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1. Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma

Author

Saner, Flurina AM, Takahashi, Kazuaki, Budden, Timothy, Pandey, Ahwan, Ariyaratne, Dinuka, Zwimpfer, Tibor A, Meagher, Nicola S, Fereday, Sian, Twomey, Laura, Pishas, Kathleen I, Hoang, Therese, Bolithon, Adelyn, Traficante, Nadia, Group, for the Australian Ovarian Cancer Study, Alsop, Kathryn, Christie, Elizabeth L, Kang, Eun-Young, Nelson, Gregg S, Ghatage, Prafull, Lee, Cheng-Han, Riggan, Marjorie J, Alsop, Jennifer, Beckmann, Matthias W, Boros, Jessica, Brand, Alison H, Brooks-Wilson, Angela, Carney, Michael E, Coulson, Penny, Courtney-Brooks, Madeleine, Cushing-Haugen, Kara L, Cybulski, Cezary, El-Bahrawy, Mona A, Elishaev, Esther, Erber, Ramona, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Gilks, C Blake, Harnett, Paul R, Harris, Holly R, Hartmann, Arndt, Hein, Alexander, Hendley, Joy, Hernandez, Brenda Y, Jakubowska, Anna, Jimenez-Linan, Mercedes, Jones, Michael E, Kaufmann, Scott H, Kennedy, Catherine J, Kluz, Tomasz, Koziak, Jennifer M, Kristjansdottir, Björg, Le, Nhu D, Lener, Marcin, Lester, Jenny, Lubiński, Jan, Mateoiu, Constantina, Orsulic, Sandra, Ruebner, Matthias, Schoemaker, Minouk J, Shah, Mitul, Sharma, Raghwa, Sherman, Mark E, Shvetsov, Yurii B, Soong, T Rinda, Steed, Helen, Sukumvanich, Paniti, Talhouk, Aline, Taylor, Sarah E, Vierkant, Robert A, Wang, Chen, Widschwendter, Martin, Wilkens, Lynne R, Winham, Stacey J, Anglesio, Michael S, Berchuck, Andrew, Brenton, James D, Campbell, Ian, Cook, Linda S, Doherty, Jennifer A, Fasching, Peter A, Fortner, Renée T, Goodman, Marc T, Gronwald, Jacek, Huntsman, David G, Karlan, Beth Y, Kelemen, Linda E, Menon, Usha, Modugno, Francesmary, Pharoah, Paul DP, Schildkraut, Joellen M, Sundfeldt, Karin, Swerdlow, Anthony J, Goode, Ellen L, DeFazio, Anna, Köbel, Martin, Ramus, Susan J, Bowtell, David DL, and Garsed, Dale W

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Genetics, Women's Health, Rare Diseases, Orphan Drug, Cancer Genomics, Ovarian Cancer, Precision Medicine, Human Genome, Cancer, 2.1 Biological and endogenous factors, Humans, Female, Ovarian Neoplasms, BRCA2 Protein, BRCA1 Protein, Cystadenocarcinoma, Serous, Retinoblastoma Binding Proteins, Prognosis, Ubiquitin-Protein Ligases, Neoplasm Grading, Lymphocytes, Tumor-Infiltrating, Middle Aged, Germ-Line Mutation, Gene Expression Regulation, Neoplastic, Aged, Biomarkers, Tumor, CD8-Positive T-Lymphocytes, Australian Ovarian Cancer Study Group, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

PurposeThe purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC).Experimental designRB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 patients with primary HGSC to characterize tumors with concurrent BRCA deficiency and RB1 loss.ResultsRB1 loss was associated with longer OS in HGSC but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1.ConclusionsCo-occurrence of RB1 loss and BRCA deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

Published
2024

2. The Prognostic Effect of Immune Cell Infiltration Depends on Molecular Subtype in Endometrioid Ovarian Carcinomas.

Author

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

Subjects
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.

Published
2023

3. p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study

Author

Köbel, Martin, Kang, Eun‐Young, Weir, Ashley, Rambau, Peter F, Lee, Cheng‐Han, Nelson, Gregg S, Ghatage, Prafull, Meagher, Nicola S, Riggan, Marjorie J, Alsop, Jennifer, Anglesio, Michael S, Beckmann, Matthias W, Bisinotto, Christiani, Boisen, Michelle, Boros, Jessica, Brand, Alison H, Brooks‐Wilson, Angela, Carney, Michael E, Coulson, Penny, Courtney‐Brooks, Madeleine, Cushing‐Haugen, Kara L, Cybulski, Cezary, Deen, Suha, El‐Bahrawy, Mona A, Elishaev, Esther, Erber, Ramona, Fereday, Sian, Group, AOCS, Fischer, Anna, Gayther, Simon A, Barquin‐Garcia, Arantzazu, Gentry‐Maharaj, Aleksandra, Gilks, C Blake, Gronwald, Helena, Grube, Marcel, Harnett, Paul R, Harris, Holly R, Hartkopf, Andreas D, Hartmann, Arndt, Hein, Alexander, Hendley, Joy, Hernandez, Brenda Y, Huang, Yajue, Jakubowska, Anna, Jimenez‐Linan, Mercedes, Jones, Michael E, Kennedy, Catherine J, Kluz, Tomasz, Koziak, Jennifer M, Lesnock, Jaime, Lester, Jenny, Lubiński, Jan, Longacre, Teri A, Lycke, Maria, Mateoiu, Constantina, McCauley, Bryan M, McGuire, Valerie, Ney, Britta, Olawaiye, Alexander, Orsulic, Sandra, Osorio, Ana, Paz‐Ares, Luis, Ramón y Cajal, Teresa, Rothstein, Joseph H, Ruebner, Matthias, Schoemaker, Minouk J, Shah, Mitul, Sharma, Raghwa, Sherman, Mark E, Shvetsov, Yurii B, Singh, Naveena, Steed, Helen, Storr, Sarah J, Talhouk, Aline, Traficante, Nadia, Wang, Chen, Whittemore, Alice S, Widschwendter, Martin, Wilkens, Lynne R, Winham, Stacey J, Benitez, Javier, Berchuck, Andrew, Bowtell, David D, dos Reis, Francisco J Candido, Campbell, Ian, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Fasching, Peter A, Fortner, Renée T, García, María J, Goodman, Marc T, Goode, Ellen L, Gronwald, Jacek, Huntsman, David G, Karlan, Beth Y, Kelemen, Linda E, Kommoss, Stefan, Le, Nhu D, and Martin, Stewart G

Subjects
Reproductive Medicine, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Rare Diseases, Ovarian Cancer, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Humans, Female, Tumor Suppressor Protein p53, Ovarian Neoplasms, Carcinoma, Ovarian Epithelial, Carcinoma, Endometrioid, ovarian cancer, high-grade serous carcinoma, endometrioid, clear cell, TP53, p53, prognosis, AOCS Group, Clinical sciences
Abstract

Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.

Published
2023

4. CCNE1 and survival of patients with tubo‐ovarian high‐grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study

Author

Kang, Eun‐Young, Weir, Ashley, Meagher, Nicola S, Farrington, Kyo, Nelson, Gregg S, Ghatage, Prafull, Lee, Cheng‐Han, Riggan, Marjorie J, Bolithon, Adelyn, Popovic, Gordana, Leung, Betty, Tang, Katrina, Lambie, Neil, Millstein, Joshua, Alsop, Jennifer, Anglesio, Michael S, Ataseven, Beyhan, Barlow, Ellen, Beckmann, Matthias W, Berger, Jessica, Bisinotto, Christiani, Bösmüller, Hans, Boros, Jessica, Brand, Alison H, Brooks‐Wilson, Angela, Brucker, Sara Y, Carney, Michael E, Casablanca, Yovanni, Cazorla‐Jiménez, Alicia, Cohen, Paul A, Conrads, Thomas P, Cook, Linda S, Coulson, Penny, Courtney‐Brooks, Madeleine, Cramer, Daniel W, Crowe, Philip, Cunningham, Julie M, Cybulski, Cezary, Darcy, Kathleen M, El‐Bahrawy, Mona A, Elishaev, Esther, Erber, Ramona, Farrell, Rhonda, Fereday, Sian, Fischer, Anna, García, María J, Gayther, Simon A, Gentry‐Maharaj, Aleksandra, Gilks, C Blake, Group, AOCS, Grube, Marcel, Harnett, Paul R, Harrington, Shariska Petersen, Harter, Philipp, Hartmann, Arndt, Hecht, Jonathan L, Heikaus, Sebastian, Hein, Alexander, Heitz, Florian, Hendley, Joy, Hernandez, Brenda Y, Polo, Susanna Hernando, Heublein, Sabine, Hirasawa, Akira, Høgdall, Estrid, Høgdall, Claus K, Horlings, Hugo M, Huntsman, David G, Huzarski, Tomasz, Jewell, Andrea, Jimenez‐Linan, Mercedes, Jones, Michael E, Kaufmann, Scott H, Kennedy, Catherine J, Khabele, Dineo, Kommoss, Felix KF, Kruitwagen, Roy FPM, Lambrechts, Diether, Le, Nhu D, Lener, Marcin, Lester, Jenny, Leung, Yee, Linder, Anna, Loverix, Liselore, Lubiński, Jan, Madan, Rashna, Maxwell, G Larry, Modugno, Francesmary, Neuhausen, Susan L, Olawaiye, Alexander, Olbrecht, Siel, Orsulic, Sandra, Palacios, José, Pearce, Celeste Leigh, Pike, Malcolm C, Quinn, Carmel M, Mohan, Ganendra Raj, Rodríguez‐Antona, Cristina, Ruebner, Matthias, and Ryan, Andy

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Clinical Research, Ovarian Cancer, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Female, Humans, Ovarian Neoplasms, Transcription Factors, Carcinoma, RNA, Messenger, Cystadenocarcinoma, Serous, Oncogene Proteins, Cyclin E, CCNE1 amplification, cyclin E1 expression, high-grade serous carcinoma, ovarian cancer, prognosis, AOCS Group, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis, Public health
Abstract

BackgroundCyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC.MethodsWithin the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated.ResultsHigh-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss.ConclusionThis study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

Published
2023

5. Increased FOXJ1 protein expression is associated with improved overall survival in high-grade serous ovarian carcinoma: an Ovarian Tumor Tissue Analysis Consortium Study

Author

Weir, Ashley, Kang, Eun-Young, Meagher, Nicola S, Nelson, Gregg S, Ghatage, Prafull, Lee, Cheng-Han, Riggan, Marjorie J, Gentry-Maharaj, Aleksandra, Ryan, Andy, Singh, Naveena, Widschwendter, Martin, Alsop, Jennifer, Anglesio, Michael S, Beckmann, Matthias W, Berger, Jessica, Bisinotto, Christiani, Boros, Jessica, Brand, Alison H, Brenton, James D, Brooks-Wilson, Angela, Carney, Michael E, Cunningham, Julie M, Cushing-Haugen, Kara L, Cybulski, Cezary, Elishaev, Esther, Erber, Ramona, Fereday, Sian, Fischer, Anna, Paz-Ares, Luis, Gayarre, Javier, Gilks, Blake C, Grube, Marcel, Harnett, Paul R, Harris, Holly R, Hartmann, Arndt, Hein, Alexander, Hendley, Joy, Hernandez, Brenda Y, Heublein, Sabine, Huang, Yajue, Huzarski, Tomasz, Jakubowska, Anna, Jimenez-Linan, Mercedes, Kennedy, Catherine J, Kommoss, Felix KF, Koziak, Jennifer M, Kraemer, Bernhard, Le, Nhu D, Lesnock, Jaime, Lester, Jenny, Lubiński, Jan, Menkiszak, Janusz, Ney, Britta, Olawaiye, Alexander, Orsulic, Sandra, Osorio, Ana, Robles-Díaz, Luis, Ruebner, Matthias, Shah, Mitul, Sharma, Raghwa, Shvetsov, Yurii B, Steed, Helen, Talhouk, Aline, Taylor, Sarah E, Traficante, Nadia, Vierkant, Robert A, Wang, Chen, Wilkens, Lynne R, Winham, Stacey J, Benitez, Javier, Berchuck, Andrew, Bowtell, David D, Candido dos Reis, Francisco J, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Fasching, Peter A, García, María J, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Huntsman, David G, Karlan, Beth Y, Kommoss, Stefan, Modugno, Francesmary, Schildkraut, Joellen M, Sinn, Hans-Peter, Staebler, Annette, Kelemen, Linda E, Ford, Caroline E, Menon, Usha, Pharoah, Paul DP, Köbel, Martin, and Ramus, Susan J

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Ovarian Cancer, Clinical Research, Rare Diseases, Cancer, Aetiology, 2.1 Biological and endogenous factors, Humans, Female, Ovarian Neoplasms, Prognosis, Survival Analysis, RNA, Messenger, Cystadenocarcinoma, Serous, Biomarkers, Tumor, Forkhead Transcription Factors, AOCs group, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundRecently, we showed a >60% difference in 5-year survival for patients with tubo-ovarian high-grade serous carcinoma (HGSC) when stratified by a 101-gene mRNA expression prognostic signature. Given the varied patient outcomes, this study aimed to translate prognostic mRNA markers into protein expression assays by immunohistochemistry and validate their survival association in HGSC.MethodsTwo prognostic genes, FOXJ1 and GMNN, were selected based on high-quality antibodies, correlation with protein expression and variation in immunohistochemical scores in a preliminary cohort (n = 134 and n = 80, respectively). Six thousand four hundred and thirty-four (FOXJ1) and 5470 (GMNN) formalin-fixed, paraffin-embedded ovarian neoplasms (4634 and 4185 HGSC, respectively) represented on tissue microarrays from the Ovarian Tumor Tissue Analysis consortium underwent immunohistochemical staining and scoring, then univariate and multivariate survival analysis.ResultsConsistent with mRNA, FOXJ1 protein expression exhibited a linear, increasing association with improved overall survival in HGSC patients. Women with >50% expression had the most favourable outcomes (HR = 0.78, 95% CI 0.67-0.91, p 35% GMNN expression showed a trend for better outcomes, though this was not significant.ConclusionWe provide foundational evidence for the prognostic value of FOXJ1 in HGSC, validating the prior mRNA-based prognostic association by immunohistochemistry.

Published
2023

6. Profiling the immune landscape in mucinous ovarian carcinoma.

Author

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

Subjects
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.

Published
2023

7. Gene expression profiling of mucinous ovarian tumors and comparison with upper and lower gastrointestinal tumors identifies markers associated with adverse outcomes.

Author

Meagher, Nicola S, Gorringe, Kylie L, Wakefield, Matthew, Bolithon, Adelyn, Pang, Chi Nam Ignatius, Chiu, Derek S, Anglesio, Michael S, Mallitt, Kylie-Ann, Doherty, Jennifer A, Harris, Holly R, Schildkraut, Joellen M, Berchuck, Andrew, Cushing-Haugen, Kara L, Chezar, Ksenia, Chou, Angela, Tan, Adeline, Alsop, Jennifer, Barlow, Ellen, Beckmann, Matthias W, Boros, Jessica, Bowtell, David DL, Group, for the AOCS, Brand, Alison H, Brenton, James D, Campbell, Ian, Cheasley, Dane, Cohen, Joshua, Cybulski, Cezary, Elishaev, Esther, Erber, Ramona, Farrell, Rhonda, Fischer, Anna, Fu, Zhuxuan, Gilks, Blake, Gill, Anthony J, Initiative, for the Australian Pancreatic Genome, Gourley, Charlie, Grube, Marcel, Harnett, Paul R, Hartmann, Arndt, Hettiaratchi, Anusha, Høgdall, Claus K, Huzarski, Tomasz, Jakubowska, Anna, Jimenez-Linan, Mercedes, Kennedy, Catherine J, Kim, Byoung-Gie, Kim, Jae-Weon, Kim, Jae-Hoon, Klett, Kayla, Koziak, Jennifer M, Lai, Tiffany, Laslavic, Angela, Lester, Jenny, Leung, Yee, Li, Na, Liauw, Winston, Lim, Belle WX, Linder, Anna, Lubiński, Jan, Mahale, Sakshi, Mateoiu, Constantina, McInerny, Simone, Menkiszak, Janusz, Minoo, Parham, Mittelstadt, Suzana, Morris, David, Orsulic, Sandra, Park, Sang-Yoon, Pearce, Celeste Leigh, Pearson, John V, Pike, Malcolm C, Quinn, Carmel M, Mohan, Ganendra Raj, Rao, Jianyu, Riggan, Marjorie J, Ruebner, Matthias, Salfinger, Stuart, Scott, Clare L, Shah, Mitul, Steed, Helen, Stewart, Colin JR, Subramanian, Deepak, Sung, Soseul, Tang, Katrina, Timpson, Paul, Ward, Robyn L, Wiedenhoefer, Rebekka, Thorne, Heather, Investigators, for the kConFab, Cohen, Paul A, Crowe, Philip, Fasching, Peter A, Gronwald, Jacek, Hawkins, Nicholas J, Høgdall, Estrid, Huntsman, David G, James, Paul A, Karlan, Beth Y, and Kelemen, Linda E

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Ovarian Cancer, Rare Diseases, Cancer, Digestive Diseases, Genetics, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Female, Humans, Neoplasm Staging, Ovarian Neoplasms, Carcinoma, Ovarian Epithelial, Adenocarcinoma, Mucinous, Prognosis, Gastrointestinal Neoplasms, AOCS Group, Australian Pancreatic Genome Initiative, kConFab Investigators, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

PurposeAdvanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features.Experimental designDiscovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55).ResultsInfiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%).ConclusionsAn infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.

Published
2022

8. Molecular subclasses of clear cell ovarian carcinoma and their impact on disease behavior and outcomes

Author

Bolton, Kelly L, Chen, Denise, de la Fuente, Rosario I Corona, Fu, Zhuxuan, Murali, Rajmohan, K�bel, Martin, Tazi, Yanis, Cunningham, Julie M, Chan, Irenaeus CC, Wiley, Brian J, Moukarzel, Lea A, Winham, Stacey J, Armasu, Sebastian M, Lester, Jenny, Elishaev, Esther, Laslavic, Angela, Kennedy, Catherine J, Piskorz, Anna, Sekowska, Magdalena, Brand, Alison H, Chiew, Yoke-Eng, Pharoah, Paul, Elias, Kevin M, Drapkin, Ronny, Churchman, Michael, Gourley, Charlie, DeFazio, Anna, Karlan, Beth, Brenton, James D, Weigelt, Britta, Anglesio, Michael S, Huntsman, David, Gayther, Simon A, Konner, Jason, Modugno, Francesmary, Lawrenson, Kate, Goode, Ellen L, and Papaemmanuil, Elli

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Women's Health, Human Genome, Genetics, Rare Diseases, Cancer, Biotechnology, Cancer Genomics, Precision Medicine, Clinical Research, 2.1 Biological and endogenous factors, Good Health and Well Being, Female, Humans, Ovarian Neoplasms, Adenocarcinoma, Clear Cell, Mutation, Endometriosis, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

PurposeTo identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes.Experimental designWe profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly defined subgroups were identified and tested for association with clinical characteristics and overall survival.ResultsWe detected a putative somatic driver mutation in at least one candidate gene in 95% (401/421) of CCOC tumors including ARID1A (in 49% of tumors), PIK3CA (49%), TERT (20%), and TP53 (16%). Clustering of cancer driver mutations and RNA expression converged upon two distinct subclasses of CCOC. The first was dominated by ARID1A-mutated tumors with enriched expression of canonical CCOC genes and markers of platinum resistance; the second was largely comprised of tumors with TP53 mutations and enriched for the expression of genes involved in extracellular matrix organization and mesenchymal differentiation. Compared with the ARID1A-mutated group, women with TP53-mutated tumors were more likely to have advanced-stage disease, no antecedent history of endometriosis, and poorer survival, driven by their advanced stage at presentation. In women with ARID1A-mutated tumors, there was a trend toward a lower rate of response to first-line platinum-based therapy.ConclusionsOur study suggests that CCOC consists of two distinct molecular subclasses with distinct clinical presentation and outcomes, with potential relevance to both traditional and experimental therapy responsiveness. See related commentary by Lheureux, p. 4838.

Published
2022

9. MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma

Author

Kang, Eun Young, Millstein, Joshua, Popovic, Gordana, Meagher, Nicola S, Bolithon, Adelyn, Talhouk, Aline, Chiu, Derek S, Anglesio, Michael S, Leung, Betty, Tang, Katrina, Lambie, Neil, Pavanello, Marina, Da-anoy, Annalyn, Lambrechts, Diether, Loverix, Liselore, Olbrecht, Siel, Bisinotto, Christiani, Garcia-Donas, Jesus, Ruiz-Llorente, Sergio, Yagüe-Fernandez, Monica, Edwards, Robert P, Elishaev, Esther, Olawaiye, Alexander, Taylor, Sarah, Ataseven, Beyhan, du Bois, Andreas, Harter, Philipp, Lester, Jenny, Høgdall, Claus K, Armasu, Sebastian M, Huang, Yajue, Vierkant, Robert A, Wang, Chen, Winham, Stacey J, Heublein, Sabine, Kommoss, Felix KF, Cramer, Daniel W, Sasamoto, Naoko, van-Wagensveld, Lilian, Lycke, Maria, Mateoiu, Constantina, Joseph, Janine, Pike, Malcolm C, Odunsi, Kunle, Tseng, Chiu-Chen, Pearce, Celeste L, Bilic, Sanela, Conrads, Thomas P, Hartmann, Arndt, Hein, Alexander, Jones, Michael E, Leung, Yee, Beckmann, Matthias W, Ruebner, Matthias, Schoemaker, Minouk J, Terry, Kathryn L, El-Bahrawy, Mona A, Coulson, Penny, Etter, John L, LaVigne-Mager, Katherine, Andress, Juergen, Grube, Marcel, Fischer, Anna, Neudeck, Nina, Robertson, Greg, Farrell, Rhonda, Barlow, Ellen, Quinn, Carmel, Hettiaratchi, Anusha, Casablanca, Yovanni, Erber, Ramona, Stewart, Colin JR, Tan, Adeline, Yu, Yu, Boros, Jessica, Brand, Alison H, Harnett, Paul R, Kennedy, Catherine J, Nevins, Nikilyn, Morgan, Terry, Fasching, Peter A, Vergote, Ignace, Swerdlow, Anthony J, Candido dos Reis, Francisco J, Maxwell, G Larry, Neuhausen, Susan L, Barquin-Garcia, Arantzazu, Modugno, Francesmary, Moysich, Kirsten B, Crowe, Philip J, Hirasawa, Akira, Heitz, Florian, Karlan, Beth Y, Goode, Ellen L, Sinn, Peter, Horlings, Hugo M, Høgdall, Estrid, Sundfeldt, Karin, Kommoss, Stefan, and Staebler, Annette

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Women's Health, Infectious Diseases, HIV/AIDS, Cancer, Rare Diseases, Sexually Transmitted Infections, Genetics, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Biomarkers, Tumor, Cell Proliferation, Cystadenocarcinoma, Serous, Female, Humans, Ki-67 Antigen, Minichromosome Maintenance Complex Component 3, Ovarian Neoplasms, RNA, Messenger, Survival Rate, High-grade serous carcinoma, Proliferation, MCM3, Clinical Sciences, Pathology, Clinical sciences
Abstract

Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan-Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81-0.92, p

Published
2022

10. Fibroblast Growth Factor Receptors and Ligands in Context of Bevacizumab Response in Ovarian Carcinoma: An Exploratory Analysis of AGO-OVAR11/ICON-7

Author

Heublein, Sabine, Pfisterer, Jacobus, du Bois, Andreas, Anglesio, Michael, Aminossadati, Behnaz, Bhatti, Irfan, Sehouli, Jalid, Wimberger, Pauline, Schochter, Fabienne, Hilpert, Felix, Hillemanns, Peter, Kalder, Matthias, Schroeder, Willibald, Mahner, Sven, Burges, Alexander, Canzler, Ulrich, Gropp-Meier, Martina, Jackisch, Christian, Harter, Philipp, Kommoss, Stefan, and Marmé, Frederik

Published
2024
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11. Single-cell transcriptomic analysis of endometriosis

Author

Fonseca, Marcos A. S., Haro, Marcela, Wright, Kelly N., Lin, Xianzhi, Abbasi, Forough, Sun, Jennifer, Hernandez, Lourdes, Orr, Natasha L., Hong, Jooyoon, Choi-Kuaea, Yunhee, Maluf, Horacio M., Balzer, Bonnie L., Fishburn, Aaron, Hickey, Ryan, Cass, Ilana, Goodridge, Helen S., Truong, Mireille, Wang, Yemin, Pisarska, Margareta D., Dinh, Huy Q., EL-Naggar, Amal, Huntsman, David G., Anglesio, Michael S., Goodman, Marc T., Medeiros, Fabiola, Siedhoff, Matthew, and Lawrenson, Kate

Published
2023
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12. Menopausal hormone therapy prior to the diagnosis of ovarian cancer is associated with improved survival

Author

Brieger, Katharine K, Peterson, Siri, Lee, Alice W, Mukherjee, Bhramar, Bakulski, Kelly M, Alimujiang, Aliya, Anton-Culver, Hoda, Anglesio, Michael S, Bandera, Elisa V, Berchuck, Andrew, Bowtell, David DL, Chenevix-Trench, Georgia, Cho, Kathleen R, Cramer, Daniel W, DeFazio, Anna, Doherty, Jennifer A, Fortner, Renée T, Garsed, Dale W, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Goode, Ellen L, Goodman, Marc T, Harris, Holly R, Høgdall, Estrid, Huntsman, David G, Shen, Hui, Jensen, Allan, Johnatty, Sharon E, Jordan, Susan J, Kjaer, Susanne K, Kupryjanczyk, Jolanta, Lambrechts, Diether, McLean, Karen, Menon, Usha, Modugno, Francesmary, Moysich, Kirsten, Ness, Roberta, Ramus, Susan J, Richardson, Jean, Risch, Harvey, Rossing, Mary Anne, Trabert, Britton, Wentzensen, Nicolas, Ziogas, Argyrios, Terry, Kathryn L, Wu, Anna H, Hanley, Gillian E, Pharoah, Paul, Webb, Penelope M, Pike, Malcolm C, Pearce, Celeste Leigh, and Consortium, for the Ovarian Cancer Association

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Estrogen, Rare Diseases, Cancer, Ovarian Cancer, Aging, Aged, Estrogen Replacement Therapy, Female, Hormone Replacement Therapy, Humans, Middle Aged, Neoplasm Staging, Neoplasm, Residual, Ovarian Neoplasms, Postmenopause, Progestins, Progression-Free Survival, Proportional Hazards Models, Survival Rate, Ovarian Cancer Association Consortium, Paediatrics and Reproductive Medicine, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis, Reproductive medicine
Abstract

PurposePrior studies of menopausal hormone therapy (MHT) and ovarian cancer survival have been limited by lack of hormone regimen detail and insufficient sample sizes. To address these limitations, a comprehensive analysis of 6419 post-menopausal women with pathologically confirmed ovarian carcinoma was conducted to examine the association between MHT use prior to diagnosis and survival.MethodsData from 15 studies in the Ovarian Cancer Association Consortium were included. MHT use was examined by type (estrogen-only (ET) or estrogen+progestin (EPT)), duration, and recency of use relative to diagnosis. Cox proportional hazards models were used to estimate the association between hormone therapy use and survival. Logistic regression and mediation analysis was used to explore the relationship between MHT use and residual disease following debulking surgery.ResultsUse of ET or EPT for at least five years prior to diagnosis was associated with better ovarian cancer survival (hazard ratio, 0.80; 95% CI, 0.74 to 0.87). Among women with advanced stage, high-grade serous carcinoma, those who used MHT were less likely to have any macroscopic residual disease at the time of primary debulking surgery (p for trend

Published
2020

13. Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium.

Author

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

Subjects
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

Published
2020

17. Refined cut-off for TP53 immunohistochemistry improves prediction of TP53 mutation status in ovarian mucinous tumors: implications for outcome analyses

Author

Kang, Eun Young, Cheasley, Dane, LePage, Cecile, Wakefield, Matthew J., da Cunha Torres, Michelle, Rowley, Simone, Salazar, Carolina, Xing, Zhongyue, Allan, Prue, Bowtell, David D.L., Mes-Masson, Anne-Marie, Provencher, Diane M., Rahimi, Kurosh, Kelemen, Linda E., Fasching, Peter A., Doherty, Jennifer A., Goodman, Marc T., Goode, Ellen L., Deen, Suha, Pharoah, Paul D.P., Brenton, James D., Sieh, Weiva, Mateoiu, Constantina, Sundfeldt, Karin, Cook, Linda S., Le, Nhu D., Anglesio, Michael S., Gilks, C. Blake, Huntsman, David G., Kennedy, Catherine J., Traficante, Nadia, Bowtell, D., Chenevix-Trench, G., Green, A., Webb, P., DeFazio, A., Gertig, D., Traficante, N., Fereday, S., Moore, S., Hung, J., Harrap, K., Sadkowsky, T., Pandeya, N., Malt, M., Mellon, A., Robertson, R., Bergh, T. Vanden, Jones, M., Mackenzie, P., Maidens, J., Nattress, K., Chiew, Y.E., Stenlake, A., Sullivan, H., Alexander, B., Ashover, P., Brown, S., Corrish, T., Green, L., Jackman, L., Ferguson, K., Martin, K., Martyn, A., Ranieri, B., White, J., Jayde, V., Mamers, P., Bowes, L., Galletta, L., Giles, D., Hendley, J., Alsop, K., Schmidt, T., Shirley, H., Ball, C., Young, C., Viduka, S., Tran, Hoa, Bilic, Sanela, Glavinas, Lydia, Brooks, Julia, Stuart-Harris, R., Kirsten, F., Rutovitz, J., Clingan, P., Glasgow, A., Proietto, A., Braye, S., Otton, G., Shannon, J., Bonaventura, T., Stewart, J., Begbie, S., Friedlander, M., Bell, D., Baron-Hay, S., Ferrier, A., Gard, G., Nevell, D., Pavlakis, N., Valmadre, S., Young, B., Camaris, C., Crouch, R., Edwards, L., Hacker, N., Marsden, D., Robertson, G., Beale, P., Beith, J., Carter, J., Dalrymple, C., Houghton, R., Russell, P., Links, M., Grygiel, J., Hill, J., Brand, A., Byth, K., Jaworski, R., Harnett, P., Sharma, R., Wain, G., Ward, B., Papadimos, D., Crandon, A., Cummings, M., Horwood, K., Obermair, A., Perrin, L., Wyld, D., Nicklin, J., Davy, M., Oehler, M.K., Hall, C., Dodd, T., Healy, T., Pittman, K., Henderson, D., Miller, J., Pierdes, J., Blomfield, P., Challis, D., McIntosh, R., Parker, A., Brown, B., Rome, R., Allen, D., Grant, P., Hyde, S., Laurie, R., Robbie, M., Healy, D., Jobling, T., Manolitsas, T., McNealage, J., Rogers, P., Susil, B., Sumithran, E., Simpson, I., Phillips, K., Rischin, D., Fox, S., Johnson, D., Lade, S., Loughrey, M., O'Callaghan, N., Murray, W., Waring, P., Billson, V., Pyman, J., Neesham, D., Quinn, M., Underhill, C., Bell, R., Ng, L.F., Blum, R., Ganju, V., Hammond, I., Leung, Y., McCartney, A., Buck, M., Haviv, I., Purdie, D., Whiteman, D., Zeps, N., DeFazio, Anna, Kaufmann, Scott, Churchman, Michael, Gourley, Charlie, Stephens, Andrew N., Meagher, Nicola S., Ramus, Susan J., Antill, Yoland C., Campbell, Ian, Scott, Clare L., Köbel, Martin, Gorringe, Kylie L., Ryland, Georgina L., Allan, Prue E., Alsop, Kathryn, Ananda, Sumitra, Au-Yeung, George, Böhm, Maret, Brand, Alison, Chenevix-Trench, Georgia, Christie, Michael, Chiew, Yoke-Eng, Dudley, Rhiannon, Fairweather, Nicole, Fereday, Sian, Fox, Stephen B., Hacker, Neville F., Hadley, Alison M., Hendley, Joy, Ho, Gwo-Yaw, Hunter, Sally M., Jobling, Tom W., Kalli, Kimberly R., Kaufmann, Scott H., Le Page, Cecile, McNally, Orla M., McAlpine, Jessica N., Mileshkin, Linda, Pyman, Jan, Samimi, Goli, Sharma, Ragwha, and Campbell, Ian G.

Published
2021
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18. Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma.

Author

Saner, Flurina, Saner, Flurina, Takahashi, Kazuaki, Budden, Timothy, Pandey, Ahwan, Ariyaratne, Dinuka, Zwimpfer, Tibor, Meagher, Nicola, Fereday, Sian, Twomey, Laura, Pishas, Kathleen, Hoang, Therese, Bolithon, Adelyn, Traficante, Nadia, Alsop, Kathryn, Christie, Elizabeth, Kang, Eun-Young, Nelson, Gregg, Ghatage, Prafull, Lee, Cheng-Han, Riggan, Marjorie, Alsop, Jennifer, Beckmann, Matthias, Boros, Jessica, Brand, Alison, Brooks-Wilson, Angela, Carney, Michael, Coulson, Penny, Courtney-Brooks, Madeleine, Cushing-Haugen, Kara, Cybulski, Cezary, El-Bahrawy, Mona, Elishaev, Esther, Erber, Ramona, Gayther, Simon, Gentry-Maharaj, Aleksandra, Gilks, C, Harnett, Paul, Harris, Holly, Hartmann, Arndt, Hein, Alexander, Hendley, Joy, Hernandez, Brenda, Jakubowska, Anna, Jimenez-Linan, Mercedes, Jones, Michael, Kaufmann, Scott, Kennedy, Catherine, Kluz, Tomasz, Koziak, Jennifer, Kristjansdottir, Björg, Le, Nhu, Lener, Marcin, Lester, Jenny, Lubiński, Jan, Mateoiu, Constantina, Orsulic, Sandra, Ruebner, Matthias, Schoemaker, Minouk, Shah, Mitul, Sharma, Raghwa, Sherman, Mark, Shvetsov, Yurii, Soong, T, Steed, Helen, Sukumvanich, Paniti, Talhouk, Aline, Taylor, Sarah, Vierkant, Robert, Wang, Chen, Widschwendter, Martin, Wilkens, Lynne, Winham, Stacey, Anglesio, Michael, Berchuck, Andrew, Brenton, James, Campbell, Ian, Cook, Linda, Doherty, Jennifer, Fasching, Peter, Fortner, Renée, Goodman, Marc, Gronwald, Jacek, Karlan, Beth, Kelemen, Linda, Menon, Usha, Modugno, Francesmary, Pharoah, Paul, Schildkraut, Joellen, Sundfeldt, Karin, Swerdlow, Anthony, Goode, Ellen, DeFazio, Anna, Köbel, Martin, Ramus, Susan, Bowtell, David, Garsed, Dale, Saner, Flurina, Saner, Flurina, Takahashi, Kazuaki, Budden, Timothy, Pandey, Ahwan, Ariyaratne, Dinuka, Zwimpfer, Tibor, Meagher, Nicola, Fereday, Sian, Twomey, Laura, Pishas, Kathleen, Hoang, Therese, Bolithon, Adelyn, Traficante, Nadia, Alsop, Kathryn, Christie, Elizabeth, Kang, Eun-Young, Nelson, Gregg, Ghatage, Prafull, Lee, Cheng-Han, Riggan, Marjorie, Alsop, Jennifer, Beckmann, Matthias, Boros, Jessica, Brand, Alison, Brooks-Wilson, Angela, Carney, Michael, Coulson, Penny, Courtney-Brooks, Madeleine, Cushing-Haugen, Kara, Cybulski, Cezary, El-Bahrawy, Mona, Elishaev, Esther, Erber, Ramona, Gayther, Simon, Gentry-Maharaj, Aleksandra, Gilks, C, Harnett, Paul, Harris, Holly, Hartmann, Arndt, Hein, Alexander, Hendley, Joy, Hernandez, Brenda, Jakubowska, Anna, Jimenez-Linan, Mercedes, Jones, Michael, Kaufmann, Scott, Kennedy, Catherine, Kluz, Tomasz, Koziak, Jennifer, Kristjansdottir, Björg, Le, Nhu, Lener, Marcin, Lester, Jenny, Lubiński, Jan, Mateoiu, Constantina, Orsulic, Sandra, Ruebner, Matthias, Schoemaker, Minouk, Shah, Mitul, Sharma, Raghwa, Sherman, Mark, Shvetsov, Yurii, Soong, T, Steed, Helen, Sukumvanich, Paniti, Talhouk, Aline, Taylor, Sarah, Vierkant, Robert, Wang, Chen, Widschwendter, Martin, Wilkens, Lynne, Winham, Stacey, Anglesio, Michael, Berchuck, Andrew, Brenton, James, Campbell, Ian, Cook, Linda, Doherty, Jennifer, Fasching, Peter, Fortner, Renée, Goodman, Marc, Gronwald, Jacek, Karlan, Beth, Kelemen, Linda, Menon, Usha, Modugno, Francesmary, Pharoah, Paul, Schildkraut, Joellen, Sundfeldt, Karin, Swerdlow, Anthony, Goode, Ellen, DeFazio, Anna, Köbel, Martin, Ramus, Susan, Bowtell, David, and Garsed, Dale

Abstract

PURPOSE: The purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC). EXPERIMENTAL DESIGN: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 patients with primary HGSC to characterize tumors with concurrent BRCA deficiency and RB1 loss. RESULTS: RB1 loss was associated with longer OS in HGSC but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. CONCLUSIONS: Co-occurrence of RB1 loss and BRCA deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

Published
2024

20. Supplementary Tables S1-10 from Cell State of Origin Impacts Development of Distinct Endometriosis-Related Ovarian Carcinoma Histotypes

Author

Beddows, Ian, primary, Fan, Huihui, primary, Heinze, Karolin, primary, Johnson, Benjamin K., primary, Leonova, Anna, primary, Senz, Janine, primary, Djirackor, Svetlana, primary, Cho, Kathleen R., primary, Pearce, Celeste Leigh, primary, Huntsman, David G., primary, Anglesio, Michael S., primary, and Shen, Hui, primary

Published
2024
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21. Supplementary Data from Cell State of Origin Impacts Development of Distinct Endometriosis-Related Ovarian Carcinoma Histotypes

Author

Beddows, Ian, primary, Fan, Huihui, primary, Heinze, Karolin, primary, Johnson, Benjamin K., primary, Leonova, Anna, primary, Senz, Janine, primary, Djirackor, Svetlana, primary, Cho, Kathleen R., primary, Pearce, Celeste Leigh, primary, Huntsman, David G., primary, Anglesio, Michael S., primary, and Shen, Hui, primary

Published
2024
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24. Targeted deep sequencing of mucinous ovarian tumors reveals multiple overlapping RAS-pathway activating mutations in borderline and cancerous neoplasms

Author

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

Subjects
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.

Published
2015

25. Multifocal endometriotic lesions associated with cancer are clonal and carry a high mutation burden

Author

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

Subjects
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.

Published
2015

26. A combination of the immunohistochemical markers CK7 and SATB2 is highly sensitive and specific for distinguishing primary ovarian mucinous tumors from colorectal and appendiceal metastases

Author

Meagher, Nicola S., Wang, Linyuan, Rambau, Peter F., Intermaggio, Maria P., Huntsman, David G., Wilkens, Lynne R., El-Bahrawy, Mona A., Ness, Roberta B., Odunsi, Kunle, Steed, Helen, Herpel, Esther, Anglesio, Michael S., Zhang, Bonnie, Lambie, Neil, Swerdlow, Anthony J., Lubiński, Jan, Vierkant, Robert A., Goode, Ellen L., Menon, Usha, Toloczko-Grabarek, Aleksandra, Oszurek, Oleg, Bilic, Sanela, Talhouk, Aline, García-Closas, Montserrat, Wang, Qin, Tan, Adeline, Farrell, Rhonda, Kennedy, Catherine J., Jimenez-Linan, Mercedes, Sundfeldt, Karin, Etter, John L., Menkiszak, Janusz, Goodman, Marc T., Klonowski, Paul, Leung, Yee, Winham, Stacey J., Moysich, Kirsten B., Behrens, Sabine, Kluz, Tomasz, Edwards, Robert P., Gronwald, Jacek, Modugno, Francesmary, Hernandez, Brenda Y, Chow, Christine, Kelemen, Linda E., Keeney, Gary L., Carney, Michael E., Natanzon, Yanina, Robertson, Gregory, Sharma, Raghwa, Gayther, Simon A., Alsop, Jennifer, Luk, Hugh, Karpinskyj, Chloe, Campbell, Ian, Sinn, Peter, Gentry-Maharaj, Aleksandra, Coulson, Penny, Chang-Claude, Jenny, Shah, Mitul, Widschwendter, Martin, Tang, Katrina, Schoemaker, Minouk J., Koziak, Jennifer M., Cook, Linda S., Brenton, James D., Daley, Frances, Kristjansdottir, Björg, Mateoiu, Constantina, Larson, Melissa C., Harnett, Paul R., Jung, Audrey, deFazio, Anna, Gorringe, Kylie L., Pharoah, Paul D.P., Minoo, Parham, Stewart, Colin, Bathe, Oliver F., Gui, Xianyong, Cohen, Paul, Ramus, Susan J., and Köbel, Martin

Published
2019
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27. Cell state of origin impacts development of distinct endometriosis-related ovarian carcinoma histotypes

Author

Beddows, Ian, primary, Fan, Huihui, additional, Heinze, Karolin, additional, Johnson, Benjamin K., additional, Leonova, Anna, additional, Senz, Janine, additional, Djirackor, Svetlana, additional, Cho, Kathleen R., additional, Pearce, Celeste Leigh., additional, Huntsman, David G., additional, Anglesio, Michael S., additional, and Shen, Hui, additional

Published
2023
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31. Supplementary Figures S1-S4 from The Prognostic Effect of Immune Cell Infiltration Depends on Molecular Subtype in Endometrioid Ovarian Carcinomas

Author

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

Published
2023
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32. Supplementary Tables S1-S5 from The Prognostic Effect of Immune Cell Infiltration Depends on Molecular Subtype in Endometrioid Ovarian Carcinomas

Author

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

Published
2023
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33. Data from The Prognostic Effect of Immune Cell Infiltration Depends on Molecular Subtype in Endometrioid Ovarian Carcinomas

Author

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

Published
2023
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37. Supplementary Figure 3 from Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma

Author

Wang, Chen, primary, Block, Matthew S., primary, Cunningham, Julie M., primary, Sherman, Mark E., primary, McCauley, Bryan M., primary, Armasu, Sebastian M., primary, Vierkant, Robert A., primary, Traficante, Nadia, primary, Talhouk, Aline, primary, Ramus, Susan J., primary, Pejovic, Nadja, primary, Köbel, Martin, primary, Jorgensen, Brooke D., primary, Garsed, Dale W., primary, Fereday, Sian, primary, Doherty, Jennifer A., primary, Ariyaratne, Dinuka, primary, Anglesio, Michael S., primary, Widschwendter, Martin, primary, Pejovic, Tanja, primary, Bosquet, Jesus Gonzalez, primary, Bowtell, David D., primary, Winham, Stacey J., primary, and Goode, Ellen L., primary

Published
2023
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38. Data from Enhanced GAB2 Expression Is Associated with Improved Survival in High-Grade Serous Ovarian Cancer and Sensitivity to PI3K Inhibition

Author

Davis, Sally J., primary, Sheppard, Karen E., primary, Anglesio, Michael S., primary, George, Joshy, primary, Traficante, Nadia, primary, Fereday, Sian, primary, Intermaggio, Maria P., primary, Menon, Usha, primary, Gentry-Maharaj, Aleksandra, primary, Lubinski, Jan, primary, Gronwald, Jacek, primary, Pearce, Celeste Leigh, primary, Pike, Malcolm C., primary, Wu, Anna, primary, Kommoss, Stefan, primary, Pfisterer, Jacobus, primary, du Bois, Andreas, primary, Hilpert, Felix, primary, Ramus, Susan J., primary, Bowtell, David D.L., primary, Huntsman, David G., primary, Pearson, Richard B., primary, Simpson, Kaylene J., primary, Campbell, Ian G., primary, and Gorringe, Kylie L., primary

Published
2023
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39. Supplementary Table 5 from Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma

Author

Wang, Chen, primary, Block, Matthew S., primary, Cunningham, Julie M., primary, Sherman, Mark E., primary, McCauley, Bryan M., primary, Armasu, Sebastian M., primary, Vierkant, Robert A., primary, Traficante, Nadia, primary, Talhouk, Aline, primary, Ramus, Susan J., primary, Pejovic, Nadja, primary, Köbel, Martin, primary, Jorgensen, Brooke D., primary, Garsed, Dale W., primary, Fereday, Sian, primary, Doherty, Jennifer A., primary, Ariyaratne, Dinuka, primary, Anglesio, Michael S., primary, Widschwendter, Martin, primary, Pejovic, Tanja, primary, Bosquet, Jesus Gonzalez, primary, Bowtell, David D., primary, Winham, Stacey J., primary, and Goode, Ellen L., primary

Published
2023
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40. Supplementary Table 1 from Enhanced GAB2 Expression Is Associated with Improved Survival in High-Grade Serous Ovarian Cancer and Sensitivity to PI3K Inhibition

Author

Davis, Sally J., primary, Sheppard, Karen E., primary, Anglesio, Michael S., primary, George, Joshy, primary, Traficante, Nadia, primary, Fereday, Sian, primary, Intermaggio, Maria P., primary, Menon, Usha, primary, Gentry-Maharaj, Aleksandra, primary, Lubinski, Jan, primary, Gronwald, Jacek, primary, Pearce, Celeste Leigh, primary, Pike, Malcolm C., primary, Wu, Anna, primary, Kommoss, Stefan, primary, Pfisterer, Jacobus, primary, du Bois, Andreas, primary, Hilpert, Felix, primary, Ramus, Susan J., primary, Bowtell, David D.L., primary, Huntsman, David G., primary, Pearson, Richard B., primary, Simpson, Kaylene J., primary, Campbell, Ian G., primary, and Gorringe, Kylie L., primary

Published
2023
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41. Data from Mutation of ERBB2 Provides a Novel Alternative Mechanism for the Ubiquitous Activation of RAS-MAPK in Ovarian Serous Low Malignant Potential Tumors

Author

Anglesio, Michael S., primary, Arnold, Jeremy M., primary, George, Joshy, primary, Tinker, Anna V., primary, Tothill, Richard, primary, Waddell, Nic, primary, Simms, Lisa, primary, Locandro, Bianca, primary, Fereday, Sian, primary, Traficante, Nadia, primary, Russell, Peter, primary, Sharma, Raghwa, primary, Birrer, Michael J., primary, deFazio, Anna, primary, Chenevix-Trench, Georgia, primary, and Bowtell, David D.L., primary

Published
2023
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42. Supplementary Table 3 from Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma

Author

Wang, Chen, primary, Block, Matthew S., primary, Cunningham, Julie M., primary, Sherman, Mark E., primary, McCauley, Bryan M., primary, Armasu, Sebastian M., primary, Vierkant, Robert A., primary, Traficante, Nadia, primary, Talhouk, Aline, primary, Ramus, Susan J., primary, Pejovic, Nadja, primary, Köbel, Martin, primary, Jorgensen, Brooke D., primary, Garsed, Dale W., primary, Fereday, Sian, primary, Doherty, Jennifer A., primary, Ariyaratne, Dinuka, primary, Anglesio, Michael S., primary, Widschwendter, Martin, primary, Pejovic, Tanja, primary, Bosquet, Jesus Gonzalez, primary, Bowtell, David D., primary, Winham, Stacey J., primary, and Goode, Ellen L., primary

Published
2023
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43. Supplementary Table 5 from Enhanced GAB2 Expression Is Associated with Improved Survival in High-Grade Serous Ovarian Cancer and Sensitivity to PI3K Inhibition

Author

Davis, Sally J., primary, Sheppard, Karen E., primary, Anglesio, Michael S., primary, George, Joshy, primary, Traficante, Nadia, primary, Fereday, Sian, primary, Intermaggio, Maria P., primary, Menon, Usha, primary, Gentry-Maharaj, Aleksandra, primary, Lubinski, Jan, primary, Gronwald, Jacek, primary, Pearce, Celeste Leigh, primary, Pike, Malcolm C., primary, Wu, Anna, primary, Kommoss, Stefan, primary, Pfisterer, Jacobus, primary, du Bois, Andreas, primary, Hilpert, Felix, primary, Ramus, Susan J., primary, Bowtell, David D.L., primary, Huntsman, David G., primary, Pearson, Richard B., primary, Simpson, Kaylene J., primary, Campbell, Ian G., primary, and Gorringe, Kylie L., primary

Published
2023
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44. Supplementary Figures and Tables from Enhanced GAB2 Expression Is Associated with Improved Survival in High-Grade Serous Ovarian Cancer and Sensitivity to PI3K Inhibition

Author

Davis, Sally J., primary, Sheppard, Karen E., primary, Anglesio, Michael S., primary, George, Joshy, primary, Traficante, Nadia, primary, Fereday, Sian, primary, Intermaggio, Maria P., primary, Menon, Usha, primary, Gentry-Maharaj, Aleksandra, primary, Lubinski, Jan, primary, Gronwald, Jacek, primary, Pearce, Celeste Leigh, primary, Pike, Malcolm C., primary, Wu, Anna, primary, Kommoss, Stefan, primary, Pfisterer, Jacobus, primary, du Bois, Andreas, primary, Hilpert, Felix, primary, Ramus, Susan J., primary, Bowtell, David D.L., primary, Huntsman, David G., primary, Pearson, Richard B., primary, Simpson, Kaylene J., primary, Campbell, Ian G., primary, and Gorringe, Kylie L., primary

Published
2023
Full Text
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45. Supplementary Data from Mutation of ERBB2 Provides a Novel Alternative Mechanism for the Ubiquitous Activation of RAS-MAPK in Ovarian Serous Low Malignant Potential Tumors

Author

Anglesio, Michael S., primary, Arnold, Jeremy M., primary, George, Joshy, primary, Tinker, Anna V., primary, Tothill, Richard, primary, Waddell, Nic, primary, Simms, Lisa, primary, Locandro, Bianca, primary, Fereday, Sian, primary, Traficante, Nadia, primary, Russell, Peter, primary, Sharma, Raghwa, primary, Birrer, Michael J., primary, deFazio, Anna, primary, Chenevix-Trench, Georgia, primary, and Bowtell, David D.L., primary

Published
2023
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46. Supplementary Figure 1 from Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma

Author

Wang, Chen, primary, Block, Matthew S., primary, Cunningham, Julie M., primary, Sherman, Mark E., primary, McCauley, Bryan M., primary, Armasu, Sebastian M., primary, Vierkant, Robert A., primary, Traficante, Nadia, primary, Talhouk, Aline, primary, Ramus, Susan J., primary, Pejovic, Nadja, primary, Köbel, Martin, primary, Jorgensen, Brooke D., primary, Garsed, Dale W., primary, Fereday, Sian, primary, Doherty, Jennifer A., primary, Ariyaratne, Dinuka, primary, Anglesio, Michael S., primary, Widschwendter, Martin, primary, Pejovic, Tanja, primary, Bosquet, Jesus Gonzalez, primary, Bowtell, David D., primary, Winham, Stacey J., primary, and Goode, Ellen L., primary

Published
2023
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47. Supplementary Table 2 from Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma

Author

Wang, Chen, primary, Block, Matthew S., primary, Cunningham, Julie M., primary, Sherman, Mark E., primary, McCauley, Bryan M., primary, Armasu, Sebastian M., primary, Vierkant, Robert A., primary, Traficante, Nadia, primary, Talhouk, Aline, primary, Ramus, Susan J., primary, Pejovic, Nadja, primary, Köbel, Martin, primary, Jorgensen, Brooke D., primary, Garsed, Dale W., primary, Fereday, Sian, primary, Doherty, Jennifer A., primary, Ariyaratne, Dinuka, primary, Anglesio, Michael S., primary, Widschwendter, Martin, primary, Pejovic, Tanja, primary, Bosquet, Jesus Gonzalez, primary, Bowtell, David D., primary, Winham, Stacey J., primary, and Goode, Ellen L., primary

Published
2023
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48. Supplementary Table 1 from Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma

Author

Wang, Chen, primary, Block, Matthew S., primary, Cunningham, Julie M., primary, Sherman, Mark E., primary, McCauley, Bryan M., primary, Armasu, Sebastian M., primary, Vierkant, Robert A., primary, Traficante, Nadia, primary, Talhouk, Aline, primary, Ramus, Susan J., primary, Pejovic, Nadja, primary, Köbel, Martin, primary, Jorgensen, Brooke D., primary, Garsed, Dale W., primary, Fereday, Sian, primary, Doherty, Jennifer A., primary, Ariyaratne, Dinuka, primary, Anglesio, Michael S., primary, Widschwendter, Martin, primary, Pejovic, Tanja, primary, Bosquet, Jesus Gonzalez, primary, Bowtell, David D., primary, Winham, Stacey J., primary, and Goode, Ellen L., primary

Published
2023
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49. Supplementary Methods 1 from Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma

Author

Wang, Chen, primary, Block, Matthew S., primary, Cunningham, Julie M., primary, Sherman, Mark E., primary, McCauley, Bryan M., primary, Armasu, Sebastian M., primary, Vierkant, Robert A., primary, Traficante, Nadia, primary, Talhouk, Aline, primary, Ramus, Susan J., primary, Pejovic, Nadja, primary, Köbel, Martin, primary, Jorgensen, Brooke D., primary, Garsed, Dale W., primary, Fereday, Sian, primary, Doherty, Jennifer A., primary, Ariyaratne, Dinuka, primary, Anglesio, Michael S., primary, Widschwendter, Martin, primary, Pejovic, Tanja, primary, Bosquet, Jesus Gonzalez, primary, Bowtell, David D., primary, Winham, Stacey J., primary, and Goode, Ellen L., primary

Published
2023
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50. Supplementary Figure 4 from Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma

Author

Wang, Chen, primary, Block, Matthew S., primary, Cunningham, Julie M., primary, Sherman, Mark E., primary, McCauley, Bryan M., primary, Armasu, Sebastian M., primary, Vierkant, Robert A., primary, Traficante, Nadia, primary, Talhouk, Aline, primary, Ramus, Susan J., primary, Pejovic, Nadja, primary, Köbel, Martin, primary, Jorgensen, Brooke D., primary, Garsed, Dale W., primary, Fereday, Sian, primary, Doherty, Jennifer A., primary, Ariyaratne, Dinuka, primary, Anglesio, Michael S., primary, Widschwendter, Martin, primary, Pejovic, Tanja, primary, Bosquet, Jesus Gonzalez, primary, Bowtell, David D., primary, Winham, Stacey J., primary, and Goode, Ellen L., primary

Published
2023
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