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

Author

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

Subjects
ovarian cancer, high‐grade serous carcinoma, endometrioid, clear cell, TP53, p53, Pathology, RB1-214
Abstract

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
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2. CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma

Author

Eun-Young, Kang, Ashley, Weir, Nicola S, Meagher, Kyo, Farrington, Gregg S, Nelson, Prafull, Ghatage, Cheng-Han, Lee, Marjorie J, Riggan, Adelyn, Bolithon, Gordana, Popovic, Betty, Leung, Katrina, Tang, Neil, Lambie, Joshua, Millstein, Jennifer, Alsop, Michael S, Anglesio, Beyhan, Ataseven, Ellen, Barlow, Matthias W, Beckmann, Jessica, Berger, Christiani, Bisinotto, Hans, Bösmüller, Jessica, Boros, Alison H, Brand, Angela, Brooks-Wilson, Sara Y, Brucker, Michael E, Carney, Yovanni, Casablanca, Alicia, Cazorla-Jiménez, Paul A, Cohen, Thomas P, Conrads, Linda S, Cook, Penny, Coulson, Madeleine, Courtney-Brooks, Daniel W, Cramer, Philip, Crowe, Julie M, Cunningham, Cezary, Cybulski, Kathleen M, Darcy, Mona A, El-Bahrawy, Esther, Elishaev, Ramona, Erber, Rhonda, Farrell, Sian, Fereday, Anna, Fischer, María J, García, Simon A, Gayther, Aleksandra, Gentry-Maharaj, C Blake, Gilks, Marcel, Grube, Paul R, Harnett, Shariska Petersen, Harrington, Philipp, Harter, Arndt, Hartmann, Jonathan L, Hecht, Sebastian, Heikaus, Alexander, Hein, Florian, Heitz, Joy, Hendley, Brenda Y, Hernandez, Susanna Hernando, Polo, Sabine, Heublein, Akira, Hirasawa, Estrid, Høgdall, Claus K, Høgdall, Hugo M, Horlings, David G, Huntsman, Tomasz, Huzarski, Andrea, Jewell, Mercedes, Jimenez-Linan, Michael E, Jones, Scott H, Kaufmann, Catherine J, Kennedy, Dineo, Khabele, Felix K F, Kommoss, Roy F P M, Kruitwagen, Diether, Lambrechts, Nhu D, Le, Marcin, Lener, Jenny, Lester, Yee, Leung, Anna, Linder, Liselore, Loverix, Jan, Lubiński, Rashna, Madan, G Larry, Maxwell, Francesmary, Modugno, Susan L, Neuhausen, Alexander, Olawaiye, Siel, Olbrecht, Sandra, Orsulic, José, Palacios, Celeste Leigh, Pearce, Malcolm C, Pike, Carmel M, Quinn, Ganendra Raj, Mohan, Cristina, Rodríguez-Antona, Matthias, Ruebner, Andy, Ryan, Stuart G, Salfinger, Naoko, Sasamoto, Joellen M, Schildkraut, Minouk J, Schoemaker, Mitul, Shah, Raghwa, Sharma, Yurii B, Shvetsov, Naveena, Singh, Gabe S, Sonke, Linda, Steele, Colin J R, Stewart, Karin, Sundfeldt, Anthony J, Swerdlow, Aline, Talhouk, Adeline, Tan, Sarah E, Taylor, Kathryn L, Terry, Aleksandra, Tołoczko, Nadia, Traficante, Koen K, Van de Vijver, Maaike A, van der Aa, Toon, Van Gorp, Els, Van Nieuwenhuysen, Lilian, van-Wagensveld, Ignace, Vergote, Robert A, Vierkant, Chen, Wang, Lynne R, Wilkens, Stacey J, Winham, Anna H, Wu, Javier, Benitez, Andrew, Berchuck, Francisco J, Candido Dos Reis, Anna, DeFazio, Peter A, Fasching, Ellen L, Goode, Marc T, Goodman, Jacek, Gronwald, Beth Y, Karlan, Stefan, Kommoss, Usha, Menon, Hans-Peter, Sinn, Annette, Staebler, James D, Brenton, David D, Bowtell, Paul D P, Pharoah, Susan J, Ramus, Martin, Köbel, MUMC+: MA Obstetrie Gynaecologie (3), MUMC+: Vrouw Moeder en Kind Centrum (3), Obstetrie & Gynaecologie, MUMC+: MA Arts Assistenten Obstetrie Gynaecologie (6), RS: GROW - R2 - Basic and Translational Cancer Biology, and AOCS Group

Subjects
Cancer Research, ovarian cancer, Oncology, high-grade serous carcinoma, Human medicine, prognosis, CCNE1 amplification, cyclin E1 expression
Abstract

BACKGROUND: Cyclin 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. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-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. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC. ispartof: CANCER vol:129 issue:5 pages:697-713 ispartof: location:United States status: published

Published
2023

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

Author

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

Subjects
Cancer Research, Oncology
Abstract

Background Recently, 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. Methods Two 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. Results Consistent 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. Conclusion We provide foundational evidence for the prognostic value of FOXJ1 in HGSC, validating the prior mRNA-based prognostic association by immunohistochemistry.

Published
2022

4. Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes

Author

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

Subjects
Ovarian Neoplasms, Cancer Research, BORDERLINE TUMORS, CARCINOMA, ADENOCARCINOMA, TRANSGELIN, Carcinoma, Ovarian Epithelial, EXPANSILE, Prognosis, INTESTINAL-TYPE, CANCER, Adenocarcinoma, Mucinous, PATTERN, RARE, Oncology, POOR-PROGNOSIS, Humans, Female, Neoplasm Staging, Gastrointestinal Neoplasms
Abstract

Purpose: Advanced-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 Design: Discovery 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). Results: Infiltrative 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%). Conclusions: An 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

5. Supplementary Methods 1 from Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes

Author

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

Abstract

Supplementary Methods

Published
2023

6. Data from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes

Author

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

Abstract

Purpose:To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes.Experimental Design:We 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.Results:We 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.Conclusions:Our 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
2023

7. Supplementary Data from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes

Author

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

Abstract

Supplementary Data from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes

Published
2023

8. Supplementary Figures S1-S13 from Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes

Author

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

Abstract

Supplementary Figures S1-S13

Published
2023

9. Data from Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes

Author

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

Abstract

Purpose:Advanced-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 Design:Discovery 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).Results:Infiltrative 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%).Conclusions:An 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
2023

10. Supplementary Tables S1-S11 from Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes

Author

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

Abstract

Supplementary Tables S1-S11

Published
2023

11. Validated biomarker assays confirm that <scp>ARID1A</scp> loss is confounded with <scp>MMR</scp> deficiency, <scp> CD8 + TIL </scp> infiltration, and provides no independent prognostic value in endometriosis‐associated ovarian carcinomas

Author

Karolin Heinze, Tayyebeh M Nazeran, Sandra Lee, Pauline Krämer, Evan S Cairns, Derek S Chiu, Samuel CY Leung, Eun Young Kang, Nicola S Meagher, Catherine J Kennedy, Jessica Boros, Friedrich Kommoss, Hans‐Walter Vollert, Florian Heitz, Andreas Bois, Philipp Harter, Marcel Grube, Bernhard Kraemer, Annette Staebler, Felix KF Kommoss, Sabine Heublein, Hans‐Peter Sinn, Naveena Singh, Angela Laslavic, Esther Elishaev, Alex Olawaiye, Kirsten Moysich, Francesmary Modugno, Raghwa Sharma, Alison H Brand, Paul R Harnett, Anna DeFazio, Renée T Fortner, Jan Lubinski, Marcin Lener, Aleksandra Tołoczko‐Grabarek, Cezary Cybulski, Helena Gronwald, Jacek Gronwald, Penny Coulson, Mona A El‐Bahrawy, Michael E Jones, Minouk J Schoemaker, Anthony J Swerdlow, Kylie L Gorringe, Ian Campbell, Linda Cook, Simon A Gayther, Michael E Carney, Yurii B Shvetsov, Brenda Y Hernandez, Lynne R Wilkens, Marc T Goodman, Constantina Mateoiu, Anna Linder, Karin Sundfeldt, Linda E Kelemen, Aleksandra Gentry‐Maharaj, Martin Widschwendter, Usha Menon, Kelly L Bolton, Jennifer Alsop, Mitul Shah, Mercedes Jimenez‐Linan, Paul DP Pharoah, James D Brenton, Kara L Cushing‐Haugen, Holly R Harris, Jennifer A Doherty, Blake Gilks, Prafull Ghatage, David G Huntsman, Gregg S Nelson, Anna V Tinker, Cheng‐Han Lee, Ellen L Goode, Brad H Nelson, Susan J Ramus, Stefan Kommoss, Aline Talhouk, Martin Köbel, and Michael S Anglesio

Subjects
Ovarian Neoplasms, Canada, Brain Neoplasms, Carcinoma, Endometriosis, Nuclear Proteins, CD8-Positive T-Lymphocytes, Prognosis, Article, Pathology and Forensic Medicine, DNA-Binding Proteins, Neoplastic Syndromes, Hereditary, Mutation, Biomarkers, Tumor, Humans, Female, Colorectal Neoplasms, Carcinoma, Endometrioid, Transcription Factors
Abstract

ARID1A (BAF250a) is a component of the SWI/SNF chromatin modifying complex, plays an important tumour suppressor role, and is considered prognostic in several malignancies. However, in ovarian carcinomas there are contradictory reports on its relationship to outcome, immune response, and correlation with clinicopathological features. We assembled a series of 1,623 endometriosis-associated ovarian carcinomas, including 1,078 endometrioid (ENOC) and 545 clear cell (CCOC) ovarian carcinomas through combining resources of the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Canadian Ovarian Unified Experimental Resource (COEUR), local, and collaborative networks. Validated immunohistochemical surrogate assays for ARID1A mutations were applied to all samples. We investigated associations between ARID1A loss/mutation, clinical features, outcome, CD8+ tumour-infiltrating lymphocytes (CD8+ TIL), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOC and 25% of ENOC. We found no associations between ARID1A loss and outcomes, stage, age, or CD8+ TIL status in CCOC. Similarly, we found no association with outcome or stage in endometrioid cases. In ENOC, ARID1A loss was more prevalent in younger patients (p=0.012), and associated with MMRd (p

Published
2022

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

Author

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

Subjects
Ovarian Neoplasms, Cancer Research, Oncology, Mutation, Endometriosis, Humans, Female, Adenocarcinoma, Clear Cell
Abstract

Purpose: To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes. Experimental Design: We 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. Results: We 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. Conclusions: Our 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

13. Older age should not be a barrier to testing for somatic variants in homologous recombination DNA repair-related genes in patients with high-grade serous ovarian carcinoma

Author

Omali Pitiyarachchi, Yeh Chen Lee, Hao-Wen Sim, Sivatharsny Srirangan, Cristina Mapagu, Judy Kirk, Paul R. Harnett, Rosemary L. Balleine, David D.L. Bowtell, Goli Samimi, Alison H. Brand, Deborah J. Marsh, Philip Beale, Lyndal Anderson, Natalie Bouantoun, Pamela Provan, Susan J. Ramus, Anna DeFazio, and Michael Friedlander

Subjects
Cancer Research, Oncology
Published
2023

14. The RANZCOG College Statement on prophylactic oophorectomy in older women undergoing hysterectomy for benign disease: is the evidence sufficient to change practice?

Author

Alison H, Brand

Subjects
Adult, Male, Ovarian Neoplasms, Health Knowledge, Attitudes, Practice, Ovariectomy, Australia, Middle Aged, Hysterectomy, Obstetrics, Gynecology, Practice Guidelines as Topic, Humans, Female, Guideline Adherence, Practice Patterns, Physicians', Societies, Medical, New Zealand
Abstract

In 2009, the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) published College Statement C-Gyn 25: "Prophylactic oophorectomy at the time of hysterectomy for benign gynaecological disease, which recommended that caution should be exercised in performing bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy for benign disease in women younger than 65 years of age."The aims of the study were to assess current practice with regard to prophylactic oophorectomy in this setting and to assess knowledge about the College Statement. We also sought to review the evidence behind the Statement.An anonymous email survey of all consultant gynaecologists and gynaecology registrars in Sydney West Area Health Service (SWAHS) was conducted.The response rate was 52%. The survey found that there was an increasing tendency to remove ovaries with increasing patient age, and over 60% of gynaecologists would routinely recommend removal of ovaries during a hysterectomy for benign disease in a 60 year old woman. The survey also revealed a lack of knowledge as to the existence or content of the College Statement. A review of the literature found that evidence suggesting benefit in retention of ovaries in postmenopausal women has been extrapolated from a modelling study, observational studies or from data on premenopausal oophorectomy.A survey of gynaecologists revealed that few currently appear to adhere to the College Statement regarding prophylactic oophorectomy at the time of hysterectomy for benign disease. High quality evidence regarding either harm or benefit following retention of ovaries after menopause is lacking. Nevertheless, dialogue between clinicians and patients on this topic is important.

Published
2011

15. The woman with postmenopausal bleeding

Author

Alison H, Brand

Subjects
Postmenopause, Genital Neoplasms, Female, Humans, Female, Uterine Hemorrhage, Middle Aged, Endometritis, Vaginitis, Algorithms
Abstract

Postmenopausal bleeding is a common complaint from women seen in general practice.This article outlines a general approach to such patients and discusses the diagnostic possibilities and their management.The most common cause of postmenopausal bleeding is atrophic vaginitis or endometritis. However, as 10% of women with postmenopausal bleeding will be found to have endometrial cancer, all patients must be properly assessed to rule out the diagnosis of malignancy. Most women with endometrial cancer will be diagnosed with early stage disease when the prognosis is excellent as postmenopausal bleeding is an early warning sign that leads women to seek medical advice.

Published
2007

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