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1. Genome-wide association analyses of ovarian cancer patients undergoing primary debulking surgery identify candidate genes for residual disease

Author: Ramachandran, Dhanya, Ramachandran, Dhanya, Tyrer, Jonathan P, Kommoss, Stefan, DeFazio, Anna, Riggan, Marjorie J, Webb, Penelope M, Fasching, Peter A, Lambrechts, Diether, García, María J, Rodríguez-Antona, Cristina, Goodman, Marc T, Modugno, Francesmary, Moysich, Kirsten B, Karlan, Beth Y, Lester, Jenny, Kjaer, Susanne K, Jensen, Allan, Høgdall, Estrid, Goode, Ellen L, Cliby, William A, Kumar, Amanika, Wang, Chen, Cunningham, Julie M, Winham, Stacey J, Monteiro, Alvaro N, Schildkraut, Joellen M, Cramer, Daniel W, Terry, Kathryn L, Titus, Linda, Bjorge, Line, Thomsen, Liv Cecilie Vestrheim, Pejovic, Tanja, Høgdall, Claus K, McNeish, Iain A, May, Taymaa, Huntsman, David G, Pfisterer, Jacobus, Canzler, Ulrich, Park-Simon, Tjoung-Won, Schröder, Willibald, Belau, Antje, Hanker, Lars, Harter, Philipp, Sehouli, Jalid, Kimmig, Rainer, de Gregorio, Nikolaus, Schmalfeldt, Barbara, Baumann, Klaus, Hilpert, Felix, Burges, Alexander, Winterhoff, Boris, Schürmann, Peter, Speith, Lisa-Marie, Hillemanns, Peter, Berchuck, Andrew, Johnatty, Sharon E, Ramus, Susan J, Chenevix-Trench, Georgia, Pharoah, Paul DP, Dörk, Thilo, Heitz, Florian, Ramachandran, Dhanya, Ramachandran, Dhanya, Tyrer, Jonathan P, Kommoss, Stefan, DeFazio, Anna, Riggan, Marjorie J, Webb, Penelope M, Fasching, Peter A, Lambrechts, Diether, García, María J, Rodríguez-Antona, Cristina, Goodman, Marc T, Modugno, Francesmary, Moysich, Kirsten B, Karlan, Beth Y, Lester, Jenny, Kjaer, Susanne K, Jensen, Allan, Høgdall, Estrid, Goode, Ellen L, Cliby, William A, Kumar, Amanika, Wang, Chen, Cunningham, Julie M, Winham, Stacey J, Monteiro, Alvaro N, Schildkraut, Joellen M, Cramer, Daniel W, Terry, Kathryn L, Titus, Linda, Bjorge, Line, Thomsen, Liv Cecilie Vestrheim, Pejovic, Tanja, Høgdall, Claus K, McNeish, Iain A, May, Taymaa, Huntsman, David G, Pfisterer, Jacobus, Canzler, Ulrich, Park-Simon, Tjoung-Won, Schröder, Willibald, Belau, Antje, Hanker, Lars, Harter, Philipp, Sehouli, Jalid, Kimmig, Rainer, de Gregorio, Nikolaus, Schmalfeldt, Barbara, Baumann, Klaus, Hilpert, Felix, Burges, Alexander, Winterhoff, Boris, Schürmann, Peter, Speith, Lisa-Marie, Hillemanns, Peter, Berchuck, Andrew, Johnatty, Sharon E, Ramus, Susan J, Chenevix-Trench, Georgia, Pharoah, Paul DP, Dörk, Thilo, and Heitz, Florian
Published: 2024

2. Identification of stably expressed microRNAs in plasma from high-grade serous ovarian carcinoma and benign tumor patients

Author: Petersen, Patrick H. D., Lopacinska-Jørgensen, Joanna, Høgdall, Claus K., Høgdall, Estrid V., Petersen, Patrick H. D., Lopacinska-Jørgensen, Joanna, Høgdall, Claus K., and Høgdall, Estrid V.
Abstract: Background: Ovarian cancer is a lethal gynecological cancer and no reliable minimally invasive early diagnosis tools exist. High grade serous ovarian carcinoma (HGSOC) is often diagnosed at advanced stages, resulting in poorer outcome than those diagnosed in early stage. Circulating microRNAs have been investigated for their biomarker potential. However, due to lack of standardization methods for microRNA detection, there is no consensus, which microRNAs should be used as stable endogenous controls. We aimed to identify microRNAs that are stably expressed in plasma of HGSOC and benign ovarian tumor patients. Methods and results: We isolated RNA from plasma samples of 60 HGSOC and 48 benign patients. RT-qPCR was accomplished with a custom panel covering 40 microRNAs and 8 controls. Stability analysis was performed using five algorithms: Normfinder, geNorm, Delta-Ct, BestKeeper and RefFinder using an R-package; RefSeeker developed by our study group [1]. Among 41 analyzed RNAs, 13 were present in all samples and eligible for stability analysis. Differences between stability rankings were observed across algorithms. In HGSOC samples, hsa-miR-126-3p and hsa-miR-23a-3p were identified as the two most stable miRNAs. In benign samples, hsa-miR-191-5p and hsa-miR-27a-3p were most stable. In the combined HGSOC and benign group, hsa-miR-23a-3p and hsa-miR-27a-3p were identified by both the RefFinder and Normfinder analysis as the most stable miRNAs. Conclusions: Consensus regarding normalization approaches in microRNA studies is needed. The choice of endogenous microRNAs used for normalization depends on the histological content of the cohort. Furthermore, normalization also depends on the algorithms used for stability analysis.
Published: 2023

3. Strategies for data normalization and missing data imputation and consequences for potential diagnostic microRNA biomarkers in epithelial ovarian cancer

Author: Lopacinska-Jørgensen, Joanna, Petersen, Patrick H. D., Oliveira, Douglas V. N. P., Høgdall, Claus K., Høgdall, Estrid V., Lopacinska-Jørgensen, Joanna, Petersen, Patrick H. D., Oliveira, Douglas V. N. P., Høgdall, Claus K., and Høgdall, Estrid V.
Published: 2023

4. Identification of stably expressed microRNAs in plasma from high-grade serous ovarian carcinoma and benign tumor patients

Author: Petersen, Patrick H. D., Lopacinska-Jørgensen, Joanna, Høgdall, Claus K., Høgdall, Estrid V., Petersen, Patrick H. D., Lopacinska-Jørgensen, Joanna, Høgdall, Claus K., and Høgdall, Estrid V.
Abstract: Background: Ovarian cancer is a lethal gynecological cancer and no reliable minimally invasive early diagnosis tools exist. High grade serous ovarian carcinoma (HGSOC) is often diagnosed at advanced stages, resulting in poorer outcome than those diagnosed in early stage. Circulating microRNAs have been investigated for their biomarker potential. However, due to lack of standardization methods for microRNA detection, there is no consensus, which microRNAs should be used as stable endogenous controls. We aimed to identify microRNAs that are stably expressed in plasma of HGSOC and benign ovarian tumor patients. Methods and results: We isolated RNA from plasma samples of 60 HGSOC and 48 benign patients. RT-qPCR was accomplished with a custom panel covering 40 microRNAs and 8 controls. Stability analysis was performed using five algorithms: Normfinder, geNorm, Delta-Ct, BestKeeper and RefFinder using an R-package; RefSeeker developed by our study group [1]. Among 41 analyzed RNAs, 13 were present in all samples and eligible for stability analysis. Differences between stability rankings were observed across algorithms. In HGSOC samples, hsa-miR-126-3p and hsa-miR-23a-3p were identified as the two most stable miRNAs. In benign samples, hsa-miR-191-5p and hsa-miR-27a-3p were most stable. In the combined HGSOC and benign group, hsa-miR-23a-3p and hsa-miR-27a-3p were identified by both the RefFinder and Normfinder analysis as the most stable miRNAs. Conclusions: Consensus regarding normalization approaches in microRNA studies is needed. The choice of endogenous microRNAs used for normalization depends on the histological content of the cohort. Furthermore, normalization also depends on the algorithms used for stability analysis.
Published: 2023

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

Author: Kang, Eun‐Young, Kang, Eun‐Young, Weir, Ashley, Meagher, Nicola S, Farrington, Kyo, Nelson, Gregg S, Ghatage, Prafull, Lee, Cheng‐Han, Riggan, Marjorie J, Bolithon, Adelyn, Popovic, Gordana, Leung, Betty, Tang, Katrina, Lambie, Neil, Millstein, Joshua, Alsop, Jennifer, Anglesio, Michael S, Ataseven, Beyhan, Barlow, Ellen, Beckmann, Matthias W, Berger, Jessica, Bisinotto, Christiani, Bösmüller, Hans, Boros, Jessica, Brand, Alison H, Brooks‐Wilson, Angela, Brucker, Sara Y, Carney, Michael E, Casablanca, Yovanni, Cazorla‐Jiménez, Alicia, Cohen, Paul A, Conrads, Thomas P, Cook, Linda S, Coulson, Penny, Courtney‐Brooks, Madeleine, Cramer, Daniel W, Crowe, Philip, Cunningham, Julie M, Cybulski, Cezary, Darcy, Kathleen M, El‐Bahrawy, Mona A, Elishaev, Esther, Erber, Ramona, Farrell, Rhonda, Fereday, Sian, Fischer, Anna, García, María J, Gayther, Simon A, Gentry‐Maharaj, Aleksandra, Gilks, C Blake, Group, AOCS, Grube, Marcel, Harnett, Paul R, Harrington, Shariska Petersen, Harter, Philipp, Hartmann, Arndt, Hecht, Jonathan L, Heikaus, Sebastian, Hein, Alexander, Heitz, Florian, Hendley, Joy, Hernandez, Brenda Y, Polo, Susanna Hernando, Heublein, Sabine, Hirasawa, Akira, Høgdall, Estrid, Høgdall, Claus K, Horlings, Hugo M, Huntsman, David G, Huzarski, Tomasz, Jewell, Andrea, Jimenez‐Linan, Mercedes, Jones, Michael E, Kaufmann, Scott H, Kennedy, Catherine J, Khabele, Dineo, Kommoss, Felix KF, Kruitwagen, Roy FPM, Lambrechts, Diether, Le, Nhu D, Lener, Marcin, Lester, Jenny, Leung, Yee, Linder, Anna, Loverix, Liselore, Lubiński, Jan, Madan, Rashna, Maxwell, G Larry, Modugno, Francesmary, Neuhausen, Susan L, Olawaiye, Alexander, Olbrecht, Siel, Orsulic, Sandra, Palacios, José, Pearce, Celeste Leigh, Pike, Malcolm C, Quinn, Carmel M, Mohan, Ganendra Raj, Rodríguez‐Antona, Cristina, Ruebner, Matthias, Ryan, Andy, Kang, Eun‐Young, Kang, Eun‐Young, Weir, Ashley, Meagher, Nicola S, Farrington, Kyo, Nelson, Gregg S, Ghatage, Prafull, Lee, Cheng‐Han, Riggan, Marjorie J, Bolithon, Adelyn, Popovic, Gordana, Leung, Betty, Tang, Katrina, Lambie, Neil, Millstein, Joshua, Alsop, Jennifer, Anglesio, Michael S, Ataseven, Beyhan, Barlow, Ellen, Beckmann, Matthias W, Berger, Jessica, Bisinotto, Christiani, Bösmüller, Hans, Boros, Jessica, Brand, Alison H, Brooks‐Wilson, Angela, Brucker, Sara Y, Carney, Michael E, Casablanca, Yovanni, Cazorla‐Jiménez, Alicia, Cohen, Paul A, Conrads, Thomas P, Cook, Linda S, Coulson, Penny, Courtney‐Brooks, Madeleine, Cramer, Daniel W, Crowe, Philip, Cunningham, Julie M, Cybulski, Cezary, Darcy, Kathleen M, El‐Bahrawy, Mona A, Elishaev, Esther, Erber, Ramona, Farrell, Rhonda, Fereday, Sian, Fischer, Anna, García, María J, Gayther, Simon A, Gentry‐Maharaj, Aleksandra, Gilks, C Blake, Group, AOCS, Grube, Marcel, Harnett, Paul R, Harrington, Shariska Petersen, Harter, Philipp, Hartmann, Arndt, Hecht, Jonathan L, Heikaus, Sebastian, Hein, Alexander, Heitz, Florian, Hendley, Joy, Hernandez, Brenda Y, Polo, Susanna Hernando, Heublein, Sabine, Hirasawa, Akira, Høgdall, Estrid, Høgdall, Claus K, Horlings, Hugo M, Huntsman, David G, Huzarski, Tomasz, Jewell, Andrea, Jimenez‐Linan, Mercedes, Jones, Michael E, Kaufmann, Scott H, Kennedy, Catherine J, Khabele, Dineo, Kommoss, Felix KF, Kruitwagen, Roy FPM, Lambrechts, Diether, Le, Nhu D, Lener, Marcin, Lester, Jenny, Leung, Yee, Linder, Anna, Loverix, Liselore, Lubiński, Jan, Madan, Rashna, Maxwell, G Larry, Modugno, Francesmary, Neuhausen, Susan L, Olawaiye, Alexander, Olbrecht, Siel, Orsulic, Sandra, Palacios, José, Pearce, Celeste Leigh, Pike, Malcolm C, Quinn, Carmel M, Mohan, Ganendra Raj, Rodríguez‐Antona, Cristina, Ruebner, Matthias, and Ryan, Andy
Abstract: BackgroundCyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC.MethodsWithin the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated.ResultsHigh-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss.ConclusionThis study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.
Published: 2023

6. A federated approach to identify women with early-stage cervical cancer at low risk of lymph node metastases

Author: Wenzel, Hans H.B., Hardie, Anna N., Moncada-Torres, Arturo, Høgdall, Claus K., Bekkers, Ruud L.M., Falconer, Henrik, Jensen, Pernille T., Nijman, Hans W., van der Aa, Maaike A., Martin, Frank, van Gestel, Anna J., Lemmens, Valery E.P.P., Dahm-Kähler, Pernilla, Alfonzo, Emilia, Persson, Jan, Ekdahl, Linnea, Salehi, Sahar, Frøding, Ligita P., Markauskas, Algirdas, Fuglsang, Katrine, Schnack, Tine H., Wenzel, Hans H.B., Hardie, Anna N., Moncada-Torres, Arturo, Høgdall, Claus K., Bekkers, Ruud L.M., Falconer, Henrik, Jensen, Pernille T., Nijman, Hans W., van der Aa, Maaike A., Martin, Frank, van Gestel, Anna J., Lemmens, Valery E.P.P., Dahm-Kähler, Pernilla, Alfonzo, Emilia, Persson, Jan, Ekdahl, Linnea, Salehi, Sahar, Frøding, Ligita P., Markauskas, Algirdas, Fuglsang, Katrine, and Schnack, Tine H.
Abstract: Objective Lymph node metastases (pN+) in presumed early-stage cervical cancer negatively impact prognosis. Using federated learning, we aimed to develop a tool to identify a group of women at low risk of pN+, to guide the shared decision-making process concerning the extent of lymph node dissection. Methods Women with cervical cancer between 2005 and 2020 were identified retrospectively from population-based registries: the Danish Gynaecological Cancer Database, Swedish Quality Registry for Gynaecologic Cancer and Netherlands Cancer Registry. Inclusion criteria were: squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma; The International Federation of Gynecology and Obstetrics 2009 IA2, IB1 and IIA1; treatment with radical hysterectomy and pelvic lymph node assessment. We applied privacy-preserving federated logistic regression to identify risk factors of pN+. Significant factors were used to stratify the risk of pN+. Results We included 3606 women (pN+ 11%). The most important risk factors of pN+ were lymphovascular space invasion (LVSI) (odds ratio [OR] 5.16, 95% confidence interval [CI], 4.59–5.79), tumour size 21–40 mm (OR 2.14, 95% CI, 1.89–2.43) and depth of invasion>10 mm (OR 1.81, 95% CI, 1.59–2.08). A group of 1469 women (41%)—with tumours without LVSI, tumour size ≤20 mm, and depth of invasion ≤10 mm—had a very low risk of pN+ (2.4%, 95% CI, 1.7–3.3%). Conclusion Early-stage cervical cancer without LVSI, a tumour size ≤20 mm and depth of invasion ≤10 mm, confers a low risk of pN+. Based on an international privacy-preserving analysis, we developed a useful tool to guide the shared decision-making process regarding lymph node dissection., Objective: Lymph node metastases (pN+) in presumed early-stage cervical cancer negatively impact prognosis. Using federated learning, we aimed to develop a tool to identify a group of women at low risk of pN+, to guide the shared decision-making process concerning the extent of lymph node dissection. Methods: Women with cervical cancer between 2005 and 2020 were identified retrospectively from population-based registries: the Danish Gynaecological Cancer Database, Swedish Quality Registry for Gynaecologic Cancer and Netherlands Cancer Registry. Inclusion criteria were: squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma; The International Federation of Gynecology and Obstetrics 2009 IA2, IB1 and IIA1; treatment with radical hysterectomy and pelvic lymph node assessment. We applied privacy-preserving federated logistic regression to identify risk factors of pN+. Significant factors were used to stratify the risk of pN+. Results: We included 3606 women (pN+ 11%). The most important risk factors of pN+ were lymphovascular space invasion (LVSI) (odds ratio [OR] 5.16, 95% confidence interval [CI], 4.59–5.79), tumour size 21–40 mm (OR 2.14, 95% CI, 1.89–2.43) and depth of invasion>10 mm (OR 1.81, 95% CI, 1.59–2.08). A group of 1469 women (41%)—with tumours without LVSI, tumour size ≤20 mm, and depth of invasion ≤10 mm—had a very low risk of pN+ (2.4%, 95% CI, 1.7–3.3%). Conclusion: Early-stage cervical cancer without LVSI, a tumour size ≤20 mm and depth of invasion ≤10 mm, confers a low risk of pN+. Based on an international privacy-preserving analysis, we developed a useful tool to guide the shared decision-making process regarding lymph node dissection.
Published: 2023

7. 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 K.F., 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 J.R., 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, Staebler, Annette, Wu, Anna H., Cohen, Paul A., DeFazio, Anna, Lee, Cheng Han, Steed, Helen, Le, Nhu D., Gayther, Simon A., Lawrenson, Kate, Pharoah, Paul D.P., Konecny, Gottfried, Cook, Linda S., Ramus, Susan J., Kelemen, Linda E., Köbel, Martin, 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 K.F., 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 J.R., 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, Staebler, Annette, Wu, Anna H., Cohen, Paul A., DeFazio, Anna, Lee, Cheng Han, Steed, Helen, Le, Nhu D., Gayther, Simon A., Lawrenson, Kate, Pharoah, Paul D.P., Konecny, Gottfried, Cook, Linda S., Ramus, Susan J., Kelemen, Linda E., and Köbel, Martin
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 < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naïve tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naïve HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36–0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC.
Published: 2022

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

Author: Dareng, Eileen O, Dareng, Eileen O, Tyrer, Jonathan P, Barnes, Daniel R, Jones, Michelle R, Yang, Xin, Aben, Katja KH, 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 BM, Colonna, Sarah, GEMO Study Collaborators, GC-HBOC Study Collaborators, EMBRACE Collaborators, 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, OPAL Study Group, AOCS Group, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hamann, Ute, Hansen, Thomas VO, Harris, Holly R, Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle AT, Høgdall, Estrid, Høgdall, Claus K, Hopper, John L, Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J, Huntsman, David G, Dareng, Eileen O, Dareng, Eileen O, Tyrer, Jonathan P, Barnes, Daniel R, Jones, Michelle R, Yang, Xin, Aben, Katja KH, 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 BM, Colonna, Sarah, GEMO Study Collaborators, GC-HBOC Study Collaborators, EMBRACE Collaborators, 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, OPAL Study Group, AOCS Group, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hamann, Ute, Hansen, Thomas VO, Harris, Holly R, Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle AT, Høgdall, Estrid, Høgdall, Claus K, Hopper, John L, Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J, and Huntsman, David G
Abstract: Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
Published: 2022

9. Correction: Polygenic risk modeling for prediction of epithelial ovarian cancer risk.

Author: Dareng, Eileen O, Dareng, Eileen O, Tyrer, Jonathan P, Barnes, Daniel R, Jones, Michelle R, Yang, Xin, Aben, Katja KH, 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 BM, Colonna, Sarah, GEMO Study Collaborators, GC-HBOC Study Collaborators, EMBRACE Collaborators, 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, OPAL Study Group, AOCS Group, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hamann, Ute, Hansen, Thomas VO, Harris, Holly R, Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle AT, Høgdall, Estrid, Høgdall, Claus K, Hopper, John L, Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J, Huntsman, David G, Dareng, Eileen O, Dareng, Eileen O, Tyrer, Jonathan P, Barnes, Daniel R, Jones, Michelle R, Yang, Xin, Aben, Katja KH, 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 BM, Colonna, Sarah, GEMO Study Collaborators, GC-HBOC Study Collaborators, EMBRACE Collaborators, 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, OPAL Study Group, AOCS Group, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hamann, Ute, Hansen, Thomas VO, Harris, Holly R, Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle AT, Høgdall, Estrid, Høgdall, Claus K, Hopper, John L, Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J, and Huntsman, David G
Published: 2022

10. Correction: Polygenic risk modeling for prediction of epithelial ovarian cancer risk.

Author: Dareng, Eileen O, Dareng, Eileen O, Tyrer, Jonathan P, Barnes, Daniel R, Jones, Michelle R, Yang, Xin, Aben, Katja KH, 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 BM, Colonna, Sarah, GEMO Study Collaborators, GC-HBOC Study Collaborators, EMBRACE Collaborators, 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, OPAL Study Group, AOCS Group, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hamann, Ute, Hansen, Thomas VO, Harris, Holly R, Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle AT, Høgdall, Estrid, Høgdall, Claus K, Hopper, John L, Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J, Huntsman, David G, Dareng, Eileen O, Dareng, Eileen O, Tyrer, Jonathan P, Barnes, Daniel R, Jones, Michelle R, Yang, Xin, Aben, Katja KH, 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 BM, Colonna, Sarah, GEMO Study Collaborators, GC-HBOC Study Collaborators, EMBRACE Collaborators, 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, OPAL Study Group, AOCS Group, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hamann, Ute, Hansen, Thomas VO, Harris, Holly R, Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle AT, Høgdall, Estrid, Høgdall, Claus K, Hopper, John L, Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J, and Huntsman, David G
Published: 2022

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

Author: Dareng, Eileen O, Dareng, Eileen O, Tyrer, Jonathan P, Barnes, Daniel R, Jones, Michelle R, Yang, Xin, Aben, Katja KH, 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 BM, Colonna, Sarah, GEMO Study Collaborators, GC-HBOC Study Collaborators, EMBRACE Collaborators, 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, OPAL Study Group, AOCS Group, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hamann, Ute, Hansen, Thomas VO, Harris, Holly R, Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle AT, Høgdall, Estrid, Høgdall, Claus K, Hopper, John L, Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J, Huntsman, David G, Dareng, Eileen O, Dareng, Eileen O, Tyrer, Jonathan P, Barnes, Daniel R, Jones, Michelle R, Yang, Xin, Aben, Katja KH, 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 BM, Colonna, Sarah, GEMO Study Collaborators, GC-HBOC Study Collaborators, EMBRACE Collaborators, 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, OPAL Study Group, AOCS Group, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hamann, Ute, Hansen, Thomas VO, Harris, Holly R, Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle AT, Høgdall, Estrid, Høgdall, Claus K, Hopper, John L, Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J, and Huntsman, David G
Abstract: Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
Published: 2022

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

Author: Kang, Eun Young, 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, Staebler, Annette, Kang, Eun Young, 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
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 < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naïve tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naïve HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36-0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC.
Published: 2022

13. CA-125 Levels Are Predictive of Survival in Low-Grade Serous Ovarian Cancer—A Multicenter Analysis

Author: Wohlmuth, Christoph, Wohlmuth, Christoph, Djedovic, Vladimir, Kjaer, Susanne K, Jensen, Allan, Glasspool, Rosalind, Roxburgh, Patricia, DeFazio, Anna, Johnatty, Sharon E, Webb, Penelope M, Modugno, Francesmary, Lambrechts, Diether, Schildkraut, Joellen M, Berchuck, Andrew, Thomsen, Liv Cecilie Vestrheim, Bjorge, Line, Høgdall, Estrid, Høgdall, Claus K, Goode, Ellen L, Winham, Stacey J, Matsuo, Keitaro, Karlan, Beth Y, Lester, Jenny, Goodman, Marc T, Thompson, Pamela J, Pejovic, Tanja, Riggan, Marjorie J, Lajkosz, Katherine, Tone, Alicia, May, Taymaa, Wohlmuth, Christoph, Wohlmuth, Christoph, Djedovic, Vladimir, Kjaer, Susanne K, Jensen, Allan, Glasspool, Rosalind, Roxburgh, Patricia, DeFazio, Anna, Johnatty, Sharon E, Webb, Penelope M, Modugno, Francesmary, Lambrechts, Diether, Schildkraut, Joellen M, Berchuck, Andrew, Thomsen, Liv Cecilie Vestrheim, Bjorge, Line, Høgdall, Estrid, Høgdall, Claus K, Goode, Ellen L, Winham, Stacey J, Matsuo, Keitaro, Karlan, Beth Y, Lester, Jenny, Goodman, Marc T, Thompson, Pamela J, Pejovic, Tanja, Riggan, Marjorie J, Lajkosz, Katherine, Tone, Alicia, and May, Taymaa
Abstract: ObjectiveStudies on low-grade serous ovarian cancer (LGSC) are limited by a low number of cases. The aim of this study was to define the prognostic significance of age, stage, and CA-125 levels on survival in a multi-institutional cohort of women with pathologically confirmed LGSC.MethodsWomen with LGSC were identified from the collaborative Ovarian Cancer Association Consortium (OCAC). Cases of newly diagnosed primary LGSC were included if peri-operative CA-125 levels were available. Age at diagnosis, FIGO stage, pre- and post-treatment CA-125 levels, residual disease, adjuvant chemotherapy, disease recurrence, and vital status were collected by the participating institutions. Progression-free (PFS) and overall survival (OS) were calculated. Multivariable (MVA) Cox proportional hazard models were used and hazard ratios (HR) calculated.ResultsA total of 176 women with LGSC were included in this study; 82% had stage III/IV disease. The median PFS was 2.3 years and the median OS was 6.4 years. Age at diagnosis was not significantly associated with worse PFS (p = 0.23) or OS (p = 0.3) (HR per year: 0.99; 95%CI, 0.96-1.01 and 0.98; 95%CI 0.95-1.01). FIGO stage III/IV was independently associated with PFS (HR 4.26, 95%CI 1.43-12.73) and OS (HR 1.69, 95%CI 0.56-5.05). Elevated CA-125 (≥35 U/mL) at diagnosis was not significantly associated with worse PFS (p = 0.87) or OS (p = 0.78) in MVA. Elevated CA-125 (≥35 U/mL) after completion of primary treatment was independently associated with worse PFS (HR 2.81, 95%CI 1.36-5.81) and OS (HR 6.62, 95%CI 2.45-17.92). In the MVA, residual disease was independently associated with PFS (0.022), but not OS (0.85).ConclusionAdvanced LGSC was associated with poor long-term prognosis. FIGO stage and abnormal post-treatment CA-125 level are key prognostic factors inversely associated with PFS and OS.Highlights1. Through a multi-center collaborative effort, data from 176 women with low-grade serous ovarian cancer were analyzed. 2. Although
Published: 2022

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

Author: Meagher, Nicola S, Meagher, Nicola S, Gorringe, Kylie L, Wakefield, Matthew, Bolithon, Adelyn, Pang, Chi Nam Ignatius, Chiu, Derek S, Anglesio, Michael S, Mallitt, Kylie-Ann, Doherty, Jennifer A, Harris, Holly R, Schildkraut, Joellen M, Berchuck, Andrew, Cushing-Haugen, Kara L, Chezar, Ksenia, Chou, Angela, Tan, Adeline, Alsop, Jennifer, Barlow, Ellen, Beckmann, Matthias W, Boros, Jessica, Bowtell, David DL, AOCS Group, Brand, Alison H, Brenton, James D, Campbell, Ian, Cheasley, Dane, Cohen, Joshua, Cybulski, Cezary, Elishaev, Esther, Erber, Ramona, Farrell, Rhonda, Fischer, Anna, Fu, Zhuxuan, Gilks, Blake, Gill, Anthony J, Australian Pancreatic Genome Initiative, Gourley, Charlie, Grube, Marcel, Harnett, Paul R, Hartmann, Arndt, Hettiaratchi, Anusha, Høgdall, Claus K, Huzarski, Tomasz, Jakubowska, Anna, Jimenez-Linan, Mercedes, Kennedy, Catherine J, Kim, Byoung-Gie, Kim, Jae-Weon, Kim, Jae-Hoon, Klett, Kayla, Koziak, Jennifer M, Lai, Tiffany, Laslavic, Angela, Lester, Jenny, Leung, Yee, Li, Na, Liauw, Winston, Lim, Belle WX, Linder, Anna, Lubiński, Jan, Mahale, Sakshi, Mateoiu, Constantina, McInerny, Simone, Menkiszak, Janusz, Minoo, Parham, Mittelstadt, Suzana, Morris, David, Orsulic, Sandra, Park, Sang-Yoon, Pearce, Celeste Leigh, Pearson, John V, Pike, Malcolm C, Quinn, Carmel M, Mohan, Ganendra Raj, Rao, Jianyu, Riggan, Marjorie J, Ruebner, Matthias, Salfinger, Stuart, Scott, Clare L, Shah, Mitul, Steed, Helen, Stewart, Colin JR, Subramanian, Deepak, Sung, Soseul, Tang, Katrina, Timpson, Paul, Ward, Robyn L, Wiedenhoefer, Rebekka, Thorne, Heather, kConFab Investigators, Cohen, Paul A, Crowe, Philip, Fasching, Peter A, Gronwald, Jacek, Hawkins, Nicholas J, Høgdall, Estrid, Huntsman, David G, James, Paul A, Karlan, Beth Y, Kelemen, Linda E, Meagher, Nicola S, Meagher, Nicola S, Gorringe, Kylie L, Wakefield, Matthew, Bolithon, Adelyn, Pang, Chi Nam Ignatius, Chiu, Derek S, Anglesio, Michael S, Mallitt, Kylie-Ann, Doherty, Jennifer A, Harris, Holly R, Schildkraut, Joellen M, Berchuck, Andrew, Cushing-Haugen, Kara L, Chezar, Ksenia, Chou, Angela, Tan, Adeline, Alsop, Jennifer, Barlow, Ellen, Beckmann, Matthias W, Boros, Jessica, Bowtell, David DL, AOCS Group, Brand, Alison H, Brenton, James D, Campbell, Ian, Cheasley, Dane, Cohen, Joshua, Cybulski, Cezary, Elishaev, Esther, Erber, Ramona, Farrell, Rhonda, Fischer, Anna, Fu, Zhuxuan, Gilks, Blake, Gill, Anthony J, Australian Pancreatic Genome Initiative, Gourley, Charlie, Grube, Marcel, Harnett, Paul R, Hartmann, Arndt, Hettiaratchi, Anusha, Høgdall, Claus K, Huzarski, Tomasz, Jakubowska, Anna, Jimenez-Linan, Mercedes, Kennedy, Catherine J, Kim, Byoung-Gie, Kim, Jae-Weon, Kim, Jae-Hoon, Klett, Kayla, Koziak, Jennifer M, Lai, Tiffany, Laslavic, Angela, Lester, Jenny, Leung, Yee, Li, Na, Liauw, Winston, Lim, Belle WX, Linder, Anna, Lubiński, Jan, Mahale, Sakshi, Mateoiu, Constantina, McInerny, Simone, Menkiszak, Janusz, Minoo, Parham, Mittelstadt, Suzana, Morris, David, Orsulic, Sandra, Park, Sang-Yoon, Pearce, Celeste Leigh, Pearson, John V, Pike, Malcolm C, Quinn, Carmel M, Mohan, Ganendra Raj, Rao, Jianyu, Riggan, Marjorie J, Ruebner, Matthias, Salfinger, Stuart, Scott, Clare L, Shah, Mitul, Steed, Helen, Stewart, Colin JR, Subramanian, Deepak, Sung, Soseul, Tang, Katrina, Timpson, Paul, Ward, Robyn L, Wiedenhoefer, Rebekka, Thorne, Heather, kConFab Investigators, Cohen, Paul A, Crowe, Philip, Fasching, Peter A, Gronwald, Jacek, Hawkins, Nicholas J, Høgdall, Estrid, Huntsman, David G, James, Paul A, Karlan, Beth Y, and Kelemen, Linda E
Abstract: PurposeAdvanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features.Experimental designDiscovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55).ResultsInfiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%).ConclusionsAn infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.
Published: 2022

15. miRNA Expression in Ovarian Cancer in Fresh Frozen, Formalin-fixed Paraffin-embedded and Plasma Samples

Author: Petersen, Patrick H.D., Lopacinska-Jørgensen, Joanna, Oliveira, Douglas V.N.P., Høgdall, Claus K., Høgdall, Estrid V., Petersen, Patrick H.D., Lopacinska-Jørgensen, Joanna, Oliveira, Douglas V.N.P., Høgdall, Claus K., and Høgdall, Estrid V.
Abstract: Background/Aim: MicroRNAs (miRNAs) are small noncoding RNAs involved in gene expression regulation and have been investigated as potential biomarkers for various diseases, including ovarian cancer (OC). However, lack of standardized protocols regarding e.g., RNA isolation, cDNA synthesis, spike-in controls for experimental steps, and data normalization, impacts cross validation of results across research groups and hinders implementation of miRNAs as clinical biomarkers. Materials and Methods: RNA was isolated from matching fresh-frozen tissue (FF), formalin-fixed paraffin embedded (FFPE) tissue, and plasma samples from twenty women diagnosed with OC using three commercial kits: miRNeasy Tissue/Cells, miRNeasy FFPE, and miRNeasy Serum/Plasma (Qiagen, Copenhagen, Denmark). RNA isolation, cDNA synthesis, and PCR performance were tested using miRCURY LNA miRNA Quality Control PCR (QC) Panels (Qiagen). Finally, miRNA stability was assessed using five algorithms: BestKeeper, Normfinder, GeNorm, comparative delta-Ct and comprehensive ranking provided by a web-based RefFinder tool. Results: RNA from FF, FFPE and plasma was extracted using commercially available kits and the differences in yield and purity were examined. We developed a simple method for identifying and potentially excluding samples based on their crossing point values from RT-qPCR data, which could improve existing manufacture guidelines. Moreover, we discussed how assessment of miRNA stability differs between algorithms, possibly leading to inconsistent results. Conclusion: We present guidelines for RNA isolation, cDNA synthesis, and data normalization for successful miRNA expression profiling using RT-qPCR in corresponding biological OC specimens. We recommend QC panels in combination with spike-in controls and interplate controls to monitor process efficiencies.
Published: 2022

16. miRNA Expression in Ovarian Cancer in Fresh Frozen, Formalin-fixed Paraffin-embedded and Plasma Samples

Author: Petersen, Patrick H.D., Lopacinska-Jørgensen, Joanna, Oliveira, Douglas V.N.P., Høgdall, Claus K., Høgdall, Estrid V., Petersen, Patrick H.D., Lopacinska-Jørgensen, Joanna, Oliveira, Douglas V.N.P., Høgdall, Claus K., and Høgdall, Estrid V.
Abstract: Background/Aim: MicroRNAs (miRNAs) are small noncoding RNAs involved in gene expression regulation and have been investigated as potential biomarkers for various diseases, including ovarian cancer (OC). However, lack of standardized protocols regarding e.g., RNA isolation, cDNA synthesis, spike-in controls for experimental steps, and data normalization, impacts cross validation of results across research groups and hinders implementation of miRNAs as clinical biomarkers. Materials and Methods: RNA was isolated from matching fresh-frozen tissue (FF), formalin-fixed paraffin embedded (FFPE) tissue, and plasma samples from twenty women diagnosed with OC using three commercial kits: miRNeasy Tissue/Cells, miRNeasy FFPE, and miRNeasy Serum/Plasma (Qiagen, Copenhagen, Denmark). RNA isolation, cDNA synthesis, and PCR performance were tested using miRCURY LNA miRNA Quality Control PCR (QC) Panels (Qiagen). Finally, miRNA stability was assessed using five algorithms: BestKeeper, Normfinder, GeNorm, comparative delta-Ct and comprehensive ranking provided by a web-based RefFinder tool. Results: RNA from FF, FFPE and plasma was extracted using commercially available kits and the differences in yield and purity were examined. We developed a simple method for identifying and potentially excluding samples based on their crossing point values from RT-qPCR data, which could improve existing manufacture guidelines. Moreover, we discussed how assessment of miRNA stability differs between algorithms, possibly leading to inconsistent results. Conclusion: We present guidelines for RNA isolation, cDNA synthesis, and data normalization for successful miRNA expression profiling using RT-qPCR in corresponding biological OC specimens. We recommend QC panels in combination with spike-in controls and interplate controls to monitor process efficiencies.
Published: 2022

17. CA-125 Levels Are Predictive of Survival in Low-Grade Serous Ovarian Cancer—A Multicenter Analysis

Author: Wohlmuth, Christoph, Djedovic, Vladimir, Kjaer, Susanne K., Jensen, Allan, Glasspool, Rosalind, Roxburgh, Patricia, Defazio, Anna, Johnatty, Sharon E., Webb, Penelope M., Modugno, Francesmary, Lambrechts, Diether, Schildkraut, Joellen M., Berchuck, Andrew, Thomsen, Liv Cecilie Vestrheim, Bjorge, Line, Høgdall, Estrid, Høgdall, Claus K., Goode, Ellen L., Winham, Stacey J., Matsuo, Keitaro, Karlan, Beth Y., Lester, Jenny, Goodman, Marc T., Thompson, Pamela J., Pejovic, Tanja, Riggan, Marjorie J., Lajkosz, Katherine, Tone, Alicia, May, Taymaa, Wohlmuth, Christoph, Djedovic, Vladimir, Kjaer, Susanne K., Jensen, Allan, Glasspool, Rosalind, Roxburgh, Patricia, Defazio, Anna, Johnatty, Sharon E., Webb, Penelope M., Modugno, Francesmary, Lambrechts, Diether, Schildkraut, Joellen M., Berchuck, Andrew, Thomsen, Liv Cecilie Vestrheim, Bjorge, Line, Høgdall, Estrid, Høgdall, Claus K., Goode, Ellen L., Winham, Stacey J., Matsuo, Keitaro, Karlan, Beth Y., Lester, Jenny, Goodman, Marc T., Thompson, Pamela J., Pejovic, Tanja, Riggan, Marjorie J., Lajkosz, Katherine, Tone, Alicia, and May, Taymaa
Abstract: Objective: Studies on low-grade serous ovarian cancer (LGSC) are limited by a low number of cases. The aim of this study was to define the prognostic significance of age, stage, and CA-125 levels on survival in a multi-institutional cohort of women with pathologically confirmed LGSC. Methods: Women with LGSC were identified from the collaborative Ovarian Cancer Association Consortium (OCAC). Cases of newly diagnosed primary LGSC were included if peri-operative CA-125 levels were available. Age at diagnosis, FIGO stage, pre-and post-treatment CA-125 levels, residual disease, adjuvant chemotherapy, disease recurrence, and vital status were collected by the participating institutions. Progression-free (PFS) and overall survival (OS) were calculated. Multivariable (MVA) Cox proportional hazard models were used and hazard ratios (HR) calculated. Results: A total of 176 women with LGSC were included in this study; 82% had stage III/IV disease. The median PFS was 2.3 years and the median OS was 6.4 years. Age at diagnosis was not significantly associated with worse PFS (p = 0.23) or OS (p = 0.3) (HR per year: 0.99; 95%CI, 0.96–1.01 and 0.98; 95%CI 0.95–1.01). FIGO stage III/IV was independently associated with PFS (HR 4.26, 95%CI 1.43–12.73) and OS (HR 1.69, 95%CI 0.56–5.05). Elevated CA-125 (≥35 U/mL) at diagnosis was not significantly associated with worse PFS (p = 0.87) or OS (p = 0.78) in MVA. Elevated CA-125 (≥35 U/mL) after completion of primary treatment was independently associated with worse PFS (HR 2.81, 95%CI 1.36–5.81) and OS (HR 6.62, 95%CI 2.45–17.92). In the MVA, residual disease was independently associated with PFS (0.022), but not OS (0.85). Conclusion: Advanced LGSC was associated with poor long-term prognosis. FIGO stage and abnormal post-treatment CA-125 level are key prognostic factors inversely associated with PFS and OS. Highlights: 1. Through a multi-center collaborative effort, data from 176 women with low-grade serous ovarian cancer were analy
Published: 2022

18. 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, Hansen, Thomas V.O., Høgdall, Estrid, Høgdall, Claus K., Jensen, Allan, Kjaer, Susanne K., Nielsen, Finn C., 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, Hansen, Thomas V.O., Høgdall, Estrid, Høgdall, Claus K., Jensen, Allan, Kjaer, Susanne K., and Nielsen, Finn C.
Abstract: Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
Published: 2022

19. 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 K.F., 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 J.R., 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, Staebler, Annette, Wu, Anna H., Cohen, Paul A., DeFazio, Anna, Lee, Cheng Han, Steed, Helen, Le, Nhu D., Gayther, Simon A., Lawrenson, Kate, Pharoah, Paul D.P., Konecny, Gottfried, Cook, Linda S., Ramus, Susan J., Kelemen, Linda E., Köbel, Martin, 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 K.F., 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 J.R., 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, Staebler, Annette, Wu, Anna H., Cohen, Paul A., DeFazio, Anna, Lee, Cheng Han, Steed, Helen, Le, Nhu D., Gayther, Simon A., Lawrenson, Kate, Pharoah, Paul D.P., Konecny, Gottfried, Cook, Linda S., Ramus, Susan J., Kelemen, Linda E., and Köbel, Martin
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 < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naïve tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naïve HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36–0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC.
Published: 2022

20. CA-125 Levels Are Predictive of Survival in Low-Grade Serous Ovarian Cancer—A Multicenter Analysis

Author: Wohlmuth, Christoph, Djedovic, Vladimir, Kjaer, Susanne K., Jensen, Allan, Glasspool, Rosalind, Roxburgh, Patricia, Defazio, Anna, Johnatty, Sharon E., Webb, Penelope M., Modugno, Francesmary, Lambrechts, Diether, Schildkraut, Joellen M., Berchuck, Andrew, Thomsen, Liv Cecilie Vestrheim, Bjorge, Line, Høgdall, Estrid, Høgdall, Claus K., Goode, Ellen L., Winham, Stacey J., Matsuo, Keitaro, Karlan, Beth Y., Lester, Jenny, Goodman, Marc T., Thompson, Pamela J., Pejovic, Tanja, Riggan, Marjorie J., Lajkosz, Katherine, Tone, Alicia, May, Taymaa, Wohlmuth, Christoph, Djedovic, Vladimir, Kjaer, Susanne K., Jensen, Allan, Glasspool, Rosalind, Roxburgh, Patricia, Defazio, Anna, Johnatty, Sharon E., Webb, Penelope M., Modugno, Francesmary, Lambrechts, Diether, Schildkraut, Joellen M., Berchuck, Andrew, Thomsen, Liv Cecilie Vestrheim, Bjorge, Line, Høgdall, Estrid, Høgdall, Claus K., Goode, Ellen L., Winham, Stacey J., Matsuo, Keitaro, Karlan, Beth Y., Lester, Jenny, Goodman, Marc T., Thompson, Pamela J., Pejovic, Tanja, Riggan, Marjorie J., Lajkosz, Katherine, Tone, Alicia, and May, Taymaa
Abstract: Objective: Studies on low-grade serous ovarian cancer (LGSC) are limited by a low number of cases. The aim of this study was to define the prognostic significance of age, stage, and CA-125 levels on survival in a multi-institutional cohort of women with pathologically confirmed LGSC. Methods: Women with LGSC were identified from the collaborative Ovarian Cancer Association Consortium (OCAC). Cases of newly diagnosed primary LGSC were included if peri-operative CA-125 levels were available. Age at diagnosis, FIGO stage, pre-and post-treatment CA-125 levels, residual disease, adjuvant chemotherapy, disease recurrence, and vital status were collected by the participating institutions. Progression-free (PFS) and overall survival (OS) were calculated. Multivariable (MVA) Cox proportional hazard models were used and hazard ratios (HR) calculated. Results: A total of 176 women with LGSC were included in this study; 82% had stage III/IV disease. The median PFS was 2.3 years and the median OS was 6.4 years. Age at diagnosis was not significantly associated with worse PFS (p = 0.23) or OS (p = 0.3) (HR per year: 0.99; 95%CI, 0.96–1.01 and 0.98; 95%CI 0.95–1.01). FIGO stage III/IV was independently associated with PFS (HR 4.26, 95%CI 1.43–12.73) and OS (HR 1.69, 95%CI 0.56–5.05). Elevated CA-125 (≥35 U/mL) at diagnosis was not significantly associated with worse PFS (p = 0.87) or OS (p = 0.78) in MVA. Elevated CA-125 (≥35 U/mL) after completion of primary treatment was independently associated with worse PFS (HR 2.81, 95%CI 1.36–5.81) and OS (HR 6.62, 95%CI 2.45–17.92). In the MVA, residual disease was independently associated with PFS (0.022), but not OS (0.85). Conclusion: Advanced LGSC was associated with poor long-term prognosis. FIGO stage and abnormal post-treatment CA-125 level are key prognostic factors inversely associated with PFS and OS. Highlights: 1. Through a multi-center collaborative effort, data from 176 women with low-grade serous ovarian cancer were analy
Published: 2022

21. 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, Hansen, Thomas V.O., Høgdall, Estrid, Høgdall, Claus K., Jensen, Allan, Kjaer, Susanne K., Nielsen, Finn C., 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, Hansen, Thomas V.O., Høgdall, Estrid, Høgdall, Claus K., Jensen, Allan, Kjaer, Susanne K., and Nielsen, Finn C.
Abstract: Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
Published: 2022

22. 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, Thompson, Deborah J, Aben, Katja Kh, Alsulimani, Ahmad, Amant, Frédéric, Annibali, Daniela, Attia, John, Barricarte, Aurelio, Beckmann, Matthias W., Berchuck, Andrew, Bermisheva, Marina, Bernardini, Marcus Q., Bischof, Katharina, Bjørge, Line, Bodelon, Clara, Brand, Alison H, Brenton, James D., Brinton, Louise A., Bruinsma, Fiona, Buchanan, Daniel D., Burghaus, Stefanie, Bützow, Ralf, Cai, Hui, Carney, Michael E., Chanock, Stephen J., Chen, Chu, Chen, Xiaoqing, Chen, Zhihua, Cook, Linda S., Cunningham, Julie M., De Vivo, Immaculata, Defazio, Anna, Doherty, Jennifer A., Dork, Thilo, Du Bois, Andreas, Dunning, Alison M, Durst, 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, Harris, Holly R, Harter, Philipp, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle A.t., 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, Lester, Jenny, Li, Andrew J, Liang, Dong, Liebrich, Clemens, Lipworth, Loren, Lissowska, Jolanta, Lu, Lingeng, Lu, Karen H., Macciotta, Alessandra, Mattiello, Amalia, May, Taymaa, Mcalpine, Jessica N., Mcguire, Valerie, Mcneish, Iain A., Menon, Usha, Modugno, Francesmary, Moysich, Kirsten B., Nevanlinna, Heli, Odunsi, Kunle, Olsson, Håkan, Orsulic, Sandra, Osorio, Ana, Palli, Domenico, Park-simon, Tjoung-won, Pearce, Celeste L., Pejovic, Tanja, Permuth, Jennifer B, Podgorska, Agnieszka, Ramus, Susan J., Rebbeck, Timothy R., Riggan, Marjorie J., Risch, Harvey A., Rothstein, Joseph H., Runnebaum, Ingo B., Scott, Rodney J., Sellers, Thomas A., Senz, Janine, Setiawan, Veronica Wendy, Siddiqui, Nadeem, Sieh, Weiva, Spiewankiewicz, Beata, Sutphen, Rebecca, Swerdlow, Anthony J., Szafron, Lukasz Michal, Teo, Soo Hwang, Thompson, Pamela J, Thomsen, Liv Cecilie Vestrheim, Titus, Linda, Tone, Alicia, Tumino, Rosario, Turman, Constance, Vanderstichele, Adriaan, Velez Edwards, Digna, Vergote, Ignace, Vierkant, Robert A., Wang, Zhaoming, Wang-gohrke, Shan, Webb, Penelope M., White, Emily, Whittemore, Alice S., Winham, Stacey J., Wu, Xifeng, Wu, Anna H., Yannoukakos, Drakoulis, Spurdle, Amanda B, O'mara, Tracy A, Glubb, Dylan M, Thompson, Deborah J, Aben, Katja Kh, Alsulimani, Ahmad, Amant, Frédéric, Annibali, Daniela, Attia, John, Barricarte, Aurelio, Beckmann, Matthias W., Berchuck, Andrew, Bermisheva, Marina, Bernardini, Marcus Q., Bischof, Katharina, Bjørge, Line, Bodelon, Clara, Brand, Alison H, Brenton, James D., Brinton, Louise A., Bruinsma, Fiona, Buchanan, Daniel D., Burghaus, Stefanie, Bützow, Ralf, Cai, Hui, Carney, Michael E., Chanock, Stephen J., Chen, Chu, Chen, Xiaoqing, Chen, Zhihua, Cook, Linda S., Cunningham, Julie M., De Vivo, Immaculata, Defazio, Anna, Doherty, Jennifer A., Dork, Thilo, Du Bois, Andreas, Dunning, Alison M, Durst, 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, Harris, Holly R, Harter, Philipp, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle A.t., 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, Lester, Jenny, Li, Andrew J, Liang, Dong, Liebrich, Clemens, Lipworth, Loren, Lissowska, Jolanta, Lu, Lingeng, Lu, Karen H., Macciotta, Alessandra, Mattiello, Amalia, May, Taymaa, Mcalpine, Jessica N., Mcguire, Valerie, Mcneish, Iain A., Menon, Usha, Modugno, Francesmary, Moysich, Kirsten B., Nevanlinna, Heli, Odunsi, Kunle, Olsson, Håkan, Orsulic, Sandra, Osorio, Ana, Palli, Domenico, Park-simon, Tjoung-won, Pearce, Celeste L., Pejovic, Tanja, Permuth, Jennifer B, Podgorska, Agnieszka, Ramus, Susan J., Rebbeck, Timothy R., Riggan, Marjorie J., Risch, Harvey A., Rothstein, Joseph H., Runnebaum, Ingo B., Scott, Rodney J., Sellers, Thomas A., Senz, Janine, Setiawan, Veronica Wendy, Siddiqui, Nadeem, Sieh, Weiva, Spiewankiewicz, Beata, Sutphen, Rebecca, Swerdlow, Anthony J., Szafron, Lukasz Michal, Teo, Soo Hwang, Thompson, Pamela J, Thomsen, Liv Cecilie Vestrheim, Titus, Linda, Tone, Alicia, Tumino, Rosario, Turman, Constance, Vanderstichele, Adriaan, Velez Edwards, Digna, Vergote, Ignace, Vierkant, Robert A., Wang, Zhaoming, Wang-gohrke, Shan, Webb, Penelope M., White, Emily, Whittemore, Alice S., Winham, Stacey J., Wu, Xifeng, Wu, Anna H., Yannoukakos, Drakoulis, Spurdle, Amanda B, and O'mara, Tracy A
Published: 2021

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

Author: Kar, Siddhartha P, 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, Schildkraut, Joellen M, Kar, Siddhartha P, 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
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

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

Author: Kar, Siddhartha P, 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, Schildkraut, Joellen M, Kar, Siddhartha P, 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
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

25. 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 A, 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, 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, Lester, Jenny, Li, Andrew J, Liang, Dong, Liebrich, Clemens, Lipworth, Loren, Lissowska, Jolanta, Lu, Lingeng, Lu, Karen H, Macciotta, Alessandra, Mattiello, Amalia, May, Taymaa, McAlpine, Jessica N, McGuire, Valerie, 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 A, 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, 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, Lester, Jenny, Li, Andrew J, Liang, Dong, Liebrich, Clemens, Lipworth, Loren, Lissowska, Jolanta, Lu, Lingeng, Lu, Karen H, Macciotta, Alessandra, Mattiello, Amalia, May, Taymaa, McAlpine, Jessica N, and McGuire, Valerie
Abstract: BackgroundAccumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers.MethodsUsing LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data.ResultsGenetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10-5). We found seven loci associated with risk for both cancers (P Bonferroni < 2.4 × 10-9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified (P < 5 × 10-7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation.ConclusionsUsing cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis.ImpactOur research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.
Published: 2021

26. Gene expression profile association with poor prognosis in epithelial ovarian cancer patients

Author: Oliveira, Douglas V.N.P., Prahm, Kira P., Christensen, Ib J., Hansen, Anker, Høgdall, Claus K., Høgdall, Estrid V., Oliveira, Douglas V.N.P., Prahm, Kira P., Christensen, Ib J., Hansen, Anker, Høgdall, Claus K., and Høgdall, Estrid V.
Abstract: Ovarian cancer (OC) is the eighth most common type of cancer for women worldwide. The current diagnostic and prognostic routine available for OC management either lack specificity or are very costly. Gene expression profiling has shown to be a very effective tool in exploring new molecular markers for patients with OC, although association of such markers with patient survival and clinical outcome is still elusive. Here, we performed gene expression profiling of different subtypes of OC to evaluate its association with patient overall survival (OS) and aggressive forms of the disease. By global mRNA microarray profiling in a total of 196 epithelial OC patients (161 serous, 15 endometrioid, 11 mucinous, and 9 clear cell carcinomas), we found four candidates-HSPA1A, CD99, RAB3A and POM121L9P, which associated with OS and poor clinicopathological features. The overexpression of all combined was correlated with shorter OS and progression-free survival (PFS). Furthermore, the combination of at least two markers were further associated with advanced grade, chemotherapy resistance, and progressive disease. These results indicate that a panel comprised of a few predictors that associates with a more aggressive form of OC may be clinically relevant, presenting a better performance than one marker alone.
Published: 2021

27. Integrated microRNA and mRNA signatures associated with overall survival in epithelial ovarian cancer

Author: Lopacinska-Jørgensen, Joanna, Oliveira, Douglas V.N.P., Novotny, Guy Wayne, Høgdall, Claus K., Høgdall, Estrid V., Lopacinska-Jørgensen, Joanna, Oliveira, Douglas V.N.P., Novotny, Guy Wayne, Høgdall, Claus K., and Høgdall, Estrid V.
Abstract: Ovarian cancer (OC), the eighth-leading cause of cancer-related death among females worldwide, is mainly represented by epithelial OC (EOC) that can be further subdivided into four subtypes: Serous (75%), endometrioid (10%), clear cell (10%), and mucinous (3%). Major reasons for high mortality are the poor biological understanding of the OC mechanisms and a lack of reliable markers defining each EOC subtype. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression primarily by targeting messenger RNA (mRNA) transcripts. Their aberrant expression patterns have been associated with cancer development, including OC. However, the role of miRNAs in tumorigenesis is still to be determined, mainly due to the lack of consensus regarding optimal methodologies for identification and validation of miRNAs and their targets. Several tools for computational target prediction exist, but false interpretations remain a problem. The experimental validation of every potential miRNA-mRNA pair is not feasible, as it is laborious and expensive. In this study, we analyzed the correlation between global miRNA and mRNA expression patterns derived from microarray profiling of 197 EOC patients to identify the signatures of miRNA-mRNA interactions associated with overall survival (OS). The aim was to investigate whether these miRNA-mRNA signatures might have a prognostic value for OS in different subtypes of EOC. The content of our cohort (162 serous carcinomas, 15 endometrioid carcinomas, 11 mucinous carcinomas, and 9 clear cell carcinomas) reflects a real-world scenario of EOC. Several interaction pairs between 6 miRNAs (hsamiR- 126-3p, hsa-miR-223-3p, hsa-miR-23a-5p, hsa-miR-27a-5p, hsa-miR-486-5p, and hsamiR- 506-3p) and 8 mRNAs (ATF3, CH25H, EMP1, HBB, HBEGF, NAMPT, POSTN, and PROCR) were identified and the findings appear to be well supported by the literature. This indicates that our study has a potential to reveal miRNA-mRNA signatures relevant for EOC. Th
Published: 2021

28. Oncomine™ Comprehensive Assay v3 vs. Oncomine™ Comprehensive Assay Plus

Author: Vestergaard, Lau K., Oliveira, Douglas N.P., Poulsen, Tim S., Høgdall, Claus K., Høgdall, Estrid V., Vestergaard, Lau K., Oliveira, Douglas N.P., Poulsen, Tim S., Høgdall, Claus K., and Høgdall, Estrid V.
Abstract: The usage of next generation sequencing in combination with targeted gene panels has enforced a better understanding of tumor compositions. The identification of key genomic bi-omarkers underlying a disease are crucial for diagnosis, prognosis, treatment and therapeutic re-sponses. The Oncomine™ Comprehensive Assay v3 (OCAv3) covers 161 cancer‐associated genes and is routinely employed to support clinical decision making for a therapeutic course. An improved version, Oncomine™ Comprehensive Assay Plus (OCA‐Plus), has been recently developed, covering 501 genes (144 overlapping with OCAv3) in addition to microsatellite instability (MSI) and tumor mutational burden (TMB) assays in one workflow. The validation of MSI and TMB was not addressed in the present study. However, the implementation of new assays must be validated and confirmed across multiple samples before it can be introduced into a clinical setting. Here, we report the comparison of DNA sequencing results from 50 ovarian cancer formalin‐fixed, paraffin‐embed-ded samples subjected to OCAv3 and OCA‐Plus. A validation assessment of gene mutations identified using OCA‐Plus was performed on the 144 overlapping genes and 313,769 intersecting nucle-otide positions of the OCAv3 and the OCA‐Plus. Our results showed a 91% concordance within variants classified as likely‐pathogenic or pathogenic. Moreover, results showed that a region of PTEN is poorly covered by the OCA‐Plus assay, hence, we implemented rescue filters for those variants. In conclusion, the OCA‐Plus can reflect the mutational profile of genomic variants com-pared with OCAv3 of 144 overlapping genes, without compromising performance.
Published: 2021

29. Genomic sub-classification of ovarian clear cell carcinoma revealed by distinct mutational signatures

Author: Oliveira, Douglas V.N.P., Schnack, Tine H., Poulsen, Tim S., Christiansen, Anne P., Høgdall, Claus K., Høgdall, Estrid V., Oliveira, Douglas V.N.P., Schnack, Tine H., Poulsen, Tim S., Christiansen, Anne P., Høgdall, Claus K., and Høgdall, Estrid V.
Abstract: Ovarian clear cell carcinoma (OCCC) is characterized by dismal prognosis, partially due to its low sensitivity to standard chemotherapy regimen. It is also well-known for presenting unique molecular features in comparison to other epithelial ovarian cancer subtypes. Here, we aim to identify potential subgroups of patients in order to (1) determine their molecular features and (2) characterize their mutational signature. Furthermore, we sought to perform the investigation based on a potentially clinically relevant setting. To that end, we assessed the mutational profile and genomic instability of 55 patients extracted from the Gynecologic Cancer Database (DGCD) by using a panel comprised of 409 cancer-associated genes and a microsatellite assay, respectively; both are currently used in our routine environment. In accordance with previous findings, ARID1A and PIK3CA were the most prevalent mutations, present in 49.1% and 41.8%, respectively. From those, the co-occurrence of ARID1A and PIK3CA mutations was observed in 36.1% of subjects, indicating that this association might be a common feature of OCCC. The microsatellite instability frequency was low across samples. An unbiased assessment of signatures identified the presence of three subgroups, where “PIK3CA” and “Double hit” (with ARID1A and PIK3CA double mutation) subgroups exhibited unique signatures, whilst “ARID1A” and “Undetermined” (no mutations on ARID1A nor PIK3CA) subgroups showed similar profiles. Those differences were further indicated by COSMIC signatures. Taken together, the current findings suggest that OCCC presents distinct mutational landscapes within its group, which may indicate different therapeutic approaches according to its subgroup. Although encouraging, it is noteworthy that the current results are limited by sample size, and further investigation on a larger group would be crucial to better elucidate them.
Published: 2021

30. Next generation sequencing technology in the clinic and its challenges

Author: Vestergaard, Lau K., Oliveira, Douglas N.P., Høgdall, Claus K., Høgdall, Estrid V., Vestergaard, Lau K., Oliveira, Douglas N.P., Høgdall, Claus K., and Høgdall, Estrid V.
Abstract: Data analysis has become a crucial aspect in clinical oncology to interpret output from next-generation sequencing-based testing. NGS being able to resolve billions of sequencing reactions in a few days has consequently increased the demand for tools to handle and analyze such large data sets. Many tools have been developed since the advent of NGS, featuring their own peculiarities. Increased awareness when interpreting alterations in the genome is therefore of utmost importance, as the same data using different tools can provide diverse outcomes. Hence, it is crucial to evaluate and validate bioinformatic pipelines in clinical settings. Moreover, personalized medicine implies treatment targeting efficacy of biological drugs for specific genomic alterations. Here, we focused on different sequencing technologies, features underlying the genome complexity, and bioinformatic tools that can impact the final annotation. Additionally, we discuss the clinical demand and design for implementing NGS.
Published: 2021

31. 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

32. Gene expression profile association with poor prognosis in epithelial ovarian cancer patients

Author: Oliveira, Douglas V.N.P., Prahm, Kira P., Christensen, Ib J., Hansen, Anker, Høgdall, Claus K., Høgdall, Estrid V., Oliveira, Douglas V.N.P., Prahm, Kira P., Christensen, Ib J., Hansen, Anker, Høgdall, Claus K., and Høgdall, Estrid V.
Abstract: Ovarian cancer (OC) is the eighth most common type of cancer for women worldwide. The current diagnostic and prognostic routine available for OC management either lack specificity or are very costly. Gene expression profiling has shown to be a very effective tool in exploring new molecular markers for patients with OC, although association of such markers with patient survival and clinical outcome is still elusive. Here, we performed gene expression profiling of different subtypes of OC to evaluate its association with patient overall survival (OS) and aggressive forms of the disease. By global mRNA microarray profiling in a total of 196 epithelial OC patients (161 serous, 15 endometrioid, 11 mucinous, and 9 clear cell carcinomas), we found four candidates-HSPA1A, CD99, RAB3A and POM121L9P, which associated with OS and poor clinicopathological features. The overexpression of all combined was correlated with shorter OS and progression-free survival (PFS). Furthermore, the combination of at least two markers were further associated with advanced grade, chemotherapy resistance, and progressive disease. These results indicate that a panel comprised of a few predictors that associates with a more aggressive form of OC may be clinically relevant, presenting a better performance than one marker alone.
Published: 2021

33. Integrated microRNA and mRNA signatures associated with overall survival in epithelial ovarian cancer

Author: Lopacinska-Jørgensen, Joanna, Oliveira, Douglas V.N.P., Novotny, Guy Wayne, Høgdall, Claus K., Høgdall, Estrid V., Lopacinska-Jørgensen, Joanna, Oliveira, Douglas V.N.P., Novotny, Guy Wayne, Høgdall, Claus K., and Høgdall, Estrid V.
Abstract: Ovarian cancer (OC), the eighth-leading cause of cancer-related death among females worldwide, is mainly represented by epithelial OC (EOC) that can be further subdivided into four subtypes: Serous (75%), endometrioid (10%), clear cell (10%), and mucinous (3%). Major reasons for high mortality are the poor biological understanding of the OC mechanisms and a lack of reliable markers defining each EOC subtype. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression primarily by targeting messenger RNA (mRNA) transcripts. Their aberrant expression patterns have been associated with cancer development, including OC. However, the role of miRNAs in tumorigenesis is still to be determined, mainly due to the lack of consensus regarding optimal methodologies for identification and validation of miRNAs and their targets. Several tools for computational target prediction exist, but false interpretations remain a problem. The experimental validation of every potential miRNA-mRNA pair is not feasible, as it is laborious and expensive. In this study, we analyzed the correlation between global miRNA and mRNA expression patterns derived from microarray profiling of 197 EOC patients to identify the signatures of miRNA-mRNA interactions associated with overall survival (OS). The aim was to investigate whether these miRNA-mRNA signatures might have a prognostic value for OS in different subtypes of EOC. The content of our cohort (162 serous carcinomas, 15 endometrioid carcinomas, 11 mucinous carcinomas, and 9 clear cell carcinomas) reflects a real-world scenario of EOC. Several interaction pairs between 6 miRNAs (hsamiR- 126-3p, hsa-miR-223-3p, hsa-miR-23a-5p, hsa-miR-27a-5p, hsa-miR-486-5p, and hsamiR- 506-3p) and 8 mRNAs (ATF3, CH25H, EMP1, HBB, HBEGF, NAMPT, POSTN, and PROCR) were identified and the findings appear to be well supported by the literature. This indicates that our study has a potential to reveal miRNA-mRNA signatures relevant for EOC. Th
Published: 2021

34. Genomic sub-classification of ovarian clear cell carcinoma revealed by distinct mutational signatures

Author: Oliveira, Douglas V.N.P., Schnack, Tine H., Poulsen, Tim S., Christiansen, Anne P., Høgdall, Claus K., Høgdall, Estrid V., Oliveira, Douglas V.N.P., Schnack, Tine H., Poulsen, Tim S., Christiansen, Anne P., Høgdall, Claus K., and Høgdall, Estrid V.
Abstract: Ovarian clear cell carcinoma (OCCC) is characterized by dismal prognosis, partially due to its low sensitivity to standard chemotherapy regimen. It is also well-known for presenting unique molecular features in comparison to other epithelial ovarian cancer subtypes. Here, we aim to identify potential subgroups of patients in order to (1) determine their molecular features and (2) characterize their mutational signature. Furthermore, we sought to perform the investigation based on a potentially clinically relevant setting. To that end, we assessed the mutational profile and genomic instability of 55 patients extracted from the Gynecologic Cancer Database (DGCD) by using a panel comprised of 409 cancer-associated genes and a microsatellite assay, respectively; both are currently used in our routine environment. In accordance with previous findings, ARID1A and PIK3CA were the most prevalent mutations, present in 49.1% and 41.8%, respectively. From those, the co-occurrence of ARID1A and PIK3CA mutations was observed in 36.1% of subjects, indicating that this association might be a common feature of OCCC. The microsatellite instability frequency was low across samples. An unbiased assessment of signatures identified the presence of three subgroups, where “PIK3CA” and “Double hit” (with ARID1A and PIK3CA double mutation) subgroups exhibited unique signatures, whilst “ARID1A” and “Undetermined” (no mutations on ARID1A nor PIK3CA) subgroups showed similar profiles. Those differences were further indicated by COSMIC signatures. Taken together, the current findings suggest that OCCC presents distinct mutational landscapes within its group, which may indicate different therapeutic approaches according to its subgroup. Although encouraging, it is noteworthy that the current results are limited by sample size, and further investigation on a larger group would be crucial to better elucidate them.
Published: 2021

35. Oncomine™ Comprehensive Assay v3 vs. Oncomine™ Comprehensive Assay Plus

Author: Vestergaard, Lau K., Oliveira, Douglas N.P., Poulsen, Tim S., Høgdall, Claus K., Høgdall, Estrid V., Vestergaard, Lau K., Oliveira, Douglas N.P., Poulsen, Tim S., Høgdall, Claus K., and Høgdall, Estrid V.
Abstract: The usage of next generation sequencing in combination with targeted gene panels has enforced a better understanding of tumor compositions. The identification of key genomic bi-omarkers underlying a disease are crucial for diagnosis, prognosis, treatment and therapeutic re-sponses. The Oncomine™ Comprehensive Assay v3 (OCAv3) covers 161 cancer‐associated genes and is routinely employed to support clinical decision making for a therapeutic course. An improved version, Oncomine™ Comprehensive Assay Plus (OCA‐Plus), has been recently developed, covering 501 genes (144 overlapping with OCAv3) in addition to microsatellite instability (MSI) and tumor mutational burden (TMB) assays in one workflow. The validation of MSI and TMB was not addressed in the present study. However, the implementation of new assays must be validated and confirmed across multiple samples before it can be introduced into a clinical setting. Here, we report the comparison of DNA sequencing results from 50 ovarian cancer formalin‐fixed, paraffin‐embed-ded samples subjected to OCAv3 and OCA‐Plus. A validation assessment of gene mutations identified using OCA‐Plus was performed on the 144 overlapping genes and 313,769 intersecting nucle-otide positions of the OCAv3 and the OCA‐Plus. Our results showed a 91% concordance within variants classified as likely‐pathogenic or pathogenic. Moreover, results showed that a region of PTEN is poorly covered by the OCA‐Plus assay, hence, we implemented rescue filters for those variants. In conclusion, the OCA‐Plus can reflect the mutational profile of genomic variants com-pared with OCAv3 of 144 overlapping genes, without compromising performance.
Published: 2021

36. 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

37. Next generation sequencing technology in the clinic and its challenges

Author: Vestergaard, Lau K., Oliveira, Douglas N.P., Høgdall, Claus K., Høgdall, Estrid V., Vestergaard, Lau K., Oliveira, Douglas N.P., Høgdall, Claus K., and Høgdall, Estrid V.
Abstract: Data analysis has become a crucial aspect in clinical oncology to interpret output from next-generation sequencing-based testing. NGS being able to resolve billions of sequencing reactions in a few days has consequently increased the demand for tools to handle and analyze such large data sets. Many tools have been developed since the advent of NGS, featuring their own peculiarities. Increased awareness when interpreting alterations in the genome is therefore of utmost importance, as the same data using different tools can provide diverse outcomes. Hence, it is crucial to evaluate and validate bioinformatic pipelines in clinical settings. Moreover, personalized medicine implies treatment targeting efficacy of biological drugs for specific genomic alterations. Here, we focused on different sequencing technologies, features underlying the genome complexity, and bioinformatic tools that can impact the final annotation. Additionally, we discuss the clinical demand and design for implementing NGS.
Published: 2021

38. 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, Thompson, Deborah J, Aben, Katja Kh, Alsulimani, Ahmad, Amant, Frédéric, Annibali, Daniela, Attia, John, Barricarte, Aurelio, Beckmann, Matthias W., Berchuck, Andrew, Bermisheva, Marina, Bernardini, Marcus Q., Bischof, Katharina, Bjørge, Line, Bodelon, Clara, Brand, Alison H, Brenton, James D., Brinton, Louise A., Bruinsma, Fiona, Buchanan, Daniel D., Burghaus, Stefanie, Bützow, Ralf, Cai, Hui, Carney, Michael E., Chanock, Stephen J., Chen, Chu, Chen, Xiaoqing, Chen, Zhihua, Cook, Linda S., Cunningham, Julie M., De Vivo, Immaculata, Defazio, Anna, Doherty, Jennifer A., Dork, Thilo, Du Bois, Andreas, Dunning, Alison M, Durst, 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, Harris, Holly R, Harter, Philipp, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle A.t., 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, Lester, Jenny, Li, Andrew J, Liang, Dong, Liebrich, Clemens, Lipworth, Loren, Lissowska, Jolanta, Lu, Lingeng, Lu, Karen H., Macciotta, Alessandra, Mattiello, Amalia, May, Taymaa, Mcalpine, Jessica N., Mcguire, Valerie, Mcneish, Iain A., Menon, Usha, Modugno, Francesmary, Moysich, Kirsten B., Nevanlinna, Heli, Odunsi, Kunle, Olsson, Håkan, Orsulic, Sandra, Osorio, Ana, Palli, Domenico, Park-simon, Tjoung-won, Pearce, Celeste L., Pejovic, Tanja, Permuth, Jennifer B, Podgorska, Agnieszka, Ramus, Susan J., Rebbeck, Timothy R., Riggan, Marjorie J., Risch, Harvey A., Rothstein, Joseph H., Runnebaum, Ingo B., Scott, Rodney J., Sellers, Thomas A., Senz, Janine, Setiawan, Veronica Wendy, Siddiqui, Nadeem, Sieh, Weiva, Spiewankiewicz, Beata, Sutphen, Rebecca, Swerdlow, Anthony J., Szafron, Lukasz Michal, Teo, Soo Hwang, Thompson, Pamela J, Thomsen, Liv Cecilie Vestrheim, Titus, Linda, Tone, Alicia, Tumino, Rosario, Turman, Constance, Vanderstichele, Adriaan, Velez Edwards, Digna, Vergote, Ignace, Vierkant, Robert A., Wang, Zhaoming, Wang-gohrke, Shan, Webb, Penelope M., White, Emily, Whittemore, Alice S., Winham, Stacey J., Wu, Xifeng, Wu, Anna H., Yannoukakos, Drakoulis, Spurdle, Amanda B, O'mara, Tracy A, Glubb, Dylan M, Thompson, Deborah J, Aben, Katja Kh, Alsulimani, Ahmad, Amant, Frédéric, Annibali, Daniela, Attia, John, Barricarte, Aurelio, Beckmann, Matthias W., Berchuck, Andrew, Bermisheva, Marina, Bernardini, Marcus Q., Bischof, Katharina, Bjørge, Line, Bodelon, Clara, Brand, Alison H, Brenton, James D., Brinton, Louise A., Bruinsma, Fiona, Buchanan, Daniel D., Burghaus, Stefanie, Bützow, Ralf, Cai, Hui, Carney, Michael E., Chanock, Stephen J., Chen, Chu, Chen, Xiaoqing, Chen, Zhihua, Cook, Linda S., Cunningham, Julie M., De Vivo, Immaculata, Defazio, Anna, Doherty, Jennifer A., Dork, Thilo, Du Bois, Andreas, Dunning, Alison M, Durst, 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, Harris, Holly R, Harter, Philipp, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle A.t., 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, Lester, Jenny, Li, Andrew J, Liang, Dong, Liebrich, Clemens, Lipworth, Loren, Lissowska, Jolanta, Lu, Lingeng, Lu, Karen H., Macciotta, Alessandra, Mattiello, Amalia, May, Taymaa, Mcalpine, Jessica N., Mcguire, Valerie, Mcneish, Iain A., Menon, Usha, Modugno, Francesmary, Moysich, Kirsten B., Nevanlinna, Heli, Odunsi, Kunle, Olsson, Håkan, Orsulic, Sandra, Osorio, Ana, Palli, Domenico, Park-simon, Tjoung-won, Pearce, Celeste L., Pejovic, Tanja, Permuth, Jennifer B, Podgorska, Agnieszka, Ramus, Susan J., Rebbeck, Timothy R., Riggan, Marjorie J., Risch, Harvey A., Rothstein, Joseph H., Runnebaum, Ingo B., Scott, Rodney J., Sellers, Thomas A., Senz, Janine, Setiawan, Veronica Wendy, Siddiqui, Nadeem, Sieh, Weiva, Spiewankiewicz, Beata, Sutphen, Rebecca, Swerdlow, Anthony J., Szafron, Lukasz Michal, Teo, Soo Hwang, Thompson, Pamela J, Thomsen, Liv Cecilie Vestrheim, Titus, Linda, Tone, Alicia, Tumino, Rosario, Turman, Constance, Vanderstichele, Adriaan, Velez Edwards, Digna, Vergote, Ignace, Vierkant, Robert A., Wang, Zhaoming, Wang-gohrke, Shan, Webb, Penelope M., White, Emily, Whittemore, Alice S., Winham, Stacey J., Wu, Xifeng, Wu, Anna H., Yannoukakos, Drakoulis, Spurdle, Amanda B, and O'mara, Tracy A
Published: 2021

39. Noncoding RNA (ncRNA) Profile Association with Patient Outcome in Epithelial Ovarian Cancer Cases

Author: Oliveira, Douglas V. N. P., Prahm, Kira P., Christensen, Ib J., Hansen, Anker, Høgdall, Claus K., Høgdall, Estrid V., Oliveira, Douglas V. N. P., Prahm, Kira P., Christensen, Ib J., Hansen, Anker, Høgdall, Claus K., and Høgdall, Estrid V.
Published: 2021

40. Noncoding RNA (ncRNA) Profile Association with Patient Outcome in Epithelial Ovarian Cancer Cases

Author: Oliveira, Douglas V. N. P., Prahm, Kira P., Christensen, Ib J., Hansen, Anker, Høgdall, Claus K., Høgdall, Estrid V., Oliveira, Douglas V. N. P., Prahm, Kira P., Christensen, Ib J., Hansen, Anker, Høgdall, Claus K., and Høgdall, Estrid V.
Published: 2021

41. 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

42. Ovariecancerbehandling i Danmark

Author: Høgdall, Claus K and Høgdall, Claus K
Published: 2020

43. Genetic Data from Nearly 63,000 Women of European Descent Predicts DNA Methylation Biomarkers and Epithelial Ovarian Cancer Risk.

Author: Yang, Yaohua, Yang, Yaohua, Wu, Lang, Shu, Xiang, Lu, Yingchang, Shu, Xiao-Ou, Cai, Qiuyin, Beeghly-Fadiel, Alicia, Li, Bingshan, Ye, Fei, Berchuck, Andrew, Anton-Culver, Hoda, Banerjee, Susana, Benitez, Javier, Bjørge, Line, Brenton, James D, Butzow, Ralf, Campbell, Ian G, Chang-Claude, Jenny, Chen, Kexin, Cook, Linda S, Cramer, Daniel W, deFazio, Anna, Dennis, Joe, Doherty, Jennifer A, Dörk, Thilo, Eccles, Diana M, Edwards, Digna Velez, Fasching, Peter A, Fortner, Renée T, Gayther, Simon A, Giles, Graham G, Glasspool, Rosalind M, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Harris, Holly R, Heitz, Florian, Hildebrandt, Michelle A, Høgdall, Estrid, Høgdall, Claus K, Huntsman, David G, Kar, Siddhartha P, Karlan, Beth Y, Kelemen, Linda E, Kiemeney, Lambertus A, Kjaer, Susanne K, Koushik, Anita, Lambrechts, Diether, Le, Nhu D, Levine, Douglas A, Massuger, Leon F, Matsuo, Keitaro, May, Taymaa, McNeish, Iain A, Menon, Usha, Modugno, Francesmary, Monteiro, Alvaro N, Moorman, Patricia G, Moysich, Kirsten B, Ness, Roberta B, Nevanlinna, Heli, Olsson, Håkan, Onland-Moret, N Charlotte, Park, Sue K, Paul, James, Pearce, Celeste L, Pejovic, Tanja, Phelan, Catherine M, Pike, Malcolm C, Ramus, Susan J, Riboli, Elio, Rodriguez-Antona, Cristina, Romieu, Isabelle, Sandler, Dale P, Schildkraut, Joellen M, Setiawan, Veronica W, Shan, Kang, Siddiqui, Nadeem, Sieh, Weiva, Stampfer, Meir J, Sutphen, Rebecca, Swerdlow, Anthony J, Szafron, Lukasz M, Teo, Soo Hwang, Tworoger, Shelley S, Tyrer, Jonathan P, Webb, Penelope M, Wentzensen, Nicolas, White, Emily, Willett, Walter C, Wolk, Alicja, Woo, Yin Ling, Wu, Anna H, Yan, Li, Yannoukakos, Drakoulis, Chenevix-Trench, Georgia, Sellers, Thomas A, Pharoah, Paul DP, Zheng, Wei, Long, Jirong, Yang, Yaohua, Yang, Yaohua, Wu, Lang, Shu, Xiang, Lu, Yingchang, Shu, Xiao-Ou, Cai, Qiuyin, Beeghly-Fadiel, Alicia, Li, Bingshan, Ye, Fei, Berchuck, Andrew, Anton-Culver, Hoda, Banerjee, Susana, Benitez, Javier, Bjørge, Line, Brenton, James D, Butzow, Ralf, Campbell, Ian G, Chang-Claude, Jenny, Chen, Kexin, Cook, Linda S, Cramer, Daniel W, deFazio, Anna, Dennis, Joe, Doherty, Jennifer A, Dörk, Thilo, Eccles, Diana M, Edwards, Digna Velez, Fasching, Peter A, Fortner, Renée T, Gayther, Simon A, Giles, Graham G, Glasspool, Rosalind M, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Harris, Holly R, Heitz, Florian, Hildebrandt, Michelle A, Høgdall, Estrid, Høgdall, Claus K, Huntsman, David G, Kar, Siddhartha P, Karlan, Beth Y, Kelemen, Linda E, Kiemeney, Lambertus A, Kjaer, Susanne K, Koushik, Anita, Lambrechts, Diether, Le, Nhu D, Levine, Douglas A, Massuger, Leon F, Matsuo, Keitaro, May, Taymaa, McNeish, Iain A, Menon, Usha, Modugno, Francesmary, Monteiro, Alvaro N, Moorman, Patricia G, Moysich, Kirsten B, Ness, Roberta B, Nevanlinna, Heli, Olsson, Håkan, Onland-Moret, N Charlotte, Park, Sue K, Paul, James, Pearce, Celeste L, Pejovic, Tanja, Phelan, Catherine M, Pike, Malcolm C, Ramus, Susan J, Riboli, Elio, Rodriguez-Antona, Cristina, Romieu, Isabelle, Sandler, Dale P, Schildkraut, Joellen M, Setiawan, Veronica W, Shan, Kang, Siddiqui, Nadeem, Sieh, Weiva, Stampfer, Meir J, Sutphen, Rebecca, Swerdlow, Anthony J, Szafron, Lukasz M, Teo, Soo Hwang, Tworoger, Shelley S, Tyrer, Jonathan P, Webb, Penelope M, Wentzensen, Nicolas, White, Emily, Willett, Walter C, Wolk, Alicja, Woo, Yin Ling, Wu, Anna H, Yan, Li, Yannoukakos, Drakoulis, Chenevix-Trench, Georgia, Sellers, Thomas A, Pharoah, Paul DP, Zheng, Wei, and Long, Jirong
Abstract: DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10-7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. SIGNIFICANCE: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.
Published: 2019

44. Diagnostic plasma miRNA-profiles for ovarian cancer in patients with pelvic mass

Author: Oliveira, Douglas Nogueira Perez, Carlsen, Anting Liu, Heegaard, Niels H.H., Prahm, Kira Philipsen, Christensen, Ib Jarle, Høgdall, Claus K., Høgdall, Estrid V., Oliveira, Douglas Nogueira Perez, Carlsen, Anting Liu, Heegaard, Niels H.H., Prahm, Kira Philipsen, Christensen, Ib Jarle, Høgdall, Claus K., and Høgdall, Estrid V.
Abstract: Background Ovarian cancer is the fifth most common cancer in women worldwide. Moreover, there are no reliable minimal invasive tests to secure the diagnosis of malignant pelvic masses. Cell-free, circulating microRNAs have the potential as diagnostic biomarkers in cancer. Here, we performed and validated a miRNA panel with the potential to distinguish OC from benign pelvic masses. Methods The profile of plasma microRNA was determined with a panel of 46 candidates in a discovery group and a validation group, each consisting of 190 pre-surgery plasma samples from age-matched patients with malignant (n = 95) and benign pelvic mass (n = 95), by real time RT-qPCR. Results Four up-regulated (miR-200c-3p, miR-221-3p, miR-21-5p, and miR-484) and two down-regulated (miR-195-5p and miR-451a) microRNAs were discovered. From those, miR-200c-3p and miR-221-3p were further confirmed in a validation cohort. A combination of these 2 microRNAs together with CA-125 yielded an overall diagnostic accuracy of AUC = 0.96. Conclusions We showed consistent plasma microRNA profiles that provide independent diagnostic information of late stage OC.
Published: 2019

45. Association of CD31 and p53 With Survival of Ovarian Cancer Patients

Author: Rask, Lene, Høgdall, Claus K., Kjaer, Susanne K., Christensen, Lise, Jensen, Allan, Blaakaer, Jan, Christensen, Ib Jarle, Høgdall, Estrid V.S., Rask, Lene, Høgdall, Claus K., Kjaer, Susanne K., Christensen, Lise, Jensen, Allan, Blaakaer, Jan, Christensen, Ib Jarle, and Høgdall, Estrid V.S.
Abstract: Background/Aim: New markers for ovarian cancer are needed. This study aimed to examine the expression of tumour cell p53 and endothelial cell CD31 proteins and correlate them to clinicopathological factors. Patients and Methods: Expression of proteins was immunohistochemically assessed using tissue sections from 585-599 ovarian cancer patients from the Danish MALOVA study. Results: High CD31 expression was found in poorly differentiated tumours (p=0.0006), and high p53 expression was found in poorly differentiated cancers (p<0.0001), high clinical stage (p<0.0001), non-radical surgery (p<0.0001) and high serum CA-125 values (p<0.0001). CD31 expression showed no prognostic survival value, but high hazard ratios were found for patients with high p53 expression (HR=2.313, p<0.0001). An interaction was found between p53 and stage of cancer, suggesting a prognostic impact of p53 in low-stage, but not in advanced-stage cancer. Conclusion: More than 5% of p53 tissue expression may predict shorter survival of ovarian cancer patients and may be useful for predicting the risk of disease progression in low-stage patients following primary surgery. CD31 has no strong prognostic value.
Published: 2019

46. Methylation and ovarian cancer:Can DNA methylation be of diagnostic use?

Author: Hentze, Julie L, Høgdall, Claus K, Høgdall, Estrid V, Hentze, Julie L, Høgdall, Claus K, and Høgdall, Estrid V
Abstract: Ovarian cancer is a silent killer and, due to late diagnosis and frequent chemo resistance in patients, the primary cause of fatality amongst the various types of gynecological cancer. The discovery of a specific and sensitive biomarker for ovarian cancer could improve early diagnosis, thereby saving lives. Biomarkers could also improve treatment, by predicting which patients will benefit from specific treatment strategies. DNA methylation is an epigenetic mechanism, and 'methylation imbalance' is characteristic of cancer. Previous research suggests that changes in DNA methylation can be used diagnostically, and that they may predict resistance to treatment. This paper gives an up-to-date overview of research investigating the potential of DNA methylation-based markers for diagnostics, prognostics, screening and prediction of drug resistance for ovarian cancer patients. DNA methylation cancer-biomarkers may be useful for cancer treatment, particularly since they are chemically stable and since cancer-associated changes in methylation typically precedes tumor growth. DNA methylation markers could improve diagnosis and treatment and might even be used for screening in the future. Furthermore, DNA methylation biomarkers could facilitate the development of precision medicine. However, at this point no biomarkers for ovarian cancer have a sufficient combination of sensitivity and specificity in a clinical setting. A reason for this is that most studies have focused on a single or a few methylation sites. More large screenings and genome-wide studies must be performed to increase the chance of identifying a DNA methylation marker which can identify ovarian cancer.
Published: 2019

47. Genetic data from nearly 63,000 women of European descent predicts DNA methylation biomarkers and epithelial ovarian cancer risk

Author: Yang, Yaohua, Wu, Lang, Shu, Xiang, Lu, Yingchang, Shu, Xiao Ou, Cai, Qiuyin, Beeghly-Fadiel, Alicia, Li, Bingshan, Ye, Fei, Berchuck, Andrew, Anton-Culver, Hoda, Banerjee, Susana, Benitez, Javier, Bjørge, Line, Brenton, James D., Butzow, Ralf, Campbell, Ian G., Chang-Claude, Jenny, Chen, Kexin, Cook, Linda S., Cramer, Daniel W., De Fazio, Anna, Dennis, Joe, Doherty, Jennifer A., Eccles, Diana M., Edwards, Digna Velez, Fasching, Peter A., Fortner, Reneé T., Gayther, Simon A., Giles, Graham G., Glasspool, Rosalind M., Goode, Ellen L., Goodman, Marc T., Gronwald, Jacek, Harris, Holly R., Heitz, Florian, Hildebrandt, Michelle A., Høgdall, Estrid, Høgdall, Claus K., Huntsman, David G., Kar, Siddhartha P., Karlan, Beth Y., Kelemen, Linda E., Kiemeney, Lambertus A., Kjaer, Susanne K., Koushik, Anita, Lambrechts, Diether, Le, Nhu D., Levine, Douglas A., Massuger, Leon F., Matsuo, Keitaro, May, Taymaa, McNeish, Iain A., Menon, Usha, Modugno, Francesmary, Monteiro, Alvaro N., Moorman, Patricia G., Moysich, Kirsten B., Ness, Roberta B., Nevanlinna, Heli, Olsson, Håkan, Charlotte Onland-Moret, N., Park, Sue K., Paul, James, Pearce, Celeste L., Pejovic, Tanja, Phelan, Catherine M., Pike, Malcolm C., Ramus, Susan J., Riboli, Elio, Rodriguez-Antona, Cristina, Romieu, Isabelle, Sandler, Dale P., Schildkraut, Joellen M., Setiawan, Veronica W., Shan, Kang, Siddiqui, Nadeem, Sieh, Weiva, Stampfer, Meir J., Sutphen, Rebecca, Swerdlow, Anthony J., Szafron, Lukasz M., Teo, Soo Hwang, Tworoger, Shelley S., Tyrer, Jonathan P., Webb, Penelope M., Wentzensen, Nicolas, White, Emily, Willett, Walter C., Wolk, Alicja, Woo, Yin Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Chenevix-Trench, Georgia, Sellers, Thomas A., Pharoah, Paul D.P., Zheng, Wei, Long, Jirong, Yang, Yaohua, Wu, Lang, Shu, Xiang, Lu, Yingchang, Shu, Xiao Ou, Cai, Qiuyin, Beeghly-Fadiel, Alicia, Li, Bingshan, Ye, Fei, Berchuck, Andrew, Anton-Culver, Hoda, Banerjee, Susana, Benitez, Javier, Bjørge, Line, Brenton, James D., Butzow, Ralf, Campbell, Ian G., Chang-Claude, Jenny, Chen, Kexin, Cook, Linda S., Cramer, Daniel W., De Fazio, Anna, Dennis, Joe, Doherty, Jennifer A., Eccles, Diana M., Edwards, Digna Velez, Fasching, Peter A., Fortner, Reneé T., Gayther, Simon A., Giles, Graham G., Glasspool, Rosalind M., Goode, Ellen L., Goodman, Marc T., Gronwald, Jacek, Harris, Holly R., Heitz, Florian, Hildebrandt, Michelle A., Høgdall, Estrid, Høgdall, Claus K., Huntsman, David G., Kar, Siddhartha P., Karlan, Beth Y., Kelemen, Linda E., Kiemeney, Lambertus A., Kjaer, Susanne K., Koushik, Anita, Lambrechts, Diether, Le, Nhu D., Levine, Douglas A., Massuger, Leon F., Matsuo, Keitaro, May, Taymaa, McNeish, Iain A., Menon, Usha, Modugno, Francesmary, Monteiro, Alvaro N., Moorman, Patricia G., Moysich, Kirsten B., Ness, Roberta B., Nevanlinna, Heli, Olsson, Håkan, Charlotte Onland-Moret, N., Park, Sue K., Paul, James, Pearce, Celeste L., Pejovic, Tanja, Phelan, Catherine M., Pike, Malcolm C., Ramus, Susan J., Riboli, Elio, Rodriguez-Antona, Cristina, Romieu, Isabelle, Sandler, Dale P., Schildkraut, Joellen M., Setiawan, Veronica W., Shan, Kang, Siddiqui, Nadeem, Sieh, Weiva, Stampfer, Meir J., Sutphen, Rebecca, Swerdlow, Anthony J., Szafron, Lukasz M., Teo, Soo Hwang, Tworoger, Shelley S., Tyrer, Jonathan P., Webb, Penelope M., Wentzensen, Nicolas, White, Emily, Willett, Walter C., Wolk, Alicja, Woo, Yin Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Chenevix-Trench, Georgia, Sellers, Thomas A., Pharoah, Paul D.P., Zheng, Wei, and Long, Jirong
Abstract: DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N ¼ 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 10 7 . Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARH-GAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression.
Published: 2019

48. Diagnostic plasma miRNA-profiles for ovarian cancer in patients with pelvic mass

Author: Oliveira, Douglas Nogueira Perez, Carlsen, Anting Liu, Heegaard, Niels H.H., Prahm, Kira Philipsen, Christensen, Ib Jarle, Høgdall, Claus K., Høgdall, Estrid V., Oliveira, Douglas Nogueira Perez, Carlsen, Anting Liu, Heegaard, Niels H.H., Prahm, Kira Philipsen, Christensen, Ib Jarle, Høgdall, Claus K., and Høgdall, Estrid V.
Abstract: Background Ovarian cancer is the fifth most common cancer in women worldwide. Moreover, there are no reliable minimal invasive tests to secure the diagnosis of malignant pelvic masses. Cell-free, circulating microRNAs have the potential as diagnostic biomarkers in cancer. Here, we performed and validated a miRNA panel with the potential to distinguish OC from benign pelvic masses. Methods The profile of plasma microRNA was determined with a panel of 46 candidates in a discovery group and a validation group, each consisting of 190 pre-surgery plasma samples from age-matched patients with malignant (n = 95) and benign pelvic mass (n = 95), by real time RT-qPCR. Results Four up-regulated (miR-200c-3p, miR-221-3p, miR-21-5p, and miR-484) and two down-regulated (miR-195-5p and miR-451a) microRNAs were discovered. From those, miR-200c-3p and miR-221-3p were further confirmed in a validation cohort. A combination of these 2 microRNAs together with CA-125 yielded an overall diagnostic accuracy of AUC = 0.96. Conclusions We showed consistent plasma microRNA profiles that provide independent diagnostic information of late stage OC.
Published: 2019

49. A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk.

Author: Lu, Yingchang, Beeghly-Fadiel, Alicia, Wu, Lang, Guo, Xingyi, Li, Bingshan, Schildkraut, Joellen M, Im, Hae Kyung, Chen, Yian A, Permuth, Jennifer B, Reid, Brett M, Teer, Jamie K, Moysich, Kirsten B, Andrulis, Irene L, Anton-Culver, Hoda, Arun, Banu K, Bandera, Elisa V, Barkardottir, Rosa B, Barnes, Daniel R, Benitez, Javier, Bjorge, Line, Brenton, James, Butzow, Ralf, Caldes, Trinidad, Caligo, Maria A, Campbell, Ian, Chang-Claude, Jenny, Claes, Kathleen B M, Couch, Fergus J, Cramer, Daniel W, Daly, Mary B, deFazio, Anna, Dennis, Joe, Diez, Orland, Domchek, Susan M, Dörk, Thilo, Easton, Douglas F, Eccles, Diana M, Fasching, Peter A, Fortner, Renée T, Fountzilas, George, Friedman, Eitan, Ganz, Patricia A, Garber, Judy, Giles, Graham G, Godwin, Andrew K, Goldgar, David E, Goodman, Marc T, Greene, Mark H, Gronwald, Jacek, Hamann, Ute, Heitz, Florian, Hildebrandt, Michelle A T, Høgdall, Claus K, Hollestelle, Antoinette, Hulick, Peter J, Huntsman, David G, Imyanitov, Evgeny N, Isaacs, Claudine, Jakubowska, Anna, James, Paul, Karlan, Beth Y, Kelemen, Linda E, Kiemeney, Lambertus A, Kjaer, Susanne K, Kwong, Ava, Le, Nhu D, Leslie, Goska, Lesueur, Fabienne, Levine, Douglas A, Mattiello, Amalia, May, Taymaa, McGuffog, Lesley, McNeish, Iain A, Merritt, Melissa A, Modugno, Francesmary, Montagna, Marco, Neuhausen, Susan L, Nevanlinna, Heli, Nielsen, Finn C, Nikitina-Zake, Liene, Nussbaum, Robert L, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Olson, Sara H, Olsson, Håkan, Osorio, Ana, Park, Sue K, Parsons, Michael T, Peeters, Petra H M, Pejovic, Tanja, Peterlongo, Paolo, Phelan, Catherine M, Pujana, Miquel Angel, Ramus, Susan J, Rennert, Gad, Risch, Harvey, Rodriguez, Gustavo C, Rodríguez-Antona, Cristina, Romieu, Isabelle, Rookus, Matti A, Rossing, Mary Anne, Rzepecka, Iwona K, Sandler, Dale P, Schmutzler, Rita K, Setiawan, Veronica W, Sharma, Priyanka, Sieh, Weiva, Simard, Jacques, Singer, Christian F, Song, Honglin, Southey, Melissa C, Spurdle, Amanda B, Sutphen, Rebecca, Swerdlow, Anthony J, Teixeira, Manuel R, Teo, Soo H, Thomassen, Mads, Tischkowitz, Marc, Toland, Amanda E, Trichopoulou, Antonia, Tung, Nadine, Tworoger, Shelley S, van Rensburg, Elizabeth J, Vanderstichele, Adriaan, Vega, Ana, Edwards, Digna Velez, Webb, Penelope M, Weitzel, Jeffrey N, Wentzensen, Nicolas, White, Emily, Wolk, Alicja, Wu, Anna H, Yannoukakos, Drakoulis, Zorn, Kristin K, Gayther, Simon A, Antoniou, Antonis C, Berchuck, Andrew, Goode, Ellen L, Chenevix-Trench, Georgia, Sellers, Thomas A, Pharoah, Paul D P, Zheng, Wei, Long, Jirong, Lu, Yingchang, Beeghly-Fadiel, Alicia, Wu, Lang, Guo, Xingyi, Li, Bingshan, Schildkraut, Joellen M, Im, Hae Kyung, Chen, Yian A, Permuth, Jennifer B, Reid, Brett M, Teer, Jamie K, Moysich, Kirsten B, Andrulis, Irene L, Anton-Culver, Hoda, Arun, Banu K, Bandera, Elisa V, Barkardottir, Rosa B, Barnes, Daniel R, Benitez, Javier, Bjorge, Line, Brenton, James, Butzow, Ralf, Caldes, Trinidad, Caligo, Maria A, Campbell, Ian, Chang-Claude, Jenny, Claes, Kathleen B M, Couch, Fergus J, Cramer, Daniel W, Daly, Mary B, deFazio, Anna, Dennis, Joe, Diez, Orland, Domchek, Susan M, Dörk, Thilo, Easton, Douglas F, Eccles, Diana M, Fasching, Peter A, Fortner, Renée T, Fountzilas, George, Friedman, Eitan, Ganz, Patricia A, Garber, Judy, Giles, Graham G, Godwin, Andrew K, Goldgar, David E, Goodman, Marc T, Greene, Mark H, Gronwald, Jacek, Hamann, Ute, Heitz, Florian, Hildebrandt, Michelle A T, Høgdall, Claus K, Hollestelle, Antoinette, Hulick, Peter J, Huntsman, David G, Imyanitov, Evgeny N, Isaacs, Claudine, Jakubowska, Anna, James, Paul, Karlan, Beth Y, Kelemen, Linda E, Kiemeney, Lambertus A, Kjaer, Susanne K, Kwong, Ava, Le, Nhu D, Leslie, Goska, Lesueur, Fabienne, Levine, Douglas A, Mattiello, Amalia, May, Taymaa, McGuffog, Lesley, McNeish, Iain A, Merritt, Melissa A, Modugno, Francesmary, Montagna, Marco, Neuhausen, Susan L, Nevanlinna, Heli, Nielsen, Finn C, Nikitina-Zake, Liene, Nussbaum, Robert L, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Olson, Sara H, Olsson, Håkan, Osorio, Ana, Park, Sue K, Parsons, Michael T, Peeters, Petra H M, Pejovic, Tanja, Peterlongo, Paolo, Phelan, Catherine M, Pujana, Miquel Angel, Ramus, Susan J, Rennert, Gad, Risch, Harvey, Rodriguez, Gustavo C, Rodríguez-Antona, Cristina, Romieu, Isabelle, Rookus, Matti A, Rossing, Mary Anne, Rzepecka, Iwona K, Sandler, Dale P, Schmutzler, Rita K, Setiawan, Veronica W, Sharma, Priyanka, Sieh, Weiva, Simard, Jacques, Singer, Christian F, Song, Honglin, Southey, Melissa C, Spurdle, Amanda B, Sutphen, Rebecca, Swerdlow, Anthony J, Teixeira, Manuel R, Teo, Soo H, Thomassen, Mads, Tischkowitz, Marc, Toland, Amanda E, Trichopoulou, Antonia, Tung, Nadine, Tworoger, Shelley S, van Rensburg, Elizabeth J, Vanderstichele, Adriaan, Vega, Ana, Edwards, Digna Velez, Webb, Penelope M, Weitzel, Jeffrey N, Wentzensen, Nicolas, White, Emily, Wolk, Alicja, Wu, Anna H, Yannoukakos, Drakoulis, Zorn, Kristin K, Gayther, Simon A, Antoniou, Antonis C, Berchuck, Andrew, Goode, Ellen L, Chenevix-Trench, Georgia, Sellers, Thomas A, Pharoah, Paul D P, Zheng, Wei, and Long, Jirong
Abstract: Abstract Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10−6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10−7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10−3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis. Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419–30. ©2018 AACR.
Published: 2018
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50. A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk.

Author: Lu, Yingchang, Lu, Yingchang, Beeghly-Fadiel, Alicia, Wu, Lang, Guo, Xingyi, Li, Bingshan, Schildkraut, Joellen M, Im, Hae Kyung, Chen, Yian A, Permuth, Jennifer B, Reid, Brett M, Teer, Jamie K, Moysich, Kirsten B, Andrulis, Irene L, Anton-Culver, Hoda, Arun, Banu K, Bandera, Elisa V, Barkardottir, Rosa B, Barnes, Daniel R, Benitez, Javier, Bjorge, Line, Brenton, James, Butzow, Ralf, Caldes, Trinidad, Caligo, Maria A, Campbell, Ian, Chang-Claude, Jenny, Claes, Kathleen BM, Couch, Fergus J, Cramer, Daniel W, Daly, Mary B, deFazio, Anna, Dennis, Joe, Diez, Orland, Domchek, Susan M, Dörk, Thilo, Easton, Douglas F, Eccles, Diana M, Fasching, Peter A, Fortner, Renée T, Fountzilas, George, Friedman, Eitan, Ganz, Patricia A, Garber, Judy, Giles, Graham G, Godwin, Andrew K, Goldgar, David E, Goodman, Marc T, Greene, Mark H, Gronwald, Jacek, Hamann, Ute, Heitz, Florian, Hildebrandt, Michelle AT, Høgdall, Claus K, Hollestelle, Antoinette, Hulick, Peter J, Huntsman, David G, Imyanitov, Evgeny N, Isaacs, Claudine, Jakubowska, Anna, James, Paul, Karlan, Beth Y, Kelemen, Linda E, Kiemeney, Lambertus A, Kjaer, Susanne K, Kwong, Ava, Le, Nhu D, Leslie, Goska, Lesueur, Fabienne, Levine, Douglas A, Mattiello, Amalia, May, Taymaa, McGuffog, Lesley, McNeish, Iain A, Merritt, Melissa A, Modugno, Francesmary, Montagna, Marco, Neuhausen, Susan L, Nevanlinna, Heli, Nielsen, Finn C, Nikitina-Zake, Liene, Nussbaum, Robert L, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Olson, Sara H, Olsson, Håkan, Osorio, Ana, Park, Sue K, Parsons, Michael T, Peeters, Petra HM, Pejovic, Tanja, Peterlongo, Paolo, Phelan, Catherine M, Pujana, Miquel Angel, Ramus, Susan J, Rennert, Gad, Risch, Harvey, Rodriguez, Gustavo C, Rodríguez-Antona, Cristina, Romieu, Isabelle, Lu, Yingchang, Lu, Yingchang, Beeghly-Fadiel, Alicia, Wu, Lang, Guo, Xingyi, Li, Bingshan, Schildkraut, Joellen M, Im, Hae Kyung, Chen, Yian A, Permuth, Jennifer B, Reid, Brett M, Teer, Jamie K, Moysich, Kirsten B, Andrulis, Irene L, Anton-Culver, Hoda, Arun, Banu K, Bandera, Elisa V, Barkardottir, Rosa B, Barnes, Daniel R, Benitez, Javier, Bjorge, Line, Brenton, James, Butzow, Ralf, Caldes, Trinidad, Caligo, Maria A, Campbell, Ian, Chang-Claude, Jenny, Claes, Kathleen BM, Couch, Fergus J, Cramer, Daniel W, Daly, Mary B, deFazio, Anna, Dennis, Joe, Diez, Orland, Domchek, Susan M, Dörk, Thilo, Easton, Douglas F, Eccles, Diana M, Fasching, Peter A, Fortner, Renée T, Fountzilas, George, Friedman, Eitan, Ganz, Patricia A, Garber, Judy, Giles, Graham G, Godwin, Andrew K, Goldgar, David E, Goodman, Marc T, Greene, Mark H, Gronwald, Jacek, Hamann, Ute, Heitz, Florian, Hildebrandt, Michelle AT, Høgdall, Claus K, Hollestelle, Antoinette, Hulick, Peter J, Huntsman, David G, Imyanitov, Evgeny N, Isaacs, Claudine, Jakubowska, Anna, James, Paul, Karlan, Beth Y, Kelemen, Linda E, Kiemeney, Lambertus A, Kjaer, Susanne K, Kwong, Ava, Le, Nhu D, Leslie, Goska, Lesueur, Fabienne, Levine, Douglas A, Mattiello, Amalia, May, Taymaa, McGuffog, Lesley, McNeish, Iain A, Merritt, Melissa A, Modugno, Francesmary, Montagna, Marco, Neuhausen, Susan L, Nevanlinna, Heli, Nielsen, Finn C, Nikitina-Zake, Liene, Nussbaum, Robert L, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Olson, Sara H, Olsson, Håkan, Osorio, Ana, Park, Sue K, Parsons, Michael T, Peeters, Petra HM, Pejovic, Tanja, Peterlongo, Paolo, Phelan, Catherine M, Pujana, Miquel Angel, Ramus, Susan J, Rennert, Gad, Risch, Harvey, Rodriguez, Gustavo C, Rodríguez-Antona, Cristina, and Romieu, Isabelle
Abstract: Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10-6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10-7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10-3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419-30. ©2018 AACR.
Published: 2018

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