16 results on '"Karnezis, Anthony"'
Search Results
2. 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, and Ng, Tony
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GENOMICS ,ELECTRICITY pricing ,MACHINE learning ,CANCER of unknown primary origin - 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. [ABSTRACT FROM AUTHOR]
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- 2022
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3. 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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FALLOPIAN tubes ,RENAL cell carcinoma ,CELLULAR signal transduction ,CELL transformation ,OVARIES ,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. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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4. 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 G Z, Pang, Brendan N K, Lim, Sherlly, P S Yeong, Joe, Karnezis, Anthony, Chiu, Derek S, Leung, Samuel, Huntsman, David G, Sedukhina, Anna S, Sato, Ko, Topp, Monique D, Scott, Clare L, Choi, Hyungwon, and Patel, Naina R
- 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 < 42). Interestingly, overexpression of RAD51 modified expression of immune‐regulatory pathways in vitro, while RAD51‐High tumours showed exclusion of cytotoxic T cells in situ. Our findings highlight RAD51 expression as a determinant of platinum resistance and suggest possible roles for therapy to overcome immune exclusion in RAD51‐High EOC. The qIHC approach is generalizable to other proteins with a continuum instead of discrete/bimodal expression. Synopsis: Quantitative immunohistochemistry (qIHC) reveals that high expression of the DNA repair protein RAD51 in epithelial ovarian cancer is associated with early relapse after platinum chemotherapy, and also with decreased cytotoxic T‐cell infiltration into tumors. High nuclear expression score for RAD51 (RAD51NES) was correlated with early relapse and shorter survival in two independent EOC patient cohorts (n = 264 + 284).RAD51NES was prognostically relevant primarily for EOCs that did not have homologous recombination deficiency (HRD).RAD51 expression was correlated with a unique immune phenotype in cancer, with increased chemokines but reduced cytotoxic T‐cell infiltration. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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5. Practical roles for molecular diagnostic testing in ovarian adult granulosa cell tumour, Sertoli–Leydig cell tumour, microcystic stromal tumour and their mimics.
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Rabban, Joseph T, Karnezis, Anthony N, and Devine, W Patrick
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GRANULOSA cells , *ADENOMATOUS polyposis coli , *TUMORS , *DIAGNOSIS methods , *OVARIAN follicle ,CANCER susceptibility - Abstract
Within the last decade, molecular advances have provided insights into the genetics of several ovarian sex cord–stromal tumours that have otherwise been enigmatic. Chief among these advances are the identification of FOXL2, DICER1 and CTNNB1 mutations in adult granulosa cell tumours, Sertoli–Leydig cell tumours (SLCTs), and microcystic stromal tumours (MCSTs), respectively. As access to molecular diagnostic laboratories continues to become more widely available, the potential roles for tumour mutation testing in the pathological diagnosis of these tumours merit discussion. Furthermore, links to inherited cancer susceptibility syndromes may exist for some women with SLCT (DICER1 syndrome) and MCST [familial adenomatous polyposis (FAP)]. This review will address practical issues in deciding when and how to apply mutation testing in the diagnosis of these three sex cord–stromal tumours. The pathologist's role in recommending referral for formal risk assessment for DICER1 syndrome and FAP will also be discussed. [ABSTRACT FROM AUTHOR]
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- 2020
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6. DICER1 hot‐spot mutations in ovarian gynandroblastoma.
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Wang, Yemin, Karnezis, Anthony N., Magrill, Jamie, Tessier‐Cloutier, Basile, Lum, Amy, Senz, Janine, Gilks, C. Blake, McCluggage, W. Glenn, Huntsman, David G., and Kommoss, Friedrich
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GRANULOSA cell tumors , *OVARIAN tumors , *LEYDIG cell tumors , *IMMUNOSTAINING , *GENETIC mutation - Abstract
Aims: Gynandroblastoma is a rare ovarian sex cord‐stromal tumour characterised by the presence of both male (Sertoli and/or Leydig cells) and female (granulosa cells) components. We investigated the mutational status of DICER1, FOXL2 and AKT1 genes at hot‐spot regions that are known to be the key driving events in the development of Sertoli–Leydig cell tumour (SLCT), adult granulosa cell tumour (aGCT) and juvenile granulosa cell tumour (jGCT), respectively, to gain insights into the molecular pathogenesis of gynandroblastoma. Methods and results: Sixteen cases of gynandroblastoma were studied. All contained SLCT or Sertoli cell tumour components. aGCT and jGCT components were identified in seven and 10 cases, respectively, with one presenting both components. Heterozygous hot‐spot mutations in the RNase IIIb domain of DICER1 were discovered in three cases, including one case with heterologous mucinous elements, all of which were composed of moderately or poorly differentiated SLCT and jGCT components, and harboured the mutations in both histological components. None of the 16 cases displayed mutations at the p.C134W (c.402C→G) of FOXL2 or within the pleckstrin‐homology domain of AKT1. All cases showed FOXL2 immunostaining in both male and female components. Conclusion: DICER1 hot‐spot mutation is the key‐driving event in a subset of gynandroblastomas containing components of SLCT and jGCT. Gynandroblastomas composed of SLCT and jGCT may represent morphological variants of SLCT. The molecular basis of gynandroblastoma containing a component of aGCT is different from pure aGCT. [ABSTRACT FROM AUTHOR]
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- 2018
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7. Evaluation of endometrial carcinoma prognostic immunohistochemistry markers in the context of molecular classification.
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Karnezis, Anthony N, Leung, Samuel, Magrill, Jamie, McConechy, Melissa K, Yang, Winnie, Chow, Christine, Kobel, Martin, Lee, Cheng-Han, Huntsman, David G, Talhouk, Aline, Kommoss, Friederich, Gilks, C Blake, and McAlpine, Jessica N
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- 2017
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8. Clear cell and endometrioid carcinomas: are their differences attributable to distinct cells of origin?
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Cochrane, Dawn R, Tessier‐Cloutier, Basile, Lawrence, Katherine M, Nazeran, Tayyebeh, Karnezis, Anthony N, Salamanca, Clara, Cheng, Angela S, McAlpine, Jessica N, Hoang, Lien N, Gilks, C Blake, and Huntsman, David G
- Abstract
Endometrial epithelium is the presumed tissue of origin for both eutopic and endometriosis-derived clear cell and endometrioid carcinomas. We had previously hypothesized that the morphological, biological and clinical differences between these carcinomas are due to histotype-specific mutations. Although some mutations and genomic landscape features are more likely to be found in one of these histotypes, we were not able to identify a single class of mutations that was exclusively present in one histotype and not the other. This lack of genomic differences led us to an alternative hypothesis that these cancers could arise from distinct cells of origin within endometrial tissue, and that it is the cellular context that accounts for their differences. In a proteomic screen, we identified cystathionine γ-lyase (CTH) as a marker for clear cell carcinoma, as it is expressed at high levels in clear cell carcinomas of the ovary and endometrium. In the current study, we analysed normal Müllerian tissues, and found that CTH is expressed in ciliated cells of endometrium (both eutopic endometrium and endometriosis) and fallopian tubes. We then demonstrated that other ciliated cell markers are expressed in clear cell carcinomas, whereas endometrial secretory cell markers are expressed in endometrioid carcinomas. The same differential staining of secretory and ciliated cells was demonstrable in a three-dimensional organoid culture system, in which stem cells were stimulated to differentiate into an admixture of secretory and ciliated cells. These data suggest that endometrioid carcinomas are derived from cells of the secretory cell lineage, whereas clear cell carcinomas are derived from, or have similarities to, cells of the ciliated cell lineage. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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9. Human papillomavirus ( HPV)-independent vulvar squamous cell carcinoma has a worse prognosis than HPV-associated disease: a retrospective cohort study.
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McAlpine, Jessica N, Leung, Samuel C Y, Cheng, Angela, Miller, Dianne, Talhouk, Aline, Gilks, C Blake, and Karnezis, Anthony N
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PAPILLOMAVIRUSES ,SQUAMOUS cell carcinoma ,RETROSPECTIVE studies ,ONCOGENIC DNA viruses ,COHORT analysis ,PROGNOSIS - Abstract
Aims Vulvar squamous cell carcinoma ( VSCC) can be subdivided by human papillomavirus ( HPV) status into two clinicopathological entities. Studies on the prognostic significance of HPV in VSCC are discordant. Methods and results We performed a retrospective analysis of overall survival ( OS), disease-specific survival ( DSS) and progression-free survival ( PFS) in 217 patients with VSCC. Cases were extracted from an era of more aggressive en-bloc radical dissections (1985-95) and more localized radical surgery through separate vulvar and groin excisions (1996-2005). p16 immunohistochemistry was used as a surrogate for HPV status. HPV status could be determined in 197 tumours, 118 HPV-independent and 79 HPV-associated tumours. Patients with HPV-associated tumours were younger (mean 58.8 versus 71.6 years for HPV-independent tumours, P < 0.0001) and more likely to have prior abnormal cervical cytology (41.1 versus 5.6% for HPV-independent tumours, P < 0.0001). In univariable analysis, patients with HPV-associated tumours had superior PFS [hazard ratio ( HR): 0.37, 95% confidence interval ( CI): 0.18-0.70], DSS ( HR: 0.19, 95% CI: 0.08-0.41) and OS ( HR: 0.35, 95% CI: 0.21-0.59). This was driven by worse outcomes ( PFS, DSS and OS) for patients with HPV-independent tumours compared with HPV-associated tumours who underwent surgery after 1995. After adjusting for age and stage in multivariable analysis, patients with HPV-associated tumours showed superior PFS ( HR: 0.25, 95% CI: 0.07-0.77) and DSS ( HR: 0.21, 95% CI: 0.04-0.78). Conclusions VSCC can be stratified into two prognostically different diseases based on p16 immunostaining. HPV status was associated only with prognosis in the cohort that underwent surgery after 1995, suggesting that more conservative surgery may have led to worse outcomes for patients with HPV-independent tumours. [ABSTRACT FROM AUTHOR]
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- 2017
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10. The histone methyltransferase EZH2 is a therapeutic target in small cell carcinoma of the ovary, hypercalcaemic type.
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Wang, Yemin, Chen, Shary Yuting, Karnezis, Anthony N, Colborne, Shane, Santos, Nancy Dos, Lang, Jessica D, Hendricks, William PD, Orlando, Krystal A, Yap, Damian, Kommoss, Friedrich, Bally, Marcel B, Morin, Gregg B, Trent, Jeffrey M, Weissman, Bernard E, and Huntsman, David G
- Abstract
Small cell carcinoma of the ovary, hypercalcaemic type ( SCCOHT) is a rare but aggressive and untreatable malignancy affecting young women. We and others recently discovered that SMARCA4, a gene encoding the ATPase of the SWI/ SNF chromatin-remodelling complex, is the only gene recurrently mutated in the majority of SCCOHT. The low somatic complexity of SCCOHT genomes and the prominent role of the SWI/ SNF chromatin-remodelling complex in transcriptional control of genes suggest that SCCOHT cells may rely on epigenetic rewiring for oncogenic transformation. Herein, we report that approximately 80% (19/24) of SCCOHT tumour samples have strong expression of the histone methyltransferase EZH2 by immunohistochemistry, with the rest expressing variable amounts of EZH2. Re-expression of SMARCA4 suppressed the expression of EZH2 in SCCOHT cells. In comparison to other ovarian cell lines, SCCOHT cells displayed hypersensitivity to EZH2 shRNAs and two selective EZH2 inhibitors, GSK126 and EPZ-6438. EZH2 inhibitors induced cell cycle arrest, apoptosis, and cell differentiation in SCCOHT cells, along with the induction of genes involved in cell cycle regulation, apoptosis, and neuron-like differentiation. EZH2 inhibitors suppressed tumour growth and improved the survival of mice bearing SCCOHT xenografts. Therefore, our data suggest that loss of SMARCA4 creates a dependency on the catalytic activity of EZH2 in SCCOHT cells and that pharmacological inhibition of EZH2 is a promising therapeutic strategy for treating this disease. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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11. Confirmation of ProMisE: A simple, genomics-based clinical classifier for endometrial cancer.
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Talhouk, Aline, McConechy, Melissa K., Leung, Samuel, Yang, Winnie, Lum, Amy, Senz, Janine, Boyd, Niki, Pike, Judith, Anglesio, Michael, Kwon, Janice S., Karnezis, Anthony N., Huntsman, David G., Gilks, C. Blake, and McAlpine, Jessica N.
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ENDOMETRIAL cancer ,MOLECULAR genetics ,GYNECOLOGIC cancer ,GENOMICS ,GENOMES - Abstract
Background: Classification of endometrial carcinomas (ECs) by morphologic features is irreproducible and imperfectly reflects tumor biology. The authors developed the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE), a molecular classification system based on The Cancer Genome Atlas genomic subgroups, and sought to confirm both feasibility and prognostic ability in a new, large cohort of ECs.Methods: Immunohistochemistry (IHC) for the presence or absence of mismatch repair (MMR) proteins (to identify MMR deficiency [MMR-D]), sequencing for polymerase-ɛ (POLE) exonuclease domain mutations (POLE EDMs), and IHC for tumor protein 53 (p53) (wild type vs null/missense mutations; p53 wt and p53 abn, respectively) were performed on 319 new EC samples. Subgroups were characterized and assessed relative to outcomes. The prognostic ability of ProMisE was compared with that of current risk-stratification systems (European Society of Medical Oncology [ESMO]).Results: ProMisE decision-tree classification achieved categorization of all cases and identified 4 prognostic subgroups with distinct overall, disease-specific, and progression-free survival (P < .001). Tumors with POLE EDMs had the most favorable prognosis, and those with p53 abn the worst prognosis, and separation of the 2 middle survival curves (p53 wt and MMR-D) was observed. There were no significant differences in survival between the ESMO low-risk and intermediate-risk groups. ProMisE improved the ability to discriminate outcomes compared with ESMO risk stratification. There was substantial overlap (89%) between the p53 abn and high-risk ESMO subgroups; but, otherwise, there were no predictable associations between molecular and ESMO risk groups.Conclusions: Molecular classification of ECs can be achieved using clinically applicable methods and provides independent prognostic information beyond established clinicopathologic risk factors available at diagnosis. Consistent, biologically relevant categorization enables stratification for clinical trials and/or targeted therapy, identification of women who are at increased risk of having Lynch syndrome, and may guide clinical management. Cancer 2017;123:802-13. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]- Published
- 2017
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12. 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
- 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- iCreER
T2 mice in which the Ovgp1 promoter controls expression of tamoxifen ( TAM)-regulated Cre recombinase in oviductal epithelium - the murine equivalent of human Fallopian tube epithelium. Ovgp1- iCreERT2 ;Apcfl/fl ;Ptenfl/fl mice treated with TAM or injected with adenovirus expressing Cre into the ovarian bursa uniformly develop oviductal or ovarian ECs, respectively. On the basis of their morphology and global gene expression profiles, the oviduct-derived tumours more closely resemble human ovarian ECs than do OSE-derived tumours. Furthermore, mice with oviductal tumours survive much longer than their counterparts with ovarian tumours. The slow progression and late metastasis of oviductal tumours resembles the relatively indolent behaviour characteristic of so-called Type I ovarian carcinomas in humans, for which EC is a prototype. Our studies demonstrate the utility of Ovgp1- iCreERT2 mice for manipulating genes of interest specifically in the oviductal epithelium, and establish that the cell of origin is an important consideration in mouse ovarian cancer GEMMs. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]- Published
- 2016
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13. Loss of SMARCA4 (BRG1) protein expression as determined by immunohistochemistry in small-cell carcinoma of the ovary, hypercalcaemic type distinguishes these tumours from their mimics.
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Clarke, Blaise A, Witkowski, Leora, Ton Nu, Tuyet N, Shaw, Patricia A, Gilks, C Blake, Huntsman, David, Karnezis, Anthony N, Sebire, Neil, Lamovec, Janez, Roth, Lawrence M, Stewart, Colin J R, Hasselblatt, Martin, Foulkes, William D, and McCluggage, W Glenn
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IMMUNOHISTOCHEMISTRY ,SMALL cell carcinoma ,GENE expression ,HYPERCALCEMIA ,GENETICS ,THERAPEUTICS - Abstract
Aims Molecular investigation of small-cell carcinoma of the ovary, hypercalcaemic type ( SCCOHT) has revealed that it is a monogenetic tumour characterized by alteration of SMARCA4 ( BRG1), encoding a member of the switch/sucrose non-fermentable ( SWI/ SNF) chromatin remodelling complex. A large majority of cases show loss of expression of the corresponding SMARCA4/ BRG1 protein. Furthermore, three cases of SCCOHT with retained SMARCA4 protein expression showed loss of SMARCB1/ INI1 expression. The aim of this study was to assess the sensitivity and specificity of loss of SMARCA4 expression as a diagnostic test for SCCOHT. Methods and results We performed SMARCA4 and SMARCB1 staining in 245 tumours, many of which were potentially in the differential diagnosis of SCCOHT. We also stained 56 cases of SCCOHT for SMARCA4 and 37 of these for SMARCB1. Fifty-four of the SCCOHT cases showed complete absence of SMARCA4 expression. The two cases with retained expression showed molecular alteration of SMARCA4. Of the 217 other neoplasms with interpretable staining, all retained SMARCA4 expression. Although the majority showed diffuse, strong nuclear expression, a heterogeneous, typically weak staining pattern was present in 13% of cases. All 37 cases of SCCOHT tested and all other neoplasms, apart from three malignant rhabdoid tumours, showed retained nuclear SMARCB1 expression. Loss of SMARCA4 expression had a sensitivity of 96.55% and specificity of 100%. Conclusions Loss of SMARCA4 expression is sensitive and specific for SCCOHT. Although some mimics show heterogeneous expression, there is retention of nuclear staining in at least a part of the tumour; therefore, only complete loss of staining should be regarded as being supportive of SCCOHT. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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14. Immunophenotypic features of dedifferentiated endometrial carcinoma - insights from BRG1/ INI1-deficient tumours.
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Hoang, Lien N, Lee, Yow‐Shan, Karnezis, Anthony N, Tessier‐Cloutier, Basile, Almandani, Noorah, Coatham, Mackenzie, Gilks, C Blake, Soslow, Robert A, Stewart, Colin J R, Köbel, Martin, and Lee, Cheng‐Han
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TREATMENT of endometrial cancer ,ENDOMETRIAL cancer ,IMMUNOPHENOTYPING ,ESTROGEN receptors ,GENETIC mutation ,IMMUNOSTAINING ,GENETICS - Abstract
Aims Dedifferentiated endometrial carcinoma ( DDEC) is defined by the presence of an undifferentiated carcinoma together with an endometrioid carcinoma. Inactivation of SMARCA4 ( BRG1) and inactivation of SMARCB1 ( INI1) were recently described as potential mechanisms underlying the histological dedifferentiation. The aim of this study was to characterize the immunophenotypic features of DDECs, particularly in cases with prototypical histological and molecular features ( BRG1/ INI1 deficiency). Methods and results We evaluated PAX8, oestrogen receptor ( ER) and p53 immunostaining in the endometrioid and the undifferentiated components of 20 BRG1/ INI1-deficient DDECs and 15 BRG1/ INI1-intact DDECs, and compared the results with those of 23 grade 3 endometrioid carcinomas. The differentiated endometrioid component was positive for PAX8 and/or ER in 19 of 20 BRG1/ INI1-deficient DDECs, whereas the corresponding undifferentiated component of all 20 tumours showed a complete absence of PAX8 and ER staining. All except one of the BRG1/ INI1-deficient tumours showed a wild-type p53 staining pattern. PAX8 and ER expression in the undifferentiated component was absent in 67% and 80% of BRG1/ INI1-intact DDECs, respectively, whereas 47% of the BRG1/ INI1-intact DDECs showed a mutated p53 staining pattern. In comparison, absent PAX8 expression and absent ER expression were each observed in the more solid area of 48% and 48% of grade 3 endometrioid carcinomas. Conclusions The consistent absence of PAX8 and ER expression in molecularly defined ( BRG1/ INI1-deficient) DDECs suggests that the loss of PAX8 and ER expression is a fundamental feature of dedifferentiation. The frequent findings of a mutated p53 staining pattern in BRG1/ INI1-intact DDECs indicate that BRG1/ INI1-intact DDECs may be biologically different from BRG1/ INI1-deficient tumours. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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15. Dual loss of the SWI/ SNF complex ATPases SMARCA4/ BRG1 and SMARCA2/ BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcaemic type.
- Author
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Karnezis, Anthony N, Wang, Yemin, Ramos, Pilar, Hendricks, William PD, Oliva, Esther, D'Angelo, Emanuela, Prat, Jaime, Nucci, Marisa R, Nielsen, Torsten O, Chow, Christine, Leung, Samuel, Kommoss, Friedrich, Kommoss, Stefan, Silva, Annacarolina, Ronnett, Brigitte M, Rabban, Joseph T, Bowtell, David D, Weissman, Bernard E, Trent, Jeffrey M, and Gilks, C Blake
- Abstract
Small cell carcinoma of the ovary, hypercalcaemic type ( SCCOHT) is a lethal and sometimes familial ovarian tumour of young women and children. We and others recently discovered that over 90% of SCCOHTs harbour inactivating mutations in the chromatin remodelling gene SMARCA4 with concomitant loss of its encoded protein SMARCA4 ( BRG1), one of two mutually exclusive ATPases of the SWI/ SNF chromatin remodelling complex. To determine the specificity of SMARCA4 loss for SCCOHT, we examined the expression of SMARCA4 by immunohistochemistry in more than 3000 primary gynaecological tumours. Among ovarian tumours, it was only absent in clear cell carcinoma (15 of 360, 4%). In the uterus, it was absent in endometrial stromal sarcomas (4 of 52, 8%) and high-grade endometrioid carcinomas (2 of 338, 1%). Recent studies have shown that SMARCA2 ( BRM), the other mutually exclusive ATPase of the SWI/ SNF complex, is necessary for survival of tumour cells lacking SMARCA4. Therefore, we examined SMARCA2 expression and discovered that all SMARCA4-negative SCCOHTs also lacked SMARCA2 protein by IHC, including the SCCOHT cell lines BIN67 and SCCOHT1. Among ovarian tumours, the SMARCA4/ SMARCA2 dual loss phenotype appears completely specific for SCCOHT. SMARCA2 loss was not due to mutation but rather from an absence of mRNA expression, which was restored by treatment with the histone deacetylase inhibitor trichostatin A. Re-expression of SMARCA4 or SMARCA2 inhibited the growth of BIN67 and SCCOHT1 cell lines. Our results indicate that SMARCA4 loss, either alone or with SMARCA2, is highly sensitive and specific for SCCOHT and that restoration of either SWI/ SNF ATPase can inhibit the growth of SCCOHT cell lines. © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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16. Multifocal endometriotic lesions associated with cancer are clonal and carry a high mutation burden.
- Author
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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
- 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. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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