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1,042 results on '"Köbel, Martin"'

152. Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma.

Author

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

Abstract

Background: Better understanding of prognostic factors in tubo-ovarian high-grade serous carcinoma (HGSC) is critical, as diagnosis confers an aggressive disease course. Variation in tumor DNA methylation shows promise predicting outcome, yet prior studies were largely platform-specific and unable to evaluate multiple molecular features. Methods: We analyzed genome-wide DNA methylation in 1,040 frozen HGSC, including 325 previously reported upon, seeking a multi-platform quantitative methylation signature that we evaluated in relation to clinical features, tumor characteristics, time to recurrence/death, extent of CD8+ tumor-infiltrating lymphocytes (TIL), gene expression molecular subtypes, and gene expression of the ATP-binding cassette transporter TAP1. Results: Methylation signature was associated with shorter time to recurrence, independent of clinical factors (N = 715 new set, hazard ratio (HR), 1.65; 95% confidence interval (CI), 1.10-2.46; P = 0.015; N = 325 published set HR, 2.87; 95% CI, 2.17-3.81; P = 2.2 × 10-13) and remained prognostic after adjustment for gene expression molecular subtype and TAP1 expression (N = 599; HR, 2.22; 95% CI, 1.66-2.95; P = 4.1 × 10-8). Methylation signature was inversely related to CD8+ TIL levels (P = 2.4 × 10-7) and TAP1 expression (P = 0.0011) and was associated with gene expression molecular subtype (P = 5.9 × 10-4) in covariate-adjusted analysis. Conclusions: Multi-center analysis identified a novel quantitative tumor methylation signature of HGSC applicable to numerous commercially available platforms indicative of shorter time to recurrence/death, adjusting for other factors. Along with immune cell composition analysis, these results suggest a role for DNA methylation in the immunosuppressive microenvironment. Impact: This work aids in identification of targetable epigenome processes and stratification of patients for whom tailored treatment may be most beneficial. [ABSTRACT FROM AUTHOR]

Published
2023
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153. Cervical Small Cell Neuroendocrine Carcinoma With Ectopic ACTH Secretion and Acute Pancreatitis.

Author

Patel, Harshil, Kishlyansky, David, Köbel, Martin, Alshamma, Zainab, Glaze, Sarah, and Ghaznavi, Sana

Abstract

Ectopic Cushing syndrome from a primary carcinoma of the cervix is an exceedingly rare phenomenon. The objective of this review is to describe our clinical case and summarize the clinical characteristics, investigations, and outcomes of all published cases. We describe a previously healthy 39-year-old woman presenting with abnormal uterine bleeding, leading to a diagnosis of stage IIIC1 small cell neuroendocrine carcinoma of the cervix, human papillomavirus-associated. She was treated with neoadjuvant chemotherapy, radical hysterectomy, adjuvant chemotherapy, and pelvic radiation. Unfortunately, she developed progressive disease with multifocal hepatic metastases and lesions in the para-aortic lymph nodes. Eighteen months after her initial diagnosis, she presented with severe Cushing syndrome and acute pancreatitis and died from a splenic artery pseudoaneurysm. A literature review identified 10 published cases of ectopic ACTH secretion in the setting of carcinoma of the cervix. The mean age of presentation was 40. The majority (70%) occurred in the small cell neuroendocrine variant. In 80% of patients, cushingoid features developed concomitantly or shortly after the discovery of metastatic disease; cushingoid features included new-onset hypertension (30% of patients), hyperglycemia (50%), and hypokalemia (50%). All 10 patients died of the disease with a median survival of 2.5 months (range, 1-10 months) from the time of presentation with Cushing syndrome. Carcinoma of the cervix is a rare cause of ectopic Cushing syndrome. Nevertheless, it should be considered as a source of ectopic ACTH secretion in all women, especially those presenting with gynecologic complaints. Despite surgical resection and systemic therapy, prognosis is poor. [ABSTRACT FROM AUTHOR]

Published
2023
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155. Cellular context determines DNA methylation profiles in SWI/SNF‐deficient cancers of the gynecologic tract

Author

Kommoss, Felix KF, primary, Tessier‐Cloutier, Basile, additional, Witkowski, Leora, additional, Forgo, Erna, additional, Koelsche, Christian, additional, Köbel, Martin, additional, Foulkes, William D, additional, Lee, Cheng‐Han, additional, Kolin, David L, additional, von Deimling, Andreas, additional, and Howitt, Brooke E, additional

Published
2022
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156. Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8+ TIL infiltration, and provides no independent prognostic value in endometriosis‐associated ovarian carcinomas

Author

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

Published
2022
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162. Testing Algorithms for the Diagnosis of Malignant Glandular Tumors of the Uterine Cervix Histotyped per the International Endocervical Adenocarcinoma Criteria and Classification (IECC) System

Author

Duggan, Máire A., primary, Duan, Qiuli, additional, Pfeiffer, Ruth M., additional, Brett, Mary Anne, additional, Lee, Sandra, additional, Abubakar, Mustapha, additional, Köbel, Martin, additional, Rodriguez, Monica, additional, and Sar, Aylin, additional

Published
2021
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163. MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma

Author

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

Published
2021
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164. The utility of color normalization for AI ‐based diagnosis of hematoxylin and eosin‐stained pathology images

Author

Boschman, Jeffrey, primary, Farahani, Hossein, additional, Darbandsari, Amirali, additional, Ahmadvand, Pouya, additional, Van Spankeren, Ashley, additional, Farnell, David, additional, Levine, Adrian B, additional, Naso, Julia R, additional, Churg, Andrew, additional, Jones, Steven JM, additional, Yip, Stephen, additional, Köbel, Martin, additional, Huntsman, David G, additional, Gilks, C Blake, additional, and Bashashati, Ali, additional

Published
2021
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167. Refined cut-off for TP53 immunohistochemistry improves prediction of TP53 mutation status in ovarian mucinous tumors: implications for outcome analyses

Author

Kang, Eun Young, Cheasley, Dane, LePage, Cecile, Wakefield, Matthew J, Da Cunha Torres, Michelle, Rowley, Simone, Salazar, Carolina, Xing, Zhongyue, Allan, Prue, Bowtell, David DL, Mes-Masson, Anne-Marie, Provencher, Diane M, Rahimi, Kurosh, Kelemen, Linda E, Fasching, Peter A, Doherty, Jennifer A, Goodman, Marc T, Goode, Ellen L, Deen, Suha, Pharoah, Paul DP, Brenton, James D, Sieh, Weiva, Mateoiu, Constantina, Sundfeldt, Karin, Cook, Linda S, Le, Nhu D, Anglesio, Michael S, Gilks, C Blake, Huntsman, David G, Kennedy, Catherine J, Traficante, Nadia, Australian Ovarian Cancer Study, DeFazio, Anna, Kaufmann, Scott, Churchman, Michael, Gourley, Charlie, Stephens, Andrew N, Meagher, Nicola S, Ramus, Susan J, Antill, Yoland C, Campbell, Ian, Scott, Clare L, Köbel, Martin, Gorringe, Kylie L, GAMuT Collaborators, LePage, Cecile [0000-0002-8020-1544], Fasching, Peter A [0000-0003-4885-8471], Pharoah, Paul DP [0000-0001-8494-732X], Anglesio, Michael S [0000-0003-1639-5003], Churchman, Michael [0000-0003-1958-7692], Meagher, Nicola S [0000-0001-9134-2118], Campbell, Ian [0000-0002-7773-4155], Scott, Clare L [0000-0002-3689-5956], Köbel, Martin [0000-0002-6615-2037], Gorringe, Kylie L [0000-0001-5681-2022], and Apollo - University of Cambridge Repository

Subjects
Adult, Observer Variation, Ovarian Neoplasms, endocrine system diseases, DNA Mutational Analysis, Australia, Reproducibility of Results, Middle Aged, Prognosis, Immunohistochemistry, Risk Assessment, United Kingdom, Predictive Value of Tests, Risk Factors, Tissue Array Analysis, Mutation, North America, Biomarkers, Tumor, Humans, Female, Tumor Suppressor Protein p53, Neoplasms, Cystic, Mucinous, and Serous, neoplasms
Abstract

TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5-14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MBOT with a higher risk of mortality.

Published
2020
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173. Abstract 1045: Combined targeting of actin/tropomyosin and microtubules underlies a potential treatment strategy of epithelial ovarian cancer with cell-cycle dependent synergy

Author

Xu, Xing, primary, Wang, Yao, additional, Bryce, Nicole, additional, Tang, Katrina, additional, Meagher, Nicola S., additional, Kang, Eun Young, additional, Kelemen, Linda E., additional, Köbel, Martin, additional, Ramus, Susan J., additional, Friedlander, Michael, additional, Ford, Caroline E., additional, Hardeman, Edna C., additional, and Gunning, Peter W., additional

Published
2021
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174. Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer

Author

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

Published
2021
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176. Joint IARC/NCI International Cancer Seminar Series Report: expert consensus on future directions for ovarian carcinoma research

Author

Virani, Shama, primary, Baiocchi, Glauco, additional, Bowtell, David, additional, Cabasag, Citadel J, additional, Cho, Kathleen R, additional, Fortner, Renée T, additional, Fujiwara, Keiichi, additional, Kim, Jae-Weon, additional, Köbel, Martin, additional, Kurtz, Jean-Emmanuel, additional, Levine, Douglas A, additional, Menon, Usha, additional, Norquist, Barbara M, additional, Pharoah, Paul D P, additional, Sood, Anil K, additional, Tworoger, Shelley T, additional, Wentzensen, Nicolas, additional, Chanock, Stephen J, additional, Brennan, Paul, additional, and Trabert, Britton, additional

Published
2021
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178. Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer

Author

Kar, Siddhartha P., Considine, Daniel P.C., 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 D.P., Gayther, Simon A., Schildkraut, Joellen M., Kar, Siddhartha P., Considine, Daniel P.C., 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 D.P., Gayther, Simon A., and Schildkraut, Joellen M.

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

182. Molecular characterization of low-grade serous ovarian carcinoma identifies genomic aberrations according to hormone receptor expression.

Author

Cheasley, Dane, Fernandez, Marta Llaurado, Köbel, Martin, Kim, Hannah, Dawson, Amy, Hoenisch, Joshua, Bittner, Madison, Chiu, Derek S., Talhouk, Aline, Gilks, C. Blake, Jayawardana, Madawa W., Pishas, Kathleen I., Mes-Masson, Anne-Marie, Provencher, Diane, Nigam, Abhimanyu, Hacker, Neville F., Gorringe, Kylie L., Campbell, Ian G., and Carey, Mark S.

Subjects
HORMONE receptors, PROGESTERONE receptors, ESTROGEN receptors, CANCER genes, SURVIVAL rate, HORMONE receptor positive breast cancer
Abstract

Hormone receptor expression is a characteristic of low-grade serous ovarian carcinoma (LGSOC). Studies investigating estrogen receptor (ER) and progesterone receptor (PR) expression levels suggest its prognostic and predictive significance, although their associations with key molecular aberrations are not well understood. As such, we sought to describe the specific genomic profiles associated with different ER/PR expression patterns and survival outcomes in a cohort of patients with advanced disease. The study comprised fifty-five advanced-staged (III/IV) LGSOCs from the Canadian Ovarian Experimental Unified Resource (COEUR) for which targeted mutation sequencing, copy-number aberration, clinical and follow-up data were available. ER, PR, and p16 expression were assessed by immunohistochemistry. Tumors were divided into low and high ER/PR expression groups based on Allred scoring. Copy number analysis revealed that PR-low tumors (Allred score <2) had a higher fraction of the genome altered by copy number changes compared to PR-high tumors (p = 0.001), with cancer genes affected within specific loci linked to altered peptidyl-tyrosine kinase, MAP-kinase, and PI3-kinase signaling. Cox regression analysis showed that ER-high (p = 0.02), PR-high (p = 0.03), stage III disease (p = 0.02), low residual disease burden (p = 0.01) and normal p16 expression (p<0.001) were all significantly associated with improved overall survival. This study provides evidence that genomic aberrations are linked to ER/PR expression in primary LGSOC. [ABSTRACT FROM AUTHOR]

Published
2022
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183. Molecular analysis suggests oligoclonality and metastasis of endometriosis lesions across anatomically defined subtypes

Author

Praetorius, Teresa H., primary, Leonova, Anna, additional, Lac, Vivian, additional, Senz, Janine, additional, Tessier-Cloutier, Basile, additional, Nazeran, Tayyebeh M., additional, Köbel, Martin, additional, Grube, Marcel, additional, Kraemer, Bernhard, additional, Yong, Paul J., additional, Kommoss, Stefan, additional, and Anglesio, Michael S., additional

Published
2021
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184. Evaluation of treatment effects in patients with endometrial cancer and POLE mutations: An individual patient data meta‐analysis

Author

McAlpine, Jessica N., primary, Chiu, Derek S., additional, Nout, Remi A., additional, Church, David N., additional, Schmidt, Pascal, additional, Lam, Stephanie, additional, Leung, Samuel, additional, Bellone, Stefania, additional, Wong, Adele, additional, Brucker, Sara Y., additional, Lee, Cheng Han, additional, Clarke, Blaise A., additional, Huntsman, David G., additional, Bernardini, Marcus Q., additional, Ngeow, Joanne, additional, Santin, Alessandro D., additional, Goodfellow, Paul, additional, Levine, Douglas A., additional, Köbel, Martin, additional, Kommoss, Stefan, additional, Bosse, Tjalling, additional, Gilks, C. Blake, additional, and Talhouk, Aline, additional

Published
2021
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185. Embryonic protein NODAL regulates the breast tumor microenvironment by reprogramming cancer-derived secretomes

Author

Dieters-Castator, Dylan, primary, Dantonio, Paola M., additional, Piaseczny, Matt, additional, Zhang, Guihua, additional, Liu, Jiahui, additional, Kuljanin, Miljan, additional, Sherman, Stephen, additional, Jewer, Michael, additional, Quesnel, Katherine, additional, Kang, Eun Young, additional, Köbel, Martin, additional, Siegers, Gabrielle M., additional, Leask, Andrew, additional, Hess, David, additional, Lajoie, Gilles, additional, and Postovit, Lynne-Marie, additional

Published
2021
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186. Prognostic and Theranostic Biomarkers in Ovarian Clear Cell Carcinoma

Author

Wiedemeyer, Katharina, primary, Wang, Linyuan, additional, Kang, Eun Young, additional, Liu, Shuhong, additional, Ou, Young, additional, Kelemen, Linda E., additional, Feil, Lukas, additional, Anglesio, Michael S., additional, Glaze, Sarah, additional, Ghatage, Prafull, additional, Nelson, Gregg S., additional, and Köbel, Martin, additional

Published
2021
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189. Abstract PO028: Embryonic protein NODAL as a potential modulator of the tumour microenvironment: Breast cancer secretome reprogramming and fibroblast activation

Author

Dieters-Castator, Dylan, primary, Dantonio, Paola M., additional, Piaseczny, Matt, additional, Zhang, Guihua, additional, Liu, Jiahui, additional, Kuljanin, Miljan, additional, Sherman, Stephen, additional, Jewer, Michael, additional, Quesnel, Katherine, additional, Kang, Eun-Young, additional, Köbel, Martin, additional, Siegers, Gabrielle M., additional, Leask, Andrew, additional, Hess, David, additional, Lajoie, Gilles, additional, and Postovit, Lynne-Marie, additional

Published
2021
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192. Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE)

Author

Talhouk, Aline, George, Joshy, Wang, Chen, Budden, Timothy, Tan, Tuan Zea, Chiu, Derek S, Kommoss, Stefan, Leong, Huei San, Chen, Stephanie, Intermaggio, Maria P, Gilks, Blake, Nazeran, Tayyebeh M, Volchek, Mila, Elatre, Wafaa, Bentley, Rex C, Senz, Janine, Lum, Amy, Chow, Veronica, Sudderuddin, Hanwei, Mackenzie, Robertson, Leong, Samuel CY, Liu, Geyi, Johnson, Dustin, Chen, Billy, Group, Aocs, Alsop, Jennifer, Banerjee, Susana N, Behrens, Sabine, Bodelon, Clara, Brand, Alison H, Brinton, Louise, Carney, Michael E, Chiew, Yoke-Eng, Cushing-Haugen, Kara L, Cybulski, Cezary, Ennis, Darren, Fereday, Sian, Fortner, Renée T, García-Donas, Jesús, Gentry-Maharaj, Aleksandra, Glasspool, Rosalind, Goranova, Teodora, Greene, Casey S, Haluska, Paul, Harris, Holly R, Hendley, Joy, Hernandez, Brenda Y, Herpel, Esther, Jimenez-Linan, Mercedes, Karpinskyj, Chloe, Kaufmann, Scott H, Keeney, Gary L, Kennedy, Catherine J, Köbel, Martin, Koziak, Jennifer M, Larson, Melissa C, Lester, Jenny, Lewsley, Liz-Anne, Lissowska, Jolanta, Lubiński, Jan, Luk, Hugh, Macintyre, Geoff, Mahner, Sven, McNeish, Iain A, Menkiszak, Janusz, Nevins, Nikilyn, Osorio, Ana, Oszurek, Oleg, Palacios, José, Hinsley, Samantha, Pearce, Celeste L, Pike, Malcolm C, Piskorz, Anna M, Ray-Coquard, Isabelle, Rhenius, Valerie, Rodriguez-Antona, Cristina, Sharma, Raghwa, Sherman, Mark E, De Silva, Dilrini, Singh, Naveena, Sinn, Peter, Slamon, Dennis, Song, Honglin, Steed, Helen, Stronach, Euan A, Thompson, Pamela J, Tołoczko, Aleksandra, Trabert, Britton, Traficante, Nadia, Tseng, Chiu-Chen, Widschwendter, Martin, Wilkens, Lynne R, Winham, Stacey J, Winterhoff, Boris, Beeghly-Fadiel, Alicia, Benitez, Javier, Berchuck, Andrew, Brenton, James D, Brown, Robert, and Chang-Claude, Jenny

Subjects
Cystadenoma, Clinical Trials and Supportive Activities, Oncology and Carcinogenesis, Rare Diseases, Clinical Research, Genetics, Humans, Lymphocytes, Tumor-Infiltrating, Oncology & Carcinogenesis, Aged, Cancer, Ovarian Neoplasms, Neoplastic, screening and diagnosis, Serous, Middle Aged, Neoplasm Proteins, Ovarian Cancer, Detection, Good Health and Well Being, Gene Expression Regulation, Residual, Neoplasm, Female, Neoplasm Grading, Transcriptome, Algorithms, Biotechnology, 4.2 Evaluation of markers and technologies
Abstract

PurposeGene expression-based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features.Experimental designAdopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting.ResultsGene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations.ConclusionsWe validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications.See related commentary by McMullen et al., p. 5271.

Published
2020

193. Celastrol Attenuates Angiotensin II-Induced Cardiac Remodeling by Targeting STAT3

Author

Ye, Shiju, Luo, Wu, Khan, Zia A., Wu, Gaojun, Xuan, Lina, Shan, Peiren, Lin, Ke, Chen, Taiwei, Quesnel, Jingying, Kang, Eun Young, Köbel, Martin, Siegers, Gabrielle M., Leask, Andrew, Hess, David, Lajoie, Gilles, and Postovit, Lynne Marie

Subjects
0301 basic medicine, STAT3 Transcription Factor, Physiology, Tripterygium, Heart failure, 030204 cardiovascular system & hematology, Pharmacology, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, Mice, Random Allocation, 0302 clinical medicine, Drug Delivery Systems, Medicine, Animals, Humans, Molecular targeted therapy, Myocytes, Cardiac, STAT3, Signal transducer and activator of transcription 3, biology, Ventricular Remodeling, business.industry, Angiotensin II, medicine.disease, Triterpenes, Protein Structure, Tertiary, Rats, 030104 developmental biology, HEK293 Cells, chemistry, Celastrol, Hypertension, cardiovascular system, Molecular targets, biology.protein, Cardiology and Cardiovascular Medicine, business, Pentacyclic Triterpenes
Abstract

Rationale: Excessive Ang II (angiotensin II) levels lead to a profibrotic and hypertrophic milieu that produces deleterious remodeling and dysfunction in hypertension-associated heart failure. Agents that disrupt Ang II–induced cardiac dysfunction may have clinical utility in the treatment of hypertension-associated heart failure. Objective: We have examined the potential effect of celastrol—a bioactive compound derived from the Celastraceae family—on Ang II–induced cardiac dysfunction. Methods and Results: In rat primary cardiomyocytes and H9C2 (rat cardiomyocyte-like H9C2) cells, celastrol attenuates Ang II–induced cellular hypertrophy and fibrotic responses. Proteome microarrays, surface plasmon resonance, competitive binding assays, and molecular simulation were used to identify the molecular target of celastrol. Our data showed that celastrol directly binds to and inhibits STAT (signal transducer and activator of transcription)-3 phosphorylation and nuclear translocation. Functional tests demonstrated that the protection of celastrol is afforded through targeting STAT3. Overexpression of STAT3 dampens the effect of celastrol by partially rescuing STAT3 activity. Finally, we investigated the in vivo effect of celastrol treatment in mice challenged with Ang II and in the transverse aortic constriction model. We show that celastrol administration protected heart function in Ang II–challenged and transverse aortic constriction–challenged mice by inhibiting cardiac fibrosis and hypertrophy. Conclusions: Our studies show that celastrol inhibits Ang II–induced cardiac dysfunction by inhibiting STAT3 activity.

Published
2020

197. PODO447:a novel antibody to a tumor-restricted epitope on the cancer antigen podocalyxin

Author

Canals Hernaez, Diana, Hughes, Michael R., Dean, Pamela, Bergqvist, Peter, Samudio, Ismael, Blixt, Ola, Wiedemeyer, Katharina, Li, Yicong, Bond, Chris, Cruz, Eric, Köbel, Martin, Gilks, Blake, Roskelley, Calvin D., McNagny, Kelly M., Canals Hernaez, Diana, Hughes, Michael R., Dean, Pamela, Bergqvist, Peter, Samudio, Ismael, Blixt, Ola, Wiedemeyer, Katharina, Li, Yicong, Bond, Chris, Cruz, Eric, Köbel, Martin, Gilks, Blake, Roskelley, Calvin D., and McNagny, Kelly M.

Abstract

BACKGROUND: The success of new targeted cancer therapies has been dependent on the identification of tumor-specific antigens. Podocalyxin (Podxl) is upregulated on tumors with high metastatic index and its presence is associated with poor outcome, thus emerging as an important prognostic and theragnostic marker in several human cancers. Moreover, in human tumor xenograft models, Podxl expression promotes tumor growth and metastasis. Although a promising target for immunotherapy, the expression of Podxl on normal vascular endothelia and kidney podocytes could hamper efforts to therapeutically target this molecule. Since pathways regulating post-translational modifications are frequently perturbed in cancer cells, we sought to produce novel anti-Podxl antibodies (Abs) that selectively recognize tumor-restricted glycoepitopes on the extracellular mucin domain of Podxl. METHODS: Splenic B cells were isolated from rabbits immunized with a Podxl-expressing human tumor cell line. Abs from these B cells were screened for potent reactivity to Podxl+ neoplastic cell lines but not Podxl+ primary endothelial cells. Transcripts encoding heavy and light chain variable regions from promising B cells were cloned and expressed as recombinant proteins. Tumor specificity was assessed using primary normal tissue and an ovarian cancer tissue microarray (TMA). Mapping of the tumor-restricted epitope was performed using enzyme-treated human tumor cell lines and a glycan array. RESULTS: One mAb (PODO447) showed strong reactivity with a variety of Podxl+ tumor cell lines but not with normal primary human tissue including Podxl+ kidney podocytes and most vascular endothelia. Screening of an ovarian carcinoma TMA (219 cases) revealed PODO447 reactivity with the majority of tumors, including 65% of the high-grade serous histotype. Subsequent biochemical analyses determined that PODO447 reacts with a highly unusual terminal N-acetylgalactosamine beta-1 (GalNAcβ1) motif predominantly found on

Published
2020

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

Author

Martins, Filipe Correia, 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, Brenton, James D, Martins, Filipe Correia, 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

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 < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016).ConclusionsPTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.

Published
2020

199. Cross-cancer genome-wide association study of endometrial cancer and epithelial ovarian cancer identifies genetic risk regions associated with risk of both cancers

Author

Glubb, Dylan M, Glubb, Dylan M, Thompson, Deborah J, Aben, Katja KH, Alsulimani, Ahmad, Amant, Frederic, Annibali, Daniela, Attia, John, Barricarte, Aurelio, Beckmann, Matthias W, Berchuck, Andrew, Bermisheva, Marina, Bernardini, Marcus Q, Bischof, Katharina, Bjorge, Line, Bodelon, Clara, Brand, Alison H, Brenton, James D, Brinton, Louise, Bruinsma, Fiona, Buchanan, Daniel D, Burghaus, Stefanie, Butzow, Ralf, Cai, Hui, Carney, Michael E, Chanock, Stephen J, Chen, Chu, Chen, Xiao Qing, Chen, Zhihua, Cook, Linda S, Cunningham, Julie M, De Vivo, Immaculata, deFazio, Anna, Doherty, Jennifer A, Dörk, Thilo, du Bois, Andreas, Dunning, Alison M, Dürst, Matthias, Edwards, Todd, Edwards, Robert P, Ekici, Arif B, Ewing, Ailith, Fasching, Peter A, Ferguson, Sarah, Flanagan, James M, Fostira, Florentia, Fountzilas, George, Friedenreich, Christine M, Gao, Bo, Gaudet, Mia M, Gawełko, Jan, Gentry-Maharaj, Aleksandra, Giles, Graham G, Glasspool, Rosalind, Goodman, Marc T, Gronwald, Jacek, Group, OPAL Study, Group, AOCS, Harris, Holly R, Harter, Philipp, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Høgdall, Estrid, Høgdall, Claus K, Holliday, Elizabeth G, Huntsman, David G, Huzarski, Tomasz, Jakubowska, Anna, Jensen, Allan, Jones, Michael E, Karlan, Beth Y, Karnezis, Anthony, Kelley, Joseph L, Khusnutdinova, Elza, Killeen, Jeffrey L, Kjaer, Susanne K, Klapdor, Rüdiger, Köbel, Martin, Konopka, Bozena, Konstantopoulou, Irene, Kopperud, Reidun K, Koti, Madhuri, Kraft, Peter, Kupryjanczyk, Jolanta, Lambrechts, Diether, Larson, Melissa C, Le Marchand, Loic, Lele, Shashikant B, Lester, Jenny, Li, Andrew J, Liang, Dong, Liebrich, Clemens, Lipworth, Loren, Lissowska, Jolanta, Lu, Lingeng, Lu, Karen H, Macciotta, Alessandra, Mattiello, Amalia, May, Taymaa, Glubb, Dylan M, Glubb, Dylan M, Thompson, Deborah J, Aben, Katja KH, Alsulimani, Ahmad, Amant, Frederic, Annibali, Daniela, Attia, John, Barricarte, Aurelio, Beckmann, Matthias W, Berchuck, Andrew, Bermisheva, Marina, Bernardini, Marcus Q, Bischof, Katharina, Bjorge, Line, Bodelon, Clara, Brand, Alison H, Brenton, James D, Brinton, Louise, Bruinsma, Fiona, Buchanan, Daniel D, Burghaus, Stefanie, Butzow, Ralf, Cai, Hui, Carney, Michael E, Chanock, Stephen J, Chen, Chu, Chen, Xiao Qing, Chen, Zhihua, Cook, Linda S, Cunningham, Julie M, De Vivo, Immaculata, deFazio, Anna, Doherty, Jennifer A, Dörk, Thilo, du Bois, Andreas, Dunning, Alison M, Dürst, Matthias, Edwards, Todd, Edwards, Robert P, Ekici, Arif B, Ewing, Ailith, Fasching, Peter A, Ferguson, Sarah, Flanagan, James M, Fostira, Florentia, Fountzilas, George, Friedenreich, Christine M, Gao, Bo, Gaudet, Mia M, Gawełko, Jan, Gentry-Maharaj, Aleksandra, Giles, Graham G, Glasspool, Rosalind, Goodman, Marc T, Gronwald, Jacek, Group, OPAL Study, Group, AOCS, Harris, Holly R, Harter, Philipp, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Høgdall, Estrid, Høgdall, Claus K, Holliday, Elizabeth G, Huntsman, David G, Huzarski, Tomasz, Jakubowska, Anna, Jensen, Allan, Jones, Michael E, Karlan, Beth Y, Karnezis, Anthony, Kelley, Joseph L, Khusnutdinova, Elza, Killeen, Jeffrey L, Kjaer, Susanne K, Klapdor, Rüdiger, Köbel, Martin, Konopka, Bozena, Konstantopoulou, Irene, Kopperud, Reidun K, Koti, Madhuri, Kraft, Peter, Kupryjanczyk, Jolanta, Lambrechts, Diether, Larson, Melissa C, Le Marchand, Loic, Lele, Shashikant B, Lester, Jenny, Li, Andrew J, Liang, Dong, Liebrich, Clemens, Lipworth, Loren, Lissowska, Jolanta, Lu, Lingeng, Lu, Karen H, Macciotta, Alessandra, Mattiello, Amalia, and May, Taymaa

Abstract

Accumulating evidence suggests a relationship between endometrial cancer and epithelial ovarian cancer. For example, endometrial cancer and epithelial ovarian cancer share epidemiological risk factors and molecular features observed across histotypes are held in common (e.g. serous, endometrioid and clear cell). Independent genome-wide association studies (GWAS) for endometrial cancer and epithelial ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. Using GWAS summary statistics, we explored the shared genetic etiology between endometrial cancer and epithelial ovarian cancer. Genetic correlation analysis using LD Score regression revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10−5). To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e. inverse-variance meta-analysis, co-localization, and M-values), and performed analyses by stratified by subtype. We found seven loci associated with risk for both cancers (PBonferroni < 2.4 × 10−9). In addition, four novel regions at 7p22.2, 7q22.1, 9p12 and 11q13.3 were identified at a sub-genome wide threshold (P < 5 × 10−7). Integration with promoter-associated HiChIP chromatin loops from immortalized endometrium and epithelial ovarian cell lines, and expression quantitative trait loci (eQTL) data highlighted candidate target genes for further investigation.

Published
2020

200. 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 D. P., Brenton, James D., 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 D. P., and Brenton, James D.

Published
2020

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