,differentiation ,EZH2 ,SMARCA4 ,ovarian cancer ,Clinical Sciences ,Pathology ,Clinical sciences ,Oncology and carcinogenesis - 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.
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- 2017
33. 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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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Rare Diseases ,Genetics ,Cancer ,Ovarian Cancer ,Aetiology ,2.1 Biological and endogenous factors ,Adenomatous Polyposis Coli Protein ,Animals ,Animals ,Genetically Modified ,Carcinoma ,Endometrioid ,Carcinoma ,Ovarian Epithelial ,Cell Differentiation ,Disease Models ,Animal ,Epithelial Cells ,Epithelium ,Fallopian Tubes ,Female ,Glycoproteins ,Humans ,Integrases ,Male ,Mice ,Neoplasms ,Glandular and Epithelial ,Ovarian Neoplasms ,Ovary ,PTEN Phosphohydrolase ,Phenotype ,Promoter Regions ,Genetic ,Tamoxifen ,mouse ovarian cancer model ,cell of origin ,Fallopian tube ,oviduct ,endometrioid carcinoma ,Clinical Sciences ,Pathology ,Clinical sciences ,Oncology and carcinogenesis - Abstract
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-iCreERT2 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.
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- 2016
34. 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 JR, Köbel, Martin, and Lee, Cheng‐Han
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Adult ,Aged ,Aged ,80 and over ,Biomarkers ,Tumor ,Carcinoma ,Endometrioid ,Cell Dedifferentiation ,DNA Helicases ,Endometrial Neoplasms ,Female ,Humans ,Immunohistochemistry ,Immunophenotyping ,Middle Aged ,Nuclear Proteins ,PAX8 Transcription Factor ,Receptors ,Estrogen ,SMARCB1 Protein ,Transcription Factors ,Tumor Suppressor Protein p53 ,BRG1 ,dedifferentiated carcinoma ,endometrial cancer ,INI1 ,PAX8 ,SMARCA4 ,SMARCB1 ,undifferentiated carcinoma ,Clinical Sciences ,Pathology ,Clinical sciences ,Oncology and carcinogenesis - Abstract
AimsDedifferentiated 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 resultsWe 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.ConclusionsThe 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.
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- 2016
35. The influence of clinical and genetic factors on patient outcome in small cell carcinoma of the ovary, hypercalcemic type
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Witkowski, Leora, Goudie, Catherine, Ramos, Pilar, Boshari, Talia, Brunet, Jean-Sebastien, Karnezis, Anthony N, Longy, Michel, Knost, James A, Saloustros, Emmanouil, McCluggage, W Glenn, Stewart, Colin JR, Hendricks, William PD, Cunliffe, Heather, Huntsman, David G, Pautier, Patricia, Levine, Douglas A, Trent, Jeffrey M, Berchuck, Andrew, Hasselblatt, Martin, and Foulkes, William D
- Subjects
Cancer ,Stem Cell Research ,Clinical Research ,Adolescent ,Adult ,Age Factors ,Carcinoma ,Small Cell ,Child ,Cohort Studies ,DNA Helicases ,Female ,Germ-Line Mutation ,Humans ,Hypercalcemia ,Kaplan-Meier Estimate ,Neoplasm Staging ,Nuclear Proteins ,Ovarian Neoplasms ,Prognosis ,Transcription Factors ,Young Adult ,Ovarian cancer ,Chemotherapy ,Stem cell rescue ,SCCOHT ,SMARCA4 ,Mutation ,Oncology and Carcinogenesis ,Paediatrics and Reproductive Medicine ,Oncology & Carcinogenesis - Abstract
ObjectiveSmall cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an aggressive tumor, with long term survival at ~30% in early stage disease. SCCOHT is caused by germline and somatic SMARCA4 mutations, but the effect of the mutation type on patients remains unknown. Furthermore, the rarity of SCCOHT has resulted in varied treatment, with no standardized protocols. We analyzed 293 cases to determine the effect of treatment modalities and SMARCA4 mutations on patient diagnosis and outcome.MethodsIn 293 SCCOHT patients we collected information on age and stage at diagnosis, treatment modality (surgery, chemotherapy, radiotherapy, and/or high-dose chemotherapy with autologous stem cell rescue (HDC-aSCR)), SMARCA4 mutation origin (germline/somatic), and overall survival. Cox analysis and log-rank tests were performed on 257 cases with available survival data.ResultsThe strongest prognostic factors were stage at diagnosis (p=2.72e-15) and treatment modality (p=3.87e-13). For FIGO stages II-IV, 5-year survival was 71% for patients who received HDC-aSCR, compared to 25% in patients who received conventional chemotherapy alone following surgery (p=0.002). Patients aged ≥40 had a worse outcome than younger patients (p=0.04). Twenty-six of 60 tested patients carried a germline SMARCA4 mutation, including all patients diagnosed
- Published
- 2016
36. Loss of switch/sucrose non-fermenting complex protein expression is associated with dedifferentiation in endometrial carcinomas
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Karnezis, Anthony N, Hoang, Lien N, Coatham, Mackenzie, Ravn, Sarah, Almadani, Noorah, Tessier-Cloutier, Basile, Irving, Julie, Meng, Bo, Li, Xiaodong, Chow, Christine, McAlpine, Jessica, Kuo, Kuan-Ting, Mao, Tsui-Lien, Djordjevic, Bojana, Soslow, Robert A, Huntsman, David G, Gilks, C Blake, Köbel, Martin, and Lee, Cheng-Han
- Subjects
Cancer ,Aged ,Cell Dedifferentiation ,Chromosomal Proteins ,Non-Histone ,DNA Mutational Analysis ,Endometrial Neoplasms ,Female ,Humans ,Immunohistochemistry ,Kaplan-Meier Estimate ,Middle Aged ,Oligonucleotide Array Sequence Analysis ,Tissue Array Analysis ,Transcription Factors ,Medical and Health Sciences ,Pathology - Abstract
Dedifferentiated endometrial carcinoma is an aggressive type of endometrial cancer that contains a mix of low-grade endometrioid and undifferentiated carcinoma components. We performed targeted sequencing of eight dedifferentiated carcinomas and identified somatic frameshift/nonsense mutations in SMARCA4, a core ATPase of the switch/sucrose non-fermenting (SWI/SNF) complex, in the undifferentiated components of four tumors. Immunohistochemical analysis confirmed the loss of SMARCA4 in the undifferentiated component of these four SMARCA4-mutated cases, whereas the corresponding low-grade endometrioid component showed retained SMARCA4 expression. An expanded survey of other members of the SWI/SNF complex showed SMARCB1 loss in the undifferentiated component of two SMARCA4-intact tumors, and all SMARCA4- or SMARCB1-deficient tumors showed concomitant loss of expression of SMARCA2. We subsequently examined the expression of SMARCA2, SMARCA4, and SMARCB1 in an additional set of 22 centrally reviewed dedifferentiated carcinomas and 31 grade 3 endometrioid carcinomas. Combining the results from the index and the expansion set, 15 of 30 (50%) of the dedifferentiated carcinomas examined showed either concurrent SMARCA4 and SMARCA2 loss (37%) or concurrent SMARCB1 and SMARCA2 loss (13%) in the undifferentiated component. The loss of SMARCA4 or SMARCB1 was mutually exclusive. All 31 grade 3 endometrioid carcinomas showed intact expression of these core SWI/SNF proteins. The majority (73%) of the SMARCA4/SMARCA2-deficient and half of SMARCB1/SMARCA2-deficient undifferentiated component developed in a mismatch repair-deficient molecular context. The observed spatial association between SWI/SNF protein loss and histologic dedifferentiation suggests that inactivation of these core SWI/SNF proteins may contribute to the development of dedifferentiated endometrial carcinoma.
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- 2016
37. 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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Human Genome ,Genetics ,Biotechnology ,Rare Diseases ,Cancer ,Ovarian Cancer ,2.1 Biological and endogenous factors ,Aetiology ,Adenocarcinoma ,Clear Cell ,Carcinoma ,Endometrioid ,Cystadenocarcinoma ,Serous ,Female ,Formaldehyde ,Gene Expression Profiling ,Humans ,Mass Spectrometry ,Neoplasm Proteins ,Ovarian Neoplasms ,Peptide Mapping ,Proteogenomics ,Proteomics ,Tissue Fixation ,Translational Research ,Biomedical - Abstract
Although re-sequencing of gene panels and mRNA expression profiling are now firmly established in clinical laboratories, in-depth proteome analysis has remained a niche technology, better suited for studying model systems rather than challenging materials such as clinical trial samples. To address this limitation, we have developed a novel and optimized platform called SP3-Clinical Tissue Proteomics (SP3-CTP) for in-depth proteome profiling of practical quantities of tumour tissues, including formalin fixed and paraffin embedded (FFPE). Using single 10 μm scrolls of clinical tumour blocks, we performed in-depth quantitative analyses of individual sections from ovarian tumours covering the high-grade serous, clear cell, and endometrioid histotypes. This examination enabled the generation of a novel high-resolution proteome map of ovarian cancer histotypes from clinical tissues. Comparison of the obtained proteome data with large-scale genome and transcriptome analyses validated the observed proteome biology for previously validated hallmarks of this disease, and also identified novel protein features. A tissue microarray analysis validated cystathionine gamma-lyase (CTH) as a novel clear cell carcinoma feature with potential clinical relevance. In addition to providing a milestone in the understanding of ovarian cancer biology, these results show that in-depth proteomic analysis of clinically annotated FFPE materials can be effectively used as a biomarker discovery tool and perhaps ultimately as a diagnostic approach.
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- 2016
38. Correction: Polygenic risk modeling for prediction of epithelial ovarian cancer risk
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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
- Full Text
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39. 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, Kommoss, Stefan, Winterhoff, Boris J, Kipp, Benjamin R, Garcia, Joaquin J, Voss, Jesse, Halling, Kevin, Karnezis, Anthony, Senz, Janine, Yang, Winnie, Prigge, Elena-Sophie, Reuschenbach, Miriam, Doeberitz, Magnus Von Knebel, Gilks, Blake C, Huntsman, David G, Bakkum-Gamez, Jamie, McAlpine, Jessica N, and Anglesio, Michael S
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Cancer ,Genetics ,Biotechnology ,Rare Diseases ,Ovarian Cancer ,Adenocarcinoma ,Mucinous ,Carcinoma ,Ovarian Epithelial ,Female ,High-Throughput Nucleotide Sequencing ,Humans ,Immunohistochemistry ,Mutation ,Mutation Rate ,Neoplasm Staging ,Neoplasms ,Glandular and Epithelial ,Ovarian Neoplasms ,Signal Transduction ,Tumor Suppressor Protein p53 ,ras Proteins ,Oncology and Carcinogenesis ,Public Health and Health Services ,Oncology & Carcinogenesis - Abstract
BackgroundMucinous ovarian tumors represent a distinct histotype of epithelial ovarian cancer. The rarest (2-4 % of ovarian carcinomas) of the five major histotypes, their genomic landscape remains poorly described. We undertook hotspot sequencing of 50 genes commonly mutated in human cancer across 69 mucinous ovarian tumors. Our goals were to establish the overall frequency of cancer-hotspot mutations across a large cohort, especially those tumors previously thought to be "RAS-pathway alteration negative", using highly-sensitive next-generation sequencing as well as further explore a small number of cases with apparent heterogeneity in RAS-pathway activating alterations.MethodsUsing the Ion Torrent PGM platform, we performed next generation sequencing analysis using the v2 Cancer Hotspot Panel. Regions of disparate ERBB2-amplification status were sequenced independently for two mucinous carcinoma (MC) cases, previously established as showing ERBB2 amplification/overexpression heterogeneity, to assess the hypothesis of subclonal populations containing either KRAS mutation or ERBB2 amplification independently or simultaneously.ResultsWe detected mutations in KRAS, TP53, CDKN2A, PIK3CA, PTEN, BRAF, FGFR2, STK11, CTNNB1, SRC, SMAD4, GNA11 and ERBB2. KRAS mutations remain the most frequently observed alteration among MC (64.9 %) and mucinous borderline tumors (MBOT) (92.3 %). TP53 mutation occurred more frequently in carcinomas than borderline tumors (56.8 % and 11.5 %, respectively), and combined IHC and mutation data suggest alterations occur in approximately 68 % of MC and as many as 20 % of MBOT. Proven and potential RAS-pathway activating changes were observed in all but one MC. Concurrent ERBB2 amplification and KRAS mutation were observed in a substantial number of cases (7/63 total), as was co-occurrence of KRAS and BRAF mutations (one case). Microdissection of ERBB2-amplified regions of tumors harboring KRAS mutation suggests these alterations are occurring in the same cell populations, while consistency of KRAS allelic frequency in both ERBB2 amplified and non-amplified regions suggests this mutation occurred in advance of the amplification event.ConclusionsOverall, the prevalence of RAS-alteration and striking co-occurrence of pathway "double-hits" supports a critical role for tumor progression in this ovarian malignancy. Given the spectrum of RAS-activating mutations, it is clear that targeting this pathway may be a viable therapeutic option for patients with recurrent or advanced stage mucinous ovarian carcinoma, however caution should be exercised in selecting one or more personalized therapeutics given the frequency of non-redundant RAS-activating alterations.
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- 2015
40. Comprehensive genomic profiles of small cell lung cancer
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George, Julie, Lim, Jing Shan, Jang, Se Jin, Cun, Yupeng, Ozretić, Luka, Kong, Gu, Leenders, Frauke, Lu, Xin, Fernández-Cuesta, Lynnette, Bosco, Graziella, Müller, Christian, Dahmen, Ilona, Jahchan, Nadine S, Park, Kwon-Sik, Yang, Dian, Karnezis, Anthony N, Vaka, Dedeepya, Torres, Angela, Wang, Maia Segura, Korbel, Jan O, Menon, Roopika, Chun, Sung-Min, Kim, Deokhoon, Wilkerson, Matt, Hayes, Neil, Engelmann, David, Pützer, Brigitte, Bos, Marc, Michels, Sebastian, Vlasic, Ignacija, Seidel, Danila, Pinther, Berit, Schaub, Philipp, Becker, Christian, Altmüller, Janine, Yokota, Jun, Kohno, Takashi, Iwakawa, Reika, Tsuta, Koji, Noguchi, Masayuki, Muley, Thomas, Hoffmann, Hans, Schnabel, Philipp A, Petersen, Iver, Chen, Yuan, Soltermann, Alex, Tischler, Verena, Choi, Chang-min, Kim, Yong-Hee, Massion, Pierre P, Zou, Yong, Jovanovic, Dragana, Kontic, Milica, Wright, Gavin M, Russell, Prudence A, Solomon, Benjamin, Koch, Ina, Lindner, Michael, Muscarella, Lucia A, la Torre, Annamaria, Field, John K, Jakopovic, Marko, Knezevic, Jelena, Castaños-Vélez, Esmeralda, Roz, Luca, Pastorino, Ugo, Brustugun, Odd-Terje, Lund-Iversen, Marius, Thunnissen, Erik, Köhler, Jens, Schuler, Martin, Botling, Johan, Sandelin, Martin, Sanchez-Cespedes, Montserrat, Salvesen, Helga B, Achter, Viktor, Lang, Ulrich, Bogus, Magdalena, Schneider, Peter M, Zander, Thomas, Ansén, Sascha, Hallek, Michael, Wolf, Jürgen, Vingron, Martin, Yatabe, Yasushi, Travis, William D, Nürnberg, Peter, Reinhardt, Christian, Perner, Sven, Heukamp, Lukas, Büttner, Reinhard, Haas, Stefan A, Brambilla, Elisabeth, Peifer, Martin, Sage, Julien, and Thomas, Roman K
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Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Oncology and Carcinogenesis ,Human Genome ,Cancer ,Rare Diseases ,Lung ,Lung Cancer ,Aetiology ,2.1 Biological and endogenous factors ,Alleles ,Animals ,Cell Line ,Tumor ,Chromosome Breakpoints ,Cyclin D1 ,DNA-Binding Proteins ,Disease Models ,Animal ,Female ,Gene Expression Profiling ,Genome ,Human ,Genomics ,Humans ,Lung Neoplasms ,Male ,Mice ,Mutation ,Neurosecretory Systems ,Nuclear Proteins ,Receptors ,Notch ,Retinoblastoma Protein ,Signal Transduction ,Small Cell Lung Carcinoma ,Tumor Protein p73 ,Tumor Suppressor Protein p53 ,Tumor Suppressor Proteins ,General Science & Technology - Abstract
We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
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- 2015
41. Multifocal endometriotic lesions associated with cancer are clonal and carry a high mutation burden
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Anglesio, Michael S, Bashashati, Ali, Wang, Yi Kan, Senz, Janine, Ha, Gavin, Yang, Winnie, Aniba, Mohamed R, Prentice, Leah M, Farahani, Hossein, Li Chang, Hector, Karnezis, Anthony N, Marra, Marco A, Yong, Paul J, Hirst, Martin, Gilks, Blake, Shah, Sohrab P, and Huntsman, David G
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Rare Diseases ,Ovarian Cancer ,Human Genome ,Cancer ,Genetics ,Endometriosis ,2.1 Biological and endogenous factors ,Aetiology ,Adenocarcinoma ,Clear Cell ,Class I Phosphatidylinositol 3-Kinases ,DNA ,Neoplasm ,DNA-Binding Proteins ,Female ,Genome-Wide Association Study ,Humans ,Mutation ,Nuclear Proteins ,Ovarian Neoplasms ,Phosphatidylinositol 3-Kinases ,Precancerous Conditions ,Sequence Analysis ,DNA ,Transcription Factors ,endometriosis ,ovarian cancer ,clear cell carcinoma ,cancer precursor ,sequencing ,Clinical Sciences ,Pathology ,Clinical sciences ,Oncology and carcinogenesis - Abstract
Endometriosis is a significant risk factor for clear cell and endometrioid ovarian cancers and is often found contiguous with these cancers. Using whole-genome shotgun sequencing of seven clear cell ovarian carcinomas (CCC) and targeted sequencing in synchronous endometriosis, we have investigated how this carcinoma may evolve from endometriosis. In every case we observed multiple tumour-associated somatic mutations in at least one concurrent endometriotic lesion. ARID1A and PIK3CA mutations appeared consistently in concurrent endometriosis when present in the primary CCC. In several cases, one or more endometriotic lesions carried the near-complete complement of somatic mutations present in the index CCC tumour. Ancestral mutations were detected in both tumour-adjacent and -distant endometriotic lesions, regardless of any cytological atypia. These findings provide objective evidence that multifocal benign endometriotic lesions are clonally related and that CCCs arising in these patients progress from endometriotic lesions that may already carry sufficient cancer-associated mutations to be considered neoplasms themselves, albeit with low malignant potential. We speculate that genomically distinct classes of endometriosis exist and that ovarian endometriosis with high mutational burden represents one class at high risk for malignant transformation.
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- 2015
42. Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4
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Ramos, Pilar, Karnezis, Anthony N, Craig, David W, Sekulic, Aleksandar, Russell, Megan L, Hendricks, William PD, Corneveaux, Jason J, Barrett, Michael T, Shumansky, Karey, Yang, Yidong, Shah, Sohrab P, Prentice, Leah M, Marra, Marco A, Kiefer, Jeffrey, Zismann, Victoria L, McEachron, Troy A, Salhia, Bodour, Prat, Jaime, D'Angelo, Emanuela, Clarke, Blaise A, Pressey, Joseph G, Farley, John H, Anthony, Stephen P, Roden, Richard BS, Cunliffe, Heather E, Huntsman, David G, and Trent, Jeffrey M
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Cancer ,Rare Diseases ,Ovarian Cancer ,Genetics ,Base Sequence ,Carcinoma ,Small Cell ,Chromatin Assembly and Disassembly ,Chromosome Mapping ,Computational Biology ,DNA Helicases ,DNA ,Complementary ,Electrophoresis ,Polyacrylamide Gel ,Exome ,Female ,Gene Library ,Humans ,Immunohistochemistry ,Molecular Sequence Data ,Mutation ,Nuclear Proteins ,Ovarian Neoplasms ,Sequence Analysis ,DNA ,Transcription Factors ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
Small cell carcinoma of the ovary of hypercalcemic type (SCCOHT) is an extremely rare, aggressive cancer affecting children and young women. We identified germline and somatic inactivating mutations in the SWI/SNF chromatin-remodeling gene SMARCA4 in 75% (9/12) of SCCOHT cases in addition to SMARCA4 protein loss in 82% (14/17) of SCCOHT tumors but in only 0.4% (2/485) of other primary ovarian tumors. These data implicate SMARCA4 in SCCOHT oncogenesis.
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- 2014
43. RAS Transformation Requires CUX1-Dependent Repair of Oxidative DNA Damage
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Ramdzan, Zubaidah M, Vadnais, Charles, Pal, Ranjana, Vandal, Guillaume, Cadieux, Chantal, Leduy, Lam, Davoudi, Sayeh, Hulea, Laura, Yao, Lu, Karnezis, Anthony N, Paquet, Marilène, Dankort, David, and Nepveu, Alain
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Genetics ,Cancer ,2.1 Biological and endogenous factors ,Aetiology ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Animals ,Cell Line ,Tumor ,Cell Transformation ,Neoplastic ,Cells ,Cultured ,Cellular Senescence ,DNA Damage ,DNA Repair ,Genes ,ras ,Homeodomain Proteins ,Humans ,Mammary Neoplasms ,Experimental ,Mice ,Transgenic ,Nuclear Proteins ,Oxidative Stress ,Repressor Proteins ,Transcription Factors ,Biological Sciences ,Agricultural and Veterinary Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
The Cut homeobox 1 (CUX1) gene is a target of loss-of-heterozygosity in many cancers, yet elevated CUX1 expression is frequently observed and is associated with shorter disease-free survival. The dual role of CUX1 in cancer is illustrated by the fact that most cell lines with CUX1 LOH display amplification of the remaining allele, suggesting that decreased CUX1 expression facilitates tumor development while increased CUX1 expression is needed in tumorigenic cells. Indeed, CUX1 was found in a genome-wide RNAi screen to identify synthetic lethal interactions with oncogenic RAS. Here we show that CUX1 functions in base excision repair as an ancillary factor for the 8-oxoG-DNA glycosylase, OGG1. Single cell gel electrophoresis (comet assay) reveals that Cux1⁺/⁻ MEFs are haploinsufficient for the repair of oxidative DNA damage, whereas elevated CUX1 levels accelerate DNA repair. In vitro base excision repair assays with purified components demonstrate that CUX1 directly stimulates OGG1's enzymatic activity. Elevated reactive oxygen species (ROS) levels in cells with sustained RAS pathway activation can cause cellular senescence. We show that elevated expression of either CUX1 or OGG1 prevents RAS-induced senescence in primary cells, and that CUX1 knockdown is synthetic lethal with oncogenic RAS in human cancer cells. Elevated CUX1 expression in a transgenic mouse model enables the emergence of mammary tumors with spontaneous activating Kras mutations. We confirmed cooperation between Kras(G12V) and CUX1 in a lung tumor model. Cancer cells can overcome the antiproliferative effects of excessive DNA damage by inactivating a DNA damage response pathway such as ATM or p53 signaling. Our findings reveal an alternate mechanism to allow sustained proliferation in RAS-transformed cells through increased DNA base excision repair capability. The heightened dependency of RAS-transformed cells on base excision repair may provide a therapeutic window that could be exploited with drugs that specifically target this pathway.
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- 2014
44. TP53 as a Diagnostic Aid in the Distinction of Ovarian Mucinous Borderline Tumors From Mucinous Carcinoma.
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Kang, Eun Young, Terzic, Tatjana, Ghatage, Prafull, Woo, Lawrence, Gorringe, Kylie L., Karnezis, Anthony N., Lee, Cheng H., and Köbel, Martin
- Published
- 2024
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45. Advanced endometrial cancer—The next generation of treatment: A society of gynecologic oncology journal club clinical commentary
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Tillmanns, Todd, Masri, Amal, Stewart, Chelsea, Chase, Dana, Karnezis, Anthony, Chen, Lee-may, and Urban, Renata
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- 2024
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46. Landscape of super-enhancers in small cell carcinoma of the ovary, hypercalcemic type and efficacy of targeting with natural product triptolide
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Lang, Jessica D., primary, Selleck, William, additional, Striker, Shawn, additional, Hipschman, Nicolle A., additional, Kofman, Rochelle, additional, Karnezis, Anthony N., additional, Kommoss, Felix K. F., additional, Kommoss, Friedrich, additional, Wendt, Jae Rim, additional, Facista, Salvatore J., additional, Hendricks, William P. D., additional, Orlando, Krystal A., additional, Pirrotte, Patrick, additional, Raupach, Elizabeth A, additional, Zismann, Victoria L., additional, Wang, Yemin, additional, Huntsman, David G., additional, Weissman, Bernard E., additional, and Trent, Jeffrey M., additional
- Published
- 2023
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47. Supplementary Figures S1-S4 from The Prognostic Effect of Immune Cell Infiltration Depends on Molecular Subtype in Endometrioid Ovarian Carcinomas
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Heinze, Karolin, primary, Cairns, Evan S., primary, Thornton, Shelby, primary, Harris, Bronwyn, primary, Milne, Katy, primary, Grube, Marcel, primary, Meyer, Charlotte, primary, Karnezis, Anthony N., primary, Fereday, Sian, primary, Garsed, Dale W., primary, Leung, Samuel C.Y., primary, Chiu, Derek S., primary, Moubarak, Malak, primary, Harter, Philipp, primary, Heitz, Florian, primary, McAlpine, Jessica N., primary, DeFazio, Anna, primary, Bowtell, David D.L., primary, Goode, Ellen L., primary, Pike, Malcolm, primary, Ramus, Susan J., primary, Pearce, C. Leigh, primary, Staebler, Annette, primary, Köbel, Martin, primary, Kommoss, Stefan, primary, Talhouk, Aline, primary, Nelson, Brad H., primary, and Anglesio, Michael S., primary
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- 2023
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48. Supplementary Tables S1-S5 from The Prognostic Effect of Immune Cell Infiltration Depends on Molecular Subtype in Endometrioid Ovarian Carcinomas
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Heinze, Karolin, primary, Cairns, Evan S., primary, Thornton, Shelby, primary, Harris, Bronwyn, primary, Milne, Katy, primary, Grube, Marcel, primary, Meyer, Charlotte, primary, Karnezis, Anthony N., primary, Fereday, Sian, primary, Garsed, Dale W., primary, Leung, Samuel C.Y., primary, Chiu, Derek S., primary, Moubarak, Malak, primary, Harter, Philipp, primary, Heitz, Florian, primary, McAlpine, Jessica N., primary, DeFazio, Anna, primary, Bowtell, David D.L., primary, Goode, Ellen L., primary, Pike, Malcolm, primary, Ramus, Susan J., primary, Pearce, C. Leigh, primary, Staebler, Annette, primary, Köbel, Martin, primary, Kommoss, Stefan, primary, Talhouk, Aline, primary, Nelson, Brad H., primary, and Anglesio, Michael S., primary
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- 2023
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49. Data from The Prognostic Effect of Immune Cell Infiltration Depends on Molecular Subtype in Endometrioid Ovarian Carcinomas
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Heinze, Karolin, primary, Cairns, Evan S., primary, Thornton, Shelby, primary, Harris, Bronwyn, primary, Milne, Katy, primary, Grube, Marcel, primary, Meyer, Charlotte, primary, Karnezis, Anthony N., primary, Fereday, Sian, primary, Garsed, Dale W., primary, Leung, Samuel C.Y., primary, Chiu, Derek S., primary, Moubarak, Malak, primary, Harter, Philipp, primary, Heitz, Florian, primary, McAlpine, Jessica N., primary, DeFazio, Anna, primary, Bowtell, David D.L., primary, Goode, Ellen L., primary, Pike, Malcolm, primary, Ramus, Susan J., primary, Pearce, C. Leigh, primary, Staebler, Annette, primary, Köbel, Martin, primary, Kommoss, Stefan, primary, Talhouk, Aline, primary, Nelson, Brad H., primary, and Anglesio, Michael S., primary
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- 2023
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50. Primary clear cell carcinoma of the vulva: A case report
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Pomerantz, Tali, primary, J. Rubin, Nicole, additional, N. Karnezis, Anthony, additional, Zhao, Xiao, additional, and Brooks, Rebecca, additional
- Published
- 2023
- Full Text
- View/download PDF
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