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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

4. 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

13. Exome Sequencing Identifies Carriers of the Autosomal Dominant Cancer Predisposition Disorders Beyond Current Practice Guideline Recommendations

Author

Samadder, N. Jewel, Gay, Emily, Lindpere, Vanda, Bublitz, Michelle L., Bandel, Lorelei A., Armasu, Sebastian M., Vierkant, Robert A., Ferber, Matthew J., Klee, Eric W., Larson, Nicholas B., Kruisselbrink, Teresa M., Egan, Jan B., Kemppainen, Jennifer L., Bidwell, Jessa S., Anderson, Jennifer L., McAllister, Tammy M., Walker, TʼNita S., Kunze, Katie L., Golafshar, Michael A., Klint, Margaret A., Presutti, Richard J., Bobo, William V., Sekulic, Aleksander, Summer-Bolster, Jolene M., Willman, Cheryl L., and Lazaridis, Konstantinos N.

Published
2024
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15. Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions

Author

Dareng, Eileen O., Coetzee, Simon G., Tyrer, Jonathan P., Peng, Pei-Chen, Rosenow, Will, Chen, Stephanie, Davis, Brian D., Dezem, Felipe Segato, Seo, Ji-Heui, Nameki, Robbin, Reyes, Alberto L., Aben, Katja K.H., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Bandera, Elisa V., Beane Freeman, Laura E., Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia V., Bolton, Kelly L., Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Cai, Hui, Campbell, Ian, Cannioto, Rikki, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chenevix-Trench, Georgia, Chiew, Yoke-Eng, Cook, Linda S., DeFazio, Anna, Dennis, Joe, Doherty, Jennifer A., Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana M., Ene, Gabrielle, Fasching, Peter A., Flanagan, James M., Fortner, Renée T., Fostira, Florentia, Gentry-Maharaj, Aleksandra, Giles, Graham G., Goodman, Marc T., Gronwald, Jacek, Haiman, Christopher A., Håkansson, Niclas, Heitz, Florian, Hildebrandt, Michelle A.T., Høgdall, Estrid, Høgdall, Claus K., Huang, Ruea-Yea, Jensen, Allan, Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony N., Kelemen, Linda E., Kennedy, Catherine J., Khusnutdinova, Elza K., Kiemeney, Lambertus A., Kjaer, Susanne K., Kupryjanczyk, Jolanta, Labrie, Marilyne, Lambrechts, Diether, Larson, Melissa C., Le, Nhu D., Lester, Jenny, Li, Lian, Lubiński, Jan, Lush, Michael, Marks, Jeffrey R., Matsuo, Keitaro, May, Taymaa, McLaughlin, John R., McNeish, Iain A., Menon, Usha, Missmer, Stacey, Modugno, Francesmary, Moffitt, Melissa, Monteiro, Alvaro N., Moysich, Kirsten B., Narod, Steven A., Nguyen-Dumont, Tu, Odunsi, Kunle, Olsson, Håkan, Onland-Moret, N. Charlotte, Park, Sue K., Pejovic, Tanja, Permuth, Jennifer B., Piskorz, Anna, Prokofyeva, Darya, Riggan, Marjorie J., Risch, Harvey A., Rodríguez-Antona, Cristina, Rossing, Mary Anne, Sandler, Dale P., Setiawan, V. Wendy, Shan, Kang, Song, Honglin, Southey, Melissa C., Steed, Helen, Sutphen, Rebecca, Swerdlow, Anthony J., Teo, Soo Hwang, Terry, Kathryn L., Thompson, Pamela J., Vestrheim Thomsen, Liv Cecilie, Titus, Linda, Trabert, Britton, Travis, Ruth, Tworoger, Shelley S., Valen, Ellen, Van Nieuwenhuysen, Els, Edwards, Digna Velez, Vierkant, Robert A., Webb, Penelope M., Weinberg, Clarice R., Weise, Rayna Matsuno, Wentzensen, Nicolas, White, Emily, Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zeinomar, Nur, Zheng, Wei, Ziogas, Argyrios, Berchuck, Andrew, Goode, Ellen L., Huntsman, David G., Pearce, Celeste L., Ramus, Susan J., Sellers, Thomas A., Freedman, Matthew L., Lawrenson, Kate, Schildkraut, Joellen M., Hazelett, Dennis, Plummer, Jasmine T., Kar, Siddhartha, Jones, Michelle R., Pharoah, Paul D.P., and Gayther, Simon A.

Published
2024
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16. 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

19. High pre-diagnosis inflammation-related risk score associated with decreased ovarian cancer survival

Author

Brieger, Katharine K, Phung, Minh Tung, Mukherjee, Bhramar, Bakulski, Kelly M, Anton-Culver, Hoda, Bandera, Elisa V, Bowtell, David DL, Cramer, Daniel W, DeFazio, Anna, Doherty, Jennifer A, Fereday, Sian, Fortner, Renée Turzanski, Gentry-Maharaj, Aleksandra, Goode, Ellen L, Goodman, Marc T, Harris, Holly R, Matsuo, Keitaro, Menon, Usha, Modugno, Francesmary, Moysich, Kirsten B, Qin, Bo, Ramus, Susan J, Risch, Harvey A, Rossing, Mary Anne, Schildkraut, Joellen M, Trabert, Britton, Vierkant, Robert A, Winham, Stacey J, Wentzensen, Nicolas, Wu, Anna H, Ziogas, Argyrios, Khoja, Lilah, Cho, Kathleen R, McLean, Karen, Richardson, Jean, Grout, Bronwyn, Chase, Anne, Deurloo, Cindy McKinnon, Odunsi, Kunle, Nelson, Brad H, Brenton, James D, Terry, Kathryn L, Pharoah, Paul DP, Berchuck, Andrew, Hanley, Gillian E, Webb, Penelope M, Pike, Malcolm C, and Pearce, Celeste Leigh

Subjects
Epidemiology, Biomedical and Clinical Sciences, Health Sciences, Tobacco Smoke and Health, Prevention, Ovarian Cancer, Tobacco, Cancer, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Aged, Carcinoma, Ovarian Epithelial, Female, Health Behavior, Humans, Inflammation, Middle Aged, Ovarian Neoplasms, Proportional Hazards Models, Risk Assessment, Ovarian Cancer Association Consortium, Medical and Health Sciences, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundThere is suggestive evidence that inflammation is related to ovarian cancer survival. However, more research is needed to identify inflammation-related factors that are associated with ovarian cancer survival and to determine their combined effects.MethodsThis analysis used pooled data on 8,147 women with invasive epithelial ovarian cancer from the Ovarian Cancer Association Consortium. The prediagnosis inflammation-related exposures of interest included alcohol use; aspirin use; other nonsteroidal anti-inflammatory drug use; body mass index; environmental tobacco smoke exposure; history of pelvic inflammatory disease, polycystic ovarian syndrome, and endometriosis; menopausal hormone therapy use; physical inactivity; smoking status; and talc use. Using Cox proportional hazards models, the relationship between each exposure and survival was assessed in 50% of the data. A weighted inflammation-related risk score (IRRS) was developed, and its association with survival was assessed using Cox proportional hazards models in the remaining 50% of the data.ResultsThere was a statistically significant trend of increasing risk of death per quartile of the IRRS [HR = 1.09; 95% confidence interval (CI), 1.03-1.14]. Women in the upper quartile of the IRRS had a 31% higher death rate compared with the lowest quartile (95% CI, 1.11-1.54).ConclusionsA higher prediagnosis IRRS was associated with an increased mortality risk after an ovarian cancer diagnosis. Further investigation is warranted to evaluate whether postdiagnosis exposures are also associated with survival.ImpactGiven that pre- and postdiagnosis exposures are often correlated and many are modifiable, our study results can ultimately motivate the development of behavioral recommendations to enhance survival among patients with ovarian cancer.

Published
2022

25. Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer.

Author

Kar, Siddhartha P, Considine, Daniel PC, Tyrer, Jonathan P, Plummer, Jasmine T, Chen, Stephanie, Dezem, Felipe S, Barbeira, Alvaro N, Rajagopal, Padma S, Rosenow, Will T, Moreno, Fernando, Bodelon, Clara, Chang-Claude, Jenny, Chenevix-Trench, Georgia, deFazio, Anna, Dörk, Thilo, Ekici, Arif B, Ewing, Ailith, Fountzilas, George, Goode, Ellen L, Hartman, Mikael, Heitz, Florian, Hillemanns, Peter, Høgdall, Estrid, Høgdall, Claus K, Huzarski, Tomasz, Jensen, Allan, Karlan, Beth Y, Khusnutdinova, Elza, Kiemeney, Lambertus A, Kjaer, Susanne K, Klapdor, Rüdiger, Köbel, Martin, Li, Jingmei, Liebrich, Clemens, May, Taymaa, Olsson, Håkan, Permuth, Jennifer B, Peterlongo, Paolo, Radice, Paolo, Ramus, Susan J, Riggan, Marjorie J, Risch, Harvey A, Saloustros, Emmanouil, Simard, Jacques, Szafron, Lukasz M, Titus, Linda, Thompson, Cheryl L, Vierkant, Robert A, Winham, Stacey J, Zheng, Wei, Doherty, Jennifer A, Berchuck, Andrew, Lawrenson, Kate, Im, Hae Kyung, Manichaikul, Ani W, Pharoah, Paul DP, Gayther, Simon A, and Schildkraut, Joellen M

Subjects
Biotechnology, Genetics, Prevention, Cancer, Breast Cancer, Human Genome, Ovarian Cancer, Rare Diseases, 2.1 Biological and endogenous factors
Abstract

Familial, sequencing, and genome-wide association studies (GWASs) and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWASs) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through application of a pleiotropy-guided conditional/conjunction false discovery rate (FDR) approach in the setting of a TWASs. This identified 14 candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR < 0.05 that were >1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. The 22 genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk.

Published
2021

26. Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer

Author

Song, Honglin, Dicks, Ed M, Tyrer, Jonathan, Intermaggio, Maria, Chenevix-Trench, Georgia, Bowtell, David D, Traficante, Nadia, Group, AOCS, Brenton, James, Goranova, Teodora, Hosking, Karen, Piskorz, Anna, van Oudenhove, Elke, Doherty, Jen, Harris, Holly R, Rossing, Mary Anne, Duerst, Matthias, Dork, Thilo, Bogdanova, Natalia V, Modugno, Francesmary, Moysich, Kirsten, Odunsi, Kunle, Ness, Roberta, Karlan, Beth Y, Lester, Jenny, Jensen, Allan, Kjaer, Susanne Krüger, Høgdall, Estrid, Campbell, Ian G, Lázaro, Conxi, Pujara, Miguel Angel, Cunningham, Julie, Vierkant, Robert, Winham, Stacey J, Hildebrandt, Michelle, Huff, Chad, Li, Donghui, Wu, Xifeng, Yu, Yao, Permuth, Jennifer B, Levine, Douglas A, Schildkraut, Joellen M, Riggan, Marjorie J, Berchuck, Andrew, Webb, Penelope M, Group, OPAL Study, Cybulski, Cezary, Gronwald, Jacek, Jakubowska, Anna, Lubinski, Jan, Alsop, Jennifer, Harrington, Patricia, Chan, Isaac, Menon, Usha, Pearce, Celeste L, Wu, Anna H, de Fazio, Anna, Kennedy, Catherine J, Goode, Ellen, Ramus, Susan, Gayther, Simon, and Pharoah, Paul

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Orphan Drug, Ovarian Cancer, Prevention, Clinical Research, Rare Diseases, Cancer, 2.1 Biological and endogenous factors, Aetiology, Case-Control Studies, Fanconi Anemia Complementation Group N Protein, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Ovarian Neoplasms, Risk Assessment, cancer, endocrine, genetic epidemiology, cancer: endocrine, Medical and Health Sciences, Genetics & Heredity, Clinical sciences
Abstract

PurposeThe known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes.MethodsWe sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics.ResultsThe ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive.ConclusionsWe have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.

Published
2021

29. The genomic and immune landscape of long-term survivors of high-grade serous ovarian cancer

Author

Garsed, Dale W., Pandey, Ahwan, Fereday, Sian, Kennedy, Catherine J., Takahashi, Kazuaki, Alsop, Kathryn, Hamilton, Phineas T., Hendley, Joy, Chiew, Yoke-Eng, Traficante, Nadia, Provan, Pamela, Ariyaratne, Dinuka, Au-Yeung, George, Bateman, Nicholas W., Bowes, Leanne, Brand, Alison, Christie, Elizabeth L., Cunningham, Julie M., Friedlander, Michael, Grout, Bronwyn, Harnett, Paul, Hung, Jillian, McCauley, Bryan, McNally, Orla, Piskorz, Anna M., Saner, Flurina A. M., Vierkant, Robert A., Wang, Chen, Winham, Stacey J., Pharoah, Paul D. P., Brenton, James D., Conrads, Thomas P., Maxwell, George L., Ramus, Susan J., Pearce, Celeste Leigh, Pike, Malcolm C., Nelson, Brad H., Goode, Ellen L., DeFazio, Anna, and Bowtell, David D. L.

Published
2022
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30. 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

38. Serum hormone levels and normal breast histology among premenopausal women

Author

Sherman, Mark E., de Bel, Thomas, Heckman, Michael G., White, Launia J., Ogony, Joshua, Stallings-Mann, Melody, Hilton, Tracy, Degnim, Amy C., Vierkant, Robert A., Hoskin, Tanya, Jensen, Matthew R., Pacheco-Spann, Laura, Henry, Jill E., Storniolo, Anna Maria, Carter, Jodi M., Winham, Stacey J., Radisky, Derek C., and van der Laak, Jeroen

Published
2022
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39. Population based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high grade serous ovarian cancer

Author

Song, Honglin, Dicks, Ed, Tyrer, Jonathan P, Intermaggio, Maria, Chenevix-Trench, Georgia, Bowtell, David D, Traficante, Nadia, Group, AOCS, Brenton, James D, Goranova, Teodora, Hosking, Karen, Piskorz, Anna, Van Oudenhove, Elke, Doherty, Jennifer Anne, Harris, Holly R, Rossing, Mary Anne, Dürst, Matthias, Dörk, Thilo, Bogdanova, Natalia V, Modugno, Francesmary, Moysich, Kirsten B, Odunsi, Kunle, Ness, Roberta B, Karlan, Beth Y, Lester, Jenny, Jensen, Allan, Kjaer, Susanne K, Høgdall, Estrid, Campbell, Ian, Lazaro, Conxi, Pujana, Miquel Angel, Cunningham, Julie M, Vierkant, Robert A, Winham, Stacey J, Hildebrandt, Michelle AT, Huff, Chad, Li, Donghui, Wu, Xifeng, Yu, Yao, Permuth, Jennifer B, Levine, Douglas A, Schildkraut, Joellen M, Riggan, Marjorie J, Berchuck, Andrew, Webb, Penelope M, Group, OPAL Study, Cybulski, Cezary, Gronwald, Jacek, Jakubowska, Anna, Lubiński, Jan, Alsop, Jennifer, Harrington, Patricia A, Chan, Isaac, Menon, Usha, Pearce, Celeste L, Wu, Anna H, de Fazio, Anna, Kennedy, Catherine J, Goode, Ellen L, Ramus, Susan J, Gayther, Simon A, and Pharoah, Paul DP

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Health Sciences, Oncology and Carcinogenesis, Orphan Drug, Clinical Research, Human Genome, Rare Diseases, Ovarian Cancer, Cancer, Prevention, 2.1 Biological and endogenous factors, Aetiology
Abstract

Abstract: Purpose: The known EOC susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes. Methods: We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases verses controls were further examined in an independent set of 14,146 EOC cases and 28,661 controls from the ovarian cancer association consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics. Results: The odds ratios (OR) associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 – 5.68; P = 0.00068), 1.99 for POLK (95% CI 1.15 – 3.43; P = 0.014), and 4.07 for SLX4 (95% CI 1.34-12.4; P = 0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 −1.00, P=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive. Conclusions: We have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.

Published
2019

41. Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Author

Dareng, Eileen O., Tyrer, Jonathan P., Barnes, Daniel R., Jones, Michelle R., Yang, Xin, Aben, Katja K. H., Adank, Muriel A., Agata, Simona, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Arun, Banu K., Augustinsson, Annelie, Balmaña, Judith, Bandera, Elisa V., Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia V., Bonanni, Bernardo, Borg, Ake, Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S., Cai, Hui, Caligo, Maria A., Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K., Claes, Kathleen B. M., Colonna, Sarah, Cook, Linda S., Couch, Fergus J., Daly, Mary B., Dao, Fanny, Davies, Eleanor, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A., Domchek, Susan M., Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana M., Eliassen, Heather A., Engel, Christoph, Evans, Gareth D., Fasching, Peter A., Flanagan, James M., Fortner, Renée T., Machackova, Eva, Friedman, Eitan, Ganz, Patricia A., Garber, Judy, Gensini, Francesca, Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hamann, Ute, Hansen, Thomas V. O., Harris, Holly R., Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle A. T., Høgdall, Estrid, Høgdall, Claus K., Hopper, John L., Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J., Huntsman, David G., Imyanitov, Evgeny N., Isaacs, Claudine, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th., John, Esther M., Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony, Kelemen, Linda E., Khusnutdinova, Elza, Kiemeney, Lambertus A., Kim, Byoung-Gie, Kjaer, Susanne K., Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W., Kwong, Ava, Lambrechts, Diether, Larson, Melissa C., Lazaro, Conxi, Le, Nhu D., Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Levine, Douglas A., Li, Lian, Li, Jingmei, Loud, Jennifer T., Lu, Karen H., Lubiński, Jan, Mai, Phuong L., Manoukian, Siranoush, Marks, Jeffrey R., Matsuno, Rayna Kim, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R., McNeish, Iain A., Mebirouk, Noura, Menon, Usha, Miller, Austin, Milne, Roger L., Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Munro, Elizabeth, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nielsen, Henriette Roed, Nielsen, Finn C., Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo I., Olson, Sara H., Olsson, Håkan, Osorio, Ana, Papi, Laura, Park, Sue K., Parsons, Michael T., Pathak, Harsha, Pedersen, Inge Sokilde, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B., Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J., Risch, Harvey A., Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P., Santamariña, Marta, Soucy, Penny, Schmutzler, Rita K., Setiawan, V. Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sokolenko, Anna P., Song, Honglin, Southey, Melissa C., Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J., Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Terry, Kathryn L., Terry, Mary Beth, Thomassen, Mads, Thompson, Pamela J., Thomsen, Liv Cecilie Vestrheim, Thull, Darcy L., Tischkowitz, Marc, Titus, Linda, Toland, Amanda E., Torres, Diana, Trabert, Britton, Travis, Ruth, Tung, Nadine, Tworoger, Shelley S., Valen, Ellen, van Altena, Anne M., van der Hout, Annemieke H., Van Nieuwenhuysen, Els, van Rensburg, Elizabeth J., Vega, Ana, Edwards, Digna Velez, Vierkant, Robert A., Wang, Frances, Wappenschmidt, Barbara, Webb, Penelope M., Weinberg, Clarice R., Weitzel, Jeffrey N., Wentzensen, Nicolas, White, Emily, Whittemore, Alice S., Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zavaglia, Katia M., Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Kleibl, Zdenek, Easton, Douglas, Lawrenson, Kate, DeFazio, Anna, Sellers, Thomas A., Ramus, Susan J., Pearce, Celeste L., Monteiro, Alvaro N., Cunningham, Julie, Goode, Ellen L., Schildkraut, Joellen M., Berchuck, Andrew, Chenevix-Trench, Georgia, Gayther, Simon A., Antoniou, Antonis C., and Pharoah, Paul D. P.

Published
2022
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42. Quality control recommendations for RNASeq using FFPE samples based on pre-sequencing lab metrics and post-sequencing bioinformatics metrics

Author

Liu, Yuanhang, Bhagwate, Aditya, Winham, Stacey J., Stephens, Melissa T., Harker, Brent W., McDonough, Samantha J., Stallings-Mann, Melody L., Heinzen, Ethan P., Vierkant, Robert A., Hoskin, Tanya L., Frost, Marlene H., Carter, Jodi M., Pfrender, Michael E., Littlepage, Laurie, Radisky, Derek C., Cunningham, Julie M., Degnim, Amy C., and Wang, Chen

Published
2022
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43. Towards defining morphologic parameters of normal parous and nulliparous breast tissues by artificial intelligence

Author

Ogony, Joshua, de Bel, Thomas, Radisky, Derek C., Kachergus, Jennifer, Thompson, E. Aubrey, Degnim, Amy C., Ruddy, Kathryn J., Hilton, Tracy, Stallings-Mann, Melody, Vachon, Celine, Hoskin, Tanya L., Heckman, Michael G., Vierkant, Robert A., White, Launia J., Moore, Raymond M., Carter, Jodi, Jensen, Matthew, Pacheco-Spann, Laura, Henry, Jill E., Storniolo, Anna Maria, Winham, Stacey J., van der Laak, Jeroen, and Sherman, Mark E.

Published
2022
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47. Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study.

Author

Rambau, Peter F, Vierkant, Robert A, Intermaggio, Maria P, Kelemen, Linda E, Goodman, Marc T, Herpel, Esther, Pharoah, Paul D, Kommoss, Stefan, Jimenez-Linan, Mercedes, Karlan, Beth Y, Gentry-Maharaj, Aleksandra, Menon, Usha, Polo, Susanna Hernando, Candido Dos Reis, Francisco J, Doherty, Jennifer Anne, Gayther, Simon A, Sharma, Raghwa, Larson, Melissa C, Harnett, Paul R, Hatfield, Emma, de Andrade, Jurandyr M, Nelson, Gregg S, Steed, Helen, Schildkraut, Joellen M, Carney, Micheal E, Høgdall, Estrid, Whittemore, Alice S, Widschwendter, Martin, Kennedy, Catherine J, Wang, Frances, Wang, Qin, Wang, Chen, Armasu, Sebastian M, Daley, Frances, Coulson, Penny, Jones, Micheal E, Anglesio, Micheal S, Chow, Christine, de Fazio, Anna, García-Closas, Montserrat, Brucker, Sara Y, Cybulski, Cezary, Harris, Holly R, Hartkopf, Andreas D, Huzarski, Tomasz, Jensen, Allan, Lubiński, Jan, Oszurek, Oleg, Benitez, Javier, Mina, Fady, Staebler, Annette, Taran, Florin Andrei, Pasternak, Jana, Talhouk, Aline, Rossing, Mary Anne, Hendley, Joy, AOCS Group, Edwards, Robert P, Fereday, Sian, Modugno, Francesmary, Ness, Roberta B, Sieh, Weiva, El-Bahrawy, Mona A, Winham, Stacey J, Lester, Jenny, Kjaer, Susanne K, Gronwald, Jacek, Sinn, Peter, Fasching, Peter A, Chang-Claude, Jenny, Moysich, Kirsten B, Bowtell, David D, Hernandez, Brenda Y, Luk, Hugh, Behrens, Sabine, Shah, Mitul, Jung, Audrey, Ghatage, Prafull, Alsop, Jennifer, Alsop, Kathryn, García-Donas, Jesús, Thompson, Pamela J, Swerdlow, Anthony J, Karpinskyj, Chloe, Cazorla-Jiménez, Alicia, García, María J, Deen, Susha, Wilkens, Lynne R, Palacios, José, Berchuck, Andrew, Koziak, Jennifer M, Brenton, James D, Cook, Linda S, Goode, Ellen L, Huntsman, David G, Ramus, Susan J, and Köbel, Martin

Subjects
AOCS Group, Ovary, Humans, Adenocarcinoma, Mucinous, Cystadenocarcinoma, Serous, Ovarian Neoplasms, Prognosis, Immunohistochemistry, Survival Rate, Adult, Aged, Middle Aged, Female, Cyclin-Dependent Kinase Inhibitor p16, RT-QPCR, immunocytochemistry, ovary, Adenocarcinoma, Mucinous, Cystadenocarcinoma, Serous, Cancer, Genetics, Ovarian Cancer, Rare Diseases, 2.1 Biological and endogenous factors
Abstract

We aimed to validate the prognostic association of p16 expression in ovarian high-grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical-grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis-associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47-2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30-2.75, p = 0.004), while absence was associated with shorter OS in low-grade serous carcinomas (HR: 2.95, 95% CI 1.61-5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype-specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low-grade serous carcinoma justifies CDK4 inhibition.

Published
2018

48. rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology.

Author

Kelemen, Linda E, Earp, Madalene, Fridley, Brooke L, Chenevix-Trench, Georgia, Australian Ovarian Cancer Study Group, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Hein, Alexander, Lambrechts, Diether, Lambrechts, Sandrina, Van Nieuwenhuysen, Els, Vergote, Ignace, Rossing, Mary Anne, Doherty, Jennifer A, Chang-Claude, Jenny, Behrens, Sabine, Moysich, Kirsten B, Cannioto, Rikki, Lele, Shashikant, Odunsi, Kunle, Goodman, Marc T, Shvetsov, Yurii B, Thompson, Pamela J, Wilkens, Lynne R, Dörk, Thilo, Antonenkova, Natalia, Bogdanova, Natalia, Hillemanns, Peter, Runnebaum, Ingo B, du Bois, Andreas, Harter, Philipp, Heitz, Florian, Schwaab, Ira, Butzow, Ralf, Pelttari, Liisa M, Nevanlinna, Heli, Modugno, Francesmary, Edwards, Robert P, Kelley, Joseph L, Ness, Roberta B, Karlan, Beth Y, Lester, Jenny, Orsulic, Sandra, Walsh, Christine, Kjaer, Susanne K, Jensen, Allan, Cunningham, Julie M, Vierkant, Robert A, Giles, Graham G, Bruinsma, Fiona, Southey, Melissa C, Hildebrandt, Michelle AT, Liang, Dong, Lu, Karen, Wu, Xifeng, Sellers, Thomas A, Levine, Douglas A, Schildkraut, Joellen M, Iversen, Edwin S, Terry, Kathryn L, Cramer, Daniel W, Tworoger, Shelley S, Poole, Elizabeth M, Bandera, Elisa V, Olson, Sara H, Orlow, Irene, Vestrheim Thomsen, Liv Cecilie, Bjorge, Line, Krakstad, Camilla, Tangen, Ingvild L, Kiemeney, Lambertus A, Aben, Katja KH, Massuger, Leon FAG, van Altena, Anne M, Pejovic, Tanja, Bean, Yukie, Kellar, Melissa, Cook, Linda S, Le, Nhu D, Brooks-Wilson, Angela, Gronwald, Jacek, Cybulski, Cezary, Jakubowska, Anna, Lubiński, Jan, Wentzensen, Nicolas, Brinton, Louise A, Lissowska, Jolanta, Hogdall, Estrid, Engelholm, Svend Aage, Hogdall, Claus, Lundvall, Lene, Nedergaard, Lotte, Pharoah, Paul DP, Dicks, Ed, Song, Honglin, Tyrer, Jonathan P, McNeish, Iain, Siddiqui, Nadeem, and Carty, Karen

Subjects
Australian Ovarian Cancer Study Group, Ovarian Cancer Association Consortium, Humans, Adenocarcinoma, Mucinous, Ovarian Neoplasms, Hydro-Lyases, Thymidylate Synthase, Proteins, RNA, Antisense, Logistic Models, Odds Ratio, Risk, Case-Control Studies, Signal Transduction, Gene Expression Regulation, Neoplastic, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Middle Aged, Female, Genetic Association Studies, consortia, enolase superfamily member 1, expression quantitative trait locus, genetics, gynecology, ovarian neoplasms, single-nucleotide polymorphism, thymidylate synthase, Ovarian Cancer, Rare Diseases, Biotechnology, Cancer, Digestive Diseases, Genetics, Chemical Physics, Other Chemical Sciences, Other Biological Sciences
Abstract

Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3' gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97⁻1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03⁻1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10-28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.

Published
2018

49. MyD88 and TLR4 Expression in Epithelial Ovarian Cancer.

Author

Block, Matthew S, Vierkant, Robert A, Rambau, Peter F, Winham, Stacey J, Wagner, Philipp, Traficante, Nadia, Tołoczko, Aleksandra, Tiezzi, Daniel G, Taran, Florin Andrei, Sinn, Peter, Sieh, Weiva, Sharma, Raghwa, Rothstein, Joseph H, Ramón Y Cajal, Teresa, Paz-Ares, Luis, Oszurek, Oleg, Orsulic, Sandra, Ness, Roberta B, Nelson, Gregg, Modugno, Francesmary, Menkiszak, Janusz, McGuire, Valerie, McCauley, Bryan M, Mack, Marie, Lubiński, Jan, Longacre, Teri A, Li, Zheng, Lester, Jenny, Kennedy, Catherine J, Kalli, Kimberly R, Jung, Audrey Y, Johnatty, Sharon E, Jimenez-Linan, Mercedes, Jensen, Allan, Intermaggio, Maria P, Hung, Jillian, Herpel, Esther, Hernandez, Brenda Y, Hartkopf, Andreas D, Harnett, Paul R, Ghatage, Prafull, García-Bueno, José M, Gao, Bo, Fereday, Sian, Eilber, Ursula, Edwards, Robert P, de Sousa, Christiani B, de Andrade, Jurandyr M, Chudecka-Głaz, Anita, Chenevix-Trench, Georgia, Cazorla, Alicia, Brucker, Sara Y, Australian Ovarian Cancer Study Group, Alsop, Jennifer, Whittemore, Alice S, Steed, Helen, Staebler, Annette, Moysich, Kirsten B, Menon, Usha, Koziak, Jennifer M, Kommoss, Stefan, Kjaer, Susanne K, Kelemen, Linda E, Karlan, Beth Y, Huntsman, David G, Høgdall, Estrid, Gronwald, Jacek, Goodman, Marc T, Gilks, Blake, García, María José, Fasching, Peter A, de Fazio, Anna, Deen, Suha, Chang-Claude, Jenny, Candido Dos Reis, Francisco J, Campbell, Ian G, Brenton, James D, Bowtell, David D, Benítez, Javier, Pharoah, Paul DP, Köbel, Martin, Ramus, Susan J, and Goode, Ellen L

Subjects
Australian Ovarian Cancer Study Group, Humans, Ovarian Neoplasms, Tissue Array Analysis, Immunohistochemistry, Survival Analysis, Adult, Aged, Middle Aged, Female, Toll-Like Receptor 4, Myeloid Differentiation Factor 88, Biomarkers, Tumor, Carcinoma, Ovarian Epithelial, Biomarkers, Tumor, Carcinoma, Ovarian Epithelial, Medical and Health Sciences
Abstract

ObjectiveTo evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival.Patients and methodsWe conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time. Tissue microarrays were stained for MyD88 and TLR4, and staining intensity was classified using a 2-tiered system for each marker (weak vs strong).ResultsExpression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P

Published
2018

50. Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer

Author

Goode, Ellen L, Block, Matthew S, Kalli, Kimberly R, Vierkant, Robert A, Chen, Wenqian, Fogarty, Zachary C, Gentry-Maharaj, Aleksandra, Tołoczko, Aleksandra, Hein, Alexander, Bouligny, Aliecia L, Jensen, Allan, Osorio, Ana, Hartkopf, Andreas D, Ryan, Andy, Chudecka-Głaz, Anita, Magliocco, Anthony M, Hartmann, Arndt, Jung, Audrey Y, Gao, Bo, Hernandez, Brenda Y, Fridley, Brooke L, McCauley, Bryan M, Kennedy, Catherine J, Wang, Chen, Karpinskyj, Chloe, de Sousa, Christiani B, Tiezzi, Daniel G, Wachter, David L, Herpel, Esther, Taran, Florin Andrei, Modugno, Francesmary, Nelson, Gregg, Lubiński, Jan, Menkiszak, Janusz, Alsop, Jennifer, Lester, Jenny, García-Donas, Jesús, Nation, Jill, Hung, Jillian, Palacios, José, Rothstein, Joseph H, Kelley, Joseph L, de Andrade, Jurandyr M, Robles-Díaz, Luis, Intermaggio, Maria P, Widschwendter, Martin, Beckmann, Matthias W, Ruebner, Matthias, Jimenez-Linan, Mercedes, Singh, Naveena, Oszurek, Oleg, Harnett, Paul R, Rambau, Peter F, Sinn, Peter, Wagner, Philipp, Ghatage, Prafull, Sharma, Raghwa, Edwards, Robert P, Ness, Roberta B, Orsulic, Sandra, Brucker, Sara Y, Johnatty, Sharon E, Longacre, Teri A, Eilber, Ursula, McGuire, Valerie, Sieh, Weiva, Natanzon, Yanina, Li, Zheng, Whittemore, Alice S, deFazio, Anna, Staebler, Annette, Karlan, Beth Y, Gilks, Blake, Bowtell, David D, Høgdall, Estrid, dos Reis, Francisco J Candido, Steed, Helen, Campbell, Ian G, Gronwald, Jacek, Benítez, Javier, Koziak, Jennifer M, Chang-Claude, Jenny, Moysich, Kirsten B, Kelemen, Linda E, Cook, Linda S, Goodman, Marc T, García, María José, Fasching, Peter A, Kommoss, Stefan, Deen, Suha, Kjaer, Susanne K, Menon, Usha, Brenton, James D, Pharoah, Paul DP, Chenevix-Trench, Georgia, Huntsman, David G, Winham, Stacey J, Köbel, Martin, and Ramus, Susan J

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Cancer, Prevention, Vaccine Related, Rare Diseases, Clinical Research, Ovarian Cancer, BRCA2 Protein, CD8 Antigens, Carcinoma, Ovarian Epithelial, Cohort Studies, Cystadenocarcinoma, Serous, Female, Humans, Lymphocytes, Tumor-Infiltrating, Middle Aged, Mutation, Neoplasm Grading, Ovarian Neoplasms, Prospective Studies, Survival Analysis, Treatment Outcome, Ovarian Tumor Tissue Analysis (OTTA) Consortium, Public Health and Health Services, Oncology and carcinogenesis
Abstract

ImportanceCytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors.ObjectiveTo define the prognostic role of CD8+ TILs in epithelial ovarian cancer.Design, setting, and participantsThis was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years.ExposuresFollowing immunohistochemical analysis, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (≥20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines.Main outcomes and measuresOverall survival time.ResultsThe final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (P value for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near-log-linear functional form.Conclusions and relevanceThis study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+ TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer.

Published
2017

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