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

Author: Köbel, Martin, Köbel, Martin, Kang, Eun‐Young, Weir, Ashley, Rambau, Peter F, Lee, Cheng‐Han, Nelson, Gregg S, Ghatage, Prafull, Meagher, Nicola S, Riggan, Marjorie J, Alsop, Jennifer, Anglesio, Michael S, Beckmann, Matthias W, Bisinotto, Christiani, Boisen, Michelle, Boros, Jessica, Brand, Alison H, Brooks‐Wilson, Angela, Carney, Michael E, Coulson, Penny, Courtney‐Brooks, Madeleine, Cushing‐Haugen, Kara L, Cybulski, Cezary, Deen, Suha, El‐Bahrawy, Mona A, Elishaev, Esther, Erber, Ramona, Fereday, Sian, Group, AOCS, Fischer, Anna, Gayther, Simon A, Barquin‐Garcia, Arantzazu, Gentry‐Maharaj, Aleksandra, Gilks, C Blake, Gronwald, Helena, Grube, Marcel, Harnett, Paul R, Harris, Holly R, Hartkopf, Andreas D, Hartmann, Arndt, Hein, Alexander, Hendley, Joy, Hernandez, Brenda Y, Huang, Yajue, Jakubowska, Anna, Jimenez‐Linan, Mercedes, Jones, Michael E, Kennedy, Catherine J, Kluz, Tomasz, Koziak, Jennifer M, Lesnock, Jaime, Lester, Jenny, Lubiński, Jan, Longacre, Teri A, Lycke, Maria, Mateoiu, Constantina, McCauley, Bryan M, McGuire, Valerie, Ney, Britta, Olawaiye, Alexander, Orsulic, Sandra, Osorio, Ana, Paz‐Ares, Luis, Ramón y Cajal, Teresa, Rothstein, Joseph H, Ruebner, Matthias, Schoemaker, Minouk J, Shah, Mitul, Sharma, Raghwa, Sherman, Mark E, Shvetsov, Yurii B, Singh, Naveena, Steed, Helen, Storr, Sarah J, Talhouk, Aline, Traficante, Nadia, Wang, Chen, Whittemore, Alice S, Widschwendter, Martin, Wilkens, Lynne R, Winham, Stacey J, Benitez, Javier, Berchuck, Andrew, Bowtell, David D, dos Reis, Francisco J Candido, Campbell, Ian, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Fasching, Peter A, Fortner, Renée T, García, María J, Goodman, Marc T, Goode, Ellen L, Gronwald, Jacek, Huntsman, David G, Karlan, Beth Y, Kelemen, Linda E, Kommoss, Stefan, Le, Nhu D, Martin, Stewart G, Köbel, Martin, Köbel, Martin, Kang, Eun‐Young, Weir, Ashley, Rambau, Peter F, Lee, Cheng‐Han, Nelson, Gregg S, Ghatage, Prafull, Meagher, Nicola S, Riggan, Marjorie J, Alsop, Jennifer, Anglesio, Michael S, Beckmann, Matthias W, Bisinotto, Christiani, Boisen, Michelle, Boros, Jessica, Brand, Alison H, Brooks‐Wilson, Angela, Carney, Michael E, Coulson, Penny, Courtney‐Brooks, Madeleine, Cushing‐Haugen, Kara L, Cybulski, Cezary, Deen, Suha, El‐Bahrawy, Mona A, Elishaev, Esther, Erber, Ramona, Fereday, Sian, Group, AOCS, Fischer, Anna, Gayther, Simon A, Barquin‐Garcia, Arantzazu, Gentry‐Maharaj, Aleksandra, Gilks, C Blake, Gronwald, Helena, Grube, Marcel, Harnett, Paul R, Harris, Holly R, Hartkopf, Andreas D, Hartmann, Arndt, Hein, Alexander, Hendley, Joy, Hernandez, Brenda Y, Huang, Yajue, Jakubowska, Anna, Jimenez‐Linan, Mercedes, Jones, Michael E, Kennedy, Catherine J, Kluz, Tomasz, Koziak, Jennifer M, Lesnock, Jaime, Lester, Jenny, Lubiński, Jan, Longacre, Teri A, Lycke, Maria, Mateoiu, Constantina, McCauley, Bryan M, McGuire, Valerie, Ney, Britta, Olawaiye, Alexander, Orsulic, Sandra, Osorio, Ana, Paz‐Ares, Luis, Ramón y Cajal, Teresa, Rothstein, Joseph H, Ruebner, Matthias, Schoemaker, Minouk J, Shah, Mitul, Sharma, Raghwa, Sherman, Mark E, Shvetsov, Yurii B, Singh, Naveena, Steed, Helen, Storr, Sarah J, Talhouk, Aline, Traficante, Nadia, Wang, Chen, Whittemore, Alice S, Widschwendter, Martin, Wilkens, Lynne R, Winham, Stacey J, Benitez, Javier, Berchuck, Andrew, Bowtell, David D, dos Reis, Francisco J Candido, Campbell, Ian, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Fasching, Peter A, Fortner, Renée T, García, María J, Goodman, Marc T, Goode, Ellen L, Gronwald, Jacek, Huntsman, David G, Karlan, Beth Y, Kelemen, Linda E, Kommoss, Stefan, Le, Nhu D, and Martin, Stewart G
Abstract: Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.
Published: 2023

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

Author: Heinze, Karolin, Heinze, Karolin, Cairns, Evan, Thornton, Shelby, Harris, Bronwyn, Milne, Katy, Grube, Marcel, Meyer, Charlotte, Fereday, Sian, Garsed, Dale, Leung, Samuel, Chiu, Derek, Moubarak, Malak, Harter, Philipp, Heitz, Florian, McAlpine, Jessica, DeFazio, Anna, Bowtell, David, Goode, Ellen, Pike, Malcolm, Ramus, Susan, Pearce, C, Staebler, Annette, Köbel, Martin, Kommoss, Stefan, Talhouk, Aline, Nelson, Brad, Anglesio, Michael, Karnezis, Anthony, Heinze, Karolin, Heinze, Karolin, Cairns, Evan, Thornton, Shelby, Harris, Bronwyn, Milne, Katy, Grube, Marcel, Meyer, Charlotte, Fereday, Sian, Garsed, Dale, Leung, Samuel, Chiu, Derek, Moubarak, Malak, Harter, Philipp, Heitz, Florian, McAlpine, Jessica, DeFazio, Anna, Bowtell, David, Goode, Ellen, Pike, Malcolm, Ramus, Susan, Pearce, C, Staebler, Annette, Köbel, Martin, Kommoss, Stefan, Talhouk, Aline, Nelson, Brad, Anglesio, Michael, and Karnezis, Anthony
Abstract: PURPOSE: Endometrioid ovarian carcinoma (ENOC) is the second most-common type of ovarian carcinoma, comprising 10%-20% of cases. Recently, the study of ENOC has benefitted from comparisons to endometrial carcinomas including defining ENOC with four prognostic molecular subtypes. Each subtype suggests differential mechanisms of progression, although tumor-initiating events remain elusive. There is evidence that the ovarian microenvironment may be critical to early lesion establishment and progression. However, while immune infiltrates have been well studied in high-grade serous ovarian carcinoma, studies in ENOC are limited. EXPERIMENTAL DESIGN: We report on 210 ENOC, with clinical follow-up and molecular subtype annotation. Using multiplex IHC and immunofluorescence, we examine the prevalence of T-cell lineage, B-cell lineage, macrophages, and populations with programmed cell death protein 1 or programmed death-ligand 1 across subtypes of ENOC. RESULTS: Immune cell infiltrates in tumor epithelium and stroma showed higher densities in ENOC subtypes with known high mutation burden (POLEmut and MMRd). While molecular subtypes were prognostically significant, immune infiltrates were not (overall survival P > 0.2). Analysis by molecular subtype revealed that immune cell density was prognostically significant in only the no specific molecular profile (NSMP) subtype, where immune infiltrates lacking B cells (TILB minus) had inferior outcome (disease-specific survival: HR, 4.0; 95% confidence interval, 1.1-14.7; P < 0.05). Similar to endometrial carcinomas, molecular subtype stratification was generally superior to immune response in predicting outcomes. CONCLUSIONS: Subtype stratification is critical for better understanding of ENOC, in particular the distribution and prognostic significance of immune cell infiltrates. The role of B cells in the immune response within NSMP tumors warrants further study.
Published: 2023

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

Author: Weir, Ashley, Weir, Ashley, Kang, Eun-Young, Meagher, Nicola S, Nelson, Gregg S, Ghatage, Prafull, Lee, Cheng-Han, Riggan, Marjorie J, Gentry-Maharaj, Aleksandra, Ryan, Andy, Singh, Naveena, Widschwendter, Martin, Alsop, Jennifer, Anglesio, Michael S, Beckmann, Matthias W, Berger, Jessica, Bisinotto, Christiani, Boros, Jessica, Brand, Alison H, Brenton, James D, Brooks-Wilson, Angela, Carney, Michael E, Cunningham, Julie M, Cushing-Haugen, Kara L, Cybulski, Cezary, Elishaev, Esther, Erber, Ramona, Fereday, Sian, Fischer, Anna, Paz-Ares, Luis, Gayarre, Javier, Gilks, Blake C, Grube, Marcel, Harnett, Paul R, Harris, Holly R, Hartmann, Arndt, Hein, Alexander, Hendley, Joy, Hernandez, Brenda Y, Heublein, Sabine, Huang, Yajue, Huzarski, Tomasz, Jakubowska, Anna, Jimenez-Linan, Mercedes, Kennedy, Catherine J, Kommoss, Felix KF, Koziak, Jennifer M, Kraemer, Bernhard, Le, Nhu D, Lesnock, Jaime, Lester, Jenny, Lubiński, Jan, Menkiszak, Janusz, Ney, Britta, Olawaiye, Alexander, Orsulic, Sandra, Osorio, Ana, Robles-Díaz, Luis, Ruebner, Matthias, Shah, Mitul, Sharma, Raghwa, Shvetsov, Yurii B, Steed, Helen, Talhouk, Aline, Taylor, Sarah E, Traficante, Nadia, Vierkant, Robert A, Wang, Chen, Wilkens, Lynne R, Winham, Stacey J, Benitez, Javier, Berchuck, Andrew, Bowtell, David D, Candido Dos Reis, Francisco J, Cook, Linda S, DeFazio, Anna, AOCs group, Doherty, Jennifer A, Fasching, Peter A, García, María J, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Huntsman, David G, Karlan, Beth Y, Kommoss, Stefan, Modugno, Francesmary, Schildkraut, Joellen M, Sinn, Hans-Peter, Staebler, Annette, Kelemen, Linda E, Ford, Caroline E, Menon, Usha, Pharoah, Paul DP, Köbel, Martin, Ramus, Susan J, Weir, Ashley, Weir, Ashley, Kang, Eun-Young, Meagher, Nicola S, Nelson, Gregg S, Ghatage, Prafull, Lee, Cheng-Han, Riggan, Marjorie J, Gentry-Maharaj, Aleksandra, Ryan, Andy, Singh, Naveena, Widschwendter, Martin, Alsop, Jennifer, Anglesio, Michael S, Beckmann, Matthias W, Berger, Jessica, Bisinotto, Christiani, Boros, Jessica, Brand, Alison H, Brenton, James D, Brooks-Wilson, Angela, Carney, Michael E, Cunningham, Julie M, Cushing-Haugen, Kara L, Cybulski, Cezary, Elishaev, Esther, Erber, Ramona, Fereday, Sian, Fischer, Anna, Paz-Ares, Luis, Gayarre, Javier, Gilks, Blake C, Grube, Marcel, Harnett, Paul R, Harris, Holly R, Hartmann, Arndt, Hein, Alexander, Hendley, Joy, Hernandez, Brenda Y, Heublein, Sabine, Huang, Yajue, Huzarski, Tomasz, Jakubowska, Anna, Jimenez-Linan, Mercedes, Kennedy, Catherine J, Kommoss, Felix KF, Koziak, Jennifer M, Kraemer, Bernhard, Le, Nhu D, Lesnock, Jaime, Lester, Jenny, Lubiński, Jan, Menkiszak, Janusz, Ney, Britta, Olawaiye, Alexander, Orsulic, Sandra, Osorio, Ana, Robles-Díaz, Luis, Ruebner, Matthias, Shah, Mitul, Sharma, Raghwa, Shvetsov, Yurii B, Steed, Helen, Talhouk, Aline, Taylor, Sarah E, Traficante, Nadia, Vierkant, Robert A, Wang, Chen, Wilkens, Lynne R, Winham, Stacey J, Benitez, Javier, Berchuck, Andrew, Bowtell, David D, Candido Dos Reis, Francisco J, Cook, Linda S, DeFazio, Anna, AOCs group, Doherty, Jennifer A, Fasching, Peter A, García, María J, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Huntsman, David G, Karlan, Beth Y, Kommoss, Stefan, Modugno, Francesmary, Schildkraut, Joellen M, Sinn, Hans-Peter, Staebler, Annette, Kelemen, Linda E, Ford, Caroline E, Menon, Usha, Pharoah, Paul DP, Köbel, Martin, and Ramus, Susan J
Abstract: BackgroundRecently, we showed a >60% difference in 5-year survival for patients with tubo-ovarian high-grade serous carcinoma (HGSC) when stratified by a 101-gene mRNA expression prognostic signature. Given the varied patient outcomes, this study aimed to translate prognostic mRNA markers into protein expression assays by immunohistochemistry and validate their survival association in HGSC.MethodsTwo prognostic genes, FOXJ1 and GMNN, were selected based on high-quality antibodies, correlation with protein expression and variation in immunohistochemical scores in a preliminary cohort (n = 134 and n = 80, respectively). Six thousand four hundred and thirty-four (FOXJ1) and 5470 (GMNN) formalin-fixed, paraffin-embedded ovarian neoplasms (4634 and 4185 HGSC, respectively) represented on tissue microarrays from the Ovarian Tumor Tissue Analysis consortium underwent immunohistochemical staining and scoring, then univariate and multivariate survival analysis.ResultsConsistent with mRNA, FOXJ1 protein expression exhibited a linear, increasing association with improved overall survival in HGSC patients. Women with >50% expression had the most favourable outcomes (HR = 0.78, 95% CI 0.67-0.91, p < 0.0001). GMNN protein expression was not significantly associated with overall HSGC patient survival. However, HGSCs with >35% GMNN expression showed a trend for better outcomes, though this was not significant.ConclusionWe provide foundational evidence for the prognostic value of FOXJ1 in HGSC, validating the prior mRNA-based prognostic association by immunohistochemistry.
Published: 2023

4. 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

5. Epidemiology, risk factors, and genetics of endometrial cancer

Author: Tempfer, Clemens, Steinke-Lange, Verena, Aretz, Stefan, Schmutzler, Rita, Ortmann, Olaf, Roemer, Thomas, Hanf, Volker, Widhalm, Simone, Reents, Nicola, Jud, Sebastian, Kommoss, Stefan, Nothacker, Monika, Bloedt, Susanne, Tempfer, Clemens, Steinke-Lange, Verena, Aretz, Stefan, Schmutzler, Rita, Ortmann, Olaf, Roemer, Thomas, Hanf, Volker, Widhalm, Simone, Reents, Nicola, Jud, Sebastian, Kommoss, Stefan, Nothacker, Monika, and Bloedt, Susanne
Abstract: Background Endometrial cancer (EC) is the fifth most common female malignancy and the most common pelvic malignancy. Effective strategies for early detection, prevention, and genetic assessment are discussed in this article. Aim To review the literature on epidemiology, risk factors, and genetics. Materials and Methods This article is based on the current recommendations of the German Society of Obstetrics and Gynecology for the diagnosis and treatment of women with EC. The current literature was summarized based on expert knowledge. Systematic searches in the Medline database and in Cochrane Reviews were performed. The quality of the evidence was rated according to the 2011 Oxford classification. Recommendations and statements were formulated by a representative group using structured consensus methods. Results In Germany, 2.7% of cancer-specific deaths are due to EC. The incidence of EC increases with age and the disease is most often diagnosed in the age group of 75- to 79-year-old women. The lifetime risk of EC is 1.9%. Risk-modulating factors of EC include long-term use of estrogens, progestogen therapy, oral contraceptives, high body mass index, and impaired glucose metabolism. In addition, physical activity and dietary aspects, such as the amount of fat and red meat consumed, as well as soja foods, dietary fibers, vitamins, and specific beverages such as tea and coffee, play an important etiological role. EC also has a genetic component. Immunohistochemical and/or molecular screening is warranted for all patients with EC and has a significant impact on the genetic counselling of affected families as well as on treatment decisions.
Published: 2022

6. 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

7. Ovarian Cancer-Specific BRCA-like Copy-Number Aberration Classifiers Detect Mutations Associated with Homologous Recombination Deficiency in the AGO-TR1 Trial

Author: Schouten, Philip C. (author), Richters, Lisa (author), Vis, Daniel J. (author), Kommoss, Stefan (author), Kluin, Roelof J.C. (author), Lips, Esther H. (author), Schmidt, Sandra (author), Nederlof, Petra M. (author), Wessels, L.F.A. (author), Schouten, Philip C. (author), Richters, Lisa (author), Vis, Daniel J. (author), Kommoss, Stefan (author), Kluin, Roelof J.C. (author), Lips, Esther H. (author), Schmidt, Sandra (author), Nederlof, Petra M. (author), and Wessels, L.F.A. (author)
Abstract: Purpose: Previously, we developed breast cancer BRCA1-like and BRCA2-like copy-number profile shrunken centroid classifiers predictive for mutation status and response to therapy, targeting homologous recombination deficiency (HRD). Therefore, we investigated BRCA1- and BRCA2-like classification in ovarian cancer, aiming to acquire classifiers with similar properties as those in breast cancer. Experimental Design: We analyzed DNA copy-number profiles of germline BRCA1- and BRCA2-mutant ovarian cancers and control tumors and observed that existing breast cancer classifiers did not sufficiently predict mutation status. Hence, we trained new shrunken centroid classifiers on this set and validated them in the independent The Cancer Genome Atlas dataset. Subsequently, we assessed BRCA1/2-like classification and obtained germline and tumor mutation and methylation status of cancer predisposition genes, among them several involved in HR repair, of 300 ovarian cancer samples derived from the consecutive cohort trial AGO-TR1 (NCT02222883). Results: The detection rate of the BRCA1-like classifier for BRCA1 mutations and promoter hypermethylation was 95.6%. The BRCA2-like classifier performed less accurately, likely due to a smaller training set. Furthermore, three quarters of the BRCA1/ 2-like tumors could be explained by (epi)genetic alterations in BRCA1/2, germline RAD51C mutations and alterations in other genes involved in HR. Around half of the non-BRCA-mutated ovarian cancer cases displayed a BRCA-like phenotype. Conclusions: The newly trained classifiers detected most BRCAmutated and methylated cancers and all tumors harboring a RAD51C germline mutations. Beyond that, we found an additional substantial proportion of ovarian cancers to be BRCA-like. _2021 The Authors; Published by the American Association for Cancer Research., Pattern Recognition and Bioinformatics
Published: 2021
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8. Ovarian Cancer-Specific BRCA-like Copy-Number Aberration Classifiers Detect Mutations Associated with Homologous Recombination Deficiency in the AGO-TR1 Trial

Author: Schouten, Philip C., Richters, Lisa, Vis, Daniel J., Kommoss, Stefan, van Dijk, Ewald, Ernst, Corinna, Kluin, Roelof J. C., Marme, Frederik, Lips, Esther H., Schmidt, Sandra, Scheerman, Esther, Prieske, Katharina, van Deurzen, Carolien H. M., Burges, Alexander, Ewing-Graham, Patricia C., Dietrich, Dimo, Jager, Agnes, de Gregorio, Nikolaus, Hauke, Jan, du Bois, Andreas, Nederlof, Petra M., Wessels, Lodewyk F., Hahnen, Eric, Harter, Philipp, Linn, Sabine C., Schmutzler, Rita K., Schouten, Philip C., Richters, Lisa, Vis, Daniel J., Kommoss, Stefan, van Dijk, Ewald, Ernst, Corinna, Kluin, Roelof J. C., Marme, Frederik, Lips, Esther H., Schmidt, Sandra, Scheerman, Esther, Prieske, Katharina, van Deurzen, Carolien H. M., Burges, Alexander, Ewing-Graham, Patricia C., Dietrich, Dimo, Jager, Agnes, de Gregorio, Nikolaus, Hauke, Jan, du Bois, Andreas, Nederlof, Petra M., Wessels, Lodewyk F., Hahnen, Eric, Harter, Philipp, Linn, Sabine C., and Schmutzler, Rita K.
Abstract: Purpose: Previously, we developed breast cancer BRCA1-like and BRCA2-like copy-number profile shrunken centroid classifiers predictive for mutation status and response to therapy, targeting homologous recombination deficiency (HRD). Therefore, we investigated BRCA1- and BRCA2-like classification in ovarian cancer, aiming to acquire classifiers with similar properties as those in breast cancer. Experimental Design: We analyzed DNA copy-number profiles of germline BRCA1- and BRCA2-mutant ovarian cancers and control tumors and observed that existing breast cancer classifiers did not sufficiently predict mutation status. Hence, we trained new shrunken centroid classifiers on this set and validated them in the independent The Cancer Genome Atlas dataset. Subsequently, we assessed BRCA1/2-like classification and obtained germline and tumor mutation and methylation status of cancer predisposition genes, among them several involved in HR repair, of 300 ovarian cancer samples derived from the consecutive cohort trial AGO-TR1 (NCT02222883). Results: The detection rate of the BRCA1-like classifier for BRCA1 mutations and promoter hypermethylation was 95.6%. The BRCA2-like classifier performed less accurately, likely due to a smaller training set. Furthermore, three quarters of the BRCA1/2-like tumors could be explained by (epi)genetic alterations in BRCA1/2, germline RAD51C mutations and alterations in other genes involved in HR. Around half of the non-BRCA-mutated ovarian cancer cases displayed a BRCA-like phenotype. Conclusions: The newly trained classifiers detected most BRCA-mutated and methylated cancers and all tumors harboring a RAD51C germline mutations. Beyond that, we found an additional substantial proportion of ovarian cancers to be BRCA-like.
Published: 2021

9. Ovarian Cancer-Specific BRCA-like Copy-Number Aberration Classifiers Detect Mutations Associated with Homologous Recombination Deficiency in the AGO-TR1 Trial

Author: Schouten, Philip C., Richters, Lisa, Vis, Daniel J., Kommoss, Stefan, van Dijk, Ewald, Ernst, Corinna, Kluin, Roelof J. C., Marme, Frederik, Lips, Esther H., Schmidt, Sandra, Scheerman, Esther, Prieske, Katharina, van Deurzen, Carolien H. M., Burges, Alexander, Ewing-Graham, Patricia C., Dietrich, Dimo, Jager, Agnes, de Gregorio, Nikolaus, Hauke, Jan, du Bois, Andreas, Nederlof, Petra M., Wessels, Lodewyk F., Hahnen, Eric, Harter, Philipp, Linn, Sabine C., Schmutzler, Rita K., Schouten, Philip C., Richters, Lisa, Vis, Daniel J., Kommoss, Stefan, van Dijk, Ewald, Ernst, Corinna, Kluin, Roelof J. C., Marme, Frederik, Lips, Esther H., Schmidt, Sandra, Scheerman, Esther, Prieske, Katharina, van Deurzen, Carolien H. M., Burges, Alexander, Ewing-Graham, Patricia C., Dietrich, Dimo, Jager, Agnes, de Gregorio, Nikolaus, Hauke, Jan, du Bois, Andreas, Nederlof, Petra M., Wessels, Lodewyk F., Hahnen, Eric, Harter, Philipp, Linn, Sabine C., and Schmutzler, Rita K.
Abstract: Purpose: Previously, we developed breast cancer BRCA1-like and BRCA2-like copy-number profile shrunken centroid classifiers predictive for mutation status and response to therapy, targeting homologous recombination deficiency (HRD). Therefore, we investigated BRCA1- and BRCA2-like classification in ovarian cancer, aiming to acquire classifiers with similar properties as those in breast cancer. Experimental Design: We analyzed DNA copy-number profiles of germline BRCA1- and BRCA2-mutant ovarian cancers and control tumors and observed that existing breast cancer classifiers did not sufficiently predict mutation status. Hence, we trained new shrunken centroid classifiers on this set and validated them in the independent The Cancer Genome Atlas dataset. Subsequently, we assessed BRCA1/2-like classification and obtained germline and tumor mutation and methylation status of cancer predisposition genes, among them several involved in HR repair, of 300 ovarian cancer samples derived from the consecutive cohort trial AGO-TR1 (NCT02222883). Results: The detection rate of the BRCA1-like classifier for BRCA1 mutations and promoter hypermethylation was 95.6%. The BRCA2-like classifier performed less accurately, likely due to a smaller training set. Furthermore, three quarters of the BRCA1/2-like tumors could be explained by (epi)genetic alterations in BRCA1/2, germline RAD51C mutations and alterations in other genes involved in HR. Around half of the non-BRCA-mutated ovarian cancer cases displayed a BRCA-like phenotype. Conclusions: The newly trained classifiers detected most BRCA-mutated and methylated cancers and all tumors harboring a RAD51C germline mutations. Beyond that, we found an additional substantial proportion of ovarian cancers to be BRCA-like.
Published: 2021

10. Ovarian Cancer-Specific BRCA-like Copy-Number Aberration Classifiers Detect Mutations Associated with Homologous Recombination Deficiency in the AGO-TR1 Trial

Author: Schouten, Philip C. (author), Richters, Lisa (author), Vis, Daniel J. (author), Kommoss, Stefan (author), Kluin, Roelof J.C. (author), Lips, Esther H. (author), Schmidt, Sandra (author), Nederlof, Petra M. (author), Wessels, L.F.A. (author), Schouten, Philip C. (author), Richters, Lisa (author), Vis, Daniel J. (author), Kommoss, Stefan (author), Kluin, Roelof J.C. (author), Lips, Esther H. (author), Schmidt, Sandra (author), Nederlof, Petra M. (author), and Wessels, L.F.A. (author)
Abstract: Purpose: Previously, we developed breast cancer BRCA1-like and BRCA2-like copy-number profile shrunken centroid classifiers predictive for mutation status and response to therapy, targeting homologous recombination deficiency (HRD). Therefore, we investigated BRCA1- and BRCA2-like classification in ovarian cancer, aiming to acquire classifiers with similar properties as those in breast cancer. Experimental Design: We analyzed DNA copy-number profiles of germline BRCA1- and BRCA2-mutant ovarian cancers and control tumors and observed that existing breast cancer classifiers did not sufficiently predict mutation status. Hence, we trained new shrunken centroid classifiers on this set and validated them in the independent The Cancer Genome Atlas dataset. Subsequently, we assessed BRCA1/2-like classification and obtained germline and tumor mutation and methylation status of cancer predisposition genes, among them several involved in HR repair, of 300 ovarian cancer samples derived from the consecutive cohort trial AGO-TR1 (NCT02222883). Results: The detection rate of the BRCA1-like classifier for BRCA1 mutations and promoter hypermethylation was 95.6%. The BRCA2-like classifier performed less accurately, likely due to a smaller training set. Furthermore, three quarters of the BRCA1/ 2-like tumors could be explained by (epi)genetic alterations in BRCA1/2, germline RAD51C mutations and alterations in other genes involved in HR. Around half of the non-BRCA-mutated ovarian cancer cases displayed a BRCA-like phenotype. Conclusions: The newly trained classifiers detected most BRCAmutated and methylated cancers and all tumors harboring a RAD51C germline mutations. Beyond that, we found an additional substantial proportion of ovarian cancers to be BRCA-like. _2021 The Authors; Published by the American Association for Cancer Research., Pattern Recognition and Bioinformatics
Published: 2021
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11. Ovarian Cancer-Specific BRCA-like Copy-Number Aberration Classifiers Detect Mutations Associated with Homologous Recombination Deficiency in the AGO-TR1 Trial

Author: Schouten, Philip C., Richters, Lisa, Vis, Daniel J., Kommoss, Stefan, Dijk, Ewald Van, Ernst, Corinna, Kluin, Roelof J.C., Marm, Frederik M., Lips, Esther H., Schmidt, Sandra, Scheerman, Esther, Prieske, Katharina, Deurzen, Carolien H.M.Van, Burges, Alexander, Ewing-Graham, Patricia C., Dietrich, Dimo, Jager, Agnes, Gregorio, Nikolaus De, Hauke, Jan, Bois, Andreas Du, Nederlof, Petra M., Wessels, Lodewyk F., Hahnen, Eric, Harter, Philipp, Linn, Sabine C., Schmutzle, Rita K., Schouten, Philip C., Richters, Lisa, Vis, Daniel J., Kommoss, Stefan, Dijk, Ewald Van, Ernst, Corinna, Kluin, Roelof J.C., Marm, Frederik M., Lips, Esther H., Schmidt, Sandra, Scheerman, Esther, Prieske, Katharina, Deurzen, Carolien H.M.Van, Burges, Alexander, Ewing-Graham, Patricia C., Dietrich, Dimo, Jager, Agnes, Gregorio, Nikolaus De, Hauke, Jan, Bois, Andreas Du, Nederlof, Petra M., Wessels, Lodewyk F., Hahnen, Eric, Harter, Philipp, Linn, Sabine C., and Schmutzle, Rita K.
Abstract: Purpose: Previously, we developed breast cancer BRCA1-like and BRCA2-like copy-number profile shrunken centroid classifiers predictive for mutation status and response to therapy, targeting homologous recombination deficiency (HRD). Therefore, we investigated BRCA1- and BRCA2-like classification in ovarian cancer, aiming to acquire classifiers with similar properties as those in breast cancer. Experimental Design: We analyzed DNA copy-number profiles of germline BRCA1- and BRCA2-mutant ovarian cancers and control tumors and observed that existing breast cancer classifiers did not sufficiently predict mutation status. Hence, we trained new shrunken centroid classifiers on this set and validated them in the independent The Cancer Genome Atlas dataset. Subsequently, we assessed BRCA1/2-like classification and obtained germline and tumor mutation and methylation status of cancer predisposition genes, among them several involved in HR repair, of 300 ovarian cancer samples derived from the consecutive cohort trial AGO-TR1 (NCT02222883). Results: The detection rate of the BRCA1-like classifier for BRCA1 mutations and promoter hypermethylation was 95.6%. The BRCA2-like classifier performed less accurately, likely due to a smaller training set. Furthermore, three quarters of the BRCA1/ 2-like tumors could be explained by (epi)genetic alterations in BRCA1/2, germline RAD51C mutations and alterations in other genes involved in HR. Around half of the non-BRCA-mutated ovarian cancer cases displayed a BRCA-like phenotype. Conclusions: The newly trained classifiers detected most BRCAmutated and methylated cancers and all tumors harboring a RAD51C germline mutations. Beyond that, we found an additional substantial proportion of ovarian cancers to be BRCA-like. _2021 The Authors; Published by the American Association for Cancer Research.
Published: 2021

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

Author: Martins, Filipe Correia, Martins, Filipe Correia, Couturier, Dominique-Laurent, Paterson, Anna, Karnezis, Anthony N, Chow, Christine, Nazeran, Tayyebeh M, Odunsi, Adekunle, Gentry-Maharaj, Aleksandra, Vrvilo, Aleksandra, Hein, Alexander, Talhouk, Aline, Osorio, Ana, Hartkopf, Andreas D, Brooks-Wilson, Angela, DeFazio, Anna, Fischer, Anna, Hartmann, Arndt, Hernandez, Brenda Y, McCauley, Bryan M, Karpinskyj, Chloe, de Sousa, Christiani B, Høgdall, Claus, Tiezzi, Daniel G, Herpel, Esther, Taran, Florin Andrei, Modugno, Francesmary, Keeney, Gary, Nelson, Gregg, Steed, Helen, Song, Honglin, Luk, Hugh, Benitez, Javier, Alsop, Jennifer, Koziak, Jennifer M, Lester, Jenny, Rothstein, Joseph H, de Andrade, Jurandyr M, Lundvall, Lene, Paz-Ares, Luis, Robles-Díaz, Luis, Wilkens, Lynne R, Garcia, Maria J, Intermaggio, Maria P, Alcaraz, Marie-Lyne, Brett, Mary A, Beckmann, Matthias W, Jimenez-Linan, Mercedes, Anglesio, Michael, Carney, Michael E, Schneider, Michael, Traficante, Nadia, Pejovic, Nadja, Singh, Naveena, Le, Nhu, Sinn, Peter, Ghatage, Prafull, Erber, Ramona, Edwards, Robert, Vierkant, Robert, Ness, Roberta B, Leung, Samuel, Orsulic, Sandra, Brucker, Sara Y, Kaufmann, Scott H, Fereday, Sian, Gayther, Simon, Winham, Stacey J, Kommoss, Stefan, Pejovic, Tanja, Longacre, Teri A, McGuire, Valerie, Rhenius, Valerie, Sieh, Weiva, Shvetsov, Yurii B, Whittemore, Alice S, Staebler, Annette, Karlan, Beth Y, Rodriguez-Antona, Cristina, Bowtell, David D, Goode, Ellen L, Høgdall, Estrid, Candido Dos Reis, Francisco J, Gronwald, Jacek, Chang-Claude, Jenny, Moysich, Kirsten B, Kelemen, Linda E, Cook, Linda S, Goodman, Marc T, Fasching, Peter A, Crawford, Robin, Deen, Suha, Menon, Usha, Huntsman, David G, Köbel, Martin, Ramus, Susan J, Pharoah, Paul DP, Brenton, James D, Martins, Filipe Correia, Martins, Filipe Correia, Couturier, Dominique-Laurent, Paterson, Anna, Karnezis, Anthony N, Chow, Christine, Nazeran, Tayyebeh M, Odunsi, Adekunle, Gentry-Maharaj, Aleksandra, Vrvilo, Aleksandra, Hein, Alexander, Talhouk, Aline, Osorio, Ana, Hartkopf, Andreas D, Brooks-Wilson, Angela, DeFazio, Anna, Fischer, Anna, Hartmann, Arndt, Hernandez, Brenda Y, McCauley, Bryan M, Karpinskyj, Chloe, de Sousa, Christiani B, Høgdall, Claus, Tiezzi, Daniel G, Herpel, Esther, Taran, Florin Andrei, Modugno, Francesmary, Keeney, Gary, Nelson, Gregg, Steed, Helen, Song, Honglin, Luk, Hugh, Benitez, Javier, Alsop, Jennifer, Koziak, Jennifer M, Lester, Jenny, Rothstein, Joseph H, de Andrade, Jurandyr M, Lundvall, Lene, Paz-Ares, Luis, Robles-Díaz, Luis, Wilkens, Lynne R, Garcia, Maria J, Intermaggio, Maria P, Alcaraz, Marie-Lyne, Brett, Mary A, Beckmann, Matthias W, Jimenez-Linan, Mercedes, Anglesio, Michael, Carney, Michael E, Schneider, Michael, Traficante, Nadia, Pejovic, Nadja, Singh, Naveena, Le, Nhu, Sinn, Peter, Ghatage, Prafull, Erber, Ramona, Edwards, Robert, Vierkant, Robert, Ness, Roberta B, Leung, Samuel, Orsulic, Sandra, Brucker, Sara Y, Kaufmann, Scott H, Fereday, Sian, Gayther, Simon, Winham, Stacey J, Kommoss, Stefan, Pejovic, Tanja, Longacre, Teri A, McGuire, Valerie, Rhenius, Valerie, Sieh, Weiva, Shvetsov, Yurii B, Whittemore, Alice S, Staebler, Annette, Karlan, Beth Y, Rodriguez-Antona, Cristina, Bowtell, David D, Goode, Ellen L, Høgdall, Estrid, Candido Dos Reis, Francisco J, Gronwald, Jacek, Chang-Claude, Jenny, Moysich, Kirsten B, Kelemen, Linda E, Cook, Linda S, Goodman, Marc T, Fasching, Peter A, Crawford, Robin, Deen, Suha, Menon, Usha, Huntsman, David G, Köbel, Martin, Ramus, Susan J, Pharoah, Paul DP, and Brenton, James D
Abstract: BackgroundPTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study.MethodsTumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests.ResultsDownregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016).ConclusionsPTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.
Published: 2020

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

Author: Talhouk, Aline, Talhouk, Aline, George, Joshy, Wang, Chen, Budden, Timothy, Tan, Tuan Zea, Chiu, Derek S, Kommoss, Stefan, Leong, Huei San, Chen, Stephanie, Intermaggio, Maria P, Gilks, Blake, Nazeran, Tayyebeh M, Volchek, Mila, Elatre, Wafaa, Bentley, Rex C, Senz, Janine, Lum, Amy, Chow, Veronica, Sudderuddin, Hanwei, Mackenzie, Robertson, Leong, Samuel CY, Liu, Geyi, Johnson, Dustin, Chen, Billy, Group, Aocs, Alsop, Jennifer, Banerjee, Susana N, Behrens, Sabine, Bodelon, Clara, Brand, Alison H, Brinton, Louise, Carney, Michael E, Chiew, Yoke-Eng, Cushing-Haugen, Kara L, Cybulski, Cezary, Ennis, Darren, Fereday, Sian, Fortner, Renée T, García-Donas, Jesús, Gentry-Maharaj, Aleksandra, Glasspool, Rosalind, Goranova, Teodora, Greene, Casey S, Haluska, Paul, Harris, Holly R, Hendley, Joy, Hernandez, Brenda Y, Herpel, Esther, Jimenez-Linan, Mercedes, Karpinskyj, Chloe, Kaufmann, Scott H, Keeney, Gary L, Kennedy, Catherine J, Köbel, Martin, Koziak, Jennifer M, Larson, Melissa C, Lester, Jenny, Lewsley, Liz-Anne, Lissowska, Jolanta, Lubiński, Jan, Luk, Hugh, Macintyre, Geoff, Mahner, Sven, McNeish, Iain A, Menkiszak, Janusz, Nevins, Nikilyn, Osorio, Ana, Oszurek, Oleg, Palacios, José, Hinsley, Samantha, Pearce, Celeste L, Pike, Malcolm C, Piskorz, Anna M, Ray-Coquard, Isabelle, Rhenius, Valerie, Rodriguez-Antona, Cristina, Sharma, Raghwa, Sherman, Mark E, De Silva, Dilrini, Singh, Naveena, Sinn, Peter, Slamon, Dennis, Song, Honglin, Steed, Helen, Stronach, Euan A, Thompson, Pamela J, Tołoczko, Aleksandra, Trabert, Britton, Traficante, Nadia, Tseng, Chiu-Chen, Widschwendter, Martin, Wilkens, Lynne R, Winham, Stacey J, Winterhoff, Boris, Beeghly-Fadiel, Alicia, Benitez, Javier, Berchuck, Andrew, Brenton, James D, Brown, Robert, Chang-Claude, Jenny, Talhouk, Aline, Talhouk, Aline, George, Joshy, Wang, Chen, Budden, Timothy, Tan, Tuan Zea, Chiu, Derek S, Kommoss, Stefan, Leong, Huei San, Chen, Stephanie, Intermaggio, Maria P, Gilks, Blake, Nazeran, Tayyebeh M, Volchek, Mila, Elatre, Wafaa, Bentley, Rex C, Senz, Janine, Lum, Amy, Chow, Veronica, Sudderuddin, Hanwei, Mackenzie, Robertson, Leong, Samuel CY, Liu, Geyi, Johnson, Dustin, Chen, Billy, Group, Aocs, Alsop, Jennifer, Banerjee, Susana N, Behrens, Sabine, Bodelon, Clara, Brand, Alison H, Brinton, Louise, Carney, Michael E, Chiew, Yoke-Eng, Cushing-Haugen, Kara L, Cybulski, Cezary, Ennis, Darren, Fereday, Sian, Fortner, Renée T, García-Donas, Jesús, Gentry-Maharaj, Aleksandra, Glasspool, Rosalind, Goranova, Teodora, Greene, Casey S, Haluska, Paul, Harris, Holly R, Hendley, Joy, Hernandez, Brenda Y, Herpel, Esther, Jimenez-Linan, Mercedes, Karpinskyj, Chloe, Kaufmann, Scott H, Keeney, Gary L, Kennedy, Catherine J, Köbel, Martin, Koziak, Jennifer M, Larson, Melissa C, Lester, Jenny, Lewsley, Liz-Anne, Lissowska, Jolanta, Lubiński, Jan, Luk, Hugh, Macintyre, Geoff, Mahner, Sven, McNeish, Iain A, Menkiszak, Janusz, Nevins, Nikilyn, Osorio, Ana, Oszurek, Oleg, Palacios, José, Hinsley, Samantha, Pearce, Celeste L, Pike, Malcolm C, Piskorz, Anna M, Ray-Coquard, Isabelle, Rhenius, Valerie, Rodriguez-Antona, Cristina, Sharma, Raghwa, Sherman, Mark E, De Silva, Dilrini, Singh, Naveena, Sinn, Peter, Slamon, Dennis, Song, Honglin, Steed, Helen, Stronach, Euan A, Thompson, Pamela J, Tołoczko, Aleksandra, Trabert, Britton, Traficante, Nadia, Tseng, Chiu-Chen, Widschwendter, Martin, Wilkens, Lynne R, Winham, Stacey J, Winterhoff, Boris, Beeghly-Fadiel, Alicia, Benitez, Javier, Berchuck, Andrew, Brenton, James D, Brown, Robert, and Chang-Claude, Jenny
Abstract: PurposeGene expression-based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features.Experimental designAdopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting.ResultsGene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations.ConclusionsWe validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications.See related commentary by McMullen et al., p. 5271.
Published: 2020

14. A Modern Approach to Endometrial Carcinoma: Will Molecular Classification Improve Precision Medicine in the Future?

Author: Marnitz, Simone, Walter, Till, Schoemig-Markiefka, Birgid, Engler, Tobias, Kommoss, Stefan, Brucker, Sara Yvonne, Marnitz, Simone, Walter, Till, Schoemig-Markiefka, Birgid, Engler, Tobias, Kommoss, Stefan, and Brucker, Sara Yvonne
Abstract: Simple Summary The scientific community widely agrees that molecular classification will be key to endometrial carcinoma therapeutic strategies in the future. Retrospective analyses of large endometrial carcinoma patient cohorts gave rise to a new understanding of one of the most relevant gynecologic malignancies. Potentially replacing the current type I and type II terminology, four molecular subtypes have been established, each of them reflecting underlying molecular aberrations and distinct clinical behavior. Future research will have to focus on how to integrate these new findings into clinical practice with the ultimate goal to drive personalized endometrial carcinoma patient care forward. Endometrial cancer has been histologically classified as either an estrogen-dependent cancer with a favorable outcome or an estrogen-independent cancer with a worse prognosis. These parameters, along with the clinical attributions, have been the basis for risk stratification. Recent molecular and histopathological findings have suggested a more complex approach to risk stratification. Findings from the Cancer Genome Atlas Research Network established four distinctive genomic groups: ultramutated, hypermutated, copy-number low and copy-number high prognostic subtypes. Subsequently, more molecular and histopathologic classifiers were evaluated for their prognostic and predictive value. The impact of molecular classification is evident and will be recognized by the upcoming WHO classification. Further research is needed to give rise to a new era of molecular-based endometrial carcinoma patient care.
Published: 2020

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

Author: Talhouk, Aline, Talhouk, Aline, George, Joshy, Wang, Chen, Budden, Timothy, Tan, Tuan Zea, Chiu, Derek S, Kommoss, Stefan, Leong, Huei San, Chen, Stephanie, Intermaggio, Maria P, Gilks, Blake, Nazeran, Tayyebeh M, Volchek, Mila, Elatre, Wafaa, Bentley, Rex C, Senz, Janine, Lum, Amy, Chow, Veronica, Sudderuddin, Hanwei, Mackenzie, Robertson, Leong, Samuel CY, Liu, Geyi, Johnson, Dustin, Chen, Billy, Group, Aocs, Alsop, Jennifer, Banerjee, Susana N, Behrens, Sabine, Bodelon, Clara, Brand, Alison H, Brinton, Louise, Carney, Michael E, Chiew, Yoke-Eng, Cushing-Haugen, Kara L, Cybulski, Cezary, Ennis, Darren, Fereday, Sian, Fortner, Renée T, García-Donas, Jesús, Gentry-Maharaj, Aleksandra, Glasspool, Rosalind, Goranova, Teodora, Greene, Casey S, Haluska, Paul, Harris, Holly R, Hendley, Joy, Hernandez, Brenda Y, Herpel, Esther, Jimenez-Linan, Mercedes, Karpinskyj, Chloe, Kaufmann, Scott H, Keeney, Gary L, Kennedy, Catherine J, Köbel, Martin, Koziak, Jennifer M, Larson, Melissa C, Lester, Jenny, Lewsley, Liz-Anne, Lissowska, Jolanta, Lubiński, Jan, Luk, Hugh, Macintyre, Geoff, Mahner, Sven, McNeish, Iain A, Menkiszak, Janusz, Nevins, Nikilyn, Osorio, Ana, Oszurek, Oleg, Palacios, José, Hinsley, Samantha, Pearce, Celeste L, Pike, Malcolm C, Piskorz, Anna M, Ray-Coquard, Isabelle, Rhenius, Valerie, Rodriguez-Antona, Cristina, Sharma, Raghwa, Sherman, Mark E, De Silva, Dilrini, Singh, Naveena, Sinn, Peter, Slamon, Dennis, Song, Honglin, Steed, Helen, Stronach, Euan A, Thompson, Pamela J, Tołoczko, Aleksandra, Trabert, Britton, Traficante, Nadia, Tseng, Chiu-Chen, Widschwendter, Martin, Wilkens, Lynne R, Winham, Stacey J, Winterhoff, Boris, Beeghly-Fadiel, Alicia, Benitez, Javier, Berchuck, Andrew, Brenton, James D, Brown, Robert, Chang-Claude, Jenny, Talhouk, Aline, Talhouk, Aline, George, Joshy, Wang, Chen, Budden, Timothy, Tan, Tuan Zea, Chiu, Derek S, Kommoss, Stefan, Leong, Huei San, Chen, Stephanie, Intermaggio, Maria P, Gilks, Blake, Nazeran, Tayyebeh M, Volchek, Mila, Elatre, Wafaa, Bentley, Rex C, Senz, Janine, Lum, Amy, Chow, Veronica, Sudderuddin, Hanwei, Mackenzie, Robertson, Leong, Samuel CY, Liu, Geyi, Johnson, Dustin, Chen, Billy, Group, Aocs, Alsop, Jennifer, Banerjee, Susana N, Behrens, Sabine, Bodelon, Clara, Brand, Alison H, Brinton, Louise, Carney, Michael E, Chiew, Yoke-Eng, Cushing-Haugen, Kara L, Cybulski, Cezary, Ennis, Darren, Fereday, Sian, Fortner, Renée T, García-Donas, Jesús, Gentry-Maharaj, Aleksandra, Glasspool, Rosalind, Goranova, Teodora, Greene, Casey S, Haluska, Paul, Harris, Holly R, Hendley, Joy, Hernandez, Brenda Y, Herpel, Esther, Jimenez-Linan, Mercedes, Karpinskyj, Chloe, Kaufmann, Scott H, Keeney, Gary L, Kennedy, Catherine J, Köbel, Martin, Koziak, Jennifer M, Larson, Melissa C, Lester, Jenny, Lewsley, Liz-Anne, Lissowska, Jolanta, Lubiński, Jan, Luk, Hugh, Macintyre, Geoff, Mahner, Sven, McNeish, Iain A, Menkiszak, Janusz, Nevins, Nikilyn, Osorio, Ana, Oszurek, Oleg, Palacios, José, Hinsley, Samantha, Pearce, Celeste L, Pike, Malcolm C, Piskorz, Anna M, Ray-Coquard, Isabelle, Rhenius, Valerie, Rodriguez-Antona, Cristina, Sharma, Raghwa, Sherman, Mark E, De Silva, Dilrini, Singh, Naveena, Sinn, Peter, Slamon, Dennis, Song, Honglin, Steed, Helen, Stronach, Euan A, Thompson, Pamela J, Tołoczko, Aleksandra, Trabert, Britton, Traficante, Nadia, Tseng, Chiu-Chen, Widschwendter, Martin, Wilkens, Lynne R, Winham, Stacey J, Winterhoff, Boris, Beeghly-Fadiel, Alicia, Benitez, Javier, Berchuck, Andrew, Brenton, James D, Brown, Robert, and Chang-Claude, Jenny
Abstract: PurposeGene expression-based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features.Experimental designAdopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting.ResultsGene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations.ConclusionsWe validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications.See related commentary by McMullen et al., p. 5271.
Published: 2020

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

Author: Martins, Filipe Correia, Martins, Filipe Correia, Couturier, Dominique-Laurent, Paterson, Anna, Karnezis, Anthony N, Chow, Christine, Nazeran, Tayyebeh M, Odunsi, Adekunle, Gentry-Maharaj, Aleksandra, Vrvilo, Aleksandra, Hein, Alexander, Talhouk, Aline, Osorio, Ana, Hartkopf, Andreas D, Brooks-Wilson, Angela, DeFazio, Anna, Fischer, Anna, Hartmann, Arndt, Hernandez, Brenda Y, McCauley, Bryan M, Karpinskyj, Chloe, de Sousa, Christiani B, Høgdall, Claus, Tiezzi, Daniel G, Herpel, Esther, Taran, Florin Andrei, Modugno, Francesmary, Keeney, Gary, Nelson, Gregg, Steed, Helen, Song, Honglin, Luk, Hugh, Benitez, Javier, Alsop, Jennifer, Koziak, Jennifer M, Lester, Jenny, Rothstein, Joseph H, de Andrade, Jurandyr M, Lundvall, Lene, Paz-Ares, Luis, Robles-Díaz, Luis, Wilkens, Lynne R, Garcia, Maria J, Intermaggio, Maria P, Alcaraz, Marie-Lyne, Brett, Mary A, Beckmann, Matthias W, Jimenez-Linan, Mercedes, Anglesio, Michael, Carney, Michael E, Schneider, Michael, Traficante, Nadia, Pejovic, Nadja, Singh, Naveena, Le, Nhu, Sinn, Peter, Ghatage, Prafull, Erber, Ramona, Edwards, Robert, Vierkant, Robert, Ness, Roberta B, Leung, Samuel, Orsulic, Sandra, Brucker, Sara Y, Kaufmann, Scott H, Fereday, Sian, Gayther, Simon, Winham, Stacey J, Kommoss, Stefan, Pejovic, Tanja, Longacre, Teri A, McGuire, Valerie, Rhenius, Valerie, Sieh, Weiva, Shvetsov, Yurii B, Whittemore, Alice S, Staebler, Annette, Karlan, Beth Y, Rodriguez-Antona, Cristina, Bowtell, David D, Goode, Ellen L, Høgdall, Estrid, Candido Dos Reis, Francisco J, Gronwald, Jacek, Chang-Claude, Jenny, Moysich, Kirsten B, Kelemen, Linda E, Cook, Linda S, Goodman, Marc T, Fasching, Peter A, Crawford, Robin, Deen, Suha, Menon, Usha, Huntsman, David G, Köbel, Martin, Ramus, Susan J, Pharoah, Paul DP, Brenton, James D, Martins, Filipe Correia, Martins, Filipe Correia, Couturier, Dominique-Laurent, Paterson, Anna, Karnezis, Anthony N, Chow, Christine, Nazeran, Tayyebeh M, Odunsi, Adekunle, Gentry-Maharaj, Aleksandra, Vrvilo, Aleksandra, Hein, Alexander, Talhouk, Aline, Osorio, Ana, Hartkopf, Andreas D, Brooks-Wilson, Angela, DeFazio, Anna, Fischer, Anna, Hartmann, Arndt, Hernandez, Brenda Y, McCauley, Bryan M, Karpinskyj, Chloe, de Sousa, Christiani B, Høgdall, Claus, Tiezzi, Daniel G, Herpel, Esther, Taran, Florin Andrei, Modugno, Francesmary, Keeney, Gary, Nelson, Gregg, Steed, Helen, Song, Honglin, Luk, Hugh, Benitez, Javier, Alsop, Jennifer, Koziak, Jennifer M, Lester, Jenny, Rothstein, Joseph H, de Andrade, Jurandyr M, Lundvall, Lene, Paz-Ares, Luis, Robles-Díaz, Luis, Wilkens, Lynne R, Garcia, Maria J, Intermaggio, Maria P, Alcaraz, Marie-Lyne, Brett, Mary A, Beckmann, Matthias W, Jimenez-Linan, Mercedes, Anglesio, Michael, Carney, Michael E, Schneider, Michael, Traficante, Nadia, Pejovic, Nadja, Singh, Naveena, Le, Nhu, Sinn, Peter, Ghatage, Prafull, Erber, Ramona, Edwards, Robert, Vierkant, Robert, Ness, Roberta B, Leung, Samuel, Orsulic, Sandra, Brucker, Sara Y, Kaufmann, Scott H, Fereday, Sian, Gayther, Simon, Winham, Stacey J, Kommoss, Stefan, Pejovic, Tanja, Longacre, Teri A, McGuire, Valerie, Rhenius, Valerie, Sieh, Weiva, Shvetsov, Yurii B, Whittemore, Alice S, Staebler, Annette, Karlan, Beth Y, Rodriguez-Antona, Cristina, Bowtell, David D, Goode, Ellen L, Høgdall, Estrid, Candido Dos Reis, Francisco J, Gronwald, Jacek, Chang-Claude, Jenny, Moysich, Kirsten B, Kelemen, Linda E, Cook, Linda S, Goodman, Marc T, Fasching, Peter A, Crawford, Robin, Deen, Suha, Menon, Usha, Huntsman, David G, Köbel, Martin, Ramus, Susan J, Pharoah, Paul DP, and Brenton, James D
Abstract: BackgroundPTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study.MethodsTumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests.ResultsDownregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016).ConclusionsPTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.
Published: 2020

17. A Modern Approach to Endometrial Carcinoma: Will Molecular Classification Improve Precision Medicine in the Future?

Author: Marnitz, Simone, Walter, Till, Schoemig-Markiefka, Birgid, Engler, Tobias, Kommoss, Stefan, Brucker, Sara Yvonne, Marnitz, Simone, Walter, Till, Schoemig-Markiefka, Birgid, Engler, Tobias, Kommoss, Stefan, and Brucker, Sara Yvonne
Abstract: Simple Summary The scientific community widely agrees that molecular classification will be key to endometrial carcinoma therapeutic strategies in the future. Retrospective analyses of large endometrial carcinoma patient cohorts gave rise to a new understanding of one of the most relevant gynecologic malignancies. Potentially replacing the current type I and type II terminology, four molecular subtypes have been established, each of them reflecting underlying molecular aberrations and distinct clinical behavior. Future research will have to focus on how to integrate these new findings into clinical practice with the ultimate goal to drive personalized endometrial carcinoma patient care forward. Endometrial cancer has been histologically classified as either an estrogen-dependent cancer with a favorable outcome or an estrogen-independent cancer with a worse prognosis. These parameters, along with the clinical attributions, have been the basis for risk stratification. Recent molecular and histopathological findings have suggested a more complex approach to risk stratification. Findings from the Cancer Genome Atlas Research Network established four distinctive genomic groups: ultramutated, hypermutated, copy-number low and copy-number high prognostic subtypes. Subsequently, more molecular and histopathologic classifiers were evaluated for their prognostic and predictive value. The impact of molecular classification is evident and will be recognized by the upcoming WHO classification. Further research is needed to give rise to a new era of molecular-based endometrial carcinoma patient care.
Published: 2020

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

Author: Martins, Filipe Correia, Couturier, Dominique-laurent, Paterson, Anna, Karnezis, Anthony N., Chow, Christine, Nazeran, Tayyebeh M., Odunsi, Adekunle, Gentry-maharaj, Aleksandra, Vrvilo, Aleksandra, Hein, Alexander, Talhouk, Aline, Osorio, Ana, Hartkopf, Andreas D., Brooks-wilson, Angela, Defazio, Anna, Fischer, Anna, Hartmann, Arndt, Hernandez, Brenda Y., Mccauley, Bryan M., Karpinskyj, Chloe, De Sousa, Christiani B., Høgdall, Claus, Tiezzi, Daniel G., Herpel, Esther, Taran, Florin Andrei, Modugno, Francesmary, Keeney, Gary, Nelson, Gregg, Steed, Helen, Song, Honglin, Luk, Hugh, Benitez, Javier, Alsop, Jennifer, Koziak, Jennifer M., Lester, Jenny, Rothstein, Joseph H., De Andrade, Jurandyr M., Lundvall, Lene, Paz-ares, Luis, Robles-díaz, Luis, Wilkens, Lynne R., Garcia, Maria J., Intermaggio, Maria P., Alcaraz, Marie-lyne, Brett, Mary A., Beckmann, Matthias W., Jimenez-linan, Mercedes, Anglesio, Michael, Carney, Michael E., Schneider, Michael, Traficante, Nadia, Pejovic, Nadja, Singh, Naveena, Le, Nhu, Sinn, Peter, Ghatage, Prafull, Erber, Ramona, Edwards, Robert, Vierkant, Robert, Ness, Roberta B., Leung, Samuel, Orsulic, Sandra, Brucker, Sara Y., Kaufmann, Scott H., Fereday, Sian, Gayther, Simon, Winham, Stacey J., Kommoss, Stefan, Pejovic, Tanja, Longacre, Teri A., Mcguire, Valerie, Rhenius, Valerie, Sieh, Weiva, Shvetsov, Yurii B., Whittemore, Alice S., Staebler, Annette, Karlan, Beth Y., Rodriguez-antona, Cristina, Bowtell, David D., Goode, Ellen L., Høgdall, Estrid, Candido Dos Reis, Francisco J., Gronwald, Jacek, Chang-claude, Jenny, Moysich, Kirsten B., Kelemen, Linda E., Cook, Linda S., Goodman, Marc T., Fasching, Peter A., Crawford, Robin, Deen, Suha, Menon, Usha, Huntsman, David G., Köbel, Martin, Ramus, Susan J., Pharoah, Paul D. P., Brenton, James D., Martins, Filipe Correia, Couturier, Dominique-laurent, Paterson, Anna, Karnezis, Anthony N., Chow, Christine, Nazeran, Tayyebeh M., Odunsi, Adekunle, Gentry-maharaj, Aleksandra, Vrvilo, Aleksandra, Hein, Alexander, Talhouk, Aline, Osorio, Ana, Hartkopf, Andreas D., Brooks-wilson, Angela, Defazio, Anna, Fischer, Anna, Hartmann, Arndt, Hernandez, Brenda Y., Mccauley, Bryan M., Karpinskyj, Chloe, De Sousa, Christiani B., Høgdall, Claus, Tiezzi, Daniel G., Herpel, Esther, Taran, Florin Andrei, Modugno, Francesmary, Keeney, Gary, Nelson, Gregg, Steed, Helen, Song, Honglin, Luk, Hugh, Benitez, Javier, Alsop, Jennifer, Koziak, Jennifer M., Lester, Jenny, Rothstein, Joseph H., De Andrade, Jurandyr M., Lundvall, Lene, Paz-ares, Luis, Robles-díaz, Luis, Wilkens, Lynne R., Garcia, Maria J., Intermaggio, Maria P., Alcaraz, Marie-lyne, Brett, Mary A., Beckmann, Matthias W., Jimenez-linan, Mercedes, Anglesio, Michael, Carney, Michael E., Schneider, Michael, Traficante, Nadia, Pejovic, Nadja, Singh, Naveena, Le, Nhu, Sinn, Peter, Ghatage, Prafull, Erber, Ramona, Edwards, Robert, Vierkant, Robert, Ness, Roberta B., Leung, Samuel, Orsulic, Sandra, Brucker, Sara Y., Kaufmann, Scott H., Fereday, Sian, Gayther, Simon, Winham, Stacey J., Kommoss, Stefan, Pejovic, Tanja, Longacre, Teri A., Mcguire, Valerie, Rhenius, Valerie, Sieh, Weiva, Shvetsov, Yurii B., Whittemore, Alice S., Staebler, Annette, Karlan, Beth Y., Rodriguez-antona, Cristina, Bowtell, David D., Goode, Ellen L., Høgdall, Estrid, Candido Dos Reis, Francisco J., Gronwald, Jacek, Chang-claude, Jenny, Moysich, Kirsten B., Kelemen, Linda E., Cook, Linda S., Goodman, Marc T., Fasching, Peter A., Crawford, Robin, Deen, Suha, Menon, Usha, Huntsman, David G., Köbel, Martin, Ramus, Susan J., Pharoah, Paul D. P., and Brenton, James D.
Published: 2020

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

Author: Martins, Filipe Correia, Couturier, Dominique-laurent, Paterson, Anna, Karnezis, Anthony N., Chow, Christine, Nazeran, Tayyebeh M., Odunsi, Adekunle, Gentry-maharaj, Aleksandra, Vrvilo, Aleksandra, Hein, Alexander, Talhouk, Aline, Osorio, Ana, Hartkopf, Andreas D., Brooks-wilson, Angela, Defazio, Anna, Fischer, Anna, Hartmann, Arndt, Hernandez, Brenda Y., Mccauley, Bryan M., Karpinskyj, Chloe, De Sousa, Christiani B., Høgdall, Claus, Tiezzi, Daniel G., Herpel, Esther, Taran, Florin Andrei, Modugno, Francesmary, Keeney, Gary, Nelson, Gregg, Steed, Helen, Song, Honglin, Luk, Hugh, Benitez, Javier, Alsop, Jennifer, Koziak, Jennifer M., Lester, Jenny, Rothstein, Joseph H., De Andrade, Jurandyr M., Lundvall, Lene, Paz-ares, Luis, Robles-díaz, Luis, Wilkens, Lynne R., Garcia, Maria J., Intermaggio, Maria P., Alcaraz, Marie-lyne, Brett, Mary A., Beckmann, Matthias W., Jimenez-linan, Mercedes, Anglesio, Michael, Carney, Michael E., Schneider, Michael, Traficante, Nadia, Pejovic, Nadja, Singh, Naveena, Le, Nhu, Sinn, Peter, Ghatage, Prafull, Erber, Ramona, Edwards, Robert, Vierkant, Robert, Ness, Roberta B., Leung, Samuel, Orsulic, Sandra, Brucker, Sara Y., Kaufmann, Scott H., Fereday, Sian, Gayther, Simon, Winham, Stacey J., Kommoss, Stefan, Pejovic, Tanja, Longacre, Teri A., Mcguire, Valerie, Rhenius, Valerie, Sieh, Weiva, Shvetsov, Yurii B., Whittemore, Alice S., Staebler, Annette, Karlan, Beth Y., Rodriguez-antona, Cristina, Bowtell, David D., Goode, Ellen L., Høgdall, Estrid, Candido Dos Reis, Francisco J., Gronwald, Jacek, Chang-claude, Jenny, Moysich, Kirsten B., Kelemen, Linda E., Cook, Linda S., Goodman, Marc T., Fasching, Peter A., Crawford, Robin, Deen, Suha, Menon, Usha, Huntsman, David G., Köbel, Martin, Ramus, Susan J., Pharoah, Paul D. P., Brenton, James D., Martins, Filipe Correia, Couturier, Dominique-laurent, Paterson, Anna, Karnezis, Anthony N., Chow, Christine, Nazeran, Tayyebeh M., Odunsi, Adekunle, Gentry-maharaj, Aleksandra, Vrvilo, Aleksandra, Hein, Alexander, Talhouk, Aline, Osorio, Ana, Hartkopf, Andreas D., Brooks-wilson, Angela, Defazio, Anna, Fischer, Anna, Hartmann, Arndt, Hernandez, Brenda Y., Mccauley, Bryan M., Karpinskyj, Chloe, De Sousa, Christiani B., Høgdall, Claus, Tiezzi, Daniel G., Herpel, Esther, Taran, Florin Andrei, Modugno, Francesmary, Keeney, Gary, Nelson, Gregg, Steed, Helen, Song, Honglin, Luk, Hugh, Benitez, Javier, Alsop, Jennifer, Koziak, Jennifer M., Lester, Jenny, Rothstein, Joseph H., De Andrade, Jurandyr M., Lundvall, Lene, Paz-ares, Luis, Robles-díaz, Luis, Wilkens, Lynne R., Garcia, Maria J., Intermaggio, Maria P., Alcaraz, Marie-lyne, Brett, Mary A., Beckmann, Matthias W., Jimenez-linan, Mercedes, Anglesio, Michael, Carney, Michael E., Schneider, Michael, Traficante, Nadia, Pejovic, Nadja, Singh, Naveena, Le, Nhu, Sinn, Peter, Ghatage, Prafull, Erber, Ramona, Edwards, Robert, Vierkant, Robert, Ness, Roberta B., Leung, Samuel, Orsulic, Sandra, Brucker, Sara Y., Kaufmann, Scott H., Fereday, Sian, Gayther, Simon, Winham, Stacey J., Kommoss, Stefan, Pejovic, Tanja, Longacre, Teri A., Mcguire, Valerie, Rhenius, Valerie, Sieh, Weiva, Shvetsov, Yurii B., Whittemore, Alice S., Staebler, Annette, Karlan, Beth Y., Rodriguez-antona, Cristina, Bowtell, David D., Goode, Ellen L., Høgdall, Estrid, Candido Dos Reis, Francisco J., Gronwald, Jacek, Chang-claude, Jenny, Moysich, Kirsten B., Kelemen, Linda E., Cook, Linda S., Goodman, Marc T., Fasching, Peter A., Crawford, Robin, Deen, Suha, Menon, Usha, Huntsman, David G., Köbel, Martin, Ramus, Susan J., Pharoah, Paul D. P., and Brenton, James D.
Published: 2020

20. Bevacizumab May Differentially Improve Ovarian Cancer Outcome in Patients with Proliferative and Mesenchymal Molecular Subtypes.

Author: Kommoss, Stefan, Kommoss, Stefan, Winterhoff, Boris, Oberg, Ann L, Konecny, Gottfried E, Wang, Chen, Riska, Shaun M, Fan, Jian-Bing, Maurer, Matthew J, April, Craig, Shridhar, Viji, Kommoss, Friedrich, du Bois, Andreas, Hilpert, Felix, Mahner, Sven, Baumann, Klaus, Schroeder, Willibald, Burges, Alexander, Canzler, Ulrich, Chien, Jeremy, Embleton, Andrew C, Parmar, Mahesh, Kaplan, Richard, Perren, Timothy, Hartmann, Lynn C, Goode, Ellen L, Dowdy, Sean C, Pfisterer, Jacobus, Kommoss, Stefan, Kommoss, Stefan, Winterhoff, Boris, Oberg, Ann L, Konecny, Gottfried E, Wang, Chen, Riska, Shaun M, Fan, Jian-Bing, Maurer, Matthew J, April, Craig, Shridhar, Viji, Kommoss, Friedrich, du Bois, Andreas, Hilpert, Felix, Mahner, Sven, Baumann, Klaus, Schroeder, Willibald, Burges, Alexander, Canzler, Ulrich, Chien, Jeremy, Embleton, Andrew C, Parmar, Mahesh, Kaplan, Richard, Perren, Timothy, Hartmann, Lynn C, Goode, Ellen L, Dowdy, Sean C, and Pfisterer, Jacobus
Abstract: Purpose: Recent progress in understanding the molecular biology of epithelial ovarian cancer has not yet translated into individualized treatment for these women or improvements in their disease outcome. Gene expression has been utilized to identify distinct molecular subtypes, but there have been no reports investigating whether or not molecular subtyping is predictive of response to bevacizumab in ovarian cancer.Experimental Design: DASL gene expression arrays were performed on FFPE tissue from patients enrolled on the ICON7 trial. Patients were stratified into four TCGA molecular subtypes. Associations between molecular subtype and the efficacy of randomly assigned therapy with bevacizumab were assessed.Results: Molecular subtypes were assigned as follows: 122 immunoreactive (34%), 96 proliferative (27%), 73 differentiated (20%), and 68 mesenchymal (19%). In univariate analysis patients with tumors of proliferative subtype obtained the greatest benefit from bevacizumab with a median PFS improvement of 10.1 months [HR, 0.55 (95% CI, 0.34-0.90), P = 0.016]. For the mesenchymal subtype, bevacizumab conferred a nonsignificant improvement in PFS of 8.2 months [HR 0.78 (95% CI, 0.44-1.40), P = 0.41]. Bevacizumab conferred modest improvements in PFS for patients with immunoreactive subtype (3.8 months; P = 0.08) or differentiated subtype (3.7 months; P = 0.61). Multivariate analysis demonstrated significant PFS improvement in proliferative subtype patients only [HR, 0.45 (95% CI, 0.27-0.74), P = 0.0015].Conclusions: Ovarian carcinoma molecular subtypes with the poorest survival (proliferative and mesenchymal) derive a comparably greater benefit from treatment that includes bevacizumab. Validation of our findings in an independent cohort could enable the use of bevacizumab for those patients most likely to benefit, thereby reducing side effects and healthcare cost. Clin Cancer Res; 23(14); 3794-801. ©2017 AACR.
Published: 2017

21. Deleterious somatic variants in 473 consecutive individuals with ovarian cancer: results of the observational AGO-TR1 study (NCT02222883)

Author: Hauke, Jan, Hahnen, Eric, Schneider, Stephanie, Reuss, Alexander, Richters, Lisa, Kommoss, Stefan, Heimbach, Andre, Marme, Frederik, Schmidt, Sandra, Prieske, Katharina, Gevensleben, Heidrun, Burges, Alexander, Borde, Julika, De Gregorio, Nikolaus, Nuernberg, Peter, El-Balat, Ahmed, Thiele, Holger, Hilpert, Felix, Altmueller, Janine, Meier, Werner, Dietrich, Dimo, Kimmig, Rainer, Schoemig-Markiefka, Birgid, Kast, Karin, Braicu, Elena, Baumann, Klaus, Jackisch, Christian, Park-Simon, Tjoung-Won, Ernst, Corinna, Hanker, Lars, Pfisterer, Jacobus, Schnelzer, Andreas, du Bois, Andreas, Schmutzler, Rita K., Harter, Philipp, Hauke, Jan, Hahnen, Eric, Schneider, Stephanie, Reuss, Alexander, Richters, Lisa, Kommoss, Stefan, Heimbach, Andre, Marme, Frederik, Schmidt, Sandra, Prieske, Katharina, Gevensleben, Heidrun, Burges, Alexander, Borde, Julika, De Gregorio, Nikolaus, Nuernberg, Peter, El-Balat, Ahmed, Thiele, Holger, Hilpert, Felix, Altmueller, Janine, Meier, Werner, Dietrich, Dimo, Kimmig, Rainer, Schoemig-Markiefka, Birgid, Kast, Karin, Braicu, Elena, Baumann, Klaus, Jackisch, Christian, Park-Simon, Tjoung-Won, Ernst, Corinna, Hanker, Lars, Pfisterer, Jacobus, Schnelzer, Andreas, du Bois, Andreas, Schmutzler, Rita K., and Harter, Philipp
Abstract: Background For individuals with ovarian cancer (OC), therapy options mainly depend on BRCA1/2 germline status. What is the prevalence of deleterious somatic variants, that is, does genetic tumour testing identify subgroups of individuals who also might benefit from targeted therapy? Methods Paired analysis of tumour-derived versus blood-derived DNA to determine the prevalence of deleterious somatic variants in OC predisposition genes (ATM, BRCA1/2, BRIP1, MSH2/6, PALB2, RAD51C/D and TP53) and the PIK3CA and PTEN genes in individuals with OC (AG O-TR1 study, NCT02222883). Results were complemented by BRCA1, PALB2 and RAD51C promoter methylation analyses and stratified by histological subtype; 473 individuals were included. Results The combined analyses revealed that deleterious germline variants in established OC predisposition genes (all: 125/473, 26.4%; BRCA1/2: 97/473, 20.5%), deleterious somatic variants in established OC predisposition genes excluding TP53 (all: 39/473, 8.2%; BRCA1/2: 30/473, 6.3%) and promoter methylation (all: 67/473, 14.2%; BRCA1: 57/473, 12.1%; RAD51C: 10/473, 2.1%; PALB2: 0/473) were mutually exclusive, with a few exceptions. The same holds true for deleterious somatic PIK3CA and/or PTEN variants (33/473, 7.0%) found to be enriched in endometrioid and clear cell OC (16/35, 45.7%); 84.3 % of the deleterious single-nucleotide/indel germline variants in established OC predisposition genes showed significantly higher variant fractions (VFs) in the tumour-derived versus blood-derived DNA, indicating a loss of the wild-type alleles. Conclusion Tumour sequencing of the BRCA1, BRCA2, PIK3CA and PTEN genes along with BRCA1 and RAD51C promoter methylation analyses identified large subgroups of germline mutation-negative individuals who may be addressed in interventional studies using PARP or PI3K/AKT/mTOR inhibitors.
Published: 2019

22. Tubo-Ovarian Transitional Cell Carcinoma and High-grade Serous Carcinoma Show Subtly Different Immunohistochemistry Profiles.

Author: Magrill, Jamie, Magrill, Jamie, Karnezis, Anthony N, Tessier-Cloutier, Basile, Talhouk, Aline, Kommoss, Stefan, Cochrane, Dawn, Chow, Christine, Cheng, Angela, Soslow, Robert, Hauptmann, Steffen, du Bois, Andreas, Pfisterer, Jacobus, Gilks, C Blake, Huntsman, David G, Kommoss, Friedrich, Magrill, Jamie, Magrill, Jamie, Karnezis, Anthony N, Tessier-Cloutier, Basile, Talhouk, Aline, Kommoss, Stefan, Cochrane, Dawn, Chow, Christine, Cheng, Angela, Soslow, Robert, Hauptmann, Steffen, du Bois, Andreas, Pfisterer, Jacobus, Gilks, C Blake, Huntsman, David G, and Kommoss, Friedrich
Abstract: Tubo-ovarian transitional cell carcinoma (TCC) is grouped with high-grade serous carcinoma (HGSC) in the current World Health Organization classification. TCC is associated with BRCA mutations and a better prognosis compared with HGSC. Previous papers examining the immunohistochemical features of TCC have studied limited numbers of samples. No marker reflecting the biological difference between TCC and HGSC is known. We collected a large cohort of TCC to determine whether TCC and HGSC could be distinguished by immunohistochemistry. A tissue microarray was built from 89 TCC and a control cohort of 232 conventional HGSC. Immunohistochemistry was performed, scored, and statistically analyzed for routine markers of HGSC and urothelial tumors: PAX8, WT1, p53, p16, ER, p63, and GATA3. Using scoring cutoffs commonly employed in clinical practice, the immunohistochemical profile of TCC was indistinguishable from HGSC for all markers. However, more detailed scoring criteria revealed statistically significant differences between the 2 groups of tumors with respect to ER, PAX8, and WT1. HGSC showed more diffuse and intense staining for PAX8 (P=0.004 and 0.001, respectively) and WT1 (P=0.002 and 0.002, respectively); conversely, TCC showed more intense staining for ER (P=0.007). TCC and HGSC therefore show subtle differences in their immunohistochemical profiles which might reflect underlying (epi)genetic differences. Further studies using proteomic analysis will focus on the identification of differentially expressed proteins that might serve as markers of TCC-like differentiation, which could help explain biologic differences between TCC and HGSC and might identify other cases of HGSC with a better prognosis.
Published: 2019

23. Deleterious somatic variants in 473 consecutive individuals with ovarian cancer: results of the observational AGO-TR1 study (NCT02222883)

Author: Hauke, Jan, Hahnen, Eric, Schneider, Stephanie, Reuss, Alexander, Richters, Lisa, Kommoss, Stefan, Heimbach, Andre, Marme, Frederik, Schmidt, Sandra, Prieske, Katharina, Gevensleben, Heidrun, Burges, Alexander, Borde, Julika, De Gregorio, Nikolaus, Nuernberg, Peter, El-Balat, Ahmed, Thiele, Holger, Hilpert, Felix, Altmueller, Janine, Meier, Werner, Dietrich, Dimo, Kimmig, Rainer, Schoemig-Markiefka, Birgid, Kast, Karin, Braicu, Elena, Baumann, Klaus, Jackisch, Christian, Park-Simon, Tjoung-Won, Ernst, Corinna, Hanker, Lars, Pfisterer, Jacobus, Schnelzer, Andreas, du Bois, Andreas, Schmutzler, Rita K., Harter, Philipp, Hauke, Jan, Hahnen, Eric, Schneider, Stephanie, Reuss, Alexander, Richters, Lisa, Kommoss, Stefan, Heimbach, Andre, Marme, Frederik, Schmidt, Sandra, Prieske, Katharina, Gevensleben, Heidrun, Burges, Alexander, Borde, Julika, De Gregorio, Nikolaus, Nuernberg, Peter, El-Balat, Ahmed, Thiele, Holger, Hilpert, Felix, Altmueller, Janine, Meier, Werner, Dietrich, Dimo, Kimmig, Rainer, Schoemig-Markiefka, Birgid, Kast, Karin, Braicu, Elena, Baumann, Klaus, Jackisch, Christian, Park-Simon, Tjoung-Won, Ernst, Corinna, Hanker, Lars, Pfisterer, Jacobus, Schnelzer, Andreas, du Bois, Andreas, Schmutzler, Rita K., and Harter, Philipp
Abstract: Background For individuals with ovarian cancer (OC), therapy options mainly depend on BRCA1/2 germline status. What is the prevalence of deleterious somatic variants, that is, does genetic tumour testing identify subgroups of individuals who also might benefit from targeted therapy? Methods Paired analysis of tumour-derived versus blood-derived DNA to determine the prevalence of deleterious somatic variants in OC predisposition genes (ATM, BRCA1/2, BRIP1, MSH2/6, PALB2, RAD51C/D and TP53) and the PIK3CA and PTEN genes in individuals with OC (AG O-TR1 study, NCT02222883). Results were complemented by BRCA1, PALB2 and RAD51C promoter methylation analyses and stratified by histological subtype; 473 individuals were included. Results The combined analyses revealed that deleterious germline variants in established OC predisposition genes (all: 125/473, 26.4%; BRCA1/2: 97/473, 20.5%), deleterious somatic variants in established OC predisposition genes excluding TP53 (all: 39/473, 8.2%; BRCA1/2: 30/473, 6.3%) and promoter methylation (all: 67/473, 14.2%; BRCA1: 57/473, 12.1%; RAD51C: 10/473, 2.1%; PALB2: 0/473) were mutually exclusive, with a few exceptions. The same holds true for deleterious somatic PIK3CA and/or PTEN variants (33/473, 7.0%) found to be enriched in endometrioid and clear cell OC (16/35, 45.7%); 84.3 % of the deleterious single-nucleotide/indel germline variants in established OC predisposition genes showed significantly higher variant fractions (VFs) in the tumour-derived versus blood-derived DNA, indicating a loss of the wild-type alleles. Conclusion Tumour sequencing of the BRCA1, BRCA2, PIK3CA and PTEN genes along with BRCA1 and RAD51C promoter methylation analyses identified large subgroups of germline mutation-negative individuals who may be addressed in interventional studies using PARP or PI3K/AKT/mTOR inhibitors.
Published: 2019

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

Author: Rambau, Peter F, Rambau, Peter F, Vierkant, Robert A, Intermaggio, Maria P, Kelemen, Linda E, Goodman, Marc T, Herpel, Esther, Pharoah, Paul D, Kommoss, Stefan, Jimenez-Linan, Mercedes, Karlan, Beth Y, Gentry-Maharaj, Aleksandra, Menon, Usha, Polo, Susanna Hernando, Candido Dos Reis, Francisco J, Doherty, Jennifer Anne, Gayther, Simon A, Sharma, Raghwa, Larson, Melissa C, Harnett, Paul R, Hatfield, Emma, de Andrade, Jurandyr M, Nelson, Gregg S, Steed, Helen, Schildkraut, Joellen M, Carney, Micheal E, Høgdall, Estrid, Whittemore, Alice S, Widschwendter, Martin, Kennedy, Catherine J, Wang, Frances, Wang, Qin, Wang, Chen, Armasu, Sebastian M, Daley, Frances, Coulson, Penny, Jones, Micheal E, Anglesio, Micheal S, Chow, Christine, de Fazio, Anna, García-Closas, Montserrat, Brucker, Sara Y, Cybulski, Cezary, Harris, Holly R, Hartkopf, Andreas D, Huzarski, Tomasz, Jensen, Allan, Lubiński, Jan, Oszurek, Oleg, Benitez, Javier, Mina, Fady, Staebler, Annette, Taran, Florin Andrei, Pasternak, Jana, Talhouk, Aline, Rossing, Mary Anne, Hendley, Joy, AOCS Group, Edwards, Robert P, Fereday, Sian, Modugno, Francesmary, Ness, Roberta B, Sieh, Weiva, El-Bahrawy, Mona A, Winham, Stacey J, Lester, Jenny, Kjaer, Susanne K, Gronwald, Jacek, Sinn, Peter, Fasching, Peter A, Chang-Claude, Jenny, Moysich, Kirsten B, Bowtell, David D, Hernandez, Brenda Y, Luk, Hugh, Behrens, Sabine, Shah, Mitul, Jung, Audrey, Ghatage, Prafull, Alsop, Jennifer, Alsop, Kathryn, García-Donas, Jesús, Thompson, Pamela J, Swerdlow, Anthony J, Karpinskyj, Chloe, Cazorla-Jiménez, Alicia, García, María J, Deen, Susha, Wilkens, Lynne R, Palacios, José, Berchuck, Andrew, Koziak, Jennifer M, Brenton, James D, Cook, Linda S, Goode, Ellen L, Huntsman, David G, Ramus, Susan J, Köbel, Martin, Rambau, Peter F, Rambau, Peter F, Vierkant, Robert A, Intermaggio, Maria P, Kelemen, Linda E, Goodman, Marc T, Herpel, Esther, Pharoah, Paul D, Kommoss, Stefan, Jimenez-Linan, Mercedes, Karlan, Beth Y, Gentry-Maharaj, Aleksandra, Menon, Usha, Polo, Susanna Hernando, Candido Dos Reis, Francisco J, Doherty, Jennifer Anne, Gayther, Simon A, Sharma, Raghwa, Larson, Melissa C, Harnett, Paul R, Hatfield, Emma, de Andrade, Jurandyr M, Nelson, Gregg S, Steed, Helen, Schildkraut, Joellen M, Carney, Micheal E, Høgdall, Estrid, Whittemore, Alice S, Widschwendter, Martin, Kennedy, Catherine J, Wang, Frances, Wang, Qin, Wang, Chen, Armasu, Sebastian M, Daley, Frances, Coulson, Penny, Jones, Micheal E, Anglesio, Micheal S, Chow, Christine, de Fazio, Anna, García-Closas, Montserrat, Brucker, Sara Y, Cybulski, Cezary, Harris, Holly R, Hartkopf, Andreas D, Huzarski, Tomasz, Jensen, Allan, Lubiński, Jan, Oszurek, Oleg, Benitez, Javier, Mina, Fady, Staebler, Annette, Taran, Florin Andrei, Pasternak, Jana, Talhouk, Aline, Rossing, Mary Anne, Hendley, Joy, AOCS Group, Edwards, Robert P, Fereday, Sian, Modugno, Francesmary, Ness, Roberta B, Sieh, Weiva, El-Bahrawy, Mona A, Winham, Stacey J, Lester, Jenny, Kjaer, Susanne K, Gronwald, Jacek, Sinn, Peter, Fasching, Peter A, Chang-Claude, Jenny, Moysich, Kirsten B, Bowtell, David D, Hernandez, Brenda Y, Luk, Hugh, Behrens, Sabine, Shah, Mitul, Jung, Audrey, Ghatage, Prafull, Alsop, Jennifer, Alsop, Kathryn, García-Donas, Jesús, Thompson, Pamela J, Swerdlow, Anthony J, Karpinskyj, Chloe, Cazorla-Jiménez, Alicia, García, María J, Deen, Susha, Wilkens, Lynne R, Palacios, José, Berchuck, Andrew, Koziak, Jennifer M, Brenton, James D, Cook, Linda S, Goode, Ellen L, Huntsman, David G, Ramus, Susan J, and Köbel, Martin
Abstract: We aimed to validate the prognostic association of p16 expression in ovarian high-grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical-grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis-associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47-2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30-2.75, p = 0.004), while absence was associated with shorter OS in low-grade serous carcinomas (HR: 2.95, 95% CI 1.61-5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype-specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low-grade serous carcinoma justifies CDK4 inhibition.
Published: 2018

25. MyD88 and TLR4 Expression in Epithelial Ovarian Cancer.

Author: Block, Matthew S, Block, Matthew S, Vierkant, Robert A, Rambau, Peter F, Winham, Stacey J, Wagner, Philipp, Traficante, Nadia, Tołoczko, Aleksandra, Tiezzi, Daniel G, Taran, Florin Andrei, Sinn, Peter, Sieh, Weiva, Sharma, Raghwa, Rothstein, Joseph H, Ramón Y Cajal, Teresa, Paz-Ares, Luis, Oszurek, Oleg, Orsulic, Sandra, Ness, Roberta B, Nelson, Gregg, Modugno, Francesmary, Menkiszak, Janusz, McGuire, Valerie, McCauley, Bryan M, Mack, Marie, Lubiński, Jan, Longacre, Teri A, Li, Zheng, Lester, Jenny, Kennedy, Catherine J, Kalli, Kimberly R, Jung, Audrey Y, Johnatty, Sharon E, Jimenez-Linan, Mercedes, Jensen, Allan, Intermaggio, Maria P, Hung, Jillian, Herpel, Esther, Hernandez, Brenda Y, Hartkopf, Andreas D, Harnett, Paul R, Ghatage, Prafull, García-Bueno, José M, Gao, Bo, Fereday, Sian, Eilber, Ursula, Edwards, Robert P, de Sousa, Christiani B, de Andrade, Jurandyr M, Chudecka-Głaz, Anita, Chenevix-Trench, Georgia, Cazorla, Alicia, Brucker, Sara Y, Australian Ovarian Cancer Study Group, Alsop, Jennifer, Whittemore, Alice S, Steed, Helen, Staebler, Annette, Moysich, Kirsten B, Menon, Usha, Koziak, Jennifer M, Kommoss, Stefan, Kjaer, Susanne K, Kelemen, Linda E, Karlan, Beth Y, Huntsman, David G, Høgdall, Estrid, Gronwald, Jacek, Goodman, Marc T, Gilks, Blake, García, María José, Fasching, Peter A, de Fazio, Anna, Deen, Suha, Chang-Claude, Jenny, Candido Dos Reis, Francisco J, Campbell, Ian G, Brenton, James D, Bowtell, David D, Benítez, Javier, Pharoah, Paul DP, Köbel, Martin, Ramus, Susan J, Goode, Ellen L, Block, Matthew S, Block, Matthew S, Vierkant, Robert A, Rambau, Peter F, Winham, Stacey J, Wagner, Philipp, Traficante, Nadia, Tołoczko, Aleksandra, Tiezzi, Daniel G, Taran, Florin Andrei, Sinn, Peter, Sieh, Weiva, Sharma, Raghwa, Rothstein, Joseph H, Ramón Y Cajal, Teresa, Paz-Ares, Luis, Oszurek, Oleg, Orsulic, Sandra, Ness, Roberta B, Nelson, Gregg, Modugno, Francesmary, Menkiszak, Janusz, McGuire, Valerie, McCauley, Bryan M, Mack, Marie, Lubiński, Jan, Longacre, Teri A, Li, Zheng, Lester, Jenny, Kennedy, Catherine J, Kalli, Kimberly R, Jung, Audrey Y, Johnatty, Sharon E, Jimenez-Linan, Mercedes, Jensen, Allan, Intermaggio, Maria P, Hung, Jillian, Herpel, Esther, Hernandez, Brenda Y, Hartkopf, Andreas D, Harnett, Paul R, Ghatage, Prafull, García-Bueno, José M, Gao, Bo, Fereday, Sian, Eilber, Ursula, Edwards, Robert P, de Sousa, Christiani B, de Andrade, Jurandyr M, Chudecka-Głaz, Anita, Chenevix-Trench, Georgia, Cazorla, Alicia, Brucker, Sara Y, Australian Ovarian Cancer Study Group, Alsop, Jennifer, Whittemore, Alice S, Steed, Helen, Staebler, Annette, Moysich, Kirsten B, Menon, Usha, Koziak, Jennifer M, Kommoss, Stefan, Kjaer, Susanne K, Kelemen, Linda E, Karlan, Beth Y, Huntsman, David G, Høgdall, Estrid, Gronwald, Jacek, Goodman, Marc T, Gilks, Blake, García, María José, Fasching, Peter A, de Fazio, Anna, Deen, Suha, Chang-Claude, Jenny, Candido Dos Reis, Francisco J, Campbell, Ian G, Brenton, James D, Bowtell, David D, Benítez, Javier, Pharoah, Paul DP, Köbel, Martin, Ramus, Susan J, and Goode, Ellen L
Abstract: ObjectiveTo evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival.Patients and methodsWe conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time. Tissue microarrays were stained for MyD88 and TLR4, and staining intensity was classified using a 2-tiered system for each marker (weak vs strong).ResultsExpression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P<.001 for both). In HGSOC, strong MyD88 expression was modestly associated with shortened overall survival (hazard ratio [HR], 1.13; 95% CI, 1.01-1.26; P=.04) but was also associated with advanced stage (P<.001). The expression of TLR4 was not associated with survival. In low-grade serous ovarian cancer (LGSOC), strong expression of both MyD88 and TLR4 was associated with favorable survival (HR [95% CI], 0.49 [0.29-0.84] and 0.44 [0.21-0.89], respectively; P=.009 and P=.02, respectively).ConclusionResults are consistent with an association between strong MyD88 staining and advanced stage and poorer survival in HGSOC and demonstrate correlation between strong MyD88 and TLR4 staining and improved survival in LGSOC, highlighting the biological differences between the 2 serous histotypes.
Published: 2018

26. Diagnosis of Li-Fraumeni Syndrome: Differentiating TP53 germline mutations from clonal hematopoiesis Results of the observational AGO-TR1 trial

Author: Weber-Lassalle, Konstantin, Harter, Philipp, Hauke, Jan, Ernst, Corinna, Kommoss, Stefan, Marme, Frederik, Weber-Lassalle, Nana, Prieske, Katharina, Dietrich, Dimo, Borde, Julika, Pohl-Rescigno, Esther, Reuss, Alexander, Ataseven, Beyhan, Engel, Christoph, Stingl, Julia C., Schmutzler, Rita K., Hahnen, Eric, Weber-Lassalle, Konstantin, Harter, Philipp, Hauke, Jan, Ernst, Corinna, Kommoss, Stefan, Marme, Frederik, Weber-Lassalle, Nana, Prieske, Katharina, Dietrich, Dimo, Borde, Julika, Pohl-Rescigno, Esther, Reuss, Alexander, Ataseven, Beyhan, Engel, Christoph, Stingl, Julia C., Schmutzler, Rita K., and Hahnen, Eric
Abstract: The Li-Fraumeni cancer predisposition syndrome (LFS1) presents with a variety of tumor types and the TP53 gene is covered by most diagnostic cancer gene panels. We demonstrate that deleterious TP53 variants identified in blood-derived DNA of 523 patients with ovarian cancer (AGO-TR1 trial) were not causal for the patients' ovarian cancer in three out of six TP53-positive cases. In three out of six patients, deleterious TP53 mutations were identified with low variant fractions in blood-derived DNA but not in the tumor of the patient seeking advice. The analysis of the TP53 and PPM1D genes, both intimately involved in chemotherapy-induced and/or age-related clonal hematopoiesis (CH), in 523 patients and 1,053 age-matched female control individuals revealed that CH represents a frequent event following chemotherapy, affecting 26 of the 523 patients enrolled (5.0%). Considering that TP53 mutations may arise from chemotherapy-induced CH, our findings help to avoid false-positive genetic diagnoses of LFS1.
Published: 2018

27. MyD88 and TLR4 Expression in Epithelial Ovarian Cancer.

Author: Block, Matthew S, Block, Matthew S, Vierkant, Robert A, Rambau, Peter F, Winham, Stacey J, Wagner, Philipp, Traficante, Nadia, Tołoczko, Aleksandra, Tiezzi, Daniel G, Taran, Florin Andrei, Sinn, Peter, Sieh, Weiva, Sharma, Raghwa, Rothstein, Joseph H, Ramón Y Cajal, Teresa, Paz-Ares, Luis, Oszurek, Oleg, Orsulic, Sandra, Ness, Roberta B, Nelson, Gregg, Modugno, Francesmary, Menkiszak, Janusz, McGuire, Valerie, McCauley, Bryan M, Mack, Marie, Lubiński, Jan, Longacre, Teri A, Li, Zheng, Lester, Jenny, Kennedy, Catherine J, Kalli, Kimberly R, Jung, Audrey Y, Johnatty, Sharon E, Jimenez-Linan, Mercedes, Jensen, Allan, Intermaggio, Maria P, Hung, Jillian, Herpel, Esther, Hernandez, Brenda Y, Hartkopf, Andreas D, Harnett, Paul R, Ghatage, Prafull, García-Bueno, José M, Gao, Bo, Fereday, Sian, Eilber, Ursula, Edwards, Robert P, de Sousa, Christiani B, de Andrade, Jurandyr M, Chudecka-Głaz, Anita, Chenevix-Trench, Georgia, Cazorla, Alicia, Brucker, Sara Y, Australian Ovarian Cancer Study Group, Alsop, Jennifer, Whittemore, Alice S, Steed, Helen, Staebler, Annette, Moysich, Kirsten B, Menon, Usha, Koziak, Jennifer M, Kommoss, Stefan, Kjaer, Susanne K, Kelemen, Linda E, Karlan, Beth Y, Huntsman, David G, Høgdall, Estrid, Gronwald, Jacek, Goodman, Marc T, Gilks, Blake, García, María José, Fasching, Peter A, de Fazio, Anna, Deen, Suha, Chang-Claude, Jenny, Candido Dos Reis, Francisco J, Campbell, Ian G, Brenton, James D, Bowtell, David D, Benítez, Javier, Pharoah, Paul DP, Köbel, Martin, Ramus, Susan J, Goode, Ellen L, Block, Matthew S, Block, Matthew S, Vierkant, Robert A, Rambau, Peter F, Winham, Stacey J, Wagner, Philipp, Traficante, Nadia, Tołoczko, Aleksandra, Tiezzi, Daniel G, Taran, Florin Andrei, Sinn, Peter, Sieh, Weiva, Sharma, Raghwa, Rothstein, Joseph H, Ramón Y Cajal, Teresa, Paz-Ares, Luis, Oszurek, Oleg, Orsulic, Sandra, Ness, Roberta B, Nelson, Gregg, Modugno, Francesmary, Menkiszak, Janusz, McGuire, Valerie, McCauley, Bryan M, Mack, Marie, Lubiński, Jan, Longacre, Teri A, Li, Zheng, Lester, Jenny, Kennedy, Catherine J, Kalli, Kimberly R, Jung, Audrey Y, Johnatty, Sharon E, Jimenez-Linan, Mercedes, Jensen, Allan, Intermaggio, Maria P, Hung, Jillian, Herpel, Esther, Hernandez, Brenda Y, Hartkopf, Andreas D, Harnett, Paul R, Ghatage, Prafull, García-Bueno, José M, Gao, Bo, Fereday, Sian, Eilber, Ursula, Edwards, Robert P, de Sousa, Christiani B, de Andrade, Jurandyr M, Chudecka-Głaz, Anita, Chenevix-Trench, Georgia, Cazorla, Alicia, Brucker, Sara Y, Australian Ovarian Cancer Study Group, Alsop, Jennifer, Whittemore, Alice S, Steed, Helen, Staebler, Annette, Moysich, Kirsten B, Menon, Usha, Koziak, Jennifer M, Kommoss, Stefan, Kjaer, Susanne K, Kelemen, Linda E, Karlan, Beth Y, Huntsman, David G, Høgdall, Estrid, Gronwald, Jacek, Goodman, Marc T, Gilks, Blake, García, María José, Fasching, Peter A, de Fazio, Anna, Deen, Suha, Chang-Claude, Jenny, Candido Dos Reis, Francisco J, Campbell, Ian G, Brenton, James D, Bowtell, David D, Benítez, Javier, Pharoah, Paul DP, Köbel, Martin, Ramus, Susan J, and Goode, Ellen L
Abstract: ObjectiveTo evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival.Patients and methodsWe conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time. Tissue microarrays were stained for MyD88 and TLR4, and staining intensity was classified using a 2-tiered system for each marker (weak vs strong).ResultsExpression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P<.001 for both). In HGSOC, strong MyD88 expression was modestly associated with shortened overall survival (hazard ratio [HR], 1.13; 95% CI, 1.01-1.26; P=.04) but was also associated with advanced stage (P<.001). The expression of TLR4 was not associated with survival. In low-grade serous ovarian cancer (LGSOC), strong expression of both MyD88 and TLR4 was associated with favorable survival (HR [95% CI], 0.49 [0.29-0.84] and 0.44 [0.21-0.89], respectively; P=.009 and P=.02, respectively).ConclusionResults are consistent with an association between strong MyD88 staining and advanced stage and poorer survival in HGSOC and demonstrate correlation between strong MyD88 and TLR4 staining and improved survival in LGSOC, highlighting the biological differences between the 2 serous histotypes.
Published: 2018

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

Author: Rambau, Peter F, Rambau, Peter F, Vierkant, Robert A, Intermaggio, Maria P, Kelemen, Linda E, Goodman, Marc T, Herpel, Esther, Pharoah, Paul D, Kommoss, Stefan, Jimenez-Linan, Mercedes, Karlan, Beth Y, Gentry-Maharaj, Aleksandra, Menon, Usha, Polo, Susanna Hernando, Candido Dos Reis, Francisco J, Doherty, Jennifer Anne, Gayther, Simon A, Sharma, Raghwa, Larson, Melissa C, Harnett, Paul R, Hatfield, Emma, de Andrade, Jurandyr M, Nelson, Gregg S, Steed, Helen, Schildkraut, Joellen M, Carney, Micheal E, Høgdall, Estrid, Whittemore, Alice S, Widschwendter, Martin, Kennedy, Catherine J, Wang, Frances, Wang, Qin, Wang, Chen, Armasu, Sebastian M, Daley, Frances, Coulson, Penny, Jones, Micheal E, Anglesio, Micheal S, Chow, Christine, de Fazio, Anna, García-Closas, Montserrat, Brucker, Sara Y, Cybulski, Cezary, Harris, Holly R, Hartkopf, Andreas D, Huzarski, Tomasz, Jensen, Allan, Lubiński, Jan, Oszurek, Oleg, Benitez, Javier, Mina, Fady, Staebler, Annette, Taran, Florin Andrei, Pasternak, Jana, Talhouk, Aline, Rossing, Mary Anne, Hendley, Joy, AOCS Group, Edwards, Robert P, Fereday, Sian, Modugno, Francesmary, Ness, Roberta B, Sieh, Weiva, El-Bahrawy, Mona A, Winham, Stacey J, Lester, Jenny, Kjaer, Susanne K, Gronwald, Jacek, Sinn, Peter, Fasching, Peter A, Chang-Claude, Jenny, Moysich, Kirsten B, Bowtell, David D, Hernandez, Brenda Y, Luk, Hugh, Behrens, Sabine, Shah, Mitul, Jung, Audrey, Ghatage, Prafull, Alsop, Jennifer, Alsop, Kathryn, García-Donas, Jesús, Thompson, Pamela J, Swerdlow, Anthony J, Karpinskyj, Chloe, Cazorla-Jiménez, Alicia, García, María J, Deen, Susha, Wilkens, Lynne R, Palacios, José, Berchuck, Andrew, Koziak, Jennifer M, Brenton, James D, Cook, Linda S, Goode, Ellen L, Huntsman, David G, Ramus, Susan J, Köbel, Martin, Rambau, Peter F, Rambau, Peter F, Vierkant, Robert A, Intermaggio, Maria P, Kelemen, Linda E, Goodman, Marc T, Herpel, Esther, Pharoah, Paul D, Kommoss, Stefan, Jimenez-Linan, Mercedes, Karlan, Beth Y, Gentry-Maharaj, Aleksandra, Menon, Usha, Polo, Susanna Hernando, Candido Dos Reis, Francisco J, Doherty, Jennifer Anne, Gayther, Simon A, Sharma, Raghwa, Larson, Melissa C, Harnett, Paul R, Hatfield, Emma, de Andrade, Jurandyr M, Nelson, Gregg S, Steed, Helen, Schildkraut, Joellen M, Carney, Micheal E, Høgdall, Estrid, Whittemore, Alice S, Widschwendter, Martin, Kennedy, Catherine J, Wang, Frances, Wang, Qin, Wang, Chen, Armasu, Sebastian M, Daley, Frances, Coulson, Penny, Jones, Micheal E, Anglesio, Micheal S, Chow, Christine, de Fazio, Anna, García-Closas, Montserrat, Brucker, Sara Y, Cybulski, Cezary, Harris, Holly R, Hartkopf, Andreas D, Huzarski, Tomasz, Jensen, Allan, Lubiński, Jan, Oszurek, Oleg, Benitez, Javier, Mina, Fady, Staebler, Annette, Taran, Florin Andrei, Pasternak, Jana, Talhouk, Aline, Rossing, Mary Anne, Hendley, Joy, AOCS Group, Edwards, Robert P, Fereday, Sian, Modugno, Francesmary, Ness, Roberta B, Sieh, Weiva, El-Bahrawy, Mona A, Winham, Stacey J, Lester, Jenny, Kjaer, Susanne K, Gronwald, Jacek, Sinn, Peter, Fasching, Peter A, Chang-Claude, Jenny, Moysich, Kirsten B, Bowtell, David D, Hernandez, Brenda Y, Luk, Hugh, Behrens, Sabine, Shah, Mitul, Jung, Audrey, Ghatage, Prafull, Alsop, Jennifer, Alsop, Kathryn, García-Donas, Jesús, Thompson, Pamela J, Swerdlow, Anthony J, Karpinskyj, Chloe, Cazorla-Jiménez, Alicia, García, María J, Deen, Susha, Wilkens, Lynne R, Palacios, José, Berchuck, Andrew, Koziak, Jennifer M, Brenton, James D, Cook, Linda S, Goode, Ellen L, Huntsman, David G, Ramus, Susan J, and Köbel, Martin
Abstract: We aimed to validate the prognostic association of p16 expression in ovarian high-grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical-grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis-associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47-2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30-2.75, p = 0.004), while absence was associated with shorter OS in low-grade serous carcinomas (HR: 2.95, 95% CI 1.61-5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype-specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low-grade serous carcinoma justifies CDK4 inhibition.
Published: 2018

29. L1CAM further stratifies endometrial carcinoma patients with no specific molecular risk profile.

Author: Kommoss, Felix Kf, Kommoss, Felix Kf, Karnezis, Anthony N, Kommoss, Friedrich, Talhouk, Aline, Taran, Florin-Andrei, Staebler, Annette, Gilks, C Blake, Huntsman, David G, Krämer, Bernhard, Brucker, Sara Y, McAlpine, Jessica N, Kommoss, Stefan, Kommoss, Felix Kf, Kommoss, Felix Kf, Karnezis, Anthony N, Kommoss, Friedrich, Talhouk, Aline, Taran, Florin-Andrei, Staebler, Annette, Gilks, C Blake, Huntsman, David G, Krämer, Bernhard, Brucker, Sara Y, McAlpine, Jessica N, and Kommoss, Stefan
Abstract: BackgroundThe newly developed Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) has consistently been shown to be prognostically significant in endometrial carcinomas (EC). Recently, we and others have demonstrated L1 cell-adhesion molecule (L1CAM) to be a significant indicator of high-risk disease in EC. In the current study, it was our aim to determine the prognostic significance of aberrant L1CAM expression in ProMisE subgroups in a large, single centre, population-based EC cohort.MethodsProMisE (POLE; MMR-D; p53 wt/NSMP; p53 abn) classification results from a cohort of 452 EC were available for analysis. L1CAM expression was studied by immunohistochemistry on whole slides. Correlations between clinicopathological data and survival were calculated.ResultsExpression of L1CAM was most frequent in p53 abnormal tumours (80%). L1CAM status was predictive of worse outcome among tumours with no specific molecular profile (p53 wt/NSMP) (p < 0.0001). Among p53 wt/NSMP EC, L1CAM remained a significant prognosticator for disease-specific survival after multivariate analysis (p = 0.035).ConclusionL1CAM status was able to significantly stratify risk among tumours of the large p53 wt/NSMP ProMisE subgroup of EC. Furthermore, our study confirms a highly significant correlation between mutation-type p53 immunostaining and abnormal L1CAM expression in EC.
Published: 2018

30. Developing a Clinico-Molecular Test for Individualized Treatment of Ovarian Cancer: The interplay of Precision Medicine Informatics with Clinical and Health Economics Dimensions.

Author: Winterhoff, Boris, Winterhoff, Boris, Kommoss, Stefan, Heitz, Florian, Konecny, Gottfried E, Dowdy, Sean C, Mullany, Sally A, Park-Simon, Tjoung-Won, Baumann, Klaus, Hilpert, Felix, Brucker, Sara, du Bois, Andreas, Schröder, Willibald, Burges, Alexander, Shen, Steven, Wang, Jinhua, Tourani, Roshan, Ma, Sisi, Pfisterer, Jacobus, Aliferis, Constantin F, Winterhoff, Boris, Winterhoff, Boris, Kommoss, Stefan, Heitz, Florian, Konecny, Gottfried E, Dowdy, Sean C, Mullany, Sally A, Park-Simon, Tjoung-Won, Baumann, Klaus, Hilpert, Felix, Brucker, Sara, du Bois, Andreas, Schröder, Willibald, Burges, Alexander, Shen, Steven, Wang, Jinhua, Tourani, Roshan, Ma, Sisi, Pfisterer, Jacobus, and Aliferis, Constantin F
Abstract: We report recent progress in the development of a precision test for individualized use of the VEGF-A targeting drug bevacizumab for treating ovarian cancer. We discuss the discovery model stage (i.e., past feasibility modeling and before conversion to the production test). Main results: (a) Informatics modeling plays a critical role in supporting driving clinical and health economic requirements. (b) The novel computational models support the creation of a precision test with sufficient predictivity to reduce healthcare system costs up to $30 billion over 10 years, and make the use of bevacizumab affordable without loss of length or quality of life.
Published: 2018

31. Diagnosis of Li-Fraumeni Syndrome: Differentiating TP53 germline mutations from clonal hematopoiesis Results of the observational AGO-TR1 trial

Author: Weber-Lassalle, Konstantin, Harter, Philipp, Hauke, Jan, Ernst, Corinna, Kommoss, Stefan, Marme, Frederik, Weber-Lassalle, Nana, Prieske, Katharina, Dietrich, Dimo, Borde, Julika, Pohl-Rescigno, Esther, Reuss, Alexander, Ataseven, Beyhan, Engel, Christoph, Stingl, Julia C., Schmutzler, Rita K., Hahnen, Eric, Weber-Lassalle, Konstantin, Harter, Philipp, Hauke, Jan, Ernst, Corinna, Kommoss, Stefan, Marme, Frederik, Weber-Lassalle, Nana, Prieske, Katharina, Dietrich, Dimo, Borde, Julika, Pohl-Rescigno, Esther, Reuss, Alexander, Ataseven, Beyhan, Engel, Christoph, Stingl, Julia C., Schmutzler, Rita K., and Hahnen, Eric
Abstract: The Li-Fraumeni cancer predisposition syndrome (LFS1) presents with a variety of tumor types and the TP53 gene is covered by most diagnostic cancer gene panels. We demonstrate that deleterious TP53 variants identified in blood-derived DNA of 523 patients with ovarian cancer (AGO-TR1 trial) were not causal for the patients' ovarian cancer in three out of six TP53-positive cases. In three out of six patients, deleterious TP53 mutations were identified with low variant fractions in blood-derived DNA but not in the tumor of the patient seeking advice. The analysis of the TP53 and PPM1D genes, both intimately involved in chemotherapy-induced and/or age-related clonal hematopoiesis (CH), in 523 patients and 1,053 age-matched female control individuals revealed that CH represents a frequent event following chemotherapy, affecting 26 of the 523 patients enrolled (5.0%). Considering that TP53 mutations may arise from chemotherapy-induced CH, our findings help to avoid false-positive genetic diagnoses of LFS1.
Published: 2018

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

Author: Rambau, Peter F, Vierkant, Robert A, Intermaggio, Maria P, Kelemen, Linda E, Goodman, Marc T, Herpel, Esther, Pharoah, Paul D, Kommoss, Stefan, Jimenez-Linan, Mercedes, Karlan, Beth Y, Gentry-Maharaj, Aleksandra, Menon, Usha, Polo, Susanna Hernando, Candido Dos Reis, Francisco J, Doherty, Jennifer Anne, Gayther, Simon A, Sharma, Raghwa, Larson, Melissa C, Harnett, Paul R, Hatfield, Emma, De Andrade, Jurandyr M, Nelson, Gregg S, Steed, Helen, Schildkraut, Joellen M, Carney, Micheal E, Høgdall, Estrid, Whittemore, Alice S, Widschwendter, Martin, Kennedy, Catherine J, Wang, Frances, Wang, Qin, Wang, Chen, Armasu, Sebastian M, Daley, Frances, Coulson, Penny, Jones, Micheal E, Anglesio, Micheal S, Chow, Christine, De Fazio, Anna, García-Closas, Montserrat, Brucker, Sara Y, Cybulski, Cezary, Harris, Holly R, Hartkopf, Andreas D, Huzarski, Tomasz, Jensen, Allan, Lubiński, Jan, Oszurek, Oleg, Benitez, Javier, Mina, Fady, Staebler, Annette, Taran, Florin Andrei, Pasternak, Jana, Talhouk, Aline, Rossing, Mary Anne, Hendley, Joy, Edwards, Robert P, Fereday, Sian, Modugno, Francesmary, Ness, Roberta B, Sieh, Weiva, El-Bahrawy, Mona A, Winham, Stacey J, Lester, Jenny, Kjaer, Susanne K, Gronwald, Jacek, Sinn, Peter, Fasching, Peter A, Chang-Claude, Jenny, Moysich, Kirsten B, Bowtell, David D, Hernandez, Brenda Y, Luk, Hugh, Behrens, Sabine, Shah, Mitul, Jung, Audrey, Ghatage, Prafull, Alsop, Jennifer, Alsop, Kathryn, García-Donas, Jesús, Thompson, Pamela J, Swerdlow, Anthony J, Karpinskyj, Chloe, Cazorla-Jiménez, Alicia, García, María J, Deen, Susha, Wilkens, Lynne R, Palacios, José, Berchuck, Andrew, Koziak, Jennifer M, Brenton, James D, Cook, Linda S, Goode, Ellen L, Huntsman, David G, Ramus, Susan J, Köbel, Martin, Rambau, Peter F, Vierkant, Robert A, Intermaggio, Maria P, Kelemen, Linda E, Goodman, Marc T, Herpel, Esther, Pharoah, Paul D, Kommoss, Stefan, Jimenez-Linan, Mercedes, Karlan, Beth Y, Gentry-Maharaj, Aleksandra, Menon, Usha, Polo, Susanna Hernando, Candido Dos Reis, Francisco J, Doherty, Jennifer Anne, Gayther, Simon A, Sharma, Raghwa, Larson, Melissa C, Harnett, Paul R, Hatfield, Emma, De Andrade, Jurandyr M, Nelson, Gregg S, Steed, Helen, Schildkraut, Joellen M, Carney, Micheal E, Høgdall, Estrid, Whittemore, Alice S, Widschwendter, Martin, Kennedy, Catherine J, Wang, Frances, Wang, Qin, Wang, Chen, Armasu, Sebastian M, Daley, Frances, Coulson, Penny, Jones, Micheal E, Anglesio, Micheal S, Chow, Christine, De Fazio, Anna, García-Closas, Montserrat, Brucker, Sara Y, Cybulski, Cezary, Harris, Holly R, Hartkopf, Andreas D, Huzarski, Tomasz, Jensen, Allan, Lubiński, Jan, Oszurek, Oleg, Benitez, Javier, Mina, Fady, Staebler, Annette, Taran, Florin Andrei, Pasternak, Jana, Talhouk, Aline, Rossing, Mary Anne, Hendley, Joy, Edwards, Robert P, Fereday, Sian, Modugno, Francesmary, Ness, Roberta B, Sieh, Weiva, El-Bahrawy, Mona A, Winham, Stacey J, Lester, Jenny, Kjaer, Susanne K, Gronwald, Jacek, Sinn, Peter, Fasching, Peter A, Chang-Claude, Jenny, Moysich, Kirsten B, Bowtell, David D, Hernandez, Brenda Y, Luk, Hugh, Behrens, Sabine, Shah, Mitul, Jung, Audrey, Ghatage, Prafull, Alsop, Jennifer, Alsop, Kathryn, García-Donas, Jesús, Thompson, Pamela J, Swerdlow, Anthony J, Karpinskyj, Chloe, Cazorla-Jiménez, Alicia, García, María J, Deen, Susha, Wilkens, Lynne R, Palacios, José, Berchuck, Andrew, Koziak, Jennifer M, Brenton, James D, Cook, Linda S, Goode, Ellen L, Huntsman, David G, Ramus, Susan J, and Köbel, Martin
Published: 2018

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

Author: Rambau, Peter F, Vierkant, Robert A, Intermaggio, Maria P, Kelemen, Linda E, Goodman, Marc T, Herpel, Esther, Pharoah, Paul D, Kommoss, Stefan, Jimenez-Linan, Mercedes, Karlan, Beth Y, Gentry-Maharaj, Aleksandra, Menon, Usha, Polo, Susanna Hernando, Candido Dos Reis, Francisco J, Doherty, Jennifer Anne, Gayther, Simon A, Sharma, Raghwa, Larson, Melissa C, Harnett, Paul R, Hatfield, Emma, De Andrade, Jurandyr M, Nelson, Gregg S, Steed, Helen, Schildkraut, Joellen M, Carney, Micheal E, Høgdall, Estrid, Whittemore, Alice S, Widschwendter, Martin, Kennedy, Catherine J, Wang, Frances, Wang, Qin, Wang, Chen, Armasu, Sebastian M, Daley, Frances, Coulson, Penny, Jones, Micheal E, Anglesio, Micheal S, Chow, Christine, De Fazio, Anna, García-Closas, Montserrat, Brucker, Sara Y, Cybulski, Cezary, Harris, Holly R, Hartkopf, Andreas D, Huzarski, Tomasz, Jensen, Allan, Lubiński, Jan, Oszurek, Oleg, Benitez, Javier, Mina, Fady, Staebler, Annette, Taran, Florin Andrei, Pasternak, Jana, Talhouk, Aline, Rossing, Mary Anne, Hendley, Joy, Edwards, Robert P, Fereday, Sian, Modugno, Francesmary, Ness, Roberta B, Sieh, Weiva, El-Bahrawy, Mona A, Winham, Stacey J, Lester, Jenny, Kjaer, Susanne K, Gronwald, Jacek, Sinn, Peter, Fasching, Peter A, Chang-Claude, Jenny, Moysich, Kirsten B, Bowtell, David D, Hernandez, Brenda Y, Luk, Hugh, Behrens, Sabine, Shah, Mitul, Jung, Audrey, Ghatage, Prafull, Alsop, Jennifer, Alsop, Kathryn, García-Donas, Jesús, Thompson, Pamela J, Swerdlow, Anthony J, Karpinskyj, Chloe, Cazorla-Jiménez, Alicia, García, María J, Deen, Susha, Wilkens, Lynne R, Palacios, José, Berchuck, Andrew, Koziak, Jennifer M, Brenton, James D, Cook, Linda S, Goode, Ellen L, Huntsman, David G, Ramus, Susan J, Köbel, Martin, Rambau, Peter F, Vierkant, Robert A, Intermaggio, Maria P, Kelemen, Linda E, Goodman, Marc T, Herpel, Esther, Pharoah, Paul D, Kommoss, Stefan, Jimenez-Linan, Mercedes, Karlan, Beth Y, Gentry-Maharaj, Aleksandra, Menon, Usha, Polo, Susanna Hernando, Candido Dos Reis, Francisco J, Doherty, Jennifer Anne, Gayther, Simon A, Sharma, Raghwa, Larson, Melissa C, Harnett, Paul R, Hatfield, Emma, De Andrade, Jurandyr M, Nelson, Gregg S, Steed, Helen, Schildkraut, Joellen M, Carney, Micheal E, Høgdall, Estrid, Whittemore, Alice S, Widschwendter, Martin, Kennedy, Catherine J, Wang, Frances, Wang, Qin, Wang, Chen, Armasu, Sebastian M, Daley, Frances, Coulson, Penny, Jones, Micheal E, Anglesio, Micheal S, Chow, Christine, De Fazio, Anna, García-Closas, Montserrat, Brucker, Sara Y, Cybulski, Cezary, Harris, Holly R, Hartkopf, Andreas D, Huzarski, Tomasz, Jensen, Allan, Lubiński, Jan, Oszurek, Oleg, Benitez, Javier, Mina, Fady, Staebler, Annette, Taran, Florin Andrei, Pasternak, Jana, Talhouk, Aline, Rossing, Mary Anne, Hendley, Joy, Edwards, Robert P, Fereday, Sian, Modugno, Francesmary, Ness, Roberta B, Sieh, Weiva, El-Bahrawy, Mona A, Winham, Stacey J, Lester, Jenny, Kjaer, Susanne K, Gronwald, Jacek, Sinn, Peter, Fasching, Peter A, Chang-Claude, Jenny, Moysich, Kirsten B, Bowtell, David D, Hernandez, Brenda Y, Luk, Hugh, Behrens, Sabine, Shah, Mitul, Jung, Audrey, Ghatage, Prafull, Alsop, Jennifer, Alsop, Kathryn, García-Donas, Jesús, Thompson, Pamela J, Swerdlow, Anthony J, Karpinskyj, Chloe, Cazorla-Jiménez, Alicia, García, María J, Deen, Susha, Wilkens, Lynne R, Palacios, José, Berchuck, Andrew, Koziak, Jennifer M, Brenton, James D, Cook, Linda S, Goode, Ellen L, Huntsman, David G, Ramus, Susan J, and Köbel, Martin
Published: 2018

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

Author: Ovarian Tumor Tissue Analysis (OTTA) Consortium, Ovarian Tumor Tissue Analysis (OTTA) Consortium, Goode, Ellen L, Block, Matthew S, Kalli, Kimberly R, Vierkant, Robert A, Chen, Wenqian, Fogarty, Zachary C, Gentry-Maharaj, Aleksandra, Tołoczko, Aleksandra, Hein, Alexander, Bouligny, Aliecia L, Jensen, Allan, Osorio, Ana, Hartkopf, Andreas, Ryan, Andy, Chudecka-Głaz, Anita, Magliocco, Anthony M, Hartmann, Arndt, Jung, Audrey Y, Gao, Bo, Hernandez, Brenda Y, Fridley, Brooke L, McCauley, Bryan M, Kennedy, Catherine J, Wang, Chen, Karpinskyj, Chloe, de Sousa, Christiani B, Tiezzi, Daniel G, Wachter, David L, Herpel, Esther, Taran, Florin Andrei, Modugno, Francesmary, Nelson, Gregg, Lubiński, Jan, Menkiszak, Janusz, Alsop, Jennifer, Lester, Jenny, García-Donas, Jesús, Nation, Jill, Hung, Jillian, Palacios, José, Rothstein, Joseph H, Kelley, Joseph L, de Andrade, Jurandyr M, Robles-Díaz, Luis, Intermaggio, Maria P, Widschwendter, Martin, Beckmann, Matthias W, Ruebner, Matthias, Jimenez-Linan, Mercedes, Singh, Naveena, Oszurek, Oleg, Harnett, Paul R, Rambau, Peter F, Sinn, Peter, Wagner, Philipp, Ghatage, Prafull, Sharma, Raghwa, Edwards, Robert P, Ness, Roberta B, Orsulic, Sandra, Brucker, Sara Y, Johnatty, Sharon E, Longacre, Teri A, Ursula, Eilber, McGuire, Valerie, Sieh, Weiva, Natanzon, Yanina, Li, Zheng, Whittemore, Alice S, Anna, deFazio, Staebler, Annette, Karlan, Beth Y, Gilks, Blake, Bowtell, David D, Høgdall, Estrid, Candido dos Reis, Francisco J, Steed, Helen, Campbell, Ian G, Gronwald, Jacek, Benítez, Javier, Koziak, Jennifer M, Chang-Claude, Jenny, Moysich, Kirsten B, Kelemen, Linda E, Cook, Linda S, Goodman, Marc T, García, María José, Fasching, Peter A, Kommoss, Stefan, Deen, Suha, Kjaer, Susanne K, Menon, Usha, Brenton, James D, Pharoah, Paul DP, Chenevix-Trench, Georgia, Huntsman, David G, Winham, Stacey J, Köbel, Martin, Ramus, Susan J, Ovarian Tumor Tissue Analysis (OTTA) Consortium, Ovarian Tumor Tissue Analysis (OTTA) Consortium, Goode, Ellen L, Block, Matthew S, Kalli, Kimberly R, Vierkant, Robert A, Chen, Wenqian, Fogarty, Zachary C, Gentry-Maharaj, Aleksandra, Tołoczko, Aleksandra, Hein, Alexander, Bouligny, Aliecia L, Jensen, Allan, Osorio, Ana, Hartkopf, Andreas, Ryan, Andy, Chudecka-Głaz, Anita, Magliocco, Anthony M, Hartmann, Arndt, Jung, Audrey Y, Gao, Bo, Hernandez, Brenda Y, Fridley, Brooke L, McCauley, Bryan M, Kennedy, Catherine J, Wang, Chen, Karpinskyj, Chloe, de Sousa, Christiani B, Tiezzi, Daniel G, Wachter, David L, Herpel, Esther, Taran, Florin Andrei, Modugno, Francesmary, Nelson, Gregg, Lubiński, Jan, Menkiszak, Janusz, Alsop, Jennifer, Lester, Jenny, García-Donas, Jesús, Nation, Jill, Hung, Jillian, Palacios, José, Rothstein, Joseph H, Kelley, Joseph L, de Andrade, Jurandyr M, Robles-Díaz, Luis, Intermaggio, Maria P, Widschwendter, Martin, Beckmann, Matthias W, Ruebner, Matthias, Jimenez-Linan, Mercedes, Singh, Naveena, Oszurek, Oleg, Harnett, Paul R, Rambau, Peter F, Sinn, Peter, Wagner, Philipp, Ghatage, Prafull, Sharma, Raghwa, Edwards, Robert P, Ness, Roberta B, Orsulic, Sandra, Brucker, Sara Y, Johnatty, Sharon E, Longacre, Teri A, Ursula, Eilber, McGuire, Valerie, Sieh, Weiva, Natanzon, Yanina, Li, Zheng, Whittemore, Alice S, Anna, deFazio, Staebler, Annette, Karlan, Beth Y, Gilks, Blake, Bowtell, David D, Høgdall, Estrid, Candido dos Reis, Francisco J, Steed, Helen, Campbell, Ian G, Gronwald, Jacek, Benítez, Javier, Koziak, Jennifer M, Chang-Claude, Jenny, Moysich, Kirsten B, Kelemen, Linda E, Cook, Linda S, Goodman, Marc T, García, María José, Fasching, Peter A, Kommoss, Stefan, Deen, Suha, Kjaer, Susanne K, Menon, Usha, Brenton, James D, Pharoah, Paul DP, Chenevix-Trench, Georgia, Huntsman, David G, Winham, Stacey J, Köbel, Martin, and Ramus, Susan J
Abstract: ImportanceCytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors.ObjectiveTo define the prognostic role of CD8+ TILs in epithelial ovarian cancer.Design, setting, and participantsThis was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years.ExposuresFollowing immunohistochemical analysis, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (≥20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines.Main outcomes and measuresOverall survival time.ResultsThe final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (P value for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+
Published: 2017

35. Prevalence of deleterious germline variants in risk genes including BRCA1/2 in consecutive ovarian cancer patients (AGO-TR-1)

Author: Harter, Philipp, Hauke, Jan, Heitz, Florian, Reuss, Alexander, Kommoss, Stefan, Marme, Frederik, Heimbach, Andre, Prieske, Katharina, Richters, Lisa, Burges, Alexander, Neidhardt, Guido, de Gregorio, Nikolaus, El-Balat, Ahmed, Hilpert, Felix, Meier, Werner, Kimmig, Rainer, Kast, Karin, Sehouli, Jalid, Baumann, Klaus, Jackisch, Christian, Park-Simon, Tjoung-Won, Hanker, Lars, Kroeber, Sandra, Pfisterer, Jacobus, Gevensleben, Heidrun, Schnelzer, Andreas, Dietrich, Dimo, Neunhoeffer, Tanja, Krockenberger, Mathias, Brucker, Sara Y., Nuernberg, Peter, Thiele, Holger, Altmueller, Janine, Lamla, Josefin, Elser, Gabriele, du Bois, Andreas, Hahnen, Eric, Schmutzler, Rita, Harter, Philipp, Hauke, Jan, Heitz, Florian, Reuss, Alexander, Kommoss, Stefan, Marme, Frederik, Heimbach, Andre, Prieske, Katharina, Richters, Lisa, Burges, Alexander, Neidhardt, Guido, de Gregorio, Nikolaus, El-Balat, Ahmed, Hilpert, Felix, Meier, Werner, Kimmig, Rainer, Kast, Karin, Sehouli, Jalid, Baumann, Klaus, Jackisch, Christian, Park-Simon, Tjoung-Won, Hanker, Lars, Kroeber, Sandra, Pfisterer, Jacobus, Gevensleben, Heidrun, Schnelzer, Andreas, Dietrich, Dimo, Neunhoeffer, Tanja, Krockenberger, Mathias, Brucker, Sara Y., Nuernberg, Peter, Thiele, Holger, Altmueller, Janine, Lamla, Josefin, Elser, Gabriele, du Bois, Andreas, Hahnen, Eric, and Schmutzler, Rita
Abstract: Background Identification of families at risk for ovarian cancer offers the opportunity to consider prophylactic surgery thus reducing ovarian cancer mortality. So far, identification of potentially affected families in Germany was solely performed via family history and numbers of affected family members with breast or ovarian cancer. However, neither the prevalence of deleterious variants in BRCA1/2 in ovarian cancer in Germany nor the reliability of family history as trigger for genetic counselling has ever been evaluated. Methods Prospective counseling and germline testing of consecutive patients with primary diagnosis or with platinum-sensitive relapse of an invasive epithelial ovarian cancer. Testing included 25 candidate and established risk genes. Among these 25 genes, 16 genes (ATM, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, NBN, PMS2, PTEN, PALB2, RAD51C, RAD51D, STK11, TP53) were defined as established cancer risk genes. A positive family history was defined as at least one relative with breast cancer or ovarian cancer or breast cancer in personal history. Results In total, we analyzed 523 patients: 281 patients with primary diagnosis of ovarian cancer and 242 patients with relapsed disease. Median age at primary diagnosis was 58 years (range 16-93) and 406 patients (77.6%) had a high-grade serous ovarian cancer. In total, 27.9% of the patients showed at least one deleterious variant in all 25 investigated genes and 26.4% in the defined 16 risk genes. Deleterious variants were most prevalent in the BRCA1 (15.5%), BRCA2 (5.5%), RAD51C (2.5%) and PALB2 (1.1%) genes. The prevalence of deleterious variants did not differ significantly between patients at primary diagnosis and relapse. The prevalence of deleterious variants in BRCA1/2 (and in all 16 risk genes) in patients <60 years was 30.2% (33.2%) versus 10.6% (18.9%) in patients >= 60 years. Family history was positive in 43% of all patients. Patients with a positive family history had a prevalence of de
Published: 2017

36. BRCA-like classification in ovarian cancer: Results from the AGO-TRi-trial.

Author: Richters, Lisa Katharina, Schouten, Philip C., Kommoss, Stefan, Hauke, Jan, Burges, Alexander, Dietrich, Dimo, Ei-Balat, Ahmed, Hilpert, Felix, Kluin, Roel, Heubner, Martin Leonhard, Kast, Karin, Heimbach, Andre, Braicu, Elena Ioana, Schmidt, Sandra, Baumann, Klaus H., Jackisch, Christian, Linn, Sabine C., Schmutzler, Rita K., Harter, Philipp, Hahnen, Eric, Richters, Lisa Katharina, Schouten, Philip C., Kommoss, Stefan, Hauke, Jan, Burges, Alexander, Dietrich, Dimo, Ei-Balat, Ahmed, Hilpert, Felix, Kluin, Roel, Heubner, Martin Leonhard, Kast, Karin, Heimbach, Andre, Braicu, Elena Ioana, Schmidt, Sandra, Baumann, Klaus H., Jackisch, Christian, Linn, Sabine C., Schmutzler, Rita K., Harter, Philipp, and Hahnen, Eric
Published: 2017

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

Author: Ovarian Tumor Tissue Analysis (OTTA) Consortium, Ovarian Tumor Tissue Analysis (OTTA) Consortium, Goode, Ellen L, Block, Matthew S, Kalli, Kimberly R, Vierkant, Robert A, Chen, Wenqian, Fogarty, Zachary C, Gentry-Maharaj, Aleksandra, Tołoczko, Aleksandra, Hein, Alexander, Bouligny, Aliecia L, Jensen, Allan, Osorio, Ana, Hartkopf, Andreas, Ryan, Andy, Chudecka-Głaz, Anita, Magliocco, Anthony M, Hartmann, Arndt, Jung, Audrey Y, Gao, Bo, Hernandez, Brenda Y, Fridley, Brooke L, McCauley, Bryan M, Kennedy, Catherine J, Wang, Chen, Karpinskyj, Chloe, de Sousa, Christiani B, Tiezzi, Daniel G, Wachter, David L, Herpel, Esther, Taran, Florin Andrei, Modugno, Francesmary, Nelson, Gregg, Lubiński, Jan, Menkiszak, Janusz, Alsop, Jennifer, Lester, Jenny, García-Donas, Jesús, Nation, Jill, Hung, Jillian, Palacios, José, Rothstein, Joseph H, Kelley, Joseph L, de Andrade, Jurandyr M, Robles-Díaz, Luis, Intermaggio, Maria P, Widschwendter, Martin, Beckmann, Matthias W, Ruebner, Matthias, Jimenez-Linan, Mercedes, Singh, Naveena, Oszurek, Oleg, Harnett, Paul R, Rambau, Peter F, Sinn, Peter, Wagner, Philipp, Ghatage, Prafull, Sharma, Raghwa, Edwards, Robert P, Ness, Roberta B, Orsulic, Sandra, Brucker, Sara Y, Johnatty, Sharon E, Longacre, Teri A, Ursula, Eilber, McGuire, Valerie, Sieh, Weiva, Natanzon, Yanina, Li, Zheng, Whittemore, Alice S, Anna, deFazio, Staebler, Annette, Karlan, Beth Y, Gilks, Blake, Bowtell, David D, Høgdall, Estrid, Candido dos Reis, Francisco J, Steed, Helen, Campbell, Ian G, Gronwald, Jacek, Benítez, Javier, Koziak, Jennifer M, Chang-Claude, Jenny, Moysich, Kirsten B, Kelemen, Linda E, Cook, Linda S, Goodman, Marc T, García, María José, Fasching, Peter A, Kommoss, Stefan, Deen, Suha, Kjaer, Susanne K, Menon, Usha, Brenton, James D, Pharoah, Paul DP, Chenevix-Trench, Georgia, Huntsman, David G, Winham, Stacey J, Köbel, Martin, Ramus, Susan J, Ovarian Tumor Tissue Analysis (OTTA) Consortium, Ovarian Tumor Tissue Analysis (OTTA) Consortium, Goode, Ellen L, Block, Matthew S, Kalli, Kimberly R, Vierkant, Robert A, Chen, Wenqian, Fogarty, Zachary C, Gentry-Maharaj, Aleksandra, Tołoczko, Aleksandra, Hein, Alexander, Bouligny, Aliecia L, Jensen, Allan, Osorio, Ana, Hartkopf, Andreas, Ryan, Andy, Chudecka-Głaz, Anita, Magliocco, Anthony M, Hartmann, Arndt, Jung, Audrey Y, Gao, Bo, Hernandez, Brenda Y, Fridley, Brooke L, McCauley, Bryan M, Kennedy, Catherine J, Wang, Chen, Karpinskyj, Chloe, de Sousa, Christiani B, Tiezzi, Daniel G, Wachter, David L, Herpel, Esther, Taran, Florin Andrei, Modugno, Francesmary, Nelson, Gregg, Lubiński, Jan, Menkiszak, Janusz, Alsop, Jennifer, Lester, Jenny, García-Donas, Jesús, Nation, Jill, Hung, Jillian, Palacios, José, Rothstein, Joseph H, Kelley, Joseph L, de Andrade, Jurandyr M, Robles-Díaz, Luis, Intermaggio, Maria P, Widschwendter, Martin, Beckmann, Matthias W, Ruebner, Matthias, Jimenez-Linan, Mercedes, Singh, Naveena, Oszurek, Oleg, Harnett, Paul R, Rambau, Peter F, Sinn, Peter, Wagner, Philipp, Ghatage, Prafull, Sharma, Raghwa, Edwards, Robert P, Ness, Roberta B, Orsulic, Sandra, Brucker, Sara Y, Johnatty, Sharon E, Longacre, Teri A, Ursula, Eilber, McGuire, Valerie, Sieh, Weiva, Natanzon, Yanina, Li, Zheng, Whittemore, Alice S, Anna, deFazio, Staebler, Annette, Karlan, Beth Y, Gilks, Blake, Bowtell, David D, Høgdall, Estrid, Candido dos Reis, Francisco J, Steed, Helen, Campbell, Ian G, Gronwald, Jacek, Benítez, Javier, Koziak, Jennifer M, Chang-Claude, Jenny, Moysich, Kirsten B, Kelemen, Linda E, Cook, Linda S, Goodman, Marc T, García, María José, Fasching, Peter A, Kommoss, Stefan, Deen, Suha, Kjaer, Susanne K, Menon, Usha, Brenton, James D, Pharoah, Paul DP, Chenevix-Trench, Georgia, Huntsman, David G, Winham, Stacey J, Köbel, Martin, and Ramus, Susan J
Abstract: ImportanceCytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors.ObjectiveTo define the prognostic role of CD8+ TILs in epithelial ovarian cancer.Design, setting, and participantsThis was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years.ExposuresFollowing immunohistochemical analysis, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (≥20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines.Main outcomes and measuresOverall survival time.ResultsThe final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (P value for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+
Published: 2017

38. BRCA-like classification in ovarian cancer: Results from the AGO-TRi-trial.

Author: Richters, Lisa Katharina, Schouten, Philip C., Kommoss, Stefan, Hauke, Jan, Burges, Alexander, Dietrich, Dimo, Ei-Balat, Ahmed, Hilpert, Felix, Kluin, Roel, Heubner, Martin Leonhard, Kast, Karin, Heimbach, Andre, Braicu, Elena Ioana, Schmidt, Sandra, Baumann, Klaus H., Jackisch, Christian, Linn, Sabine C., Schmutzler, Rita K., Harter, Philipp, Hahnen, Eric, Richters, Lisa Katharina, Schouten, Philip C., Kommoss, Stefan, Hauke, Jan, Burges, Alexander, Dietrich, Dimo, Ei-Balat, Ahmed, Hilpert, Felix, Kluin, Roel, Heubner, Martin Leonhard, Kast, Karin, Heimbach, Andre, Braicu, Elena Ioana, Schmidt, Sandra, Baumann, Klaus H., Jackisch, Christian, Linn, Sabine C., Schmutzler, Rita K., Harter, Philipp, and Hahnen, Eric
Published: 2017

39. Prevalence of deleterious germline variants in risk genes including BRCA1/2 in consecutive ovarian cancer patients (AGO-TR-1)

Author: Harter, Philipp, Hauke, Jan, Heitz, Florian, Reuss, Alexander, Kommoss, Stefan, Marme, Frederik, Heimbach, Andre, Prieske, Katharina, Richters, Lisa, Burges, Alexander, Neidhardt, Guido, de Gregorio, Nikolaus, El-Balat, Ahmed, Hilpert, Felix, Meier, Werner, Kimmig, Rainer, Kast, Karin, Sehouli, Jalid, Baumann, Klaus, Jackisch, Christian, Park-Simon, Tjoung-Won, Hanker, Lars, Kroeber, Sandra, Pfisterer, Jacobus, Gevensleben, Heidrun, Schnelzer, Andreas, Dietrich, Dimo, Neunhoeffer, Tanja, Krockenberger, Mathias, Brucker, Sara Y., Nuernberg, Peter, Thiele, Holger, Altmueller, Janine, Lamla, Josefin, Elser, Gabriele, du Bois, Andreas, Hahnen, Eric, Schmutzler, Rita, Harter, Philipp, Hauke, Jan, Heitz, Florian, Reuss, Alexander, Kommoss, Stefan, Marme, Frederik, Heimbach, Andre, Prieske, Katharina, Richters, Lisa, Burges, Alexander, Neidhardt, Guido, de Gregorio, Nikolaus, El-Balat, Ahmed, Hilpert, Felix, Meier, Werner, Kimmig, Rainer, Kast, Karin, Sehouli, Jalid, Baumann, Klaus, Jackisch, Christian, Park-Simon, Tjoung-Won, Hanker, Lars, Kroeber, Sandra, Pfisterer, Jacobus, Gevensleben, Heidrun, Schnelzer, Andreas, Dietrich, Dimo, Neunhoeffer, Tanja, Krockenberger, Mathias, Brucker, Sara Y., Nuernberg, Peter, Thiele, Holger, Altmueller, Janine, Lamla, Josefin, Elser, Gabriele, du Bois, Andreas, Hahnen, Eric, and Schmutzler, Rita
Abstract: Background Identification of families at risk for ovarian cancer offers the opportunity to consider prophylactic surgery thus reducing ovarian cancer mortality. So far, identification of potentially affected families in Germany was solely performed via family history and numbers of affected family members with breast or ovarian cancer. However, neither the prevalence of deleterious variants in BRCA1/2 in ovarian cancer in Germany nor the reliability of family history as trigger for genetic counselling has ever been evaluated. Methods Prospective counseling and germline testing of consecutive patients with primary diagnosis or with platinum-sensitive relapse of an invasive epithelial ovarian cancer. Testing included 25 candidate and established risk genes. Among these 25 genes, 16 genes (ATM, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, NBN, PMS2, PTEN, PALB2, RAD51C, RAD51D, STK11, TP53) were defined as established cancer risk genes. A positive family history was defined as at least one relative with breast cancer or ovarian cancer or breast cancer in personal history. Results In total, we analyzed 523 patients: 281 patients with primary diagnosis of ovarian cancer and 242 patients with relapsed disease. Median age at primary diagnosis was 58 years (range 16-93) and 406 patients (77.6%) had a high-grade serous ovarian cancer. In total, 27.9% of the patients showed at least one deleterious variant in all 25 investigated genes and 26.4% in the defined 16 risk genes. Deleterious variants were most prevalent in the BRCA1 (15.5%), BRCA2 (5.5%), RAD51C (2.5%) and PALB2 (1.1%) genes. The prevalence of deleterious variants did not differ significantly between patients at primary diagnosis and relapse. The prevalence of deleterious variants in BRCA1/2 (and in all 16 risk genes) in patients <60 years was 30.2% (33.2%) versus 10.6% (18.9%) in patients >= 60 years. Family history was positive in 43% of all patients. Patients with a positive family history had a prevalence of de
Published: 2017

40. Prevalence of deleterious germline variants in risk genes including BRCA1/2 in consecutive ovarian cancer patients (AGO-TR-1)

Author: Galli, Alvaro, Harter, Philipp, Hauke, Jan, Heitz, Florian, Reuss, Alexander, Kommoss, Stefan, Marmé, Frederik, Heimbach, André, Prieske, Katharina, Richters, Lisa, Burges, Alexander, Neidhardt, Guido, Gregorio, Nikolaus de, Balat, Ahmed el, Hilpert, Felix, Meier, Werner, Kimmig, Rainer, Kast, Karin, Sehouli, Jalid, Baumann, Klaus, Jackisch, Christian, Park-Simon, Tjoung-Won, Hanker, Lars, Kröber, Sandra, Pfisterer, Jacobus, Gevensleben, Heidrun, Schnelzer, Andreas, Dietrich, Dimo, Neunhöffer, Tanja, Krockenberger, Mathias Heinric, Brucker, Sara, Nürnberg, Peter, Thiele, Holger, Altmüller, Janine, Lamla, Josefin, Elser, Gabriele, Du Bois, Andreas, Hahnen, Eric Thomas, Schmutzler, Rita Katharina, Galli, Alvaro, Harter, Philipp, Hauke, Jan, Heitz, Florian, Reuss, Alexander, Kommoss, Stefan, Marmé, Frederik, Heimbach, André, Prieske, Katharina, Richters, Lisa, Burges, Alexander, Neidhardt, Guido, Gregorio, Nikolaus de, Balat, Ahmed el, Hilpert, Felix, Meier, Werner, Kimmig, Rainer, Kast, Karin, Sehouli, Jalid, Baumann, Klaus, Jackisch, Christian, Park-Simon, Tjoung-Won, Hanker, Lars, Kröber, Sandra, Pfisterer, Jacobus, Gevensleben, Heidrun, Schnelzer, Andreas, Dietrich, Dimo, Neunhöffer, Tanja, Krockenberger, Mathias Heinric, Brucker, Sara, Nürnberg, Peter, Thiele, Holger, Altmüller, Janine, Lamla, Josefin, Elser, Gabriele, Du Bois, Andreas, Hahnen, Eric Thomas, and Schmutzler, Rita Katharina
Abstract: Background: Identification of families at risk for ovarian cancer offers the opportunity to consider prophylactic surgery thus reducing ovarian cancer mortality. So far, identification of potentially affected families in Germany was solely performed via family history and numbers of affected family members with breast or ovarian cancer. However, neither the prevalence of deleterious variants in BRCA1/2 in ovarian cancer in Germany nor the reliability of family history as trigger for genetic counselling has ever been evaluated. Methods: Prospective counseling and germline testing of consecutive patients with primary diagnosis or with platinum-sensitive relapse of an invasive epithelial ovarian cancer. Testing included 25 candidate and established risk genes. Among these 25 genes, 16 genes (ATM, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, NBN, PMS2, PTEN, PALB2, RAD51C, RAD51D, STK11, TP53) were defined as established cancer risk genes. A positive family history was defined as at least one relative with breast cancer or ovarian cancer or breast cancer in personal history. Results: In total, we analyzed 523 patients: 281 patients with primary diagnosis of ovarian cancer and 242 patients with relapsed disease. Median age at primary diagnosis was 58 years (range 16–93) and 406 patients (77.6%) had a high-grade serous ovarian cancer. In total, 27.9% of the patients showed at least one deleterious variant in all 25 investigated genes and 26.4% in the defined 16 risk genes. Deleterious variants were most prevalent in the BRCA1 (15.5%), BRCA2 (5.5%), RAD51C (2.5%) and PALB2 (1.1%) genes. The prevalence of deleterious variants did not differ significantly between patients at primary diagnosis and relapse. The prevalence of deleterious variants in BRCA1/2 (and in all 16 risk genes) in patients <60 years was 30.2% (33.2%) versus 10.6% (18.9%) in patients ≥60 years. Family history was positive in 43% of all patients. Patients with a positive family history had a prevalence of d
Published: 2017

41. Incidence of gernnline mutations in risk genes including BRCA1/2 in consecutive ovarian cancer (OC) patients (AGO TR-1).

Author: Harter, Philipp, Hauke, Jan, Heitz, Florian, Reuss, Alexander, Kommoss, Stefan, Marme, Frederik, Heimbach, Andre, Prieske, Katharina, Richters, Lisa Katharina, Burges, Alexander, Neidhardt, Guido, de Gregorio, Nikolaus, El-Balat, Ahmed, Hilpert, Felix, Meier, Werner, Heubner, Martin Leonhard, Kast, Karin, Braicu, Ioana, Hahnen, Eric, Schmutzler, Rita K., Harter, Philipp, Hauke, Jan, Heitz, Florian, Reuss, Alexander, Kommoss, Stefan, Marme, Frederik, Heimbach, Andre, Prieske, Katharina, Richters, Lisa Katharina, Burges, Alexander, Neidhardt, Guido, de Gregorio, Nikolaus, El-Balat, Ahmed, Hilpert, Felix, Meier, Werner, Heubner, Martin Leonhard, Kast, Karin, Braicu, Ioana, Hahnen, Eric, and Schmutzler, Rita K.
Published: 2016

42. Prevalence of somatic mutations in risk genes including BRCA1/2 in consecutive ovarian cancer patients (AGO-TR-1 study).

Author: Hahnen, Eric, Baumann, Klaus H., Heimbach, Andre, Reuss, Alexander, Jackisch, Christian, Hauke, Jan, Park-Simon, Tjoung-Won, Richters, Lisa Katharina, Hanker, Lars Christian, Kroeber, Sandra, Pfisterer, Jacobus, Gevensleben, Heidrun, Schnelzer, Andreas, Dietrich, Dimo, Schneider, Stephanie, Kommoss, Stefan, Marme, Frederic, Prieske, Katharina, Schmutzler, Rita K., Harter, Philipp, Hahnen, Eric, Baumann, Klaus H., Heimbach, Andre, Reuss, Alexander, Jackisch, Christian, Hauke, Jan, Park-Simon, Tjoung-Won, Richters, Lisa Katharina, Hanker, Lars Christian, Kroeber, Sandra, Pfisterer, Jacobus, Gevensleben, Heidrun, Schnelzer, Andreas, Dietrich, Dimo, Schneider, Stephanie, Kommoss, Stefan, Marme, Frederic, Prieske, Katharina, Schmutzler, Rita K., and Harter, Philipp
Published: 2016

43. USP14 is a predictor of recurrence in endometrial cancer and a molecular target for endometrial cancer treatment.

Author: Vogel, Rachel Isaksson, Vogel, Rachel Isaksson, Pulver, Tanya, Heilmann, Wiebke, Mooneyham, Ashley, Mullany, Sally, Zhao, Xianda, Shahi, Maryam, Richter, James, Klein, Molly, Chen, Liqiang, Ding, Rui, Konecny, Gottfried, Kommoss, Stefan, Winterhoff, Boris, Ghebre, Rahel, Bazzaro, Martina, Vogel, Rachel Isaksson, Vogel, Rachel Isaksson, Pulver, Tanya, Heilmann, Wiebke, Mooneyham, Ashley, Mullany, Sally, Zhao, Xianda, Shahi, Maryam, Richter, James, Klein, Molly, Chen, Liqiang, Ding, Rui, Konecny, Gottfried, Kommoss, Stefan, Winterhoff, Boris, Ghebre, Rahel, and Bazzaro, Martina
Abstract: Endometrial adenocarcinoma is the most common gynecologic malignancy in the United States. Most endometrial cancer cases are diagnosed at an early stage and have good prognosis. Unfortunately a subset of patients with early stage and low grade disease experience recurrence for reasons that remain unclear. Recurrence is often accompanied by chemoresistance and high mortality.Deubiquitinating enzymes (DUBs) are key components of the ubiquitin-dependent protein degradation pathway and act as master regulators in a number of metabolic processes including cell growth, differentiation, and apoptosis. DUBs have been shown to be upregulated in a number of human cancers and their aberrant activity has been linked to cancer progression, initiation and onset of chemoresistance. Thus, selective inhibition of DUBs has been proposed as a targeted therapy for cancer treatment.This study suggests the DUB USP14 as a promising biomarker for stratifying endometrial cancer patients at diagnosis based on their risk of recurrence. Further USP14 is expressed along with the marker of proliferation Ki67 in endometrial cancer cells in situ. Lastly, pharmacological targeting of USP14 with the FDA approved small-molecule inhibitor VLX1570, decreases cell viability in chemotherapy resistant endometrial cancer cells with a mechanism consistent with cell cycle arrest and caspase-3 mediated apoptosis.
Published: 2016

44. Prevalence of somatic mutations in risk genes including BRCA1/2 in consecutive ovarian cancer patients (AGO-TR-1 study).

Author: Hahnen, Eric, Baumann, Klaus H., Heimbach, Andre, Reuss, Alexander, Jackisch, Christian, Hauke, Jan, Park-Simon, Tjoung-Won, Richters, Lisa Katharina, Hanker, Lars Christian, Kroeber, Sandra, Pfisterer, Jacobus, Gevensleben, Heidrun, Schnelzer, Andreas, Dietrich, Dimo, Schneider, Stephanie, Kommoss, Stefan, Marme, Frederic, Prieske, Katharina, Schmutzler, Rita K., Harter, Philipp, Hahnen, Eric, Baumann, Klaus H., Heimbach, Andre, Reuss, Alexander, Jackisch, Christian, Hauke, Jan, Park-Simon, Tjoung-Won, Richters, Lisa Katharina, Hanker, Lars Christian, Kroeber, Sandra, Pfisterer, Jacobus, Gevensleben, Heidrun, Schnelzer, Andreas, Dietrich, Dimo, Schneider, Stephanie, Kommoss, Stefan, Marme, Frederic, Prieske, Katharina, Schmutzler, Rita K., and Harter, Philipp
Published: 2016

45. Incidence of gernnline mutations in risk genes including BRCA1/2 in consecutive ovarian cancer (OC) patients (AGO TR-1).

Author: Harter, Philipp, Hauke, Jan, Heitz, Florian, Reuss, Alexander, Kommoss, Stefan, Marme, Frederik, Heimbach, Andre, Prieske, Katharina, Richters, Lisa Katharina, Burges, Alexander, Neidhardt, Guido, de Gregorio, Nikolaus, El-Balat, Ahmed, Hilpert, Felix, Meier, Werner, Heubner, Martin Leonhard, Kast, Karin, Braicu, Ioana, Hahnen, Eric, Schmutzler, Rita K., Harter, Philipp, Hauke, Jan, Heitz, Florian, Reuss, Alexander, Kommoss, Stefan, Marme, Frederik, Heimbach, Andre, Prieske, Katharina, Richters, Lisa Katharina, Burges, Alexander, Neidhardt, Guido, de Gregorio, Nikolaus, El-Balat, Ahmed, Hilpert, Felix, Meier, Werner, Heubner, Martin Leonhard, Kast, Karin, Braicu, Ioana, Hahnen, Eric, and Schmutzler, Rita K.
Published: 2016

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

Author: Mackenzie, Robertson, Mackenzie, Robertson, Kommoss, Stefan, Winterhoff, Boris J, Kipp, Benjamin R, Garcia, Joaquin J, Voss, Jesse, Halling, Kevin, Karnezis, Anthony, Senz, Janine, Yang, Winnie, Prigge, Elena-Sophie, Reuschenbach, Miriam, Doeberitz, Magnus Von Knebel, Gilks, Blake C, Huntsman, David G, Bakkum-Gamez, Jamie, McAlpine, Jessica N, Anglesio, Michael S, Mackenzie, Robertson, Mackenzie, Robertson, Kommoss, Stefan, Winterhoff, Boris J, Kipp, Benjamin R, Garcia, Joaquin J, Voss, Jesse, Halling, Kevin, Karnezis, Anthony, Senz, Janine, Yang, Winnie, Prigge, Elena-Sophie, Reuschenbach, Miriam, Doeberitz, Magnus Von Knebel, Gilks, Blake C, Huntsman, David G, Bakkum-Gamez, Jamie, McAlpine, Jessica N, and Anglesio, Michael S
Abstract: BackgroundMucinous ovarian tumors represent a distinct histotype of epithelial ovarian cancer. The rarest (2-4 % of ovarian carcinomas) of the five major histotypes, their genomic landscape remains poorly described. We undertook hotspot sequencing of 50 genes commonly mutated in human cancer across 69 mucinous ovarian tumors. Our goals were to establish the overall frequency of cancer-hotspot mutations across a large cohort, especially those tumors previously thought to be "RAS-pathway alteration negative", using highly-sensitive next-generation sequencing as well as further explore a small number of cases with apparent heterogeneity in RAS-pathway activating alterations.MethodsUsing the Ion Torrent PGM platform, we performed next generation sequencing analysis using the v2 Cancer Hotspot Panel. Regions of disparate ERBB2-amplification status were sequenced independently for two mucinous carcinoma (MC) cases, previously established as showing ERBB2 amplification/overexpression heterogeneity, to assess the hypothesis of subclonal populations containing either KRAS mutation or ERBB2 amplification independently or simultaneously.ResultsWe detected mutations in KRAS, TP53, CDKN2A, PIK3CA, PTEN, BRAF, FGFR2, STK11, CTNNB1, SRC, SMAD4, GNA11 and ERBB2. KRAS mutations remain the most frequently observed alteration among MC (64.9 %) and mucinous borderline tumors (MBOT) (92.3 %). TP53 mutation occurred more frequently in carcinomas than borderline tumors (56.8 % and 11.5 %, respectively), and combined IHC and mutation data suggest alterations occur in approximately 68 % of MC and as many as 20 % of MBOT. Proven and potential RAS-pathway activating changes were observed in all but one MC. Concurrent ERBB2 amplification and KRAS mutation were observed in a substantial number of cases (7/63 total), as was co-occurrence of KRAS and BRAF mutations (one case). Microdissection of ERBB2-amplified regions of tumors harboring KRAS mutation suggests these alterations are occurring in
Published: 2015

47. Clonal Hematopoiesis-Associated Gene Mutations in a Clinical Cohort of 448 Patients With Ovarian Cancer

Author: Weber-Lassalle, Konstantin, Ernst, Corinna, Reuss, Alexander, Mollenhoff, Kathrin, Baumann, Klaus, Jackisch, Christian, Hauke, Jan, Dietrich, Dimo, Borde, Julika, Park-Simon, Tjoung-Won, Hanker, Lars, Prieske, Katharina, Schmidt, Sandra, Weber-Lassalle, Nana, Pohl-Rescigno, Esther, Kommoss, Stefan, Marme, Frederik, Heitz, Florian, Stingl, Julia C., Schmutzler, Rita K., Harter, Philipp, Hahnen, Eric, Weber-Lassalle, Konstantin, Ernst, Corinna, Reuss, Alexander, Mollenhoff, Kathrin, Baumann, Klaus, Jackisch, Christian, Hauke, Jan, Dietrich, Dimo, Borde, Julika, Park-Simon, Tjoung-Won, Hanker, Lars, Prieske, Katharina, Schmidt, Sandra, Weber-Lassalle, Nana, Pohl-Rescigno, Esther, Kommoss, Stefan, Marme, Frederik, Heitz, Florian, Stingl, Julia C., Schmutzler, Rita K., Harter, Philipp, and Hahnen, Eric
Abstract: Background Cancer patients are at risk of secondary therapy-related myeloid neoplasms (t-MNs). Acquired blood-specific mutations in clonal hematopoiesis (CH)-associated genes are t-MN risk factors, and their occurrence associated with cancer therapy and age. Patients with ovarian cancer (OC) showed a particularly high prevalence of CH-associated gene mutations, which may additionally be explained by the high proportion of a hereditary disease cause in this cancer entity. Methods We performed a retrospective analysis of 448 OC patients enrolled in the AGO-TR1 study; 249 were enrolled at primary diagnosis and 199 at platinum-sensitive recurrence. Analyses included the most frequently altered CH-associated genes (ASXL1, DNMT3A, GNAS, JAK2, PPM1D, SF3B1, SH2B3, SRSF2, TET2, TP53). Results were analyzed according to the BRCA1/2 germline (gBRCA1/2) mutation status. All statistical tests were 2-sided. Results Advanced age at blood draw and a high number of prior platinum-based chemotherapy lines were risk factors to acquire CH-associated gene mutations, with gene-specific effects observed. Binomial logistic regression suggested increased probabilities for gBRCA1/2 mutation carriers to acquire CH-associated PPM1D and TP53 gene mutations (PPM1D: odds ratio = 4.30, 95% confidence interval = 1.48 to 12.46, P = .007; TP53: odds ratio = 6.20, 95% confidence interval = 0.98 to 53.9, P = .06). This observation was due to a statistically significantly increased number of platinum-based chemotherapy lines in gBRCA1/2 mutation carriers vs noncarriers (PPM1D: mean [SD] = 2.04 [1.27] vs 1.04 [0.99], P < .001; TP53: mean [SD] = 2.83 [1.33] vs 1.07 [1.01], P < .001). No interaction between platinum-based chemotherapy and gBRCA1/2 mutation status with the occurrence of CH-associated gene mutations was observed. Conclusions A positive gBRCA1/2 mutation status is not a risk factor to acquire CH-associated gene mutations. OC patients may benefit from monitoring CH-associated gene mutations

48. Clonal Hematopoiesis-Associated Gene Mutations in a Clinical Cohort of 448 Patients With Ovarian Cancer

Author: Weber-Lassalle, Konstantin, Ernst, Corinna, Reuss, Alexander, Mollenhoff, Kathrin, Baumann, Klaus, Jackisch, Christian, Hauke, Jan, Dietrich, Dimo, Borde, Julika, Park-Simon, Tjoung-Won, Hanker, Lars, Prieske, Katharina, Schmidt, Sandra, Weber-Lassalle, Nana, Pohl-Rescigno, Esther, Kommoss, Stefan, Marme, Frederik, Heitz, Florian, Stingl, Julia C., Schmutzler, Rita K., Harter, Philipp, Hahnen, Eric, Weber-Lassalle, Konstantin, Ernst, Corinna, Reuss, Alexander, Mollenhoff, Kathrin, Baumann, Klaus, Jackisch, Christian, Hauke, Jan, Dietrich, Dimo, Borde, Julika, Park-Simon, Tjoung-Won, Hanker, Lars, Prieske, Katharina, Schmidt, Sandra, Weber-Lassalle, Nana, Pohl-Rescigno, Esther, Kommoss, Stefan, Marme, Frederik, Heitz, Florian, Stingl, Julia C., Schmutzler, Rita K., Harter, Philipp, and Hahnen, Eric
Abstract: Background Cancer patients are at risk of secondary therapy-related myeloid neoplasms (t-MNs). Acquired blood-specific mutations in clonal hematopoiesis (CH)-associated genes are t-MN risk factors, and their occurrence associated with cancer therapy and age. Patients with ovarian cancer (OC) showed a particularly high prevalence of CH-associated gene mutations, which may additionally be explained by the high proportion of a hereditary disease cause in this cancer entity. Methods We performed a retrospective analysis of 448 OC patients enrolled in the AGO-TR1 study; 249 were enrolled at primary diagnosis and 199 at platinum-sensitive recurrence. Analyses included the most frequently altered CH-associated genes (ASXL1, DNMT3A, GNAS, JAK2, PPM1D, SF3B1, SH2B3, SRSF2, TET2, TP53). Results were analyzed according to the BRCA1/2 germline (gBRCA1/2) mutation status. All statistical tests were 2-sided. Results Advanced age at blood draw and a high number of prior platinum-based chemotherapy lines were risk factors to acquire CH-associated gene mutations, with gene-specific effects observed. Binomial logistic regression suggested increased probabilities for gBRCA1/2 mutation carriers to acquire CH-associated PPM1D and TP53 gene mutations (PPM1D: odds ratio = 4.30, 95% confidence interval = 1.48 to 12.46, P = .007; TP53: odds ratio = 6.20, 95% confidence interval = 0.98 to 53.9, P = .06). This observation was due to a statistically significantly increased number of platinum-based chemotherapy lines in gBRCA1/2 mutation carriers vs noncarriers (PPM1D: mean [SD] = 2.04 [1.27] vs 1.04 [0.99], P < .001; TP53: mean [SD] = 2.83 [1.33] vs 1.07 [1.01], P < .001). No interaction between platinum-based chemotherapy and gBRCA1/2 mutation status with the occurrence of CH-associated gene mutations was observed. Conclusions A positive gBRCA1/2 mutation status is not a risk factor to acquire CH-associated gene mutations. OC patients may benefit from monitoring CH-associated gene mutations

49. PALB2, CHEK2 and ATM rare variants and cancer risk : data from COGS

Author: Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana, Southey, Melissa C., Goldgar, David E., Winqvist, Robert, Pylkas, Katri, Couch, Fergus, Tischkowitz, Marc, Foulkes, William D., Dennis, Joe, Michailidou, Kyriaki, van Rensburg, Elizabeth J., Heikkinen, Tuomas, Nevanlinna, Heli, Hopper, John L., Doerk, Thilo, Claes, Kathleen B. M., Reis Filho, Jorge, Teo, Zhi Ling, Radice, Paolo, Catucci, Irene, Peterlongo, Paolo, Tsimiklis, Helen, Odefrey, Fabrice A., Dowty, James G., Schmidt, Marjanka K., Broeks, Annegien, Hogervorst, Frans B., Verhoef, Senno, Carpenter, Jane, Clarke, Christine, Scott, Rodney J., Fasching, Peter A., Haeberle, Lothar, Ekici, Arif B., Beckmann, Matthias W., Peto, Julian, dos Santos Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Bolla, Manjeet K., Sawyer, Elinor J., Tomlinson, Ian, Kerin, Michael J., Miller, Nicola, Marme, Federik, Burwinkel, Barbara, Yang, Rongxi, Guenel, Pascal, Therese Truong, Sanchez, Marie, Bojesen, Stig, Nielsen, Sune F., Flyger, Henrik, Benitez, Javier, Pilar Zamora, M., Arias Perez, Jose Ignacio, Menendez, Primitiva, Anton Culver, Hoda, Neuhausen, Susan, Ziogas, Argyrios, Clarke, Christina A., Brenner, Hermann, Arndt, Volker, Stegmaier, Christa, Brauch, Hiltrud, Bruening, Thomas, Ko, Yon Dschun, Muranen, Taru A., Aittomaki, Kristiina, Blomqvist, Carl, Bogdanova, Natalia V., Antonenkova, Natalia N., Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli Matti, Hartikainen, Jaana M., Spurdle, Amanda B., Wauters, Els, Smeets, Dominiek, Beuselinck, Benoit, Floris, Giuseppe, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch Janys, Dieter, Olson, Janet E., Vachon, Celine, Pankratz, Vernon S., McLean, Catriona, Haiman, Christopher A., Henderson, Brian E., Schumacher, Fredrick, Le Marchand, Loic, Kristensen, Vessela, Alnaes, Grethe Grenaker, Zheng, Wei, Hunter, David J., Lindstrom, Sara, Hankinson, Susan E., Kraft, Peter, Andrulis, Irene, Knight, Julia A., Glendon, Gord, Mulligan, Anna Marie, Jukkola Vuorinen, Arja, Grip, Mervi, Kauppila, Saila, Devilee, Peter, Tollenaar, Robert A. E. M., Seynaeve, Caroline, Hollestelle, Antoinette, Garcia Closas, Montserrat, Figueroa, Jonine, Chanock, Stephen J., Lissowska, Jolanta, Czene, Kamila, Darabi, Hatef, Eriksson, Mikael, Eccles, Diana M., Rafiq, Sajjad, Tapper, William J., Gerty, Sue M., Hooning, Maartje J., Martens, John W. M., Collee, J. Margriet, Tilanus-Linthorst, Madeleine, Hall, Per, Li, Jingmei, Brand, Judith S., Humphreys, Keith, Cox, Angela, Reed, Malcolm W. R., Luccarini, Craig, Baynes, Caroline, Dunning, Alison M., Hamann, Ute, Torres López, Diana María, Ulmer, Hans Ulrich, Ruediger, Thomas, Jakubowska, Anna, Lubinski, Jan, Jaworska, Katarzyna, Durda, Katarzyna, Slager, Susan, Toland, Amanda E., Ambrosone, Christine B., Yannoukakos, Drakoulis, Swerdlow, Anthony, Ashworth, Alan, Orr, Nick, Jones, Michael, Gonzalez Neira, Anna, Pita, Guillermo, Rosario Alonso, M., Alvarez, Nuria, Herrero, Daniel, Tessier, Daniel C., Vincent, Daniel, Bacot, Francois, Simard, Jacques, Dumont, Martine, Soucy, Penny, Eeles, Rosalind, Muir, Kenneth, Wiklund, Fredrik, Gronberg, Henrik, Schleutker, Johanna, Nordestgaard, Borge G., Weischer, Maren, Travis, Ruth C., Neal, David, Donovan, Jenny L., Hamdy, Freddie C., Khaw, Kay Tee, Stanford, Janet L., Blot, William J., Thibodeau, Stephen, Schaid, Daniel J., Kelley, Joseph L., Maier, Christiane, Kibel, Adam S., Cybulski, Cezary, Cannon Albright, Lisa, Butterbach, Katja, Park, Jong, Kaneva, Radka, Batra, Jyotsna, Teixeira, Manuel R., Kote-Jarai, Zsofia, Al Olama, Ali Amin, Benlloch, Sara, Renner, Stefan P., Hartmann, Arndt, Hein, Alexander, Ruebner, Matthias, Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Lambretchs, Sandrina, Doherty, Jennifer A., Rossing, Mary Anne, Nickels, Stefan, Eilber, Ursula, Wang Gohrke, Shan, Odunsi, Kunle, Sucheston Campbell, Lara E., Friel, Grace, Lurie, Galina, Killeen, Jeffrey L., Wilkens, Lynne R., Goodman, Marc T., Runnebaum, Ingo, Hillemanns, Peter A., Pelttari, Liisa M., Butzow, Ralf, Modugno, Francesmary, Edwards, Robert P., Ness, Roberta B., Moysich, Kirsten B., du Bois, Andreas, Heitz, Florian, Harter, Philipp, Kommoss, Stefan, Karlan, Beth Y., Walsh, Christine, Lester, Jenny, Jensen, Allan, Kjaer, Susanne Kruger, Hogdall, Estrid, Peissel, Bernard, Bonanni, Bernardo, Bernard, Loris, Goode, Ellen L., Fridley, Brooke L., Vierkant, Robert A., Cunningham, Julie M., Larson, Melissa C., Fogarty, Zachary C., Kalli, Kimberly R., Liang, Dong, Lu, Karen H., Hildebrandt, Michelle A. T., Wu, Xifeng, Levine, Douglas A., Dao, Fanny, Bisogna, Maria, Berchuck, Andrew, Iversen, Edwin S., Marks, Jeffrey R., Akushevich, Lucy, Cramer, Daniel W., Schildkraut, Joellen, Terry, Kathryn L., Poole, Elizabeth M., Stampfer, Meir, Tworoger, Shelley S., Bandera, Elisa V., Orlow, Irene, Olson, Sara H., Bjorge, Line, Salvesen, Helga B., van Altena, Anne M., Aben, Katja K. H., Kiemeney, Lambertus A., Massuger, Leon F. A. G., Pejovic, Tanja, Bean, Yukie, Brooks Wilson, Angela, Kelemen, Linda E., Cook, Linda S., Le, Nhu D., Grski, Bohdan, Gronwald, Jacek, Menkiszak, Janusz, Hogdall, Claus K., Lundvall, Lene, Nedergaard, Lotte, Engelholm, Svend Aage, Dicks, Ed, Tyrer, Jonathan, Campbell, Ian, McNeish, Iain, Paul, James, Siddiqui, Nadeem, Glasspool, Rosalind, Whittemore, Alice S., Rothstein, Joseph H., McGuire, Valerie, Sieh, Weiva, Cai, Hui, Shu, Xiao-Ou, Teten, Rachel T., Sutphen, Rebecca, McLaughlin, John R., Narod, Steven A., Phelan, Catherine M., Monteiro, Alvaro N., Fenstermacher, David, Lin, Hui Yi, Permuth, Jennifer B., Sellers, Thomas A., Chen, Y. Ann, Tsai, Ya Yu, Chen, Zhihua, Gentry Maharaj, Aleksandra, Gayther, Simon A., Ramus, Susan J., Menon, Usha, Wu, Anna H., Pearce, Celeste L., Van den Berg, David, Pike, Malcolm C., Dansonka Mieszkowska, Agnieszka, Plisiecka Halasa, Joanna, Moes Sosnowska, Joanna, Kupryjanczyk, Jolanta, Pharoah, Paul D. P., Song, Honglin, Winship, Ingrid, Chenevix Trench, Georgia, Giles, Graham G., Tavtigian, Sean V., Easton, Doug F., Milne, Roger L., Menegaux, Florence, Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana, Southey, Melissa C., Goldgar, David E., Winqvist, Robert, Pylkas, Katri, Couch, Fergus, Tischkowitz, Marc, Foulkes, William D., Dennis, Joe, Michailidou, Kyriaki, van Rensburg, Elizabeth J., Heikkinen, Tuomas, Nevanlinna, Heli, Hopper, John L., Doerk, Thilo, Claes, Kathleen B. M., Reis Filho, Jorge, Teo, Zhi Ling, Radice, Paolo, Catucci, Irene, Peterlongo, Paolo, Tsimiklis, Helen, Odefrey, Fabrice A., Dowty, James G., Schmidt, Marjanka K., Broeks, Annegien, Hogervorst, Frans B., Verhoef, Senno, Carpenter, Jane, Clarke, Christine, Scott, Rodney J., Fasching, Peter A., Haeberle, Lothar, Ekici, Arif B., Beckmann, Matthias W., Peto, Julian, dos Santos Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Bolla, Manjeet K., Sawyer, Elinor J., Tomlinson, Ian, Kerin, Michael J., Miller, Nicola, Marme, Federik, Burwinkel, Barbara, Yang, Rongxi, Guenel, Pascal, Therese Truong, Sanchez, Marie, Bojesen, Stig, Nielsen, Sune F., Flyger, Henrik, Benitez, Javier, Pilar Zamora, M., Arias Perez, Jose Ignacio, Menendez, Primitiva, Anton Culver, Hoda, Neuhausen, Susan, Ziogas, Argyrios, Clarke, Christina A., Brenner, Hermann, Arndt, Volker, Stegmaier, Christa, Brauch, Hiltrud, Bruening, Thomas, Ko, Yon Dschun, Muranen, Taru A., Aittomaki, Kristiina, Blomqvist, Carl, Bogdanova, Natalia V., Antonenkova, Natalia N., Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli Matti, Hartikainen, Jaana M., Spurdle, Amanda B., Wauters, Els, Smeets, Dominiek, Beuselinck, Benoit, Floris, Giuseppe, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch Janys, Dieter, Olson, Janet E., Vachon, Celine, Pankratz, Vernon S., McLean, Catriona, Haiman, Christopher A., Henderson, Brian E., Schumacher, Fredrick, Le Marchand, Loic, Kristensen, Vessela, Alnaes, Grethe Grenaker, Zheng, Wei, Hunter, David J., Lindstrom, Sara, Hankinson, Susan E., Kraft, Peter, Andrulis, Irene, Knight, Julia A., Glendon, Gord, Mulligan, Anna Marie, Jukkola Vuorinen, Arja, Grip, Mervi, Kauppila, Saila, Devilee, Peter, Tollenaar, Robert A. E. M., Seynaeve, Caroline, Hollestelle, Antoinette, Garcia Closas, Montserrat, Figueroa, Jonine, Chanock, Stephen J., Lissowska, Jolanta, Czene, Kamila, Darabi, Hatef, Eriksson, Mikael, Eccles, Diana M., Rafiq, Sajjad, Tapper, William J., Gerty, Sue M., Hooning, Maartje J., Martens, John W. M., Collee, J. Margriet, Tilanus-Linthorst, Madeleine, Hall, Per, Li, Jingmei, Brand, Judith S., Humphreys, Keith, Cox, Angela, Reed, Malcolm W. R., Luccarini, Craig, Baynes, Caroline, Dunning, Alison M., Hamann, Ute, Torres López, Diana María, Ulmer, Hans Ulrich, Ruediger, Thomas, Jakubowska, Anna, Lubinski, Jan, Jaworska, Katarzyna, Durda, Katarzyna, Slager, Susan, Toland, Amanda E., Ambrosone, Christine B., Yannoukakos, Drakoulis, Swerdlow, Anthony, Ashworth, Alan, Orr, Nick, Jones, Michael, Gonzalez Neira, Anna, Pita, Guillermo, Rosario Alonso, M., Alvarez, Nuria, Herrero, Daniel, Tessier, Daniel C., Vincent, Daniel, Bacot, Francois, Simard, Jacques, Dumont, Martine, Soucy, Penny, Eeles, Rosalind, Muir, Kenneth, Wiklund, Fredrik, Gronberg, Henrik, Schleutker, Johanna, Nordestgaard, Borge G., Weischer, Maren, Travis, Ruth C., Neal, David, Donovan, Jenny L., Hamdy, Freddie C., Khaw, Kay Tee, Stanford, Janet L., Blot, William J., Thibodeau, Stephen, Schaid, Daniel J., Kelley, Joseph L., Maier, Christiane, Kibel, Adam S., Cybulski, Cezary, Cannon Albright, Lisa, Butterbach, Katja, Park, Jong, Kaneva, Radka, Batra, Jyotsna, Teixeira, Manuel R., Kote-Jarai, Zsofia, Al Olama, Ali Amin, Benlloch, Sara, Renner, Stefan P., Hartmann, Arndt, Hein, Alexander, Ruebner, Matthias, Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Lambretchs, Sandrina, Doherty, Jennifer A., Rossing, Mary Anne, Nickels, Stefan, Eilber, Ursula, Wang Gohrke, Shan, Odunsi, Kunle, Sucheston Campbell, Lara E., Friel, Grace, Lurie, Galina, Killeen, Jeffrey L., Wilkens, Lynne R., Goodman, Marc T., Runnebaum, Ingo, Hillemanns, Peter A., Pelttari, Liisa M., Butzow, Ralf, Modugno, Francesmary, Edwards, Robert P., Ness, Roberta B., Moysich, Kirsten B., du Bois, Andreas, Heitz, Florian, Harter, Philipp, Kommoss, Stefan, Karlan, Beth Y., Walsh, Christine, Lester, Jenny, Jensen, Allan, Kjaer, Susanne Kruger, Hogdall, Estrid, Peissel, Bernard, Bonanni, Bernardo, Bernard, Loris, Goode, Ellen L., Fridley, Brooke L., Vierkant, Robert A., Cunningham, Julie M., Larson, Melissa C., Fogarty, Zachary C., Kalli, Kimberly R., Liang, Dong, Lu, Karen H., Hildebrandt, Michelle A. T., Wu, Xifeng, Levine, Douglas A., Dao, Fanny, Bisogna, Maria, Berchuck, Andrew, Iversen, Edwin S., Marks, Jeffrey R., Akushevich, Lucy, Cramer, Daniel W., Schildkraut, Joellen, Terry, Kathryn L., Poole, Elizabeth M., Stampfer, Meir, Tworoger, Shelley S., Bandera, Elisa V., Orlow, Irene, Olson, Sara H., Bjorge, Line, Salvesen, Helga B., van Altena, Anne M., Aben, Katja K. H., Kiemeney, Lambertus A., Massuger, Leon F. A. G., Pejovic, Tanja, Bean, Yukie, Brooks Wilson, Angela, Kelemen, Linda E., Cook, Linda S., Le, Nhu D., Grski, Bohdan, Gronwald, Jacek, Menkiszak, Janusz, Hogdall, Claus K., Lundvall, Lene, Nedergaard, Lotte, Engelholm, Svend Aage, Dicks, Ed, Tyrer, Jonathan, Campbell, Ian, McNeish, Iain, Paul, James, Siddiqui, Nadeem, Glasspool, Rosalind, Whittemore, Alice S., Rothstein, Joseph H., McGuire, Valerie, Sieh, Weiva, Cai, Hui, Shu, Xiao-Ou, Teten, Rachel T., Sutphen, Rebecca, McLaughlin, John R., Narod, Steven A., Phelan, Catherine M., Monteiro, Alvaro N., Fenstermacher, David, Lin, Hui Yi, Permuth, Jennifer B., Sellers, Thomas A., Chen, Y. Ann, Tsai, Ya Yu, Chen, Zhihua, Gentry Maharaj, Aleksandra, Gayther, Simon A., Ramus, Susan J., Menon, Usha, Wu, Anna H., Pearce, Celeste L., Van den Berg, David, Pike, Malcolm C., Dansonka Mieszkowska, Agnieszka, Plisiecka Halasa, Joanna, Moes Sosnowska, Joanna, Kupryjanczyk, Jolanta, Pharoah, Paul D. P., Song, Honglin, Winship, Ingrid, Chenevix Trench, Georgia, Giles, Graham G., Tavtigian, Sean V., Easton, Doug F., Milne, Roger L., and Menegaux, Florence

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