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

Author: 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, AOCS Group, 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, Candido Dos Reis, Francisco J, 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, Menon, Usha, Modugno, Francesmary, Pharoah, Paul Dp, Schildkraut, Joellen M, Sieh, Weiva, Staebler, Annette, Sundfeldt, Karin, Swerdlow, Anthony J, Ramus, Susan J, Brenton, James D, Köbel, Martin [0000-0002-6615-2037], Weir, Ashley [0000-0002-3072-2616], Anglesio, Michael S [0000-0003-1639-5003], Erber, Ramona [0000-0003-0315-1229], Gilks, C Blake [0000-0001-7889-8250], Shvetsov, Yurii B [0000-0001-5131-9618], Campbell, Ian [0000-0002-7773-4155], Huntsman, David G [0000-0003-4934-3322], and Apollo - University of Cambridge Repository
Subjects: clear cell, p53, Ovarian Neoplasms, ovarian cancer, high-grade serous carcinoma, Humans, Female, TP53, prognosis, Tumor Suppressor Protein p53, Carcinoma, Ovarian Epithelial, endometrioid, Carcinoma, Endometrioid
Abstract: Funder: Biomedical Research Centre, Funder: European Regional Development Fund, Funder: Mayo Foundation for Medical Education and Research, Funder: Pomeranian Medical University, Funder: Pomorski Uniwersytet Medyczny W Szczecinie, Funder: Cancer Council NSW, Funder: Cancer Institute NSW, Funder: Deutsches Krebsforschungszentrum, Funder: The BC Cancer Foundation, Funder: University College London Hospitals Biomedical Research Centre, Funder: Breast Cancer Now, Funder: Cancer Council Tasmania, Funder: Clinical Academic Reserve, Funder: ELAN Funds of the University of Erlangen-Nuremberg, Funder: Fondo Europeo de Desarrollo Regional, Funder: National Institute for Health Research (NIHR), Funder: National Institute for Health and Care Research, Funder: Ovarian Cancer Australia, Funder: Queensland Cancer Fund, Funder: Cancer Council New South Wales, Funder: Fred C. and Katherine B. Andersen Foundation, Funder: German Cancer Research Center, Funder: Institute of Cancer Research, Funder: Mayo Foundation, Funder: Minnesota Ovarian Cancer Alliance, Funder: Peter MacCallum Foundation, Funder: University of Cambridge, Funder: Cancer Foundation of Western Australia, Funder: VGH and UBC Hospital Foundation, Funder: Cancer Council Victoria, Funder: NHS, Funder: UK National Institute for Health Research, Funder: Cancer Council South Australia, Funder: Oak Foundation, Funder: Sydney West Translational Cancer Research Centre, 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. p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study

Author: 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, 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, Candido Dos Reis, Francisco J, 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, Menon, Usha, Modugno, Francesmary, Pharoah, Paul DP, Schildkraut, Joellen M, Sieh, Weiva, Staebler, Annette, Sundfeldt, Karin, Swerdlow, Anthony J, Ramus, Susan J, Brenton, James D, Köbel, Martin [0000-0002-6615-2037], Weir, Ashley [0000-0002-3072-2616], Anglesio, Michael S [0000-0003-1639-5003], Erber, Ramona [0000-0003-0315-1229], Gilks, C Blake [0000-0001-7889-8250], Shvetsov, Yurii B [0000-0001-5131-9618], Campbell, Ian [0000-0002-7773-4155], Huntsman, David G [0000-0003-4934-3322], and Apollo - University of Cambridge Repository
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 [HGSC], endometrioid [EC] and clear cell carcinomas [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6678 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, cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93% (4630/4957) 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 (HR=2.18, 95% CI 1.36-3.47, p=0.0011) as well as with CCC (HR=1.57, 95% CI 1.11-2.22, p=0.012). Abnormal p53 was also associated with shorter overall survival in FIGO 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., CRUK
Published: 2023
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3. CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study

Author: Kang, Eun-Young, Weir, Ashley, Meagher, Nicola S, Farrington, Kyo, Nelson, Gregg S, Ghatage, Prafull, Lee, Cheng-Han, Riggan, Marjorie J, Bolithon, Adelyn, Popovic, Gordana, Leung, Betty, Tang, Katrina, Lambie, Neil, Millstein, Joshua, Alsop, Jennifer, Anglesio, Michael S, Ataseven, Beyhan, Barlow, Ellen, Beckmann, Matthias W, Berger, Jessica, Bisinotto, Christiani, Bösmüller, Hans, Boros, Jessica, Brand, Alison H, Brooks-Wilson, Angela, Brucker, Sara Y, Carney, Michael E, Casablanca, Yovanni, Cazorla-Jiménez, Alicia, Cohen, Paul A, Conrads, Thomas P, Cook, Linda S, Coulson, Penny, Courtney-Brooks, Madeleine, Cramer, Daniel W, Crowe, Philip, Cunningham, Julie M, Cybulski, Cezary, Darcy, Kathleen M, El-Bahrawy, Mona A, Elishaev, Esther, Erber, Ramona, Farrell, Rhonda, Fereday, Sian, Fischer, Anna, García, María J, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Gilks, C Blake, AOCS Group, Grube, Marcel, Harnett, Paul R, Harrington, Shariska Petersen, Harter, Philipp, Hartmann, Arndt, Hecht, Jonathan L, Heikaus, Sebastian, Hein, Alexander, Heitz, Florian, Hendley, Joy, Hernandez, Brenda Y, Polo, Susanna Hernando, Heublein, Sabine, Hirasawa, Akira, Høgdall, Estrid, Høgdall, Claus K, Horlings, Hugo M, Huntsman, David G, Huzarski, Tomasz, Jewell, Andrea, Jimenez-Linan, Mercedes, Jones, Michael E, Kaufmann, Scott H, Kennedy, Catherine J, Khabele, Dineo, Kommoss, Felix KF, Kruitwagen, Roy FPM, Lambrechts, Diether, Le, Nhu D, Lener, Marcin, Lester, Jenny, Leung, Yee, Linder, Anna, Loverix, Liselore, Lubiński, Jan, Madan, Rashna, Maxwell, G Larry, Modugno, Francesmary, Neuhausen, Susan L, Olawaiye, Alexander, Olbrecht, Siel, Orsulic, Sandra, Palacios, José, Pearce, Celeste Leigh, Pike, Malcolm C, Quinn, Carmel M, Mohan, Ganendra Raj, Rodríguez-Antona, Cristina, Ruebner, Matthias, Ryan, Andy, Salfinger, Stuart G, Sasamoto, Naoko, Schildkraut, Joellen M, Schoemaker, Minouk J, Shah, Mitul, Sharma, Raghwa, Shvetsov, Yurii B, Singh, Naveena, Sonke, Gabe S, Steele, Linda, Stewart, Colin, Sundfeldt, Karin, Swerdlow, Anthony J, Talhouk, Aline, Tan, Adeline, Taylor, Sarah E, Terry, Kathryn L, Tołoczko, Aleksandra, Traficante, Nadia, Van De Vijver, Koen K, Van Der Aa, Maaike A, Van Gorp, Toon, Van Nieuwenhuysen, Els, Van-Wagensveld, Lilian, Vergote, Ignace, Vierkant, Robert A, Wang, Chen, Wilkens, Lynne R, Winham, Stacey J, Wu, Anna H, Benitez, Javier, Berchuck, Andrew, Candido Dos Reis, Francisco J, DeFazio, Anna, Fasching, Peter A, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Karlan, Beth Y, Kommoss, Stefan, Menon, Usha, Sinn, Hans-Peter, Staebler, Annette, Brenton, James D, Bowtell, David D, Pharoah, Paul DP, Ramus, Susan J, Köbel, Martin, Meagher, Nicola S [0000-0001-9134-2118], Lee, Cheng-Han [0000-0003-2094-1222], Fereday, Sian [0000-0002-8559-8579], Kennedy, Catherine J [0000-0002-4465-5784], Sasamoto, Naoko [0000-0002-4526-2181], Schildkraut, Joellen M [0000-0002-0990-9339], Talhouk, Aline [0000-0001-7760-410X], Vergote, Ignace [0000-0002-7589-8981], Köbel, Martin [0000-0002-6615-2037], and Apollo - University of Cambridge Repository
Subjects: Ovarian Neoplasms, Oncogene Proteins, Carcinoma, Cystadenocarcinoma, Serous, ovarian cancer, high-grade serous carcinoma, Cyclin E, Humans, Female, prognosis, RNA, Messenger, CCNE1 amplification, cyclin E1 expression, Transcription Factors
Abstract: BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.
Published: 2023
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4. Increased FOXJ1 protein expression is associated with improved overall survival in high-grade serous ovarian carcinoma: an Ovarian Tumor Tissue Analysis Consortium Study

Author: Weir, Ashley, Kang, Eun-Young, Meagher, Nicola S, Nelson, Gregg S, Ghatage, Prafull, Lee, Cheng-Han, Riggan, Marjorie J, Gentry-Maharaj, Aleksandra, Ryan, Andy, Singh, Naveena, Widschwendter, Martin, Alsop, Jennifer, Anglesio, Michael S, Beckmann, Matthias W, Berger, Jessica, Bisinotto, Christiani, Boros, Jessica, Brand, Alison H, Brenton, James D, Brooks-Wilson, Angela, Carney, Michael E, Cunningham, Julie M, Cushing-Haugen, Kara L, Cybulski, Cezary, Elishaev, Esther, Erber, Ramona, Fereday, Sian, Fischer, Anna, Paz-Ares, Luis, Gayarre, Javier, Gilks, Blake C, Grube, Marcel, Harnett, Paul R, Harris, Holly R, Hartmann, Arndt, Hein, Alexander, Hendley, Joy, Hernandez, Brenda Y, Heublein, Sabine, Huang, Yajue, Huzarski, Tomasz, Jakubowska, Anna, Jimenez-Linan, Mercedes, Kennedy, Catherine J, Kommoss, Felix KF, Koziak, Jennifer M, Kraemer, Bernhard, Le, Nhu D, Lesnock, Jaime, Lester, Jenny, Lubiński, Jan, Menkiszak, Janusz, Ney, Britta, Olawaiye, Alexander, Orsulic, Sandra, Osorio, Ana, Robles-Díaz, Luis, Ruebner, Matthias, Shah, Mitul, Sharma, Raghwa, Shvetsov, Yurii B, Steed, Helen, Talhouk, Aline, Taylor, Sarah E, Traficante, Nadia, Vierkant, Robert A, Wang, Chen, Wilkens, Lynne R, Winham, Stacey J, Benitez, Javier, Berchuck, Andrew, Bowtell, David D, Candido Dos Reis, Francisco J, Cook, Linda S, DeFazio, Anna, 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, Meagher, Nicola S [0000-0001-9134-2118], Ghatage, Prafull [0000-0002-2371-0844], Riggan, Marjorie J [0000-0002-3701-8031], Widschwendter, Martin [0000-0002-7778-8380], Brenton, James D [0000-0002-5738-6683], Cunningham, Julie M [0000-0002-8159-3025], Hein, Alexander [0000-0003-2601-3398], Jakubowska, Anna [0000-0002-5650-0501], Kennedy, Catherine J [0000-0002-4465-5784], Kommoss, Felix KF [0000-0003-0876-9087], Osorio, Ana [0000-0001-8124-3984], Vierkant, Robert A [0000-0001-6242-5221], Winham, Stacey J [0000-0002-8492-9102], Bowtell, David D [0000-0001-9089-7525], Candido Dos Reis, Francisco J [0000-0001-5758-5917], DeFazio, Anna [0000-0003-0057-4744], Doherty, Jennifer A [0000-0002-1454-8187], Fasching, Peter A [0000-0003-4885-8471], García, María J [0000-0002-2236-9912], Karlan, Beth Y [0000-0002-9451-2933], Sinn, Hans-Peter [0000-0003-2836-6699], Ford, Caroline E [0000-0002-4438-2309], Menon, Usha [0000-0003-3708-1732], Pharoah, Paul DP [0000-0001-8494-732X], Ramus, Susan J [0000-0003-0005-7798], and Apollo - University of Cambridge Repository
Subjects: Ovarian Neoplasms, Biomarkers, Tumor, Humans, Female, Forkhead Transcription Factors, RNA, Messenger, Prognosis, Survival Analysis, Cystadenocarcinoma, Serous
Abstract: Funder: Funder: Calgary Laboratory Services (research support fund) Grant reference number: RS19-612, Funder: Funder: National Cancer Institute: National Institutes of Health Grant reference number: R01CA172404, BACKGROUND: Recently, we showed a >60% difference in 5-year survival for patients with tubo-ovarian high-grade serous carcinoma (HGSC) when stratified by a 101-gene mRNA expression prognostic signature. Given the varied patient outcomes, this study aimed to translate prognostic mRNA markers into protein expression assays by immunohistochemistry and validate their survival association in HGSC. METHODS: Two prognostic genes, FOXJ1 and GMNN, were selected based on high-quality antibodies, correlation with protein expression and variation in immunohistochemical scores in a preliminary cohort (n = 134 and n = 80, respectively). Six thousand four hundred and thirty-four (FOXJ1) and 5470 (GMNN) formalin-fixed, paraffin-embedded ovarian neoplasms (4634 and 4185 HGSC, respectively) represented on tissue microarrays from the Ovarian Tumor Tissue Analysis consortium underwent immunohistochemical staining and scoring, then univariate and multivariate survival analysis. RESULTS: Consistent with mRNA, FOXJ1 protein expression exhibited a linear, increasing association with improved overall survival in HGSC patients. Women with >50% expression had the most favourable outcomes (HR = 0.78, 95% CI 0.67-0.91, p < 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. CONCLUSION: We provide foundational evidence for the prognostic value of FOXJ1 in HGSC, validating the prior mRNA-based prognostic association by immunohistochemistry.
Published: 2023

5. Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci

Author: DeVries, Amber A, Dennis, Joe, Tyrer, Jonathan P, Peng, Pei-Chen, Coetzee, Simon G, Reyes, Alberto L, Plummer, Jasmine T, Davis, Brian D, Chen, Stephanie S, Dezem, Felipe Segato, Aben, Katja KH, Anton-Culver, Hoda, Antonenkova, Natalia N, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Berchuck, Andrew, Bogdanova, Natalia V, Bogdanova-Markov, Nadja, Brenton, James D, Butzow, Ralf, Campbell, Ian, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Dörk, Thilo, Eccles, Diana M, Eliassen, A Heather, Fasching, Peter A, Fortner, Renée T, Giles, Graham G, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, OPAL Study Group, AOCS Group, Håkansson, Niclas, Hildebrandt, Michelle AT, Huff, Chad, Huntsman, David G, Jensen, Allan, Kar, Siddhartha, Karlan, Beth Y, Khusnutdinova, Elza K, Kiemeney, Lambertus A, Kjaer, Susanne K, Kupryjanczyk, Jolanta, Labrie, Marilyne, Lambrechts, Diether, Le, Nhu D, Lubiński, Jan, May, Taymaa, Menon, Usha, Milne, Roger L, Modugno, Francesmary, Monteiro, Alvaro N, Moysich, Kirsten B, Odunsi, Kunle, Olsson, Håkan, Pearce, Celeste L, Pejovic, Tanja, Ramus, Susan J, Riboli, Elio, Riggan, Marjorie J, Romieu, Isabelle, Sandler, Dale P, Schildkraut, Joellen M, Setiawan, V Wendy, Sieh, Weiva, Song, Honglin, Sutphen, Rebecca, Terry, Kathryn L, Thompson, Pamela J, Titus, Linda, Tworoger, Shelley S, Van Nieuwenhuysen, Els, Edwards, Digna Velez, Webb, Penelope M, Wentzensen, Nicolas, Whittemore, Alice S, Wolk, Alicja, Wu, Anna H, Ziogas, Argyrios, Freedman, Matthew L, Lawrenson, Kate, Pharoah, Paul DP, Easton, Douglas F, Gayther, Simon A, and Jones, Michelle R
Subjects: Ovarian Neoplasms, DNA Copy Number Variations, Prevention, Carcinoma, Human Genome, Oncology and Carcinogenesis, AOCS Group, Single Nucleotide, Ovarian Cancer, Rare Diseases, Ovarian Epithelial, OPAL Study Group, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Female, Genetic Testing, Oncology & Carcinogenesis, Polymorphism, Aetiology, Alleles, Genome-Wide Association Study, Cancer
Abstract: BackgroundKnown risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort.MethodsSingle nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types.ResultsWe identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P
Published: 2022

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

Author: Dareng, Eileen O., Tyrer, Jonathan P., Barnes, Daniel R., Jones, Michelle R., Yang, Xin, Aben, Katja K. H., Adank, Muriel A., Agata, Simona, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Arun, Banu K., Augustinsson, Annelie, Balmaña, Judith, Bandera, Elisa V., Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia V., Bonanni, Bernardo, Borg, Ake, Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S., Cai, Hui, Caligo, Maria A., Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K., Claes, Kathleen, Colonna, Sarah, Lesueur, Fabienne, Mebirouk, Noura, Engel, Christoph, Schmutzler, Rita K., Davies, Eleanor, Eccles, Diana M., Evans, D. Gareth, Cook, Linda S., Couch, Fergus J., Daly, Mary B., Dao, Fanny, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A., Domchek, Susan M., Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eliassen, Heather A., Evans, Gareth D., Fasching, Peter A., Flanagan, James M., Fortner, Renée T., Machackova, Eva, Friedman, Eitan, Ganz, Patricia A., Garber, Judy, Gensini, Francesca, Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hamann, Ute, Hansen, Thomas V. O., Harris, Holly R., Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle A. T., Høgdall, Estrid, Høgdall, Claus K., Hopper, John L., Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J., Huntsman, David G., Imyanitov, Evgeny N., Chenevix-Trench, Georgia, van der Hout, Annemieke H., Isaacs, Claudine, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th., John, Esther M., Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony, Kelemen, Linda E., Khusnutdinova, Elza, Kiemeney, Lambertus A., Kim, Byoung-Gie, Kjaer, Susanne K., Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W., Kwong, Ava, Lambrechts, Diether, Larson, Melissa C., Lazaro, Conxi, Le, Nhu D., Leslie, Goska, Lester, Jenny, Levine, Douglas A., Li, Lian, Li, Jingmei, Loud, Jennifer T., Lu, Karen H., Lubiński, Jan, Mai, Phuong L., Manoukian, Siranoush, Marks, Jeffrey R., Matsuno, Rayna Kim, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R., McNeish, Iain A., Menon, Usha, Miller, Austin, Milne, Roger L., Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Munro, Elizabeth, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nielsen, Henriette Roed, Nielsen, Finn C., Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo I., Olson, Sara H., Olsson, Håkan, Osorio, Ana, Papi, Laura, Park, Sue K., Parsons, Michael T., Pathak, Harsha, Pedersen, Inge Sokilde, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B., Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J., Risch, Harvey A., Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P., Santamariña, Marta, Soucy, Penny, Setiawan, V. Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sokolenko, Anna P., Song, Honglin, Southey, Melissa C., Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J., Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Terry, Kathryn L., Terry, Mary Beth, Thompson, Pamela J., Thomsen, Liv Cecilie Vestrheim, Titus, Linda, Trabert, Britton, Travis, Ruth, Tworoger, Shelley S., Valen, Ellen, van Altena, Anne M., Van Nieuwenhuysen, Els, Edwards, Digna Velez, Vierkant, Robert A., Wang, Frances, Webb, Penelope M., Weinberg, Clarice R., Wentzensen, Nicolas, White, Emily, Whittemore, Alice S., Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zheng, Wei, Ziogas, Argyrios, Lawrenson, Kate, deFazio, Anna, Ramus, Susan J., Pearce, Celeste L., Monteiro, Alvaro N., Cunningham, Julie M., Goode, Ellen L., Schildkraut, Joellen M., Berchuck, Andrew, Gayther, Simon A., Pharoah, Paul D. P., Claes, Kathleen B. M., Thomassen, Mads, Thull, Darcy L., Tischkowitz, Marc, Toland, Amanda E., Torres, Diana, Tung, Nadine, van Rensburg, Elizabeth J., Vega, Ana, Wappenschmidt, Barbara, Weitzel, Jeffrey N., Zavaglia, Katia M., Zorn, Kristin K., Sellers, Thomas A., Antoniou, Antonis C., Kleibl, Zdenek, Easton, Douglas, DeFazio, Anna, Cunningham, Julie, GEMO Study Collaborators, [missing], GC-HBOC Study Collaborators, [missing], EMBRACE Collaborators, [missing], OPAL Study Group, [missing], AOCS Group, [missing], KConFab Investigators, [missing], HEBON Investigators, [missing], The OCAC Consortium, [missing], The CIMBA Consortium, [missing], Clinicum, Department of Pathology, HUSLAB, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, Faculteit Medische Wetenschappen/UMCG, Institut Català de la Salut, [Dareng EO, Barnes DR, Yang X] University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Cambridge, UK. [Tyrer JP] University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of Oncology, Cambridge, UK. [Jones MR] Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA. [Aben KKH] Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands. Netherlands Comprehensive Cancer Organisation, Utrecht, The Netherlands. [Balmaña J] Hereditary cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Diez O] Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Ovarian Cancer Action, and National Institute for Health Research
Subjects: Male, Biochemistry & Molecular Biology, OCAC Consortium, Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES], Breast Neoplasms, Ovaris - Càncer - Aspectes genètics, Carcinoma, Ovarian Epithelial, SUSCEPTIBILITY, Polymorphism, Single Nucleotide, GEMO Study Collaborators, Risk Factors, OPAL Study Group, Other subheadings::Other subheadings::/genetics [Other subheadings], Medicine and Health Sciences, Genetics, Ovaris - Càncer - Propensió, Humans, Genetic Predisposition to Disease, Prospective Studies, EMBRACE Collaborators, GC-HBOC Study Collaborators, Genetics (clinical), HEBON Investigators, fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS], Medicinsk genetik, Ovarian Neoplasms, Genetics & Heredity, 0604 Genetics, Science & Technology, Otros calificadores::Otros calificadores::/genética [Otros calificadores], 1184 Genetics, developmental biology, physiology, Neoplasms::Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian Neoplasms::Carcinoma, Ovarian Epithelial [DISEASES], 1103 Clinical Sciences, Bayes Theorem, AOCS Group, neoplasias::neoplasias::neoplasias por localización::neoplasias de las glándulas endocrinas::neoplasias ováricas::carcinoma epitelial de ovario [ENFERMEDADES], Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Carcinoma, Ovarian Epithelial/genetics, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], CIMBA Consortium, 1182 Biochemistry, cell and molecular biology, Female, KConFab Investigators, Ovarian Neoplasms/epidemiology, Medical Genetics, Life Sciences & Biomedicine
Abstract: Clinical genetics; Genetic markers; Risk factors Genética clínica; Marcadores genéticos; Factores de riesgo Genètica clínica; Marcadors genètics; Factors de risc Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28–1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08–1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21–1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29–1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35–1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
Published: 2022

7. Pancreatic Pain-Knowledge Gaps and Research Opportunities in Children and Adults: Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop

Author: Uc, Aliye, Andersen, Dana K, Apkarian, A Vania, Bellin, Melena D, Colloca, Luana, Drewes, Asbjørn M, Dunbar, Ellyn K, Forsmark, Christopher E, Goodman, Marc T, Kapural, Leonardo, Koob, George F, Palermo, Tonya M, Pandol, Stephen J, Pasricha, Pankaj, Phillips, Anna E, Piomelli, Daniele, Saloman, Jami L, Schwarzenberg, Sarah Jane, Singh, Vikesh K, Sowa, Gwendolyn, Strouse, Thomas, Treisman, Glenn J, Windsor, John A, and Yadav, Dhiraj
Subjects: Adult, Biomedical Research, pancreatic cancer, Clinical Sciences, pancreatitis, peripheral sensitization, quantitative sensory testing, Pancreatic Cancer, Rare Diseases, Humans, Pain Management, 2.1 Biological and endogenous factors, Aetiology, Child, Cancer, Gastroenterology & Hepatology, Pain Research, Neurosciences, Pancreatic Diseases, central sensitization, United States, Abdominal Pain, National Institute of Diabetes and Digestive and Kidney Diseases (U.S.), placebo, Chronic Pain, Digestive Diseases
Abstract: A workshop was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases to focus on research gaps and opportunities in pancreatic pain. The event was held on July 21, 2021, and structured into 4 sessions: (1) pathophysiology; (2) biomarkers, mediators, and pharmacology of pain; (3) pain assessment; and (4) pain treatment challenges and opportunities. The current state of knowledge was reviewed; many knowledge gaps and research needs were identified that require further investigation. Common themes included the need to better understand the underlying mechanisms of pain in pancreatic diseases, the relationship of visceral neural pathways and central pain centers, the role of behavioral factors and disorders on the perception of pain, and differences in pain perception and processes in children when compared with adults. In addition, the role of genetic risk factors for pain and the mechanisms and role of placebos in pain treatment were discussed. Methods of pain assessment including quantitative sensory testing were examined, as well as the process of central sensitization of pain. Finally, newer approaches to pain management including cognitive behavioral therapy, nerve stimulation, experimental (nonopioid) drugs, and cannabinoid compounds were covered.
Published: 2021

8. Menopausal hormone therapy prior to the diagnosis of ovarian cancer is associated with improved survival

Author: Brieger, Katharine K, Peterson, Siri, Lee, Alice W, Mukherjee, Bhramar, Bakulski, Kelly M, Alimujiang, Aliya, Anton-Culver, Hoda, Anglesio, Michael S, Bandera, Elisa V, Berchuck, Andrew, Bowtell, David DL, Chenevix-Trench, Georgia, Cho, Kathleen R, Cramer, Daniel W, DeFazio, Anna, Doherty, Jennifer A, Fortner, Renée T, Garsed, Dale W, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Goode, Ellen L, Goodman, Marc T, Harris, Holly R, Høgdall, Estrid, Huntsman, David G, Shen, Hui, Jensen, Allan, Johnatty, Sharon E, Jordan, Susan J, Kjaer, Susanne K, Kupryjanczyk, Jolanta, Lambrechts, Diether, McLean, Karen, Menon, Usha, Modugno, Francesmary, Moysich, Kirsten, Ness, Roberta, Ramus, Susan J, Richardson, Jean, Risch, Harvey, Rossing, Mary Anne, Trabert, Britton, Wentzensen, Nicolas, Ziogas, Argyrios, Terry, Kathryn L, Wu, Anna H, Hanley, Gillian E, Pharoah, Paul, Webb, Penelope M, Pike, Malcolm C, Pearce, Celeste Leigh, and Ovarian Cancer Association Consortium
Subjects: Ovarian Neoplasms, Aging, Hormone Replacement Therapy, Ovarian Cancer Association Consortium, Estrogen Replacement Therapy, Oncology and Carcinogenesis, Middle Aged, Estrogen, Progression-Free Survival, Ovarian Cancer, Survival Rate, Postmenopause, Paediatrics and Reproductive Medicine, Rare Diseases, Residual, Humans, Neoplasm, Female, Oncology & Carcinogenesis, Progestins, Neoplasm Staging, Proportional Hazards Models, Aged, Cancer
Abstract: PurposePrior studies of menopausal hormone therapy (MHT) and ovarian cancer survival have been limited by lack of hormone regimen detail and insufficient sample sizes. To address these limitations, a comprehensive analysis of 6419 post-menopausal women with pathologically confirmed ovarian carcinoma was conducted to examine the association between MHT use prior to diagnosis and survival.MethodsData from 15 studies in the Ovarian Cancer Association Consortium were included. MHT use was examined by type (estrogen-only (ET) or estrogen+progestin (EPT)), duration, and recency of use relative to diagnosis. Cox proportional hazards models were used to estimate the association between hormone therapy use and survival. Logistic regression and mediation analysis was used to explore the relationship between MHT use and residual disease following debulking surgery.ResultsUse of ET or EPT for at least five years prior to diagnosis was associated with better ovarian cancer survival (hazard ratio, 0.80; 95% CI, 0.74 to 0.87). Among women with advanced stage, high-grade serous carcinoma, those who used MHT were less likely to have any macroscopic residual disease at the time of primary debulking surgery (p for trend
Published: 2020

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

Author: Kang, Eun Young, Cheasley, Dane, LePage, Cecile, Wakefield, Matthew J, Da Cunha Torres, Michelle, Rowley, Simone, Salazar, Carolina, Xing, Zhongyue, Allan, Prue, Bowtell, David DL, Mes-Masson, Anne-Marie, Provencher, Diane M, Rahimi, Kurosh, Kelemen, Linda E, Fasching, Peter A, Doherty, Jennifer A, Goodman, Marc T, Goode, Ellen L, Deen, Suha, Pharoah, Paul DP, Brenton, James D, Sieh, Weiva, Mateoiu, Constantina, Sundfeldt, Karin, Cook, Linda S, Le, Nhu D, Anglesio, Michael S, Gilks, C Blake, Huntsman, David G, Kennedy, Catherine J, Traficante, Nadia, Australian Ovarian Cancer Study, DeFazio, Anna, Kaufmann, Scott, Churchman, Michael, Gourley, Charlie, Stephens, Andrew N, Meagher, Nicola S, Ramus, Susan J, Antill, Yoland C, Campbell, Ian, Scott, Clare L, Köbel, Martin, Gorringe, Kylie L, GAMuT Collaborators, LePage, Cecile [0000-0002-8020-1544], Fasching, Peter A [0000-0003-4885-8471], Pharoah, Paul DP [0000-0001-8494-732X], Anglesio, Michael S [0000-0003-1639-5003], Churchman, Michael [0000-0003-1958-7692], Meagher, Nicola S [0000-0001-9134-2118], Campbell, Ian [0000-0002-7773-4155], Scott, Clare L [0000-0002-3689-5956], Köbel, Martin [0000-0002-6615-2037], Gorringe, Kylie L [0000-0001-5681-2022], and Apollo - University of Cambridge Repository
Subjects: Adult, Observer Variation, Ovarian Neoplasms, endocrine system diseases, DNA Mutational Analysis, Australia, Reproducibility of Results, Middle Aged, Prognosis, Immunohistochemistry, Risk Assessment, United Kingdom, Predictive Value of Tests, Risk Factors, Tissue Array Analysis, Mutation, North America, Biomarkers, Tumor, Humans, Female, Tumor Suppressor Protein p53, Neoplasms, Cystic, Mucinous, and Serous, neoplasms
Abstract: TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5-14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MBOT with a higher risk of mortality.
Published: 2020
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10. Association between genetically predicted polycystic ovary syndrome and ovarian cancer: a Mendelian randomization study

Author: Harris, Holly R, Cushing-Haugen, Kara L, Webb, Penelope M, Nagle, Christina M, Jordan, Susan J, Australian Ovarian Cancer Study Group, Risch, Harvey A, Rossing, Mary Anne, Doherty, Jennifer A, Goodman, Marc T, Modugno, Francesmary, Ness, Roberta B, Moysich, Kirsten B, Kjær, Susanne K, Høgdall, Estrid, Jensen, Allan, Schildkraut, Joellen M, Berchuck, Andrew, Cramer, Daniel W, Bandera, Elisa V, Rodriguez, Lorna, Wentzensen, Nicolas, Kotsopoulos, Joanne, Narod, Steven A, McLaughlin, John R, Anton-Culver, Hoda, Ziogas, Argyrios, Pearce, Celeste L, Wu, Anna H, Lindström, Sara, and Terry, Kathryn L
Subjects: Australian Ovarian Cancer Study Group, Endometrioid, Epidemiology, Reproductive health and childbirth, Adenocarcinoma, Clear Cell, Cystic, Rare Diseases, histotype, Clinical Research, Neoplasms, Mendelian randomization, Genetics, Humans, Mucinous, Polycystic ovary syndrome, Cancer, Ovarian Neoplasms, and Serous, Prevention, Contraception/Reproduction, Carcinoma, Statistics, Mendelian Randomization Analysis, Ovarian Cancer, Good Health and Well Being, Infertility, Public Health and Health Services, Female
Abstract: BackgroundPolycystic ovary syndrome (PCOS) is a complex endocrine disorder with an estimated prevalence of 4-21% in reproductive aged women. Recently, the Ovarian Cancer Association Consortium (OCAC) reported a decreased risk of invasive ovarian cancer among women with self-reported PCOS. However, given the limitations of self-reported PCOS, the validity of these observed associations remains uncertain. Therefore, we sought to use Mendelian randomization with genetic markers as a proxy for PCOS, to examine the association between PCOS and ovarian cancer.MethodsUtilizing 14 single nucleotide polymorphisms (SNPs) previously associated with PCOS we assessed the association between genetically predicted PCOS and ovarian cancer risk, overall and by histotype, using summary statistics from a previously conducted genome-wide association study (GWAS) of ovarian cancer among European ancestry women within the OCAC (22406 with invasive disease, 3103 with borderline disease and 40941 controls).ResultsAn inverse association was observed between genetically predicted PCOS and invasive ovarian cancer risk: odds ratio (OR)=0.92 [95% confidence interval (CI)=0.85-0.99; P = 0.03]. When results were examined by histotype, the strongest inverse association was observed between genetically predicted PCOS and endometrioid tumors (OR = 0.77; 95% CI = 0.65-0.92; P = 0.003). Adjustment for individual-level body mass index, oral contraceptive use and parity did not materially change the associations.ConclusionOur study provides evidence for a relationship between PCOS and reduced ovarian cancer risk, overall and among specific histotypes of invasive ovarian cancer. These results lend support to our previous observational study results. Future studies are needed to understand mechanisms underlying this association.
Published: 2019

11. Genome-wide association studies identify susceptibility loci for epithelial ovarian cancer in east Asian women

Author: Lawrenson, Kate, Song, Fengju, Hazelett, Dennis J, Kar, Siddhartha P, Tyrer, Jonathan, Phelan, Catherine M, Corona, Rosario I, Rodríguez-Malavé, Norma I, Seo, Ji-Hei, Adler, Emily, Coetzee, Simon G, Segato, Felipe, Fonseca, Marcos AS, Amos, Christopher I, Carney, Michael E, Chenevix-Trench, Georgia, Choi, Jiyeob, Doherty, Jennifer A, Jia, Weihua, Jin, Gang J, Kim, Byoung-Gie, Le, Nhu D, Lee, Juyeon, Li, Lian, Lim, Boon K, Adenan, Noor A, Mizuno, Mika, Park, Boyoung, Pearce, Celeste L, Shan, Kang, Shi, Yongyong, Shu, Xiao-Ou, Sieh, Weiva, Australian Ovarian Cancer Study Group, Thompson, Pamela J, Wilkens, Lynne R, Wei, Qingyi, Woo, Yin L, Yan, Li, Karlan, Beth Y, Freedman, Matthew L, Noushmehr, Houtan, Goode, Ellen L, Berchuck, Andrew, Sellers, Thomas A, Teo, Soo-Hwang, Zheng, Wei, Matsuo, Keitaro, Park, Sue, Chen, Kexin, Pharoah, Paul DP, Gayther, Simon A, Goodman, Marc T, Tyrer, Jonathan [0000-0003-3724-4757], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: Australian Ovarian Cancer Study Group, Genome-wide association study, Quantitative Trait Loci, Oncology and Carcinogenesis, Carcinoma, Ovarian Epithelial, eQTL, Polymorphism, Single Nucleotide, Asian ancestry, Paediatrics and Reproductive Medicine, Rare Diseases, Asian People, Clinical Research, Ovarian Epithelial, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Polymorphism, Aetiology, Cancer, Base Sequence, Prevention, Carcinoma, Human Genome, Single Nucleotide, Epithelial ovarian cancer, Gene regulation, Ovarian Cancer, Case-Control Studies, Female, Enhancer, Biotechnology
Abstract: OBJECTIVE: Genome-wide association studies (GWASs) for epithelial ovarian cancer (EOC) have focused largely on populations of European ancestry. We aimed to identify common germline variants associated with EOC risk in Asian women. METHODS: Genotyping was performed as part of the OncoArray project. Samples with >60% Asian ancestry were included in the analysis. Genotyping was performed on 533,631 SNPs in 3238 Asian subjects diagnosed with invasive or borderline EOC and 4083 unaffected controls. After imputation, genotypes were available for 11,595,112 SNPs to identify associations. RESULTS: At chromosome 6p25.2, SNP rs7748275 was associated with risk of serous EOC (odds ratio [OR] = 1.34, P = 8.7 × 10-9) and high-grade serous EOC (HGSOC) (OR = 1.34, P = 4.3 × 10-9). SNP rs6902488 at 6p25.2 (r2 = 0.97 with rs7748275) lies in an active enhancer and is predicted to impact binding of STAT3, P300 and ELF1. We identified additional risk loci with low Bayesian false discovery probability (BFDP) scores, indicating they are likely to be true risk associations (BFDP
Published: 2019

12. Microbiome and bile acid profiles in duodenal aspirates from patients with liver cirrhosis: The Microbiome, Microbial Markers and Liver Disease Study

Author: Jacobs, Jonathan P, Dong, Tien S, Agopian, Vatche, Lagishetty, Venu, Sundaram, Vinay, Noureddin, Mazen, Ayoub, Walid S, Durazo, Francisco, Benhammou, Jihane, Enayati, Pedram, Elashoff, David, Goodman, Marc T, Pisegna, Joseph, and Hussain, Shehnaz
Subjects: bile acids, Liver Cancer, Gastroenterology & Hepatology, cirrhosis, Prevention, Liver Disease, Chronic Liver Disease and Cirrhosis, Human Genome, Clinical Sciences, microbiome, Oral and gastrointestinal, Hepatitis, Rare Diseases, Infectious Diseases, Emerging Infectious Diseases, Good Health and Well Being, Clinical Research, Genetics, Digestive Diseases, Cancer
Abstract: AimCirrhosis is a leading cause of death worldwide, yet there are no well-established risk stratifying tools for lethal complications, including hepatocellular carcinoma (HCC). Patients with liver cirrhosis undergo routine endoscopic surveillance, providing ready access to duodenal aspirate samples that could be a source for identifying novel biomarkers. The aim of this study was to characterize the microbiome and bile acid profiles in duodenal aspirates from patients with liver cirrhosis to assess the feasibility of developing biomarkers for HCC risk stratification.MethodsThirty patients with liver cirrhosis were enrolled in the Microbiome, Microbial Markers, and Liver Disease study between May 2015 and March 2017. Detailed clinical and epidemiological data were collected at baseline and at 6-monthly follow-up visits. Duodenal aspirate fluid was collected at baseline for microbial characterization using 16S ribosomal RNA sequencing and bile acid quantification using mass spectroscopy.ResultsAlcohol-related cirrhosis was associated with reductions in the Bacteroidetes phylum, particularly Prevotella (13-fold reduction), and expansion of Staphylococcus (13-fold increase), compared to hepatitis C virus-related cirrhosis. Participants with hepatic encephalopathy (HE) had less microbial diversity compared to patients without HE (P
Published: 2018

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

Author: Lu, Yingchang, Beeghly-Fadiel, Alicia, Wu, Lang, Guo, Xingyi, Li, Bingshan, Schildkraut, Joellen M, Im, Hae Kyung, Chen, Yian A, Permuth, Jennifer B, Reid, Brett M, Teer, Jamie K, Moysich, Kirsten B, Andrulis, Irene L, Anton-Culver, Hoda, Arun, Banu K, Bandera, Elisa V, Barkardottir, Rosa B, Barnes, Daniel R, Benitez, Javier, Bjorge, Line, Brenton, James, Butzow, Ralf, Caldes, Trinidad, Caligo, Maria A, Campbell, Ian, Chang-Claude, Jenny, Claes, Kathleen BM, Couch, Fergus J, Cramer, Daniel W, Daly, Mary B, deFazio, Anna, Dennis, Joe, Diez, Orland, Domchek, Susan M, Dörk, Thilo, Easton, Douglas F, Eccles, Diana M, Fasching, Peter A, Fortner, Renée T, Fountzilas, George, Friedman, Eitan, Ganz, Patricia A, Garber, Judy, Giles, Graham G, Godwin, Andrew K, Goldgar, David E, Goodman, Marc T, Greene, Mark H, Gronwald, Jacek, Hamann, Ute, Heitz, Florian, Hildebrandt, Michelle AT, Høgdall, Claus K, Hollestelle, Antoinette, Hulick, Peter J, Huntsman, David G, Imyanitov, Evgeny N, Isaacs, Claudine, Jakubowska, Anna, James, Paul, Karlan, Beth Y, Kelemen, Linda E, Kiemeney, Lambertus A, Kjaer, Susanne K, Kwong, Ava, Le, Nhu D, Leslie, Goska, Lesueur, Fabienne, Levine, Douglas A, Mattiello, Amalia, May, Taymaa, McGuffog, Lesley, McNeish, Iain A, Merritt, Melissa A, Modugno, Francesmary, Montagna, Marco, Neuhausen, Susan L, Nevanlinna, Heli, Nielsen, Finn C, Nikitina-Zake, Liene, Nussbaum, Robert L, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Olson, Sara H, Olsson, Håkan, Osorio, Ana, Park, Sue K, Parsons, Michael T, Peeters, Petra HM, Pejovic, Tanja, Peterlongo, Paolo, Phelan, Catherine M, Pujana, Miquel Angel, Ramus, Susan J, Rennert, Gad, Risch, Harvey, Rodriguez, Gustavo C, Rodríguez-Antona, Cristina, and Romieu, Isabelle
Subjects: endocrine system diseases, Genotype, Carcinogenesis, Quantitative Trait Loci, Oncology and Carcinogenesis, Cohort Studies, Rare Diseases, Risk Factors, Ovarian Epithelial, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Polymorphism, Aetiology, Cancer, Ovarian Neoplasms, Gene Expression Profiling, Prevention, Carcinoma, Human Genome, Single Nucleotide, Prognosis, female genital diseases and pregnancy complications, Ovarian Cancer, Female, Transcriptome, Genome-Wide Association Study
Abstract: Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10-6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10-7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10-3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419-30. ©2018 AACR.
Published: 2018

14. Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study

Author: Dixon-Suen, Suzanne C, Nagle, Christina M, Thrift, Aaron P, Pharoah, Paul DP, Ewing, Ailith, Pearce, Celeste Leigh, Zheng, Wei, Australian Ovarian Cancer Study Group, Chenevix-Trench, Georgia, Fasching, Peter A, Beckmann, Matthias W, Lambrechts, Diether, Vergote, Ignace, Lambrechts, Sandrina, Van Nieuwenhuysen, Els, Rossing, Mary Anne, Doherty, Jennifer A, Wicklund, Kristine G, Chang-Claude, Jenny, Jung, Audrey Y, Moysich, Kirsten B, Odunsi, Kunle, Goodman, Marc T, Wilkens, Lynne R, Thompson, Pamela J, Shvetsov, Yurii B, Dörk, Thilo, Park-Simon, Tjoung-Won, Hillemanns, Peter, Bogdanova, Natalia, Butzow, Ralf, Nevanlinna, Heli, Pelttari, Liisa M, Leminen, Arto, Modugno, Francesmary, Ness, Roberta B, Edwards, Robert P, Kelley, Joseph L, Heitz, Florian, du Bois, Andreas, Harter, Philipp, Schwaab, Ira, Karlan, Beth Y, Lester, Jenny, Orsulic, Sandra, Rimel, Bobbie J, Kjær, Susanne K, Høgdall, Estrid, Jensen, Allan, Goode, Ellen L, Fridley, Brooke L, Cunningham, Julie M, Winham, Stacey J, Giles, Graham G, Bruinsma, Fiona, Milne, Roger L, Southey, Melissa C, Hildebrandt, Michelle AT, Wu, Xifeng, Lu, Karen H, Liang, Dong, Levine, Douglas A, Bisogna, Maria, Schildkraut, Joellen M, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Bandera, Elisa V, Olson, Sara H, Salvesen, Helga B, Thomsen, Liv Cecilie Vestrheim, Kopperud, Reidun K, Bjorge, Line, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Bruegl, Amanda, Cook, Linda S, Le, Nhu D, Swenerton, Kenneth D, Brooks-Wilson, Angela, Kelemen, Linda E, Lubiński, Jan, Huzarski, Tomasz, Gronwald, Jacek, Menkiszak, Janusz, Wentzensen, Nicolas, Brinton, Louise, Yang, Hannah, Lissowska, Jolanta, Høgdall, Claus K, Lundvall, Lene, Song, Honglin, Tyrer, Jonathan P, Campbell, Ian, Eccles, Diana, Paul, James, Glasspool, Rosalind, Siddiqui, Nadeem, and Whittemore, Alice S
Subjects: Australian Ovarian Cancer Study Group, Adult, Adolescent, Ovarian Cancer Association Consortium, Oncology and Carcinogenesis, Young Adult, Rare Diseases, Risk Factors, Clinical Research, Ovarian Epithelial, 80 and over, Genetics, Humans, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Aged, Cancer, Ovarian Neoplasms, Geography, Carcinoma, Middle Aged, Mendelian Randomization Analysis, Body Height, Ovarian Cancer, Case-Control Studies, Public Health and Health Services, Female
Abstract: BackgroundObservational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias.MethodsWe pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted geneticrisk score combining 609 single-nucleotide polymorphisms. Study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted height and risk were pooled using random-effects meta-analysis.ResultsGreater genetically predicted height was associated with increased ovarian cancer risk overall (pooled-OR (pOR) = 1.06; 95% CI: 1.01-1.11 per 5 cm increase in height), and separately for invasive (pOR = 1.06; 95% CI: 1.01-1.11) and borderline (pOR = 1.15; 95% CI: 1.02-1.29) tumours.ConclusionsWomen with a genetic propensity to being taller have increased risk of ovarian cancer. This suggests genes influencing height are involved in pathways promoting ovarian carcinogenesis.
Published: 2018

15. Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study

Author: Dixon-Suen, Suzanne C, Nagle, Christina M, Thrift, Aaron P, Pharoah, Paul DP, Ewing, Ailith, Pearce, Celeste Leigh, Zheng, Wei, Australian Ovarian Cancer Study Group, Chenevix-Trench, Georgia, Fasching, Peter A, Beckmann, Matthias W, Lambrechts, Diether, Vergote, Ignace, Lambrechts, Sandrina, Van Nieuwenhuysen, Els, Rossing, Mary Anne, Doherty, Jennifer A, Wicklund, Kristine G, Chang-Claude, Jenny, Jung, Audrey Y, Moysich, Kirsten B, Odunsi, Kunle, Goodman, Marc T, Wilkens, Lynne R, Thompson, Pamela J, Shvetsov, Yurii B, Dörk, Thilo, Park-Simon, Tjoung-Won, Hillemanns, Peter, Bogdanova, Natalia, Butzow, Ralf, Nevanlinna, Heli, Pelttari, Liisa M, Leminen, Arto, Modugno, Francesmary, Ness, Roberta B, Edwards, Robert P, Kelley, Joseph L, Heitz, Florian, du Bois, Andreas, Harter, Philipp, Schwaab, Ira, Karlan, Beth Y, Lester, Jenny, Orsulic, Sandra, Rimel, Bobbie J, Kjær, Susanne K, Høgdall, Estrid, Jensen, Allan, Goode, Ellen L, Fridley, Brooke L, Cunningham, Julie M, Winham, Stacey J, Giles, Graham G, Bruinsma, Fiona, Milne, Roger L, Southey, Melissa C, Hildebrandt, Michelle AT, Wu, Xifeng, Lu, Karen H, Liang, Dong, Levine, Douglas A, Bisogna, Maria, Schildkraut, Joellen M, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Bandera, Elisa V, Olson, Sara H, Salvesen, Helga B, Thomsen, Liv Cecilie Vestrheim, Kopperud, Reidun K, Bjorge, Line, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Bruegl, Amanda, Cook, Linda S, Le, Nhu D, Swenerton, Kenneth D, Brooks-Wilson, Angela, Kelemen, Linda E, Lubiński, Jan, Huzarski, Tomasz, Gronwald, Jacek, Menkiszak, Janusz, Wentzensen, Nicolas, Brinton, Louise, Yang, Hannah, Lissowska, Jolanta, Høgdall, Claus K, Lundvall, Lene, Song, Honglin, Tyrer, Jonathan P, Campbell, Ian, Eccles, Diana, Paul, James, Glasspool, Rosalind, Siddiqui, Nadeem, Whittemore, Alice S, Sieh, Weiva, McGuire, Valerie, Rothstein, Joseph H, Narod, Steven A, Phelan, Catherine, Risch, Harvey A, McLaughlin, John R, Anton-Culver, Hoda, Ziogas, Argyrios, Menon, Usha, Gayther, Simon A, Ramus, Susan J, Gentry-Maharaj, Aleksandra, Wu, Anna H, Pike, Malcolm C, Tseng, Chiu-Chen, Kupryjanczyk, Jolanta, Dansonka-Mieszkowska, Agnieszka, Budzilowska, Agnieszka, Rzepecka, Iwona K, Webb, Penelope M, Ovarian Cancer Association Consortium, Dixon-Suen, Suzanne C [0000-0003-3714-8386], Zheng, Wei [0000-0003-1226-070X], Brinton, Louise [0000-0003-3853-8562], Glasspool, Rosalind [0000-0002-5000-1680], and Apollo - University of Cambridge Repository
Subjects: Adult, Aged, 80 and over, Ovarian Neoplasms, Adolescent, Geography, Carcinoma, Ovarian Epithelial, Mendelian Randomization Analysis, Middle Aged, Body Height, Young Adult, Risk Factors, Case-Control Studies, Humans, Female, Genetic Predisposition to Disease, Aged
Abstract: BACKGROUND: Observational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias. METHODS: We pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted genetic risk score combining 609 single-nucleotide polymorphisms. Study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted height and risk were pooled using random-effects meta-analysis. RESULTS: Greater genetically predicted height was associated with increased ovarian cancer risk overall (pooled-OR (pOR) = 1.06; 95% CI: 1.01-1.11 per 5 cm increase in height), and separately for invasive (pOR = 1.06; 95% CI: 1.01-1.11) and borderline (pOR = 1.15; 95% CI: 1.02-1.29) tumours. CONCLUSIONS: Women with a genetic propensity to being taller have increased risk of ovarian cancer. This suggests genes influencing height are involved in pathways promoting ovarian carcinogenesis.
Published: 2018

16. MyD88 and TLR4 Expression in Epithelial Ovarian Cancer

Author: Block, Matthew S, Vierkant, Robert A, Rambau, Peter F, Winham, Stacey J, Wagner, Philipp, Traficante, Nadia, Tołoczko, Aleksandra, Tiezzi, Daniel G, Taran, Florin Andrei, Sinn, Peter, Sieh, Weiva, Sharma, Raghwa, Rothstein, Joseph H, Ramón Y Cajal, Teresa, Paz-Ares, Luis, Oszurek, Oleg, Orsulic, Sandra, Ness, Roberta B, Nelson, Gregg, Modugno, Francesmary, Menkiszak, Janusz, McGuire, Valerie, McCauley, Bryan M, Mack, Marie, Lubiński, Jan, Longacre, Teri A, Li, Zheng, Lester, Jenny, Kennedy, Catherine J, Kalli, Kimberly R, Jung, Audrey Y, Johnatty, Sharon E, Jimenez-Linan, Mercedes, Jensen, Allan, Intermaggio, Maria P, Hung, Jillian, Herpel, Esther, Hernandez, Brenda Y, Hartkopf, Andreas D, Harnett, Paul R, Ghatage, Prafull, García-Bueno, José M, Gao, Bo, Fereday, Sian, Eilber, Ursula, Edwards, Robert P, de Sousa, Christiani B, de Andrade, Jurandyr M, Chudecka-Głaz, Anita, Chenevix-Trench, Georgia, Cazorla, Alicia, Brucker, Sara Y, Australian Ovarian Cancer Study Group, Alsop, Jennifer, Whittemore, Alice S, Steed, Helen, Staebler, Annette, Moysich, Kirsten B, Menon, Usha, Koziak, Jennifer M, Kommoss, Stefan, Kjaer, Susanne K, Kelemen, Linda E, Karlan, Beth Y, Huntsman, David G, Høgdall, Estrid, Gronwald, Jacek, Goodman, Marc T, Gilks, Blake, García, María José, Fasching, Peter A, de Fazio, Anna, Deen, Suha, Chang-Claude, Jenny, Candido Dos Reis, Francisco J, Campbell, Ian G, Brenton, James D, Bowtell, David D, Benítez, Javier, Pharoah, Paul DP, Köbel, Martin, Ramus, Susan J, Goode, Ellen L, Brenton, James [0000-0002-5738-6683], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: Australian Ovarian Cancer Study Group, Ovarian Neoplasms, Adult, Tumor, Carcinoma, Carcinoma, Ovarian Epithelial, Middle Aged, Immunohistochemistry, Survival Analysis, Medical and Health Sciences, Ovarian Cancer, Toll-Like Receptor 4, Rare Diseases, Clinical Research, Tissue Array Analysis, Ovarian Epithelial, Myeloid Differentiation Factor 88, Biomarkers, Tumor, Humans, Female, Biomarkers, Cancer, Aged
Abstract: OBJECTIVE: To 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 METHODS: We 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). RESULTS: Expression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P
Published: 2018

17. Polycystic Ovary Syndrome, Oligomenorrhea, and Risk of Ovarian Cancer Histotypes: Evidence from the Ovarian Cancer Association Consortium

Author: Harris, Holly R, Babic, Ana, Webb, Penelope M, Nagle, Christina M, Jordan, Susan J, Risch, Harvey A, Rossing, Mary Anne, Doherty, Jennifer A, Goodman, Marc T, Modugno, Francesmary, Ness, Roberta B, Moysich, Kirsten B, Kjær, Susanne K, Høgdall, Estrid, Jensen, Allan, Schildkraut, Joellen M, Berchuck, Andrew, Cramer, Daniel W, Bandera, Elisa V, Wentzensen, Nicolas, Kotsopoulos, Joanne, Narod, Steven A, Phelan, Catherine M, McLaughlin, John R, Anton-Culver, Hoda, Ziogas, Argyrios, Pearce, Celeste L, Wu, Anna H, Terry, Kathryn L, Ovarian Cancer Association Consortium, and Australian Ovarian Cancer Study Group
Subjects: Australian Ovarian Cancer Study Group, Ovarian Neoplasms, Adult, Time Factors, Epidemiology, Ovarian Cancer Association Consortium, Contraception/Reproduction, Prevention, Middle Aged, Medical and Health Sciences, Ovarian Cancer, Oligomenorrhea, Logistic Models, Rare Diseases, Risk Factors, Clinical Research, Case-Control Studies, Infertility, Odds Ratio, Humans, Female, Self Report, Menstrual Cycle, Polycystic Ovary Syndrome, Cancer
Abstract: Background: Polycystic ovary syndrome (PCOS), and one of its distinguishing characteristics, oligomenorrhea, have both been associated with ovarian cancer risk in some but not all studies. However, these associations have been rarely examined by ovarian cancer histotypes, which may explain the lack of clear associations reported in previous studies.Methods: We analyzed data from 14 case-control studies including 16,594 women with invasive ovarian cancer (n = 13,719) or borderline ovarian disease (n = 2,875) and 17,718 controls. Adjusted study-specific ORs were calculated using logistic regression and combined using random-effects meta-analysis. Pooled histotype-specific ORs were calculated using polytomous logistic regression.Results: Women reporting menstrual cycle length >35 days had decreased risk of invasive ovarian cancer compared with women reporting cycle length ≤35 days [OR = 0.70; 95% confidence interval (CI) = 0.58-0.84]. Decreased risk of invasive ovarian cancer was also observed among women who reported irregular menstrual cycles compared with women with regular cycles (OR = 0.83; 95% CI = 0.76-0.89). No significant association was observed between self-reported PCOS and invasive ovarian cancer risk (OR = 0.87; 95% CI = 0.65-1.15). There was a decreased risk of all individual invasive histotypes for women with menstrual cycle length >35 days, but no association with serous borderline tumors (Pheterogeneity = 0.006). Similarly, we observed decreased risks of most invasive histotypes among women with irregular cycles, but an increased risk of borderline serous and mucinous tumors (Pheterogeneity < 0.0001).Conclusions: Our results suggest that menstrual cycle characteristics influence ovarian cancer risk differentially based on histotype.Impact: These results highlight the importance of examining ovarian cancer risk factors associations by histologic subtype. Cancer Epidemiol Biomarkers Prev; 27(2); 174-82. ©2017 AACR.
Published: 2018

18. Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility

Author: Earp, Madalene, Tyrer, Jonathan P, Winham, Stacey J, Lin, Hui-Yi, Chornokur, Ganna, Dennis, Joe, Aben, Katja KH, Anton-Culver, Hoda, Antonenkova, Natalia, Bandera, Elisa V, Bean, Yukie T, Beckmann, Matthias W, Bjorge, Line, Bogdanova, Natalia, Brinton, Louise A, Brooks-Wilson, Angela, Bruinsma, Fiona, Bunker, Clareann H, Butzow, Ralf, Campbell, Ian G, Carty, Karen, Chang-Claude, Jenny, Cook, Linda S, Cramer, Daniel W, Cunningham, Julie M, Cybulski, Cezary, Dansonka-Mieszkowska, Agnieszka, Despierre, Evelyn, Doherty, Jennifer A, Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Easton, Douglas F, Eccles, Diana M, Edwards, Robert P, Ekici, Arif B, Fasching, Peter A, Fridley, Brooke L, Gentry-Maharaj, Aleksandra, Giles, Graham G, Glasspool, Rosalind, Goodman, Marc T, Gronwald, Jacek, Harter, Philipp, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Hogdall, Claus K, Høgdall, Estrid, Hosono, Satoyo, Iversen, Edwin S, Jakubowska, Anna, Jensen, Allan, Ji, Bu-Tian, Jung, Audrey Y, Karlan, Beth Y, Kellar, Melissa, Kiemeney, Lambertus A, Kiong Lim, Boon, Kjaer, Susanne K, Krakstad, Camilla, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D, Lele, Shashi, Lester, Jenny, Levine, Douglas A, Li, Zheng, Liang, Dong, Lissowska, Jolanta, Lu, Karen, Lubinski, Jan, Lundvall, Lene, Massuger, Leon FAG, Matsuo, Keitaro, McGuire, Valerie, McLaughlin, John R, McNeish, Iain, Menon, Usha, Milne, Roger L, Modugno, Francesmary, Moysich, Kirsten B, Ness, Roberta B, Nevanlinna, Heli, Odunsi, Kunle, Olson, Sara H, Orlow, Irene, Orsulic, Sandra, Paul, James, Pejovic, Tanja, Pelttari, Liisa M, Permuth, Jenny B, Pike, Malcolm C, Poole, Elizabeth M, Rosen, Barry, Rossing, Mary Anne, Rothstein, Joseph H, Runnebaum, Ingo B, and Scott, Rodney John
Subjects: endocrine system diseases, Genotype, General Science & Technology, Quantitative Trait Loci, Carcinoma, Human Genome, A Kinase Anchor Proteins, Single Nucleotide, female genital diseases and pregnancy complications, Ovarian Cancer, Rare Diseases, Risk Factors, Ovarian Epithelial, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Female, Polymorphism, Aetiology, Genetic Association Studies, Rho Guanine Nucleotide Exchange Factors, Monomeric GTP-Binding Proteins, Biotechnology, Cancer
Abstract: Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.
Published: 2018

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

Author: 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, Brenton, James [0000-0002-5738-6683], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: CD8 Antigens, Oncology and Carcinogenesis, Cystadenocarcinoma, chemical and pharmacologic phenomena, Carcinoma, Ovarian Epithelial, Cohort Studies, Vaccine Related, Lymphocytes, Tumor-Infiltrating, Rare Diseases, Clinical Research, Ovarian Epithelial, Humans, Lymphocytes, Tumor-Infiltrating, Prospective Studies, Ovarian Tumor Tissue Analysis (OTTA) Consortium, Cancer, Ovarian Neoplasms, BRCA2 Protein, Prevention, Carcinoma, Serous, Middle Aged, Survival Analysis, Cystadenocarcinoma, Serous, Ovarian Cancer, Treatment Outcome, Mutation, Public Health and Health Services, Female, Neoplasm Grading
Abstract: IMPORTANCE: Cytotoxic 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. OBJECTIVE: To define the prognostic role of CD8+ TILs in epithelial ovarian cancer. DESIGN, SETTING, AND PARTICIPANTS: This 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. EXPOSURES: Following 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 MEASURES: Overall survival time. RESULTS: The final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (P value for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near-log-linear functional form. CONCLUSIONS AND RELEVANCE: This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+ TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer.
Published: 2017

20. History of Comorbidities and Survival of Ovarian Cancer Patients, Results from the Ovarian Cancer Association Consortium

Author: Minlikeeva, Albina N, Freudenheim, Jo L, Eng, Kevin H, Cannioto, Rikki A, Friel, Grace, Szender, J Brian, Segal, Brahm, Odunsi, Kunle, Mayor, Paul, Diergaarde, Brenda, Zsiros, Emese, Kelemen, Linda E, Köbel, Martin, Steed, Helen, deFazio, Anna, Jordan, Susan J, Fasching, Peter A, Beckmann, Matthias W, Risch, Harvey A, Rossing, Mary Anne, Doherty, Jennifer A, Chang-Claude, Jenny, Goodman, Marc T, Dörk, Thilo, Edwards, Robert, Modugno, Francesmary, Ness, Roberta B, Matsuo, Keitaro, Mizuno, Mika, Karlan, Beth Y, Goode, Ellen L, Kjær, Susanne K, Høgdall, Estrid, Schildkraut, Joellen M, Terry, Kathryn L, Cramer, Daniel W, Bandera, Elisa V, Paddock, Lisa E, Kiemeney, Lambertus A, Massuger, Leon FAG, Sutphen, Rebecca, Anton-Culver, Hoda, Ziogas, Argyrios, Menon, Usha, Gayther, Simon A, Ramus, Susan J, Gentry-Maharaj, Aleksandra, Pearce, Celeste L, Wu, Anna H, Kupryjanczyk, Jolanta, Jensen, Allan, Webb, Penelope M, Moysich, Kirsten B, Ovarian Cancer Association Consortium, and Australian Ovarian Cancer Study Group
Subjects: Australian Ovarian Cancer Study Group, Ovarian Neoplasms, screening and diagnosis, Aging, Epidemiology, Ovarian Cancer Association Consortium, Liver Disease, Comorbidity, Survival Analysis, Medical and Health Sciences, Disease-Free Survival, Ovarian Cancer, 4.1 Discovery and preclinical testing of markers and technologies, Detection, Rare Diseases, Clinical Research, Humans, Osteoporosis, 2.1 Biological and endogenous factors, Female, Aetiology, Digestive Diseases, Cancer
Abstract: Background: Comorbidities can affect survival of ovarian cancer patients by influencing treatment efficacy. However, little evidence exists on the association between individual concurrent comorbidities and prognosis in ovarian cancer patients.Methods: Among patients diagnosed with invasive ovarian carcinoma who participated in 23 studies included in the Ovarian Cancer Association Consortium, we explored associations between histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, and neurological diseases and overall and progression-free survival. Using Cox proportional hazards regression models adjusted for age at diagnosis, stage of disease, histology, and study site, we estimated pooled HRs and 95% confidence intervals to assess associations between each comorbidity and ovarian cancer outcomes.Results: None of the comorbidities were associated with ovarian cancer outcome in the overall sample nor in strata defined by histologic subtype, weight status, age at diagnosis, or stage of disease (local/regional vs. advanced).Conclusions: Histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, or neurologic diseases were not associated with ovarian cancer overall or progression-free survival.Impact: These previously diagnosed chronic diseases do not appear to affect ovarian cancer prognosis. Cancer Epidemiol Biomarkers Prev; 26(9); 1470-3. ©2017 AACR.
Published: 2017

21. Cigarette smoking is associated with adverse survival among women with ovarian cancer: Results from a pooled analysis of 19 studies

Author: Praestegaard, Camilla, Jensen, Allan, Jensen, Signe M, Nielsen, Thor SS, Webb, Penelope M, Nagle, Christina M, DeFazio, Anna, Australian Ovarian Cancer Study Group, Høgdall, Estrid, Rossing, Mary Anne, Doherty, Jennifer A, Wicklund, Kristine G, Goodman, Marc T, Modugno, Francesmary, Moysich, Kirsten, Ness, Roberta B, Edwards, Robert, Matsuo, Keitaro, Hosono, Satoyo, Goode, Ellen L, Winham, Stacey J, Fridley, Brooke L, Cramer, Daniel W, Terry, Kathryn L, Schildkraut, Joellen M, Berchuck, Andrew, Bandera, Elisa V, Paddock, Lisa E, Massuger, Leon F, Wentzensen, Nicolas, Pharoah, Paul, Song, Honglin, Whittemore, Alice, McGuire, Valerie, Sieh, Weiva, Rothstein, Joseph, Anton-Culver, Hoda, Ziogas, Argyrios, Menon, Usha, Gayther, Simon A, Ramus, Susan J, Gentry-Maharaj, Alexandra, Wu, Anna H, Pearce, Celeste L, Pike, Malcolm, Lee, Alice W, Sutphen, Rebecca, Chang-Claude, Jenny, Risch, Harvey A, Kjaer, Susanne K, and Ovarian Cancer Association Consortium
Subjects: Australian Ovarian Cancer Study Group, Adult, Ovarian Cancer Association Consortium, Oncology and Carcinogenesis, cigarette smoking, survival, Young Adult, Rare Diseases, Risk Factors, Neoplasms, Ovarian Epithelial, Tobacco, 80 and over, Humans, Oncology & Carcinogenesis, Proportional Hazards Models, Aged, Cancer, Ovarian Neoplasms, Tobacco Smoke and Health, Prevention, Smoking, Carcinoma, Glandular and Epithelial, Middle Aged, Ovarian Cancer, Case-Control Studies, Female, pooled analysis
Abstract: Cigarette smoking is associated with an increased risk of developing mucinous ovarian tumors but whether it is associated with ovarian cancer survival overall or for the different histotypes is unestablished. Furthermore, it is unknown whether the association between cigarette smoking and survival differs according to strata of ovarian cancer stage at diagnosis. In a large pooled analysis, we evaluated the association between various measures of cigarette smoking and survival among women with epithelial ovarian cancer. We obtained data from 19 case-control studies in the Ovarian Cancer Association Consortium (OCAC), including 9,114 women diagnosed with ovarian cancer. Cox regression models were used to estimate adjusted study-specific hazard ratios (HRs), which were combined into pooled hazard ratios (pHR) with corresponding 95% confidence intervals (CIs) under random effects models. Overall, 5,149 (57%) women died during a median follow-up period of 7.0 years. Among women diagnosed with ovarian cancer, both current (pHR = 1.17, 95% CI: 1.08-1.28) and former smokers (pHR = 1.10, 95% CI: 1.02-1.18) had worse survival compared with never smoking women. In histotype-stratified analyses, associations were observed for mucinous (current smoking: pHR = 1.91, 95% CI: 1.01-3.65) and serous histotypes (current smoking: pHR = 1.11, 95% CI: 1.00-1.23; former smoking: pHR = 1.12, 95% CI: 1.04-1.20). Further, our results suggested that current smoking has a greater impact on survival among women with localized than disseminated disease. The identification of cigarette smoking as a modifiable factor associated with survival has potential clinical importance as a focus area to improve ovarian cancer prognosis.
Published: 2017

22. No Evidence That Genetic Variation in the Myeloid-Derived Suppressor Cell Pathway Influences Ovarian Cancer Survival

Author: Sucheston-Campbell, Lara E, Cannioto, Rikki, Clay, Alyssa I, Etter, John Lewis, Eng, Kevin H, Liu, Song, Battaglia, Sebastiano, Hu, Qiang, Szender, J Brian, Minlikeeva, Albina, Joseph, Janine M, Mayor, Paul, Abrams, Scott I, Segal, Brahm H, Wallace, Paul K, Soh, Kah Teong, Zsiros, Emese, Anton-Culver, Hoda, Bandera, Elisa V, Beckmann, Matthias W, Berchuck, Andrew, Bjorge, Line, Bruegl, Amanda, Campbell, Ian G, Campbell, Shawn Patrice, Chenevix-Trench, Georgia, Cramer, Daniel W, Dansonka-Mieszkowska, Agnieszka, Dao, Fanny, Diergaarde, Brenda, Doerk, Thilo, Doherty, Jennifer A, du Bois, Andreas, Eccles, Diana, Engelholm, Svend Aage, Fasching, Peter A, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Glasspool, Rosalind M, Goodman, Marc T, Gronwald, Jacek, Harter, Philipp, Hein, Alexander, Heitz, Florian, Hillemmanns, Peter, Høgdall, Claus, Høgdall, Estrid VS, Huzarski, Tomasz, Jensen, Allan, Johnatty, Sharon E, Jung, Audrey, Karlan, Beth Y, Klapdor, Reudiger, Kluz, Tomasz, Konopka, Bożena, Kjær, Susanne Krüger, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lester, Jenny, Lubiński, Jan, Levine, Douglas A, Lundvall, Lene, McGuire, Valerie, McNeish, Iain A, Menon, Usha, Modugno, Francesmary, Ness, Roberta B, Orsulic, Sandra, Paul, James, Pearce, Celeste Leigh, Pejovic, Tanja, Pharoah, Paul, Ramus, Susan J, Rothstein, Joseph, Rossing, Mary Anne, Rübner, Matthias, Schildkraut, Joellen M, Schmalfeldt, Barbara, Schwaab, Ira, Siddiqui, Nadeem, Sieh, Weiva, Sobiczewski, Piotr, Song, Honglin, Terry, Kathryn L, Van Nieuwenhuysen, Els, Vanderstichele, Adriaan, Vergote, Ignace, Walsh, Christine S, Webb, Penelope M, Wentzensen, Nicolas, Whittemore, Alice S, Wu, Anna H, Ziogas, Argyrios, Odunsi, Kunle, Chang-Claude, Jenny, Goode, Ellen L, Moysich, Kirsten B, and Australian Ovarian Cancer Study
Subjects: Ovarian Neoplasms, endocrine system diseases, Epidemiology, Myeloid-Derived Suppressor Cells, Prevention, Carcinoma, Glandular and Epithelial, Genetic Variation, Australian Ovarian Cancer Study, Medical and Health Sciences, female genital diseases and pregnancy complications, Ovarian Cancer, Rare Diseases, Clinical Research, Neoplasms, Ovarian Epithelial, Genetics, Humans, 2.1 Biological and endogenous factors, Female, Genetic Testing, Aetiology, Genetic Association Studies, Cancer
Abstract: Background: The precise mechanism by which the immune system is adversely affected in cancer patients remains poorly understood, but the accumulation of immunosuppressive/protumorigenic myeloid-derived suppressor cells (MDSCs) is thought to be a prominent mechanism contributing to immunologic tolerance of malignant cells in epithelial ovarian cancer (EOC). To this end, we hypothesized genetic variation in MDSC pathway genes would be associated with survival after EOC diagnoses.Methods: We measured the hazard of death due to EOC within 10 years of diagnosis, overall and by invasive subtype, attributable to SNPs in 24 genes relevant in the MDSC pathway in 10,751 women diagnosed with invasive EOC. Versatile Gene-based Association Study and the admixture likelihood method were used to test gene and pathway associations with survival.Results: We did not identify individual SNPs that were significantly associated with survival after correction for multiple testing (P < 3.5 × 10-5), nor did we identify significant associations between the MDSC pathway overall, or the 24 individual genes and EOC survival.Conclusions: In this well-powered analysis, we observed no evidence that inherited variations in MDSC-associated SNPs, individual genes, or the collective genetic pathway contributed to EOC survival outcomes.Impact: Common inherited variation in genes relevant to MDSCs was not associated with survival in women diagnosed with invasive EOC. Cancer Epidemiol Biomarkers Prev; 26(3); 420-4. ©2016 AACR.
Published: 2017

23. Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk

Author: Permuth, Jennifer B, Pirie, Ailith, Ann Chen, Y, Lin, Hui-Yi, Reid, Brett M, Chen, Zhihua, Monteiro, Alvaro, Dennis, Joe, Mendoza-Fandino, Gustavo, AOCS Study Group, Australian Cancer Study (Ovarian Cancer), Anton-Culver, Hoda, Bandera, Elisa V, Bisogna, Maria, Brinton, Louise, Brooks-Wilson, Angela, Carney, Michael E, Chenevix-Trench, Georgia, Cook, Linda S, Cramer, Daniel W, Cunningham, Julie M, Cybulski, Cezary, D'Aloisio, Aimee A, Anne Doherty, Jennifer, Earp, Madalene, Edwards, Robert P, Fridley, Brooke L, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Goodman, Marc T, Gronwald, Jacek, Hogdall, Estrid, Iversen, Edwin S, Jakubowska, Anna, Jensen, Allan, Karlan, Beth Y, Kelemen, Linda E, Kjaer, Suzanne K, Kraft, Peter, Le, Nhu D, Levine, Douglas A, Lissowska, Jolanta, Lubinski, Jan, Matsuo, Keitaro, Menon, Usha, Modugno, Rosemary, Moysich, Kirsten B, Nakanishi, Toru, Ness, Roberta B, Olson, Sara, Orlow, Irene, Pearce, Celeste L, Pejovic, Tanja, Poole, Elizabeth M, Ramus, Susan J, Anne Rossing, Mary, Sandler, Dale P, Shu, Xiao-Ou, Song, Honglin, Taylor, Jack A, Teo, Soo-Hwang, Terry, Kathryn L, Thompson, Pamela J, Tworoger, Shelley S, Webb, Penelope M, Wentzensen, Nicolas, Wilkens, Lynne R, Winham, Stacey, Woo, Yin-Ling, Wu, Anna H, Yang, Hannah, Zheng, Wei, Ziogas, Argyrios, Phelan, Catherine M, Schildkraut, Joellen M, Berchuck, Andrew, Goode, Ellen L, Pharoah, Paul DP, Sellers, Thomas A, and Ovarian Cancer Association Consortium
Subjects: Genotype, Ovarian Cancer Association Consortium, Medical and Health Sciences, Rare Diseases, Australian Cancer Study, Neoplasms, Ovarian Epithelial, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Exome, Aetiology, Polymorphism, Cancer, Ovarian Neoplasms, Genetics & Heredity, Biotinidase, Prevention, Keratin-13, Carcinoma, Human Genome, Glandular and Epithelial, AOCS Study Group, Single Nucleotide, Biological Sciences, Actins, Neoplasm Proteins, Ovarian Cancer, Melanocortin, Female, Type 2, Receptor, Genome-Wide Association Study
Abstract: Rare and low frequency variants are not well covered in most germline genotyping arrays and are understudied in relation to epithelial ovarian cancer (EOC) risk. To address this gap, we used genotyping arrays targeting rarer protein-coding variation in 8,165 EOC cases and 11,619 controls from the international Ovarian Cancer Association Consortium (OCAC). Pooled association analyses were conducted at the variant and gene level for 98,543 variants directly genotyped through two exome genotyping projects. Only common variants that represent or are in strong linkage disequilibrium (LD) with previously-identified signals at established loci reached traditional thresholds for exome-wide significance (P P≥5.0 ×10 - 7) were detected for rare and low-frequency variants at 16 novel loci. Four rare missense variants were identified (ACTBL2 rs73757391 (5q11.2), BTD rs200337373 (3p25.1), KRT13 rs150321809 (17q21.2) and MC2R rs104894658 (18p11.21)), but only MC2R rs104894668 had a large effect size (OR = 9.66). Genes most strongly associated with EOC risk included ACTBL2 (PAML = 3.23 × 10 - 5; PSKAT-o = 9.23 × 10 - 4) and KRT13 (PAML = 1.67 × 10 - 4; PSKAT-o = 1.07 × 10 - 5), reaffirming variant-level analysis. In summary, this large study identified several rare and low-frequency variants and genes that may contribute to EOC susceptibility, albeit with possible small effects. Future studies that integrate epidemiology, sequencing, and functional assays are needed to further unravel the unexplained heritability and biology of this disease.
Published: 2016

24. Assessment of Multifactor Gene-Environment Interactions and Ovarian Cancer Risk: Candidate Genes, Obesity, and Hormone-Related Risk Factors

Author: Usset, Joseph L, Raghavan, Rama, Tyrer, Jonathan P, McGuire, Valerie, Sieh, Weiva, Webb, Penelope, Chang-Claude, Jenny, Rudolph, Anja, Anton-Culver, Hoda, Berchuck, Andrew, Brinton, Louise, Cunningham, Julie M, DeFazio, Anna, Doherty, Jennifer A, Edwards, Robert P, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Goodman, Marc T, Høgdall, Estrid, Jensen, Allan, Johnatty, Sharon E, Kiemeney, Lambertus A, Kjaer, Susanne K, Larson, Melissa C, Lurie, Galina, Massuger, Leon, Menon, Usha, Modugno, Francesmary, Moysich, Kirsten B, Ness, Roberta B, Pike, Malcolm C, Ramus, Susan J, Rossing, Mary Anne, Rothstein, Joseph, Song, Honglin, Thompson, Pamela J, van den Berg, David J, Vierkant, Robert A, Wang-Gohrke, Shan, Wentzensen, Nicolas, Whittemore, Alice S, Wilkens, Lynne R, Wu, Anna H, Yang, Hannah, Pearce, Celeste Leigh, Schildkraut, Joellen M, Pharoah, Paul, Goode, Ellen L, Fridley, Brooke L, and Ovarian Cancer Association Consortium and the Australian Cancer Study
Subjects: Ovarian Neoplasms, Epidemiology, Prevention, Contraception/Reproduction, Single Nucleotide, Middle Aged, Estrogen, Medical and Health Sciences, Ovarian Cancer, Rare Diseases, Risk Factors, Clinical Research, Genetics, Ovarian Cancer Association Consortium and the Australian Cancer Study, Humans, 2.1 Biological and endogenous factors, Female, Gene-Environment Interaction, Obesity, Polymorphism, Aetiology, Cancer, Nutrition
Abstract: BackgroundMany epithelial ovarian cancer (EOC) risk factors relate to hormone exposure and elevated estrogen levels are associated with obesity in postmenopausal women. Therefore, we hypothesized that gene-environment interactions related to hormone-related risk factors could differ between obese and non-obese women.MethodsWe considered interactions between 11,441 SNPs within 80 candidate genes related to hormone biosynthesis and metabolism and insulin-like growth factors with six hormone-related factors (oral contraceptive use, parity, endometriosis, tubal ligation, hormone replacement therapy, and estrogen use) and assessed whether these interactions differed between obese and non-obese women. Interactions were assessed using logistic regression models and data from 14 case-control studies (6,247 cases; 10,379 controls). Histotype-specific analyses were also completed.ResultsSNPs in the following candidate genes showed notable interaction: IGF1R (rs41497346, estrogen plus progesterone hormone therapy, histology = all, P = 4.9 × 10(-6)) and ESR1 (rs12661437, endometriosis, histology = all, P = 1.5 × 10(-5)). The most notable obesity-gene-hormone risk factor interaction was within INSR (rs113759408, parity, histology = endometrioid, P = 8.8 × 10(-6)).ConclusionsWe have demonstrated the feasibility of assessing multifactor interactions in large genetic epidemiology studies. Follow-up studies are necessary to assess the robustness of our findings for ESR1, CYP11A1, IGF1R, CYP11B1, INSR, and IGFBP2 Future work is needed to develop powerful statistical methods able to detect these complex interactions.ImpactAssessment of multifactor interaction is feasible, and, here, suggests that the relationship between genetic variants within candidate genes and hormone-related risk factors may vary EOC susceptibility. Cancer Epidemiol Biomarkers Prev; 25(5); 780-90. ©2016 AACR.
Published: 2016

25. Common variants at 19p13 are associated with susceptibility to ovarian cancer (vol 42, pg 880, 2010)

Author: Bolton, Kelly L, Tyrer, Jonathan, Song, Honglin, Ramus, Susan J, Notaridou, Maria, Jones, Chris, Sher, Tanya, Gentry-Maharaj, Aleksandra, Wozniak, Eva, Tsai, Ya-Yu, Weidhaas, Joanne, Paik, Daniel, Van den Berg, David J, Stram, Daniel O, Pearce, Celeste Leigh, Wu, Anna H, Brewster, Wendy, Anton-Culver, Hoda, Ziogas, Argyrios, Narod, Steven A, Levine, Douglas A, Kaye, Stanley B, Brown, Robert, Paul, Jim, Flanagan, James, Sieh, Weiva, McGuire, Valerie, Whittemore, Alice S, Campbell, Ian, Gore, Martin E, Lissowska, Jolanta, Yang, Hanna P, Medrek, Krzysztof, Gronwald, Jacek, Lubinski, Jan, Jakubowska, Anna, Le, Nhu D, Cook, Linda S, Kelemen, Linda E, Brooks-Wilson, Angela, Massuger, Leon FAG, Kiemeney, Lambertus A, Aben, Katja KH, van Altena, Anne M, Houlston, Richard, Tomlinson, Ian, Palmieri, Rachel T, Moorman, Patricia G, Schildkraut, Joellen, Iversen, Edwin S, Phelan, Catherine, Vierkant, Robert A, Cunningham, Julie M, Goode, Ellen L, Fridley, Brooke L, Kruger-Kjaer, Susan, Blaeker, Jan, Hogdall, Estrid, Hogdall, Claus, Gross, Jenny, Karlan, Beth Y, Ness, Roberta B, Edwards, Robert P, Odunsi, Kunle, Moyisch, Kirsten B, Baker, Julie A, Modugno, Francesmary, Heikkinenen, Tuomas, Butzow, Ralf, Nevanlinna, Heli, Leminen, Arto, Bogdanova, Natalia, Antonenkova, Natalia, Doerk, Thilo, Hillemanns, Peter, Duerst, Matthias, Runnebaum, Ingo, Thompson, Pamela J, Carney, Michael E, Goodman, Marc T, Lurie, Galina, Wang-Gohrke, Shan, Hein, Rebecca, Chang-Claude, Jenny, Rossing, Mary Anne, Cushing-Haugen, Kara L, Doherty, Jennifer, Chen, Chu, Rafnar, Thorunn, Besenbacher, Soren, Sulem, Patrick, Stefansson, Kari, Birrer, Michael J, Terry, Kathryn L, Hernandez, Dena, Cramer, Daniel W, Vergote, Ignace, Amant, Frederic, Lambrechts, Diether, and Despierre, Evelyn
Subjects: Biological Sciences, Medical and Health Sciences, Developmental Biology
Published: 2016

26. Corrigendum: Common variants at 19p13 are associated with susceptibility to ovarian cancer

Author: Bolton, Kelly L, Tyrer, Jonathan, Song, Honglin, Ramus, Susan J, Notaridou, Maria, Jones, Chris, Sher, Tanya, Gentry-Maharaj, Aleksandra, Wozniak, Eva, Tsai, Ya-Yu, Weidhaas, Joanne, Paik, Daniel, Van Den Berg, David J, Stram, Daniel O, Pearce, Celeste Leigh, Wu, Anna H, Brewster, Wendy, Anton-Culver, Hoda, Ziogas, Argyrios, Narod, Steven A, Levine, Douglas A, Kaye, Stanley B, Brown, Robert, Paul, Jim, Flanagan, James, Sieh, Weiva, McGuire, Valerie, Whittemore, Alice S, Campbell, Ian, Gore, Martin E, Lissowska, Jolanta, Yang, Hanna P, Medrek, Krzysztof, Gronwald, Jacek, Lubinski, Jan, Jakubowska, Anna, Le, Nhu D, Cook, Linda S, Kelemen, Linda E, Brooks-Wilson, Angela, Massuger, Leon FAG, Kiemeney, Lambertus A, Aben, Katja KH, van Altena, Anne M, Houlston, Richard, Tomlinson, Ian, Palmieri, Rachel T, Moorman, Patricia G, Schildkraut, Joellen, Iversen, Edwin S, Phelan, Catherine, Vierkant, Robert A, Cunningham, Julie M, Goode, Ellen L, Fridley, Brooke L, Kruger-Kjaer, Susan, Blaeker, Jan, Hogdall, Estrid, Hogdall, Claus, Gross, Jenny, Karlan, Beth Y, Ness, Roberta B, Edwards, Robert P, Odunsi, Kunle, Moyisch, Kirsten B, Baker, Julie A, Modugno, Francesmary, Heikkinenen, Tuomas, Butzow, Ralf, Nevanlinna, Heli, Leminen, Arto, Bogdanova, Natalia, Antonenkova, Natalia, Doerk, Thilo, Hillemanns, Peter, Dürst, Matthias, Runnebaum, Ingo, Thompson, Pamela J, Carney, Michael E, Goodman, Marc T, Lurie, Galina, Wang-Gohrke, Shan, Hein, Rebecca, Chang-Claude, Jenny, Rossing, Mary Anne, Cushing-Haugen, Kara L, Doherty, Jennifer, Chen, Chu, Rafnar, Thorunn, Besenbacher, Soren, Sulem, Patrick, Stefansson, Kari, Birrer, Michael J, Terry, Kathryn L, Hernandez, Dena, Cramer, Daniel W, Vergote, Ignace, Amant, Frederic, Lambrechts, Diether, and Despierre, Evelyn
Subjects: Australian Ovarian Cancer Study Group, Rare Diseases, Biological Sciences, Medical and Health Sciences, Ovarian Cancer, Cancer, Developmental Biology
Published: 2016

27. Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk

Author: Amankwah, Ernest K, Lin, Hui-Yi, Tyrer, Jonathan P, Lawrenson, Kate, Dennis, Joe, Chornokur, Ganna, Aben, Katja KH, Anton-Culver, Hoda, Antonenkova, Natalia, Bruinsma, Fiona, Bandera, Elisa V, Bean, Yukie T, Beckmann, Matthias W, Bisogna, Maria, Bjorge, Line, Bogdanova, Natalia, Brinton, Louise A, Brooks-Wilson, Angela, Bunker, Clareann H, Butzow, Ralf, Campbell, Ian G, Carty, Karen, Chen, Zhihua, Chen, Y Ann, Chang-Claude, Jenny, Cook, Linda S, Cramer, Daniel W, Cunningham, Julie M, Cybulski, Cezary, Dansonka-Mieszkowska, Agnieszka, du Bois, Andreas, Despierre, Evelyn, Dicks, Ed, Doherty, Jennifer A, Dörk, Thilo, Dürst, Matthias, Easton, Douglas F, Eccles, Diana M, Edwards, Robert P, Ekici, Arif B, Fasching, Peter A, Fridley, Brooke L, Gao, Yu-Tang, Gentry-Maharaj, Aleksandra, Giles, Graham G, Glasspool, Rosalind, Goodman, Marc T, Gronwald, Jacek, Harrington, Patricia, Harter, Philipp, Hasmad, Hanis N, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Hogdall, Claus K, Hogdall, Estrid, Hosono, Satoyo, Iversen, Edwin S, Jakubowska, Anna, Jensen, Allan, Ji, Bu-Tian, Karlan, Beth Y, Jim, Heather, Kellar, Melissa, Kiemeney, Lambertus A, Krakstad, Camilla, Kjaer, Susanne K, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D, Lee, Alice W, Lele, Shashi, Leminen, Arto, Lester, Jenny, Levine, Douglas A, Liang, Dong, Lim, Boon Kiong, Lissowska, Jolanta, Lu, Karen, Lubinski, Jan, Lundvall, Lene, Massuger, Leon FAG, Matsuo, Keitaro, McGuire, Valerie, McLaughlin, John R, McNeish, Ian, Menon, Usha, Milne, Roger L, Modugno, Francesmary, Moysich, Kirsten B, Ness, Roberta B, Nevanlinna, Heli, Eilber, Ursula, Odunsi, Kunle, Olson, Sara H, Orlow, Irene, Orsulic, Sandra, and Weber, Rachel Palmieri
Subjects: Risk, Adult, Epithelial-Mesenchymal Transition, Genotype, Epidemiology, European Continental Ancestry Group, White People, Rare Diseases, Neoplasms, Ovarian Epithelial, single-nucleotide polymorphisms, Odds Ratio, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Polymorphism, Aetiology, Aged, Cancer, Ovarian Neoplasms, Carcinoma, Human Genome, Glandular and Epithelial, Single Nucleotide, Middle Aged, Georgia Chenevix-Trench on behalf of the AOCS management group, Ovarian Cancer, Public Health and Health Services, Female, Genome-Wide Association Study, Biotechnology
Abstract: Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value
Published: 2015

28. Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium

Author: Johnatty, Sharon E., Tyrer, Jonathan P., Kar, Siddhartha, Beesley, Jonathan, Lu, Yi, Gao, Bo, Fasching, Peter A., Hein, Alexander, Ekici, Arif B., Beckmann, Matthias W., Lambrechts, Diether, Nieuwenhuysen, Els Van, Vergote, Ignace, Lambrechts, Sandrina, Rossing, Mary Anne, Doherty, Jennifer A., Chang-Claude, Jenny, Modugno, Francesmary, Ness, Roberta B., Moysich, Kirsten B., Levine, Douglas A., Kiemeney, Lambertus A., Massuger, Leon F.A.G., Gronwald, Jacek, Lubiński, Jan, Jakubowska, Anna, Cybulski, Cezary, Brinton, Louise, Lissowska, Jolanta, Wentzensen, Nicolas, Song, Honglin, Rhenius, Valerie, Campbell, Ian, Eccles, Diana, Sieh, Weiva, Whittemore, Alice S., McGuire, Valerie, Rothstein, Joseph H., Sutphen, Rebecca, Anton-Culver, Hoda, Ziogas, Argyrios, Gayther, Simon A., Gentry-Maharaj, Aleksandra, Menon, Usha, Ramus, Susan J., Pearce, Celeste L, Pike, Malcolm C, Stram, Daniel O., Wu, Anna H., Kupryjanczyk, Jolanta, Dansonka-Mieszkowska, Agnieszka, Rzepecka, Iwona K., Spiewankiewicz, Beata, Goodman, Marc T., Wilkens, Lynne R., Carney, Michael E., Thompson, Pamela J, Heitz, Florian, du Bois, Andreas, Schwaab, Ira, Harter, Philipp, Pisterer, Jacobus, Hillemanns, Peter, Karlan, Beth Y., Walsh, Christine, Lester, Jenny, Orsulic, Sandra, Winham, Stacey J, Earp, Madalene, Larson, Melissa C., Fogarty, Zachary C., Høgdall, Estrid, Jensen, Allan, Kjaer, Susanne Kruger, Fridley, Brooke L., Cunningham, Julie M., Vierkant, Robert A., Schildkraut, Joellen M., Iversen, Edwin S., Terry, Kathryn L., Cramer, Daniel W., Bandera, Elisa V., Orlow, Irene, Pejovic, Tanja, Bean, Yukie, Høgdall, Claus, Lundvall, Lene, McNeish, Ian, Paul, James, Carty, Karen, Siddiqui, Nadeem, Glasspool, Rosalind, Sellers, Thomas, Kennedy, Catherine, Chiew, Yoke-Eng, Berchuck, Andrew, MacGregor, Stuart, deFazio, Anna, Pharoah, Paul D.P., Goode, Ellen L., Webb, Penelope M., and Chenevix-Trench, Georgia
Subjects: Oncology, Cancer Research, Genome-wide association study, AGO Study Group, Kaplan-Meier Estimate, Carcinoma, Ovarian Epithelial, Bioinformatics, chemistry.chemical_compound, Neoplasms, Ovarian Epithelial, 2.1 Biological and endogenous factors, Neoplasms, Glandular and Epithelial, Aetiology, Cancer, Ovarian Neoplasms, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Glandular and Epithelial, Single Nucleotide, Prognosis, Ovarian Cancer, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Australian Ovarian Cancer Study Group, medicine.medical_specialty, Genotype, Quantitative Trait Loci, Oncology and Carcinogenesis, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Article, Rare Diseases, Meta-Analysis as Topic, Clinical Research, Internal medicine, Carcinoma, medicine, Genetics, SNP, Humans, Progression-free survival, Oncology & Carcinogenesis, Polymorphism, Alleles, business.industry, Human Genome, Computational Biology, medicine.disease, Carboplatin, Patient Outcome Assessment, Regimen, Orphan Drug, chemistry, Ovarian cancer, business, Genome-Wide Association Study
Abstract: Purpose: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. Experimental Design: We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis. Results: Five SNPs were significantly associated (P ≤ 1.0 × 10−5) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23), and rs6674079 (1q22), were located in long noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P ≤ 7.1 × 10−6). ENCODE ChIP-seq data at 1q22 for normal ovary show evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression and high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA ≤6 × 10−3). Conclusions: We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies. Clin Cancer Res; 21(23); 5264–76. ©2015 AACR.
Published: 2015

29. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

Author: Lawrenson, Kate, Li, Qiyuan, Kar, Siddhartha, Seo, Ji-Heui, Tyrer, Jonathan, Spindler, Tassja J, Lee, Janet, Chen, Yibu, Karst, Alison, Drapkin, Ronny, Aben, Katja KH, Anton-Culver, Hoda, Antonenkova, Natalia, Australian Ovarian Cancer Study Group, Baker, Helen, Bandera, Elisa V, Bean, Yukie, Beckmann, Matthias W, Berchuck, Andrew, Bisogna, Maria, Bjorge, Line, Bogdanova, Natalia, Brinton, Louise A, Brooks-Wilson, Angela, Bruinsma, Fiona, Butzow, Ralf, Campbell, Ian G, Carty, Karen, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Chen, Anne, Chen, Zhihua, Cook, Linda S, Cramer, Daniel W, Cunningham, Julie M, Cybulski, Cezary, Dansonka-Mieszkowska, Agnieszka, Dennis, Joe, Dicks, Ed, Doherty, Jennifer A, Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana, Easton, Douglas T, Edwards, Robert P, Eilber, Ursula, Ekici, Arif B, Fasching, Peter A, Fridley, Brooke L, Gao, Yu-Tang, Gentry-Maharaj, Aleksandra, Giles, Graham G, Glasspool, Rosalind, Goode, Ellen L, Goodman, Marc T, Grownwald, Jacek, Harrington, Patricia, Harter, Philipp, Hasmad, Hanis Nazihah, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Hogdall, Estrid, Hogdall, Claus, Hosono, Satoyo, Iversen, Edwin S, Jakubowska, Anna, James, Paul, Jensen, Allan, Ji, Bu-Tian, Karlan, Beth Y, Kruger Kjaer, Susanne, Kelemen, Linda E, Kellar, Melissa, Kelley, Joseph L, Kiemeney, Lambertus A, Krakstad, Camilla, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D, Lee, Alice W, Lele, Shashi, Leminen, Arto, Lester, Jenny, Levine, Douglas A, Liang, Dong, Lissowska, Jolanta, Lu, Karen, Lubinski, Jan, Lundvall, Lene, Massuger, Leon FAG, Matsuo, Keitaro, McGuire, Valerie, McLaughlin, John R, Nevanlinna, Heli, McNeish, Ian, and Menon, Usha
Subjects: Australian Ovarian Cancer Study Group, Quantitative Trait Loci, Cell Line, Nuchal Cord, Rare Diseases, Neoplasms, Ovarian Epithelial, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Aetiology, Genetic Association Studies, Cancer, Ovarian Neoplasms, Homeodomain Proteins, Neoplastic, Tumor, Prevention, Carcinoma, Human Genome, Glandular and Epithelial, Neoplasm Proteins, Ovarian Cancer, Gene Expression Regulation, Female, Protein Binding, Biotechnology
Abstract: Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10(-5)). For three cis-eQTL associations (P
Published: 2015

30. Genome-wide significant risk associations for mucinous ovarian carcinoma (vol 47, pg 888, 2015)

Author: Kelemen, Linda E, Lawrenson, Kate, Tyrer, Jonathan, Li, Qiyuan, Lee, Janet M, Seo, Ji-Heui, Phelan, Catherine M, Beesley, Jonathan, Chen, Xiaoqing, Spindler, Tassja J, Aben, Katja KH, Anton-Culver, Hoda, Antonenkova, Natalia, Baker, Helen, Bandera, Elisa V, Bean, Yukie, Beckmann, Matthias W, Bisogna, Maria, Bjorge, Line, Bogdanova, Natalia, Brinton, Louise A, Brooks-Wilson, Angela, Bruinsma, Fiona, Butzow, Ralf, Campbell, Ian G, Carty, Karen, Chang-Claude, Jenny, Chen, Y Ann, Chen, Zhihua, Cook, Linda S, Cramer, Daniel W, Cunningham, Julie M, Cybulski, Cezary, Dansonka-Mieszkowska, Agnieszka, Dennis, Joe, Dicks, Ed, Doherty, Jennifer A, Doerk, Thilo, du Bois, Andreas, Duerst, Matthias, Eccles, Diana, Easton, Douglas T, Edwards, Robert P, Eilber, Ursula, Ekici, Arif B, Engelholm, Svend Aage, Fasching, Peter A, Fridley, Brooke L, Gao, Yu-Tang, Gentry-Maharaj, Aleksandra, Giles, Graham G, Glasspool, Rosalind, Goode, Ellen L, Goodman, Marc T, Grownwald, Jacek, Harrington, Patricia, Harter, Philipp, Hasmad, Hanis Nazihah, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Hogdall, Estrid, Hogdall, Claus, Hosono, Satoyo, Iversen, Edwin S, Jakubowska, Anna, Jensen, Allan, Ji, Bu-Tian, Karlan, Beth Y, Kellar, Melissa, Kelley, Joseph L, Kiemeney, Lambertus A, Krakstad, Camilla, Kjaer, Susanne K, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D, Lee, Alice W, Lele, Shashi, Leminen, Arto, Lester, Jenny, Levine, Douglas A, Liang, Dong, Lissowska, Jolanta, Lu, Karen, Lubinski, Jan, Lundvall, Lene, Massuger, Leon FAG, Matsuo, Keitaro, McGuire, Valerie, McLaughlin, John R, McNeish, Iain, Menon, Usha, Modugno, Francesmary, Moes-Sosnowska, Joanna, Moysich, Kirsten B, Narod, Steven A, and Nedergaard, Lotte
Subjects: Biological Sciences, Medical and Health Sciences, Developmental Biology
Published: 2015

31. Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC)

Author: Jim, Heather SL, Lin, Hui-Yi, Tyrer, Jonathan P, Lawrenson, Kate, Dennis, Joe, Chornokur, Ganna, Chen, Zhihua, Chen, Ann Y, Permuth-Wey, Jennifer, Aben, Katja Kh, Anton-Culver, Hoda, Antonenkova, Natalia, Bruinsma, Fiona, Bandera, Elisa V, Bean, Yukie T, Beckmann, Matthias W, Bisogna, Maria, Bjorge, Line, Bogdanova, Natalia, Brinton, Louise A, Brooks-Wilson, Angela, Bunker, Clareann H, Butzow, Ralf, Campbell, Ian G, Carty, Karen, Chang-Claude, Jenny, Cook, Linda S, Cramer, Daniel W, Cunningham, Julie M, Cybulski, Cezary, Dansonka-Mieszkowska, Agnieszka, du Bois, Andreas, Despierre, Evelyn, Sieh, Weiva, Doherty, Jennifer A, Dörk, Thilo, Dürst, Matthias, Easton, Douglas F, Eccles, Diana M, Edwards, Robert P, Ekici, Arif B, Fasching, Peter A, Fridley, Brooke L, Gao, Yu-Tang, Gentry-Maharaj, Aleksandra, Giles, Graham G, Glasspool, Rosalind, Goodman, Marc T, Gronwald, Jacek, Harter, Philipp, Hasmad, Hanis N, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Hogdall, Claus K, Hogdall, Estrid, Hosono, Satoyo, Iversen, Edwin S, Jakubowska, Anna, Jensen, Allan, Ji, Bu-Tian, Karlan, Beth Y, Kellar, Melissa, Kiemeney, Lambertus A, Krakstad, Camilla, Kjaer, Susanne K, Kupryjanczyk, Jolanta, Vierkant, Robert A, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D, Lee, Alice W, Lele, Shashi, Leminen, Arto, Lester, Jenny, Levine, Douglas A, Liang, Dong, Lim, Boon Kiong, Lissowska, Jolanta, Lu, Karen, Lubinski, Jan, Lundvall, Lene, Massuger, Leon FAG, Matsuo, Keitaro, McGuire, Valerie, McLaughlin, John R, McNeish, Ian, Menon, Usha, Milne, Roger L, Modugno, Francesmary, Thomsen, Lotte, Moysich, Kirsten B, Ness, Roberta B, Nevanlinna, Heli, Eilber, Ursula, Odunsi, Kunle, Olson, Sara H, Orlow, Irene, and Orsulic, Sandra
Subjects: endocrine system, Georgia Chenevix-Trench on behalf of the AOCS management group 95, Orphan Drug, Rare Diseases, Prevention, Genetics, 2.1 Biological and endogenous factors, Aetiology, Sleep Research, Cancer, Ovarian Cancer
Abstract: Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68-0.90, p = 5.59 × 10-4]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.
Published: 2015

32. Variation in NF-κB signaling pathways and survival in invasive epithelial ovarian cancer

Author: Block, Matthew S, Charbonneau, Bridget, Vierkant, Robert A, Fogarty, Zachary, Bamlet, William R, Pharoah, Paul DP, Georgia Chenevix-Trench, for AOCS, ACS Group, Rossing, Mary Anne, Cramer, Daniel, Pearce, Celeste Leigh, Schildkraut, Joellen, Menon, Usha, Kjaer, Susanne K, Levine, Douglas A, Gronwald, Jacek, Culver, Hoda Anton, Whittemore, Alice S, Karlan, Beth Y, Lambrechts, Diether, Wentzensen, Nicolas, Kupryjanczyk, Jolanta, Chang-Claude, Jenny, Bandera, Elisa V, Hogdall, Estrid, Heitz, Florian, Kaye, Stanley B, Fasching, Peter A, Campbell, Ian, Goodman, Marc T, Pejovic, Tanja, Bean, Yukie T, Hays, Laura E, Lurie, Galina, Eccles, Diana, Hein, Alexander, Beckmann, Matthias W, Ekici, Arif B, Paul, James, Brown, Robert, Flanagan, James M, Harter, Philipp, du Bois, Andreas, Schwaab, Ira, Hogdall, Claus K, Lundvall, Lene, Olson, Sara H, Orlow, Irene, Paddock, Lisa E, Rudolph, Anja, Eilber, Ursula, Dansonka-Mieszkowska, Agnieszka, Rzepecka, Iwona K, Ziolkowska-Seta, Izabela, Brinton, Louise A, Yang, Hannah, Garcia-Closas, Montserrat, Despierre, Evelyn, Lambrechts, Sandrina, Vergote, Ignace, Walsh, Christine S, Lester, Jenny, Sieh, Weiva, McGuire, Valerie, Rothstein, Joseph H, Ziogas, Argyrios, Lubiński, Jan, Cybulski, Cezary, Menkiszak, Janusz, Jensen, Allan, Gayther, Simon A, Ramus, Susan J, Gentry-Maharaj, Aleksandra, Berchuck, Andrew, Wu, Anna H, Pike, Malcolm C, Van Den Berg, David, Terry, Kathryn L, Vitonis, Allison F, Ramirez, Starr M, Rider, David N, Knutson, Keith L, Sellers, Thomas A, Phelan, Catherine M, Doherty, Jennifer A, Johnatty, Sharon E, deFazio, Anna, Song, Honglin, Tyrer, Jonathan, Kalli, Kimberly R, Fridley, Brooke L, Cunningham, Julie M, and Goode, Ellen L
Subjects: Adult, endocrine system diseases, Genotype, Epidemiology, Medical and Health Sciences, ACS Group, Georgia Chenevix-Trench, Rare Diseases, Neoplasms, Ovarian Epithelial, Genetics, Humans, 2.1 Biological and endogenous factors, Neoplasm Invasiveness, Aetiology, Polymorphism, Proportional Hazards Models, Aged, Cancer, Ovarian Neoplasms, Prevention, Inflammatory and immune system, Carcinoma, NF-kappa B, Glandular and Epithelial, Single Nucleotide, Middle Aged, female genital diseases and pregnancy complications, Ovarian Cancer, for AOCS, Female, Signal Transduction
Abstract: Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-κB (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance, P < 2.5 × 10(-5)). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41-2.35; P = 4.13 × 10(-6)] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56-0.82; P = 2.33 × 10(-5)). Other associations of note included TNF receptor-associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77-0.92; P = 6.49 × 10(-5)) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26-0.73; P = 4.56 × 10(-4)). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies.
Published: 2014

33. Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA

Author: Earp, Madalene A, Kelemen, Linda E, Magliocco, Anthony M, Swenerton, Kenneth D, Chenevix-Trench, Georgia, Australian Cancer Study, Australian Ovarian Cancer Study Group, Lu, Yi, Hein, Alexander, Ekici, Arif B, Beckmann, Matthias W, Fasching, Peter A, Lambrechts, Diether, Despierre, Evelyn, Vergote, Ignace, Lambrechts, Sandrina, Doherty, Jennifer A, Rossing, Mary Anne, Chang-Claude, Jenny, Rudolph, Anja, Friel, Grace, Moysich, Kirsten B, Odunsi, Kunle, Sucheston-Campbell, Lara, Lurie, Galina, Goodman, Marc T, Carney, Michael E, Thompson, Pamela J, Runnebaum, Ingo B, Dürst, Matthias, Hillemanns, Peter, Dörk, Thilo, Antonenkova, Natalia, Bogdanova, Natalia, Leminen, Arto, Nevanlinna, Heli, Pelttari, Liisa M, Butzow, Ralf, Bunker, Clareann H, Modugno, Francesmary, Edwards, Robert P, Ness, Roberta B, du Bois, Andreas, Heitz, Florian, Schwaab, Ira, Harter, Philipp, Karlan, Beth Y, Walsh, Christine, Lester, Jenny, Jensen, Allan, Kjær, Susanne K, Høgdall, Claus K, Høgdall, Estrid, Lundvall, Lene, Sellers, Thomas A, Fridley, Brooke L, Goode, Ellen L, Cunningham, Julie M, Vierkant, Robert A, Giles, Graham G, Baglietto, Laura, Severi, Gianluca, Southey, Melissa C, Liang, Dong, Wu, Xifeng, Lu, Karen, Hildebrandt, Michelle AT, Levine, Douglas A, Bisogna, Maria, Schildkraut, Joellen M, Iversen, Edwin S, Weber, Rachel Palmieri, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Poole, Elizabeth M, Tworoger, Shelley S, Bandera, Elisa V, Chandran, Urmila, Orlow, Irene, Olson, Sara H, Wik, Elisabeth, Salvesen, Helga B, Bjorge, Line, Halle, Mari K, van Altena, Anne M, Aben, Katja KH, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Bean, Yukie T, Cybulski, Cezary, Gronwald, Jacek, Lubinski, Jan, Wentzensen, Nicolas, Brinton, Louise A, Lissowska, Jolanta, Garcia-Closas, Montserrat, Dicks, Ed, and Dennis, Joe
Subjects: Australian Ovarian Cancer Study Group, Quality Control, Ovarian Cancer Association Consortium, Paediatrics and Reproductive Medicine, Rare Diseases, Complementary and Alternative Medicine, Australian Cancer Study, Neoplasms, Ovarian Epithelial, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Polymorphism, Aetiology, Alleles, Cancer, Ovarian Neoplasms, Genetics & Heredity, Prevention, Carcinoma, Human Genome, Glandular and Epithelial, DNA, Single Nucleotide, Ovarian Cancer, Female, Genome-Wide Association Study
Abstract: Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95% confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P&nbsp
Published: 2014

34. Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA

Author: Earp, Madalene A, Kelemen, Linda E, Magliocco, Anthony M, Swenerton, Kenneth D, Chenevix-Trench, Georgia, Australian Cancer Study, Australian Ovarian Cancer Study Group, Lu, Yi, Hein, Alexander, Ekici, Arif B, Beckmann, Matthias W, Fasching, Peter A, Lambrechts, Diether, Despierre, Evelyn, Vergote, Ignace, Lambrechts, Sandrina, Doherty, Jennifer A, Rossing, Mary Anne, Chang-Claude, Jenny, Rudolph, Anja, Friel, Grace, Moysich, Kirsten B, Odunsi, Kunle, Sucheston-Campbell, Lara, Lurie, Galina, Goodman, Marc T, Carney, Michael E, Thompson, Pamela J, Runnebaum, Ingo B, Dürst, Matthias, Hillemanns, Peter, Dörk, Thilo, Antonenkova, Natalia, Bogdanova, Natalia, Leminen, Arto, Nevanlinna, Heli, Pelttari, Liisa M, Butzow, Ralf, Bunker, Clareann H, Modugno, Francesmary, Edwards, Robert P, Ness, Roberta B, du Bois, Andreas, Heitz, Florian, Schwaab, Ira, Harter, Philipp, Karlan, Beth Y, Walsh, Christine, Lester, Jenny, Jensen, Allan, Kjær, Susanne K, Høgdall, Claus K, Høgdall, Estrid, Lundvall, Lene, Sellers, Thomas A, Fridley, Brooke L, Goode, Ellen L, Cunningham, Julie M, Vierkant, Robert A, Giles, Graham G, Baglietto, Laura, Severi, Gianluca, Southey, Melissa C, Liang, Dong, Wu, Xifeng, Lu, Karen, Hildebrandt, Michelle AT, Levine, Douglas A, Bisogna, Maria, Schildkraut, Joellen M, Iversen, Edwin S, Weber, Rachel Palmieri, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Poole, Elizabeth M, Tworoger, Shelley S, Bandera, Elisa V, Chandran, Urmila, Orlow, Irene, Olson, Sara H, Wik, Elisabeth, Salvesen, Helga B, Bjorge, Line, Halle, Mari K, van Altena, Anne M, Aben, Katja KH, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Bean, Yukie T, Cybulski, Cezary, Gronwald, Jacek, Lubinski, Jan, Wentzensen, Nicolas, Brinton, Louise A, Lissowska, Jolanta, Garcia-Closas, Montserrat, Dicks, Ed, and Dennis, Joe
Subjects: Australian Ovarian Cancer Study Group, Ovarian Neoplasms, Quality Control, Genetics & Heredity, endocrine system diseases, Ovarian Cancer Association Consortium, Carcinoma, Glandular and Epithelial, DNA, Single Nucleotide, female genital diseases and pregnancy complications, Paediatrics and Reproductive Medicine, Complementary and Alternative Medicine, Australian Cancer Study, Neoplasms, Ovarian Epithelial, Genetics, Humans, Genetic Predisposition to Disease, Female, Polymorphism, Alleles, Genome-Wide Association Study
Abstract: Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95% confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P&nbsp
Published: 2014

35. Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome

Author: Charbonneau, Bridget, Moysich, Kirsten B, Kalli, Kimberly R, Oberg, Ann L, Vierkant, Robert A, Fogarty, Zachary C, Block, Matthew S, Maurer, Matthew J, Goergen, Krista M, Fridley, Brooke L, Cunningham, Julie M, Rider, David N, Preston, Claudia, Hartmann, Lynn C, Lawrenson, Kate, Wang, Chen, Tyrer, Jonathan, Song, Honglin, deFazio, Anna, Johnatty, Sharon E, Doherty, Jennifer A, Phelan, Catherine M, Sellers, Thomas A, Ramirez, Starr M, Vitonis, Allison F, Terry, Kathryn L, Van Den Berg, David, Pike, Malcolm C, Wu, Anna H, Berchuck, Andrew, Gentry-Maharaj, Aleksandra, Ramus, Susan J, Diergaarde, Brenda, Shen, Howard, Jensen, Allan, Menkiszak, Janusz, Cybulski, Cezary, Lubiłski, Jan, Ziogas, Argyrios, Rothstein, Joseph H, McGuire, Valerie, Sieh, Weiva, Lester, Jenny, Walsh, Christine, Vergote, Ignace, Lambrechts, Sandrina, Despierre, Evelyn, Garcia-Closas, Montserrat, Yang, Hannah, Brinton, Louise A, Spiewankiewicz, Beata, Rzepecka, Iwona K, Dansonka-Mieszkowska, Agnieszka, Seibold, Petra, Rudolph, Anja, Paddock, Lisa E, Orlow, Irene, Lundvall, Lene, Olson, Sara H, Hogdall, Claus K, Schwaab, Ira, du Bois, Andreas, Harter, Philipp, Flanagan, James M, Brown, Robert, Paul, James, Ekici, Arif B, Beckmann, Matthias W, Hein, Alexander, Eccles, Diana, Lurie, Galina, Hays, Laura E, Bean, Yukie T, Pejovic, Tanja, Goodman, Marc T, Campbell, Ian, Fasching, Peter A, Konecny, Gottfried, Kaye, Stanley B, Heitz, Florian, Hogdall, Estrid, Bandera, Elisa V, Chang-Claude, Jenny, Kupryjanczyk, Jolanta, Wentzensen, Nicolas, Lambrechts, Diether, Karlan, Beth Y, Whittemore, Alice S, Culver, Hoda Anton, Gronwald, Jacek, Levine, Douglas A, Kjaer, Susanne K, Menon, Usha, Schildkraut, Joellen M, Pearce, Celeste Leigh, Cramer, Daniel W, Rossing, Mary Anne, Chenevix-Trench, Georgia, AOCS group, and ACS
Subjects: T-Lymphocytes, Immunology, Oncology and Carcinogenesis, Gene Expression, AOCS group, Rare Diseases, Genetics, Humans, 2.1 Biological and endogenous factors, Neoplasm Invasiveness, Genetic Predisposition to Disease, Aetiology, Polymorphism, Germ-Line Mutation, Cancer, Ovarian Neoplasms, Gene Expression Profiling, Interleukin-2 Receptor alpha Subunit, Genetic Variation, Single Nucleotide, Pharmacology and Pharmaceutical Sciences, ACS, Prognosis, Regulatory, Ovarian Cancer, Patient Outcome Assessment, Female, Neoplasm Grading
Abstract: The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22-1.64; P = 5.7 × 10(-6)], rs791587 (HR, 1.36; 95% CI, 1.17-1.57; P = 6.2 × 10(-5)), rs2476491 (HR, = 1.40; 95% CI, 1.19-1.64; P = 5.6 × 10(-5)), and rs10795763 (HR, 1.35; 95% CI, 1.17-1.57; P = 7.9 × 10(-5)), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54-0.82; P = 9.3 × 10(-5)) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer.
Published: 2014

36. Risk of ovarian cancer and the NF-κB pathway: genetic association with IL1A and TNFSF10

Author: Charbonneau, Bridget, Block, Matthew S, Bamlet, William R, Vierkant, Robert A, Kalli, Kimberly R, Fogarty, Zachary, Rider, David N, Sellers, Thomas A, Tworoger, Shelley S, Poole, Elizabeth, Risch, Harvey A, Salvesen, Helga B, Kiemeney, Lambertus A, Baglietto, Laura, Giles, Graham G, Severi, Gianluca, Trabert, Britton, Wentzensen, Nicolas, Chenevix-Trench, Georgia, for AOCS/ACS group, Whittemore, Alice S, Sieh, Weiva, Chang-Claude, Jenny, Bandera, Elisa V, Orlow, Irene, Terry, Kathryn, Goodman, Marc T, Thompson, Pamela J, Cook, Linda S, Rossing, Mary Anne, Ness, Roberta B, Narod, Steven A, Kupryjanczyk, Jolanta, Lu, Karen, Butzow, Ralf, Dörk, Thilo, Pejovic, Tanja, Campbell, Ian, Le, Nhu D, Bunker, Clareann H, Bogdanova, Natalia, Runnebaum, Ingo B, Eccles, Diana, Paul, James, Wu, Anna H, Gayther, Simon A, Hogdall, Estrid, Heitz, Florian, Kaye, Stanley B, Karlan, Beth Y, Anton-Culver, Hoda, Gronwald, Jacek, Hogdall, Claus K, Lambrechts, Diether, Fasching, Peter A, Menon, Usha, Schildkraut, Joellen, Pearce, Celeste Leigh, Levine, Douglas A, Kjaer, Susanne Kruger, Cramer, Daniel, Flanagan, James M, Phelan, Catherine M, Brown, Robert, Massuger, Leon FAG, Song, Honglin, Doherty, Jennifer A, Krakstad, Camilla, Liang, Dong, Odunsi, Kunle, Berchuck, Andrew, Jensen, Allan, Lubinski, Jan, Nevanlinna, Heli, Bean, Yukie T, Lurie, Galina, Ziogas, Argyrios, Walsh, Christine, Despierre, Evelyn, Brinton, Louise, Hein, Alexander, Rudolph, Anja, Dansonka-Mieszkowska, Agnieszka, Olson, Sara H, Harter, Philipp, Tyrer, Jonathan, Vitonis, Allison F, Brooks-Wilson, Angela, Aben, Katja K, Pike, Malcolm C, Ramus, Susan J, Wik, Elisabeth, Cybulski, Cezary, Lin, Jie, Sucheston, Lara, Edwards, Robert, McGuire, Valerie, Lester, Jenny, du Bois, Andreas, and Lundvall, Lene
Subjects: Ovarian Neoplasms, Risk, Prevention, Human Genome, Oncology and Carcinogenesis, NF-kappa B, Single Nucleotide, for AOCS/ACS group, Ovarian Cancer, TNF-Related Apoptosis-Inducing Ligand, Rare Diseases, Clinical Research, Case-Control Studies, Interleukin-1alpha, Genetics, Humans, 2.1 Biological and endogenous factors, Female, Oncology & Carcinogenesis, Polymorphism, Aetiology, Genetic Association Studies, Signal Transduction, Cancer
Abstract: A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76-0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75-0.95; P = 0.006). Considering a multiple-testing-corrected significance threshold of P < 2.5 × 10(-5), only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79-0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted.
Published: 2014

37. Eurogin Roadmap: Comparative epidemiology of HPV infection and associated cancers of the head and neck and cervix

Author: Gillison, Maura L., Castellsague, Xavier, Chaturvedi, Anil, Goodman, Marc T., Snijders, Peter, Tommasino, Massimo, Arbyn, Marc, Franceschi, Silvia, Pathology, and CCA - Oncogenesis
Subjects: stomatognathic diseases, Human medicine
Abstract: The EUROGIN 2012 roadmap is focused on the comparative epidemiology of human papillomavirus (HPV) associated head and neck squamous cell cancers (HNSCC) and cervical cancers. Discussed are the similarities and differences between the two cancers with regard to global disease burden, HPV prevalence and type distribution, disease cofactors, molecular pathogenesis, treatment approaches, prognostic factors and primary and secondary prevention. The global incidence of HNSCC and cervical cancer is similar; however, a minority of HNSCC in comparison to virtually all cervical cancers is caused by HPV. HPV infection prevalence is considerably lower in the oral than genital regions for reasons that are as yet unclear. Infection at both sites is strongly associated with sexual behavior, but this association does not appear to explain the male predominance of oral HPV infection. Studies of the molecular pathogenesis of HPV-associated HNSCC (predominantly oropharyngeal cancers) are hampered by the lack of a readily detectable intermediate clinical endpoint analogous to cervix intraepithelial neoplasia. Nevertheless, similarities in chromosomal aberrations, gene expression, methylation and microRNA profiles between HPV-positive HNSCC and cervical cancer argue for shared carcinogenic pathways. Treatment approaches to oropharyngeal and cervical cancers are remarkably similar, with the development of HPV-targeted therapies as the ultimate treatment goal. Key research challenges include understanding oral HPV transmission and male predominance, clarifying the role of cofactors, and developing new screening and treatment methods for HPV-associated HNSCC.
Published: 2014

38. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer

Author: Bojesen, Stig E, Pooley, Karen A, Johnatty, Sharon E, Beesley, Jonathan, Michailidou, Kyriaki, Tyrer, Jonathan P, Edwards, Stacey L, Pickett, Hilda A, Shen, Howard C, Smart, Chanel E, Hillman, Kristine M, Mai, Phuong L, Lawrenson, Kate, Stutz, Michael D, Lu, Yi, Karevan, Rod, Woods, Nicholas, Johnston, Rebecca L, French, Juliet D, Chen, Xiaoqing, Weischer, Maren, Nielsen, Sune F, Maranian, Melanie J, Ghoussaini, Maya, Ahmed, Shahana, Baynes, Caroline, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, McGuffog, Lesley, Barrowdale, Daniel, Lee, Andrew, Healey, Sue, Lush, Michael, Tessier, Daniel C, Vincent, Daniel, Bacot, Françis, Australian Cancer Study, Australian Ovarian Cancer Study, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab), Gene Environment Interaction and Breast Cancer (GENICA), Swedish Breast Cancer Study (SWE-BRCA), Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Epidemiological study of BRCA1 & BRCA2 Mutation Carriers (EMBRACE), Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers (GEMO), Vergote, Ignace, Lambrechts, Sandrina, Despierre, Evelyn, Risch, Harvey A, González-Neira, Anna, Rossing, Mary Anne, Pita, Guillermo, Doherty, Jennifer A, Alvarez, Nuria, Larson, Melissa C, Fridley, Brooke L, Schoof, Nils, Chang-Claude, Jenny, Cicek, Mine S, Peto, Julian, Kalli, Kimberly R, Broeks, Annegien, Armasu, Sebastian M, Schmidt, Marjanka K, Braaf, Linde M, Winterhoff, Boris, Nevanlinna, Heli, Konecny, Gottfried E, Lambrechts, Diether, Rogmann, Lisa, Guénel, Pascal, Teoman, Attila, Milne, Roger L, Garcia, Joaquin J, Cox, Angela, Shridhar, Vijayalakshmi, Burwinkel, Barbara, Marme, Frederik, Hein, Rebecca, Sawyer, Elinor J, Haiman, Christopher A, Wang-Gohrke, Shan, Andrulis, Irene L, Moysich, Kirsten B, Hopper, John L, Odunsi, Kunle, Lindblom, Annika, Giles, Graham G, Brenner, Hermann, Simard, Jacques, Lurie, Galina, Fasching, Peter A, Carney, Michael E, Radice, Paolo, Wilkens, Lynne R, Swerdlow, Anthony, Goodman, Marc T, Brauch, Hiltrud, Garcia-Closas, Montserrat, and Hillemanns, Peter
Subjects: Swedish Breast Cancer Study, Genotype, Messenger, Australian Ovarian Cancer Study, Breast Neoplasms, Real-Time Polymerase Chain Reaction, Medical and Health Sciences, Rare Diseases, Risk Factors, Australian Cancer Study, Breast Cancer, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Polymorphism, Aetiology, Luciferases, Telomerase, Gene Environment Interaction and Breast Cancer, Oligonucleotide Array Sequence Analysis, Cancer, Epidemiological study of BRCA1 & BRCA2 Mutation Carriers, Ovarian Neoplasms, Tumor, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Prevention, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, Single Nucleotide, Telomere, DNA Methylation, Biological Sciences, Chromatin, Ovarian Cancer, Alternative Splicing, Genetic Loci, Case-Control Studies, RNA, Female, Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers, Hereditary Breast and Ovarian Cancer Research Group Netherlands, Biomarkers, Genome-Wide Association Study, Developmental Biology
Abstract: TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
Published: 2013

39. Common variants at 19p13 are associated with susceptibility to ovarian cancer

Author: Bolton, Kelly L, Tyrer, Jonathan, Song, Honglin, Ramus, Susan J, Notaridou, Maria, Jones, Chris, Sher, Tanya, Gentry-Maharaj, Aleksandra, Wozniak, Eva, Tsai, Ya-Yu, Weidhaas, Joanne, Paik, Daniel, Van Den Berg, David J, Stram, Daniel O, Pearce, Celeste Leigh, Wu, Anna H, Brewster, Wendy, Anton-Culver, Hoda, Ziogas, Argyrios, Narod, Steven A, Levine, Douglas A, Kaye, Stanley B, Brown, Robert, Paul, Jim, Flanagan, James, Sieh, Weiva, McGuire, Valerie, Whittemore, Alice S, Campbell, Ian, Gore, Martin E, Lissowska, Jolanta, Yang, Hanna P, Medrek, Krzysztof, Gronwald, Jacek, Lubinski, Jan, Jakubowska, Anna, Le, Nhu D, Cook, Linda S, Kelemen, Linda E, Brooks-Wilson, Angela, Massuger, Leon FAG, Kiemeney, Lambertus A, Aben, Katja KH, van Altena, Anne M, Houlston, Richard, Tomlinson, Ian, Palmieri, Rachel T, Moorman, Patricia G, Schildkraut, Joellen, Iversen, Edwin S, Phelan, Catherine, Vierkant, Robert A, Cunningham, Julie M, Goode, Ellen L, Fridley, Brooke L, Kruger-Kjaer, Susan, Blaeker, Jan, Hogdall, Estrid, Hogdall, Claus, Gross, Jenny, Karlan, Beth Y, Ness, Roberta B, Edwards, Robert P, Odunsi, Kunle, Moyisch, Kirsten B, Baker, Julie A, Modugno, Francesmary, Heikkinenen, Tuomas, Butzow, Ralf, Nevanlinna, Heli, Leminen, Arto, Bogdanova, Natalia, Antonenkova, Natalia, Doerk, Thilo, Hillemanns, Peter, Dürst, Matthias, Runnebaum, Ingo, Thompson, Pamela J, Carney, Michael E, Goodman, Marc T, Lurie, Galina, Wang-Gohrke, Shan, Hein, Rebecca, Chang-Claude, Jenny, Rossing, Mary Anne, Cushing-Haugen, Kara L, Doherty, Jennifer, Chen, Chu, Rafnar, Thorunn, Besenbacher, Soren, Sulem, Patrick, Stefansson, Kari, Birrer, Michael J, Terry, Kathryn L, Hernandez, Dena, Cramer, Daniel W, Vergote, Ignace, Amant, Frederic, Lambrechts, Diether, and Despierre, Evelyn
Subjects: Australian Ovarian Cancer Study Group, endocrine system diseases, Genotype, Ovarian Cancer Association Consortium, Cystadenocarcinoma, Adenocarcinoma, Medical and Health Sciences, Chromosomes, Clear Cell, Rare Diseases, Clinical Research, Australian Cancer Study, Genetics, Humans, 2.1 Biological and endogenous factors, Mucinous, Genetic Predisposition to Disease, Aetiology, Polymorphism, Oligonucleotide Array Sequence Analysis, Cancer, Ovarian Neoplasms, Cultured, Genome, Tumor, Pair 19, Prevention, Gene Expression Profiling, Ovary, Human Genome, Signal Transducing, Serous, Adaptor Proteins, Single Nucleotide, Middle Aged, Biological Sciences, female genital diseases and pregnancy complications, Tumor Cells, Endometrial Neoplasms, Ovarian Cancer, Orphan Drug, Case-Control Studies, Female, Biomarkers, Human, Genome-Wide Association Study, Developmental Biology
Abstract: Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women. We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available survival time data and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P = 5 × 10⁻⁴ and P = 6 × 10⁻⁴, respectively), but they did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P = 3 × 10⁻⁹ and P = 4 × 10⁻¹¹, respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1-interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development.
Published: 2010

40. Analysis of Over 10,000 Cases Finds No Association between Previously Reported Candidate Polymorphisms and Ovarian Cancer Outcome

Author: White, Kristen L., Vierkant, Robert A., Fogarty, Zachary C., Charbonneau, Bridget, Block, Matthew S., Pharoah, Paul D.P., Chenevix-Trench, Georgia, Rossing, Mary Ann, Cramer, Daniel W., Pearce, Celeste Leigh, Schildkraut, Joellen M., Menon, Usha, Kjaer, Sussanne Kruger, Levine, Douglas A., Gronwald, Jacek, Culver, Hoda Anton, Whittemore, Alice S., Karlan, Beth Y., Lambrechts, Diether, Kupryjanczyk, Jolanta, Wentzensen, Nicolas, Chang-Claude, Jenny, Bandera, Elisa V., Hogdall, Estrid, Heitz, Florian, Kaye, Stanley B., Fasching, Peter A., Campbell, Ian, Pejovic, Tanja, Goodman, Marc T., Bean, Yukie, Lurie, Galina, Eccles, Diana, Hein, Alexander, Beckmann, Matthias W., Ekici, Arif B., Paul, James, Brown, Robert, Flanagan, James M., Harter, Philipp, Schwaab, Ira, Du Bois, Andreas, Hogdall, Claus K., Lundvall, Lene, Olson, Sara H., Orlow, Irene, Paddock, Lisa E., Rudolph, Anja, Eilber, Ursula, Dansonka-Mieszkowska, Agnieszka, Rzepecka, Iwona K., Ziolkowska-Seta, Izabela, Brinton, Louise, Yang, Hannah, Garcia-Closas, Montserrat, Despierre, Evelyn, Lambrechts, Sandrina, Vergote, Ignace, Walsh, Christine, Lester, Jenny, Sieh, Weiva, McGuire, Valerie, Rothstein, Joseph H., Ziogas, Argyrios, Lubinksi, Jan, Cybulski, Cezary, Menkiszak, Janusz, Jensen, Allan, Gayther, Simon A., Ramus, Susan J., Gentry-Maharaj, Aleksandra, Berchuck, Andrew, Wu, Anna H., Pike, Malcolm C., Van Den Berg, David, Terry, Kathryn L., Vitonis, Allison F., Doherty, Jennifer A., Johnatty, Sharon E., DeFazio, Anna, Song, Honglin, Tyrer, Jonathan, Sellers, Thomas A., Phelan, Catherine M., Kalli, Kimberly R., Cunningham, Julie M., Fridley, Brooke L., and Goode, Ellen L.
Subjects: Public health, Oncology, 3. Good health
Abstract: Background: Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNP) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes. Methods: Twenty-seven SNPs in VHL, HGF, IL18, PRKACB, ABCB1, CYP2C8, ERCC2, and ERCC1 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000-observed person-years and 4,478 deaths. Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates. Results: We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined. Conclusions: These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies. Impact: These variants should not be used in prognostic models. Alternate approaches to uncovering inherited prognostic factors, if they exist, are needed.

41. MyD88 and TLR4 Expression in Epithelial Ovarian Cancer

Author: Block, Matthew S, Vierkant, Robert A, Rambau, Peter F, Winham, Stacey J, Wagner, Philipp, Traficante, Nadia, Tołoczko, Aleksandra, Tiezzi, Daniel G, Taran, Florin Andrei, Sinn, Peter, Sieh, Weiva, Sharma, Raghwa, Rothstein, Joseph H, Ramón Y Cajal, Teresa, Paz-Ares, Luis, Oszurek, Oleg, Orsulic, Sandra, Ness, Roberta B, Nelson, Gregg, Modugno, Francesmary, Menkiszak, Janusz, McGuire, Valerie, McCauley, Bryan M, Mack, Marie, Lubiński, Jan, Longacre, Teri A, Li, Zheng, Lester, Jenny, Kennedy, Catherine J, Kalli, Kimberly R, Jung, Audrey Y, Johnatty, Sharon E, Jimenez-Linan, Mercedes, Jensen, Allan, Intermaggio, Maria P, Hung, Jillian, Herpel, Esther, Hernandez, Brenda Y, Hartkopf, Andreas D, Harnett, Paul R, Ghatage, Prafull, García-Bueno, José M, Gao, Bo, Fereday, Sian, Eilber, Ursula, Edwards, Robert P, De Sousa, Christiani B, De Andrade, Jurandyr M, Chudecka-Głaz, Anita, Chenevix-Trench, Georgia, Cazorla, Alicia, Brucker, Sara Y, Australian Ovarian Cancer Study Group, Alsop, Jennifer, Whittemore, Alice S, Steed, Helen, Staebler, Annette, Moysich, Kirsten B, Menon, Usha, Koziak, Jennifer M, Kommoss, Stefan, Kjaer, Susanne K, Kelemen, Linda E, Karlan, Beth Y, Huntsman, David G, Høgdall, Estrid, Gronwald, Jacek, Goodman, Marc T, Gilks, Blake, García, María José, Fasching, Peter A, De Fazio, Anna, Deen, Suha, Chang-Claude, Jenny, Candido Dos Reis, Francisco J, Campbell, Ian G, Brenton, James D, Bowtell, David D, Benítez, Javier, Pharoah, Paul DP, Köbel, Martin, Ramus, Susan J, and Goode, Ellen L
Subjects: Adult, Ovarian Neoplasms, Carcinoma, Ovarian Epithelial, Middle Aged, Immunohistochemistry, Survival Analysis, 3. Good health, Toll-Like Receptor 4, Tissue Array Analysis, Myeloid Differentiation Factor 88, Biomarkers, Tumor, Humans, Female, Aged
Abstract: OBJECTIVE: To 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 METHODS: We 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). RESULTS: Expression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P

42. Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC)

Author: Jim, Heather S. L., Lin, Hui-Yi, Tyrer, Jonathan P., Lawrenson, Kate, Dennis, Joe, Chornokur, Ganna, Chen, Zhihua, Chen, Ann Y., Permuth-Wey, Jennifer, Aben, Katja Kh, Anton-Culver, Hoda, Antonenkova, Natalia, Bruinsma, Fiona, Bandera, Elisa V., Bean, Yukie T., Beckmann, Matthias W., Bisogna, Maria, Bjorge, Line, Bogdanova, Natalia, Brinton, Louise A., Brooks-Wilson, Angela, Bunker, Clareann H., Butzow, Ralf, Campbell, Ian G., Carty, Karen, Chang-Claude, Jenny, Cook, Linda S., Cramer, Daniel W., Cunningham, Julie M., Cybulski, Cezary, Dansonka-Mieszkowska, Agnieszka, Du Bois, Andreas, Despierre, Evelyn, Sieh, Weiva, Doherty, Jennifer A., Dork, Thilo, Durst, Matthias, Easton, Douglas F., Eccles, Diana M., Edwards, Robert P., Ekici, Arif B., Fasching, Peter A., Fridley, Brooke L., Gao, Yu-Tang, Gentry-Maharaj, Aleksandra, Giles, Graham G., Glasspool, Rosalind, Goodman, Marc T., Gronwald, Jacek, Harter, Philipp, Hasmad, Hanis N., Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle A. T., Hillemanns, Peter, Hogdall, Claus K., Hogdall, Estrid, Hosono, Satoyo, Iversen, Edwin S., Jakubowska, Anna, Jensen, Allan, Ji, Bu-Tian, Karlan, Beth Y., Kellar, Melissa, Lambertus Kiemeney, Krakstad, Camilla, Kjaer, Susanne K., Kupryjanczyk, Jolanta, Vierkant, Robert A., Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D., Lee, Alice W., Lele, Shashi, Leminen, Arto, Lester, Jenny, Levine, Douglas A., Liang, Dong, Lim, Boon Kiong, Lissowska, Jolanta, Lu, Karen, Lubinski, Jan, Lundvall, Lene, Massuger, Leon F. A. G., Matsuo, Keitaro, Mcguire, Valerie, Mclaughlin, John R., Mcneish, Ian, Menon, Usha, Milne, Roger L., Modugno, Francesmary, Thomsen, Lotte, Moysich, Kirsten B., Ness, Roberta B., Nevanlinna, Heli, Eilber, Ursula, Odunsi, Kunle, Olson, Sara H., Orlow, Irene, Orsulic, Sandra, Palmieri Weber, Rachel, Paul, James, Pearce, Celeste L., Pejovic, Tanja, Pelttari, Liisa M., Pike, Malcolm C., Poole, Elizabeth M., Schernhammer, Eva, Risch, Harvey A., Rosen, Barry, Rossing, Mary Anne, Rothstein, Joseph H., Rudolph, Anja, Runnebaum, Ingo B., Rzepecka, Iwona K., Salvesen, Helga B., Schwaab, Ira, Shu, Xiao-Ou, Shvetsov, Yurii B., Siddiqui, Nadeem, Song, Honglin, Southey, Melissa C., Spiewankiewicz, Beata, Sucheston-Campbell, Lara, Teo, Soo-Hwang, Terry, Kathryn L., Thompson, Pamela J., Tangen, Ingvild L., Tworoger, Shelley S., Altena, Anne M., Vergote, Ignace, Walsh, Christine S., Wang-Gohrke, Shan, Wentzensen, Nicolas, Whittemore, Alice S., Wicklund, Kristine G., Wilkens, Lynne R., Wu, Anna H., Wu, Xifeng, Woo, Yin-Ling, Yang, Hannah, Zheng, Wei, Ziogas, Argyrios, Amankwah, Ernest, Berchuck, Andrew, Georgia Chenevix-Trench on behalf of the AOCS management group 95,96, Schildkraut, Joellen M., Kelemen, Linda E., Ramus, Susan J., Monteiro, Alvaro N. A., Goode, Ellen L., Narod, Steven A., Gayther, Simon A., Pharoah, Paul D. P., Sellers, Thomas A., and Phelan, Catherine M.
Subjects: endocrine system, Georgia Chenevix-Trench on behalf of the AOCS management group 95,96
Abstract: Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68-0.90, p = 5.59 × 10(-4)]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.

43. A comprehensive gene-environment interaction analysis in Ovarian Cancer using genome-wide significant common variants

Author: Kim, Sehee, Wang, Miao, Tyrer, Jonathan P, Jensen, Allan, Wiensch, Ashley, Liu, Gang, Lee, Alice W, Ness, Roberta B, Salvatore, Maxwell, Tworoger, Shelley S, Whittemore, Alice S, Anton-Culver, Hoda, Sieh, Weiva, Olson, Sara H, Berchuck, Andrew, Goode, Ellen L, Goodman, Marc T, Doherty, Jennifer Anne, Chenevix-Trench, Georgia, Rossing, Mary Anne, Webb, Penelope M, Giles, Graham G, Terry, Kathryn L, Ziogas, Argyrios, Fortner, Renée T, Menon, Usha, Gayther, Simon A, Wu, Anna H, Song, Honglin, Brooks-Wilson, Angela, Bandera, Elisa V, Cook, Linda S, Cramer, Daniel W, Milne, Roger L, Winham, Stacey J, Kjaer, Susanne K, Modugno, Francesmary, Thompson, Pamela J, Chang-Claude, Jenny, Harris, Holly R, Schildkraut, Joellen M, Le, Nhu D, Wentzensen, Nico, Trabert, Britton, Høgdall, Estrid, Huntsman, David, Pike, Malcolm C, Pharoah, Paul DP, Pearce, Celeste Leigh, and Mukherjee, Bhramar
Subjects: additive interaction, G × E, ovarian cancer, genetics, 3. Good health
Abstract: As a follow-up to genome-wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well-known ovarian cancer risk factors and their interactions with 28 genome-wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case-control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 × 10-4 ). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI = 0.46-0.60) compared to 0.71 (95%CI = 0.66-0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1-5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene-environment analysis in ovarian cancer.

44. Common variants at 19p13 are associated with susceptibility to ovarian cancer (vol 42, pg 880, 2010)

Author: Bolton, Kelly L., Tyrer, Jonathan, Song, Honglin, Ramus, Susan J., Notaridou, Maria, Jones, Chris, Sher, Tanya, Gentry-Maharaj, Aleksandra, Wozniak, Eva, Tsai, Ya-Yu, Weidhaas, Joanne, Paik, Daniel, Den Berg, David J., Stram, Daniel O., Pearce, Celeste Leigh, Wu, Anna H., Brewster, Wendy, Anton-Culver, Hoda, Ziogas, Argyrios, Narod, Steven A., Levine, Douglas A., Kaye, Stanley B., Brown, Robert, Paul, Jim, Flanagan, James, Sieh, Weiva, Mcguire, Valerie, Whittemore, Alice S., Campbell, Ian, Gore, Martin E., Lissowska, Jolanta, Yang, Hanna P., Medrek, Krzysztof, Gronwald, Jacek, Lubinski, Jan, Jakubowska, Anna, Le, Nhu D., Cook, Linda S., Kelemen, Linda E., Brooks-Wilson, Angela, Massuger, Leon F. A. G., Lambertus Kiemeney, Aben, Katja K. H., Altena, Anne M., Houlston, Richard, Tomlinson, Ian, Palmieri, Rachel T., Moorman, Patricia G., Schildkraut, Joellen, Iversen, Edwin S., Phelan, Catherine, Vierkant, Robert A., Cunningham, Julie M., Goode, Ellen L., Fridley, Brooke L., Kruger-Kjaer, Susan, Blaeker, Jan, Hogdall, Estrid, Hogdall, Claus, Gross, Jenny, Karlan, Beth Y., Ness, Roberta B., Edwards, Robert P., Odunsi, Kunle, Moyisch, Kirsten B., Baker, Julie A., Modugno, Francesmary, Heikkinenen, Tuomas, Butzow, Ralf, Nevanlinna, Heli, Leminen, Arto, Bogdanova, Natalia, Antonenkova, Natalia, Doerk, Thilo, Hillemanns, Peter, Duerst, Matthias, Runnebaum, Ingo, Thompson, Pamela J., Carney, Michael E., Goodman, Marc T., Lurie, Galina, Wang-Gohrke, Shan, Hein, Rebecca, Chang-Claude, Jenny, Rossing, Mary Anne, Cushing-Haugen, Kara L., Doherty, Jennifer, Chen, Chu, Rafnar, Thorunn, Besenbacher, Soren, Sulem, Patrick, Stefansson, Kari, Birrer, Michael J., Terry, Kathryn L., Hernandez, Dena, Cramer, Daniel W., Vergote, Ignace, Amant, Frederic, Lambrechts, Diether, Despierre, Evelyn, Fasching, Peter A., Beckmann, Matthias W., Thiel, Falk C., Ekici, Arif B., Chen, Xiaoqing, Johnatty, Sharon E., Webb, Penelope M., Beesley, Jonathan, Chanock, Stephen, Garcia-Closas, Montserrat, Sellers, Tom, Easton, Douglas F., Berchuck, Andrew, Chenevix-Trench, Georgia, Pharoah, Paul D. P., Gayther, Simon A., Australian Ovarian Canc Study Grp, Australian Canc Study Ovarian Canc, and Ovarian Canc Assoc Consortium

45. Polygenic Risk Modelling for Prediction of Epithelial Ovarian Cancer Risk

Author: Dareng, Eileen O, Tyrer, Jonathan, Barnes, Daniel, Jones, Michelle R, Yang, Xin, Aben, Katja KH, Adank, Muriel A, Agata, Simona, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Aravantinos, Gerasimos, Arun, Banu K, Augustinsson, Annelie, Balma��a, Judith, Bandera, Elisa V, Barkardottir, Rosa B, Barrowdale, Daniel, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q, Bjorge, Line, Black, Amanda, Bogdanova, Natalia V, Bonanni, Bernardo, Borg, Ake, Brenton, James, Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S, Cai, Hui, Caligo, Maria A, Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K, Claes, Kathleen BM, Colanna, Sarah, Cook, Linda S, Couch, Fergus J, Daly, Mary B, Dao, Fanny, Davies, Eleanor, De La Hoya, Miguel, Putter, Robin De, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A, Domchek, Susan M, D��rk, Thilo, Bois, Andreas Du, D��rst, Matthias, Eccles, Diana M, Eliassen, Heather A, Engel, Christoph, Evans, D Gareth, Fasching, Peter A, Flanagan, James M, Foretova, Lenka, Fortner, Ren��e T, Friedman, Eitan, Ganz, Patricia A, Garber, Judy, Gensini, Francesca, Giles, Graham G, Glendon, Gord, Godwin, Andrew K, Goodman, Marc T, Greene, Mark H, Gronwald, Jacek, Hahnen, Eric, Haiman, Christopher A, H��kansson, Niclas, Hamann, Ute, Hansen, Thomas VO, Harris, Holly R, Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle AT, H��gdall, Estrid, H��gdall, Claus K, Hopper, John L, Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J, Huntsman, David G, Imyanitov, Evgeny N, Isaacs, Claudine, Jakubowska, Anna, James, Paul A, Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th, John, Esther M, Jones, Michael E, Kang, Daehee, Karlan, Beth Y, Karnezis, Anthony, Kelemen, Linda E, Khusnutdinova, Elza, Kiemeney, Lambertus A, Kim, Byoung-Gie, Kjaer, Susanne K, Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W, Kwong, Ava, Lambrechts, Diether, Larson, Melissa C, Lazaro, Conxi, Le, Nhu D, Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Levine, Douglas A, Li, Lian, Li, Jingmei, Loud, Jennifer T, Lu, Karen H, Lubi��ski, Jan, Machackova, Eva, Mai, Phuong L, Manoukian, Siranoush, Marks, Jeffrey R, Matsuno, Rayna Kim, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R, McNeish, Iain A, Mebirouk, Noura, Menon, Usha, Miller, Austin, Milne, Roger L, Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B, Munro, Elizabeth, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nielsen, Henriette Roed, Nielsen, Finn C, Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo I, Olson, Sara H, Olsson, H��kan, Osorio, Ana, Papi, Laura, Park, Sue K, Parsons, Michael T, Pathak, Harsha, Pedersen, Inge Sokilde, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B, Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J, Risch, Harvey A, Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P, Santamari��a, Marta, Soucy, Penny, Schmutzler, Rita K, Setiawan, V Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F, Sokolenko, Anna P, Song, Honglin, Southey, Melissa C, Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J, Tan, Yen Yen, Teixeira, Manuel R, Teo, Soo Hwang, Terry, Kathryn L, Terry, Mary Beth, Thomassen, Mads, Thompson, Pamela J, Vestrheim Thomsen, Liv Cecilie, Thull, Darcy L, Tischkowitz, Marc, Titus, Linda, Toland, Amanda E, Torres, Diana, Trabert, Britton, Travis, Ruth, Tung, Nadine, Tworoger, Shelley S, Valen, Ellen, Van Altena, Anne M, Van Der Hout, Annemieke H, Van Nieuwenhuysen, Els, Van Rensburg, Elizabeth J, Vega, Ana, Edwards, Digna Velez, Vierkant, Robert A, Wang, Frances, Wappenschmidt, Barbara, Webb, Penelope M, Weinberg, Clarice R, Weitzel, Jeffrey N, Wentzensen, Nicolas, White, Emily, Whittemore, Alice S, Winham, Stacey J, Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H, Yan, Li, Yannoukakos, Drakoulis, Zavaglia, Katia M, Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K, Easton, Douglas, Lawrenson, Kate, DeFazio, Anna, Sellers, Thomas A, Ramus, Susan J, Pearce, Celeste L, Monteiro, Alvaro N, Cunningham, Julie, Goode, Ellen L, Schildkraut, Joellen M, Berchuck, Andrew, Chenevix-Trench, Georgia, Gayther, Simon A, Antoniou, Antonis C, and Pharoah, Paul DP
Subjects: 3. Good health
Abstract: Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally-efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, ��select and shrink for summary statistics�� (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestry; 7,669 women of East Asian ancestry; 1,072 women of African ancestry, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestry. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38(95%CI:1.28��1.48,AUC:0.588) per unit standard deviation, in women of European ancestry; 1.14(95%CI:1.08��1.19,AUC:0.538) in women of East Asian ancestry; 1.38(95%CI:1.21-1.58,AUC:0.593) in women of African ancestry; hazard ratios of 1.37(95%CI:1.30��1.44,AUC:0.592) in BRCA1 pathogenic variant carriers and 1.51(95%CI:1.36-1.67,AUC:0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

46. Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility

Author: Earp, Madalene, Tyrer, Jonathan P, Winham, Stacey J, Lin, Hui-Yi, Chornokur, Ganna, Dennis, Joe, Aben, Katja KH, Anton-Culver, Hoda, Antonenkova, Natalia, Bandera, Elisa V, Bean, Yukie T, Beckmann, Matthias W, Bjorge, Line, Bogdanova, Natalia, Brinton, Louise A, Brooks-Wilson, Angela, Bruinsma, Fiona, Bunker, Clareann H, Butzow, Ralf, Campbell, Ian G, Carty, Karen, Chang-Claude, Jenny, Cook, Linda S, Cramer, Daniel W, Cunningham, Julie M, Cybulski, Cezary, Dansonka-Mieszkowska, Agnieszka, Despierre, Evelyn, Doherty, Jennifer A, Dörk, Thilo, Du Bois, Andreas, Dürst, Matthias, Easton, Douglas F, Eccles, Diana M, Edwards, Robert P, Ekici, Arif B, Fasching, Peter A, Fridley, Brooke L, Gentry-Maharaj, Aleksandra, Giles, Graham G, Glasspool, Rosalind, Goodman, Marc T, Gronwald, Jacek, Harter, Philipp, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Hogdall, Claus K, Høgdall, Estrid, Hosono, Satoyo, Iversen, Edwin S, Jakubowska, Anna, Jensen, Allan, Ji, Bu-Tian, Jung, Audrey Y, Karlan, Beth Y, Kellar, Melissa, Kiemeney, Lambertus A, Kiong Lim, Boon, Kjaer, Susanne K, Krakstad, Camilla, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D, Lele, Shashi, Lester, Jenny, Levine, Douglas A, Li, Zheng, Liang, Dong, Lissowska, Jolanta, Lu, Karen, Lubinski, Jan, Lundvall, Lene, Massuger, Leon FAG, Matsuo, Keitaro, McGuire, Valerie, McLaughlin, John R, McNeish, Iain, Menon, Usha, Milne, Roger L, Modugno, Francesmary, Moysich, Kirsten B, Ness, Roberta B, Nevanlinna, Heli, Odunsi, Kunle, Olson, Sara H, Orlow, Irene, Orsulic, Sandra, Paul, James, Pejovic, Tanja, Pelttari, Liisa M, Permuth, Jenny B, Pike, Malcolm C, Poole, Elizabeth M, Rosen, Barry, Rossing, Mary Anne, Rothstein, Joseph H, Runnebaum, Ingo B, Rzepecka, Iwona K, Schernhammer, Eva, Schwaab, Ira, Shu, Xiao-Ou, Shvetsov, Yurii B, Siddiqui, Nadeem, Sieh, Weiva, Song, Honglin, Southey, Melissa C, Spiewankiewicz, Beata, Sucheston-Campbell, Lara, Tangen, Ingvild L, Teo, Soo-Hwang, Terry, Kathryn L, Thompson, Pamela J, Thomsen, Lotte, Tworoger, Shelley S, Van Altena, Anne M, Vergote, Ignace, Vestrheim Thomsen, Liv Cecilie, Vierkant, Robert A, Walsh, Christine S, Wang-Gohrke, Shan, Wentzensen, Nicolas, Whittemore, Alice S, Wicklund, Kristine G, Wilkens, Lynne R, Woo, Yin-Ling, Wu, Anna H, Wu, Xifeng, Xiang, Yong-Bing, Yang, Hannah, Zheng, Wei, Ziogas, Argyrios, Lee, Alice W, Pearce, Celeste L, Berchuck, Andrew, Schildkraut, Joellen M, Ramus, Susan J, Monteiro, Alvaro NA, Narod, Steven A, Sellers, Thomas A, Gayther, Simon A, Kelemen, Linda E, Chenevix-Trench, Georgia, Risch, Harvey A, Pharoah, Paul DP, Goode, Ellen L, and Phelan, Catherine M
Subjects: endocrine system diseases, Genotype, Quantitative Trait Loci, A Kinase Anchor Proteins, Carcinoma, Ovarian Epithelial, Polymorphism, Single Nucleotide, female genital diseases and pregnancy complications, 3. Good health, Risk Factors, Humans, Female, Genetic Predisposition to Disease, Genetic Association Studies, Rho Guanine Nucleotide Exchange Factors, Monomeric GTP-Binding Proteins
Abstract: Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.

47. Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study

Author: Dixon-Suen, Suzanne C, Nagle, Christina M, Thrift, Aaron P, Pharoah, Paul DP, Ewing, Ailith, Pearce, Celeste Leigh, Zheng, Wei, Australian Ovarian Cancer Study Group, Chenevix-Trench, Georgia, Fasching, Peter A, Beckmann, Matthias W, Lambrechts, Diether, Vergote, Ignace, Lambrechts, Sandrina, Van Nieuwenhuysen, Els, Rossing, Mary Anne, Doherty, Jennifer A, Wicklund, Kristine G, Chang-Claude, Jenny, Jung, Audrey Y, Moysich, Kirsten B, Odunsi, Kunle, Goodman, Marc T, Wilkens, Lynne R, Thompson, Pamela J, Shvetsov, Yurii B, Dörk, Thilo, Park-Simon, Tjoung-Won, Hillemanns, Peter, Bogdanova, Natalia, Butzow, Ralf, Nevanlinna, Heli, Pelttari, Liisa M, Leminen, Arto, Modugno, Francesmary, Ness, Roberta B, Edwards, Robert P, Kelley, Joseph L, Heitz, Florian, Du Bois, Andreas, Harter, Philipp, Schwaab, Ira, Karlan, Beth Y, Lester, Jenny, Orsulic, Sandra, Rimel, Bobbie J, Kjær, Susanne K, Høgdall, Estrid, Jensen, Allan, Goode, Ellen L, Fridley, Brooke L, Cunningham, Julie M, Winham, Stacey J, Giles, Graham G, Bruinsma, Fiona, Milne, Roger L, Southey, Melissa C, Hildebrandt, Michelle AT, Wu, Xifeng, Lu, Karen H, Liang, Dong, Levine, Douglas A, Bisogna, Maria, Schildkraut, Joellen M, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Bandera, Elisa V, Olson, Sara H, Salvesen, Helga B, Thomsen, Liv Cecilie Vestrheim, Kopperud, Reidun K, Bjorge, Line, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Bruegl, Amanda, Cook, Linda S, Le, Nhu D, Swenerton, Kenneth D, Brooks-Wilson, Angela, Kelemen, Linda E, Lubiński, Jan, Huzarski, Tomasz, Gronwald, Jacek, Menkiszak, Janusz, Wentzensen, Nicolas, Brinton, Louise, Yang, Hannah, Lissowska, Jolanta, Høgdall, Claus K, Lundvall, Lene, Song, Honglin, Tyrer, Jonathan P, Campbell, Ian, Eccles, Diana, Paul, James, Glasspool, Rosalind, Siddiqui, Nadeem, Whittemore, Alice S, Sieh, Weiva, McGuire, Valerie, Rothstein, Joseph H, Narod, Steven A, Phelan, Catherine, Risch, Harvey A, McLaughlin, John R, Anton-Culver, Hoda, Ziogas, Argyrios, Menon, Usha, Gayther, Simon A, Ramus, Susan J, Gentry-Maharaj, Aleksandra, Wu, Anna H, Pike, Malcolm C, Tseng, Chiu-Chen, Kupryjanczyk, Jolanta, Dansonka-Mieszkowska, Agnieszka, Budzilowska, Agnieszka, Rzepecka, Iwona K, Webb, Penelope M, and Ovarian Cancer Association Consortium
Subjects: Adult, Aged, 80 and over, Ovarian Neoplasms, Adolescent, Geography, Carcinoma, Ovarian Epithelial, Mendelian Randomization Analysis, Middle Aged, Body Height, 3. Good health, Young Adult, Risk Factors, Case-Control Studies, Humans, Female, Genetic Predisposition to Disease, Aged
Abstract: BACKGROUND: Observational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias. METHODS: We pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted genetic risk score combining 609 single-nucleotide polymorphisms. Study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted height and risk were pooled using random-effects meta-analysis. RESULTS: Greater genetically predicted height was associated with increased ovarian cancer risk overall (pooled-OR (pOR) = 1.06; 95% CI: 1.01-1.11 per 5 cm increase in height), and separately for invasive (pOR = 1.06; 95% CI: 1.01-1.11) and borderline (pOR = 1.15; 95% CI: 1.02-1.29) tumours. CONCLUSIONS: Women with a genetic propensity to being taller have increased risk of ovarian cancer. This suggests genes influencing height are involved in pathways promoting ovarian carcinogenesis.

48. Genome-wide significant risk associations for mucinous ovarian carcinoma (vol 47, pg 888, 2015)

Author: Kelemen, Linda E., Lawrenson, Kate, Tyrer, Jonathan, Li, Qiyuan, Lee, Janet M., Seo, Ji-Heui, Phelan, Catherine M., Beesley, Jonathan, Chen, Xiaoqing, Spindler, Tassja J., Aben, Katja K. H., Anton-Culver, Hoda, Antonenkova, Natalia, Baker, Helen, Bandera, Elisa V., Bean, Yukie, Beckmann, Matthias W., Bisogna, Maria, Bjorge, Line, Bogdanova, Natalia, Brinton, Louise A., Brooks-Wilson, Angela, Bruinsma, Fiona, Butzow, Ralf, Campbell, Ian G., Carty, Karen, Chang-Claude, Jenny, Chen, Y. Ann, Chen, Zhihua, Cook, Linda S., Cramer, Daniel W., Cunningham, Julie M., Cybulski, Cezary, Dansonka-Mieszkowska, Agnieszka, Dennis, Joe, Dicks, Ed, Doherty, Jennifer A., Doerk, Thilo, Du Bois, Andreas, Duerst, Matthias, Eccles, Diana, Easton, Douglas T., Edwards, Robert P., Eilber, Ursula, Ekici, Arif B., Engelholm, Svend Aage, Fasching, Peter A., Fridley, Brooke L., Gao, Yu-Tang, Gentry-Maharaj, Aleksandra, Giles, Graham G., Glasspool, Rosalind, Goode, Ellen L., Goodman, Marc T., Grownwald, Jacek, Harrington, Patricia, Harter, Philipp, Hasmad, Hanis Nazihah, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle A. T., Hillemanns, Peter, Hogdall, Estrid, Hogdall, Claus, Hosono, Satoyo, Iversen, Edwin S., Jakubowska, Anna, Jensen, Allan, Ji, Bu-Tian, Karlan, Beth Y., Kellar, Melissa, Kelley, Joseph L., Kiemeney, Lambertus A., Krakstad, Camilla, Kjaer, Susanne K., Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D., Lee, Alice W., Lele, Shashi, Leminen, Arto, Lester, Jenny, Levine, Douglas A., Liang, Dong, Jolanta Lissowska, Lu, Karen, Lubinski, Jan, Lundvall, Lene, Massuger, Leon F. A. G., Matsuo, Keitaro, Mcguire, Valerie, Mclaughlin, John R., Mcneish, Iain, Menon, Usha, Modugno, Francesmary, Moes-Sosnowska, Joanna, Moysich, Kirsten B., Narod, Steven A., Nedergaard, Lotte, Ness, Roberta B., Nevanlinna, Heli, Adenan, Noor Azmi Mat, Odunsi, Kunle, Olson, Sara H., Orlow, Irene, Orsulic, Sandra, Weber, Rachel Palmieri, Paul, James, Pearce, Celeste Leigh, Pejovic, Tanja, Pelttari, Liisa M., Permuth-Wey, Jennifer, Pike, Malcolm C., Poole, Elizabeth M., Ramus, Susan J., Risch, Harvey A., Rosen, Barry, Rossing, Mary Anne, Rothstein, Joseph H., Rudolph, Anja, Runnebaum, Ingo B., Rzepecka, Iwona K., Salvesen, Helga B., Schildkraut, Joellen M., Schwaab, Ira, Shu, Xiao-Ou, Shvetsov, Yurii B., Siddiqui, Nadeem, Sieh, Weiva, Song, Honglin, Southey, Melissa C., Sucheston, Lara, Tangen, Ingvild L., Teo, Soo-Hwang, Terry, Kathryn L., Thompson, Pamela J., Tworoger, Shelley S., Altena, Anne M., Nieuwenhuysen, Els, Vergote, Ignace, Vierkant, Robert A., Wang-Gohrke, Shan, Walsh, Christine, Wentzensen, Nicolas, Whittemore, Alice S., Wicklund, Kristine G., Wilkens, Lynne R., Sawicki, Wlodzimierz, Woo, Yin-Ling, Wu, Xifeng, Wu, Anna H., Yang, Hannah, Zheng, Wei, Ziogas, Argyrios, Sellers, Thomas A., Freedman, Matthew L., Chenevix-Trench, Georgia, Pharoah, Paul D. P., Gayther, Simon A., and Berchuck, Andrew

49. Shared heritability and functional enrichment across six solid cancers

Author: Jiang, Xia, Finucane, Hilary K, Schumacher, Fredrick R, Schmit, Stephanie L, Tyrer, Jonathan P, Han, Younghun, Michailidou, Kyriaki, Lesseur, Corina, Kuchenbaecker, Karoline B, Dennis, Joe, Conti, David V, Casey, Graham, Gaudet, Mia M, Huyghe, Jeroen R, Albanes, Demetrius, Aldrich, Melinda C, Andrew, Angeline S, Andrulis, Irene L, Anton-Culver, Hoda, Antoniou, Antonis C, Antonenkova, Natalia N, Arnold, Susanne M, Aronson, Kristan J, Arun, Banu K, Bandera, Elisa V, Barkardottir, Rosa B, Barnes, Daniel R, Batra, Jyotsna, Beckmann, Matthias W, Benitez, Javier, Benlloch, Sara, Berchuck, Andrew, Berndt, Sonja I, Bickeböller, Heike, Bien, Stephanie A, Blomqvist, Carl, Boccia, Stefania, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Brauch, Hiltrud, Brenner, Hermann, Brenton, James D, Brook, Mark N, Brunet, Joan, Brunnström, Hans, Buchanan, Daniel D, Burwinkel, Barbara, Butzow, Ralf, Cadoni, Gabriella, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Campbell, Peter T, Cancel-Tassin, Géraldine, Cannon-Albright, Lisa, Campa, Daniele, Caporaso, Neil, Carvalho, André L, Chan, Andrew T, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Chu, Christiani, David C, Claes, Kathleen BM, Claessens, Frank, Clements, Judith, Collée, J Margriet, Correa, Marcia Cruz, Couch, Fergus J, Cox, Angela, Cunningham, Julie M, Cybulski, Cezary, Czene, Kamila, Daly, Mary B, DeFazio, Anna, Devilee, Peter, Diez, Orland, Gago-Dominguez, Manuela, Donovan, Jenny L, Dörk, Thilo, Duell, Eric J, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Edlund, Christopher K, Edwards, Digna R Velez, Ellberg, Carolina, Evans, D Gareth, Fasching, Peter A, Ferris, Robert L, Liloglou, Triantafillos, Figueiredo, Jane C, Fletcher, Olivia, Fortner, Renée T, Fostira, Florentia, Franceschi, Silvia, Friedman, Eitan, Gallinger, Steven J, Ganz, Patricia A, Garber, Judy, García-Sáenz, José A, Gayther, Simon A, Giles, Graham G, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, Goode, Ellen L, Goodman, Marc T, Goodman, Gary, Grankvist, Kjell, Greene, Mark H, Gronberg, Henrik, Gronwald, Jacek, Guénel, Pascal, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hamdy, Freddie C, Hamilton, Robert J, Hampe, Jochen, Haugen, Aage, Heitz, Florian, Herrero, Rolando, Hillemanns, Peter, Hoffmeister, Michael, Høgdall, Estrid, Hong, Yun-Chul, Hopper, John L, Houlston, Richard, Hulick, Peter J, Hunter, David J, Huntsman, David G, Idos, Gregory, Imyanitov, Evgeny N, Ingles, Sue Ann, Isaacs, Claudine, Jakubowska, Anna, James, Paul, Jenkins, Mark A, Johansson, Mattias, Johansson, Mikael, John, Esther M, Joshi, Amit D, Kaneva, Radka, Karlan, Beth Y, Kelemen, Linda E, Kühl, Tabea, Khaw, Kay-Tee, Khusnutdinova, Elza, Kibel, Adam S, Kiemeney, Lambertus A, Kim, Jeri, Kjaer, Susanne K, Knight, Julia A, Kogevinas, Manolis, Kote-Jarai, Zsofia, Koutros, Stella, Kristensen, Vessela N, Kupryjanczyk, Jolanta, Lacko, Martin, Lam, Stephan, Lambrechts, Diether, Landi, Maria Teresa, Lazarus, Philip, Le, Nhu D, Lee, Eunjung, Lejbkowicz, Flavio, Lenz, Heinz-Josef, Leslie, Goska, Lessel, Davor, Lester, Jenny, Levine, Douglas A, Li, Li, Li, Christopher I, Lindblom, Annika, Lindor, Noralane M, Liu, Geoffrey, Loupakis, Fotios, Lubiński, Jan, Maehle, Lovise, Maier, Christiane, Mannermaa, Arto, Marchand, Loic Le, Margolin, Sara, May, Taymaa, McGuffog, Lesley, Meindl, Alfons, Middha, Pooja, Miller, Austin, Milne, Roger L, MacInnis, Robert J, Modugno, Francesmary, Montagna, Marco, Moreno, Victor, Moysich, Kirsten B, Mucci, Lorelei, Muir, Kenneth, Mulligan, Anna Marie, Nathanson, Katherine L, Neal, David E, Ness, Andrew R, Neuhausen, Susan L, Nevanlinna, Heli, Newcomb, Polly A, Newcomb, Lisa F, Nielsen, Finn Cilius, Nikitina-Zake, Liene, Nordestgaard, Børge G, Nussbaum, Robert L, Offit, Kenneth, Olah, Edith, Olama, Ali Amin Al, Olopade, Olufunmilayo I, Olshan, Andrew F, Olsson, Håkan, Osorio, Ana, Pandha, Hardev, Park, Jong Y, Pashayan, Nora, Parsons, Michael T, Pejovic, Tanja, Penney, Kathryn L, Peters, Wilbert HM, Phelan, Catherine M, Phipps, Amanda I, Plaseska-Karanfilska, Dijana, Pring, Miranda, Prokofyeva, Darya, Radice, Paolo, Stefansson, Kari, Ramus, Susan J, Raskin, Leon, Rennert, Gad, Rennert, Hedy S, Van Rensburg, Elizabeth J, Riggan, Marjorie J, Risch, Harvey A, Risch, Angela, Roobol, Monique J, Rosenstein, Barry S, Rossing, Mary Anne, De Ruyck, Kim, Saloustros, Emmanouil, Sandler, Dale P, Sawyer, Elinor J, Schabath, Matthew B, Schleutker, Johanna, Schmidt, Marjanka K, Setiawan, V Wendy, Shen, Hongbing, Siegel, Erin M, Sieh, Weiva, Singer, Christian F, Slattery, Martha L, Sorensen, Karina Dalsgaard, Southey, Melissa C, Spurdle, Amanda B, Stanford, Janet L, Stevens, Victoria L, Stintzing, Sebastian, Stone, Jennifer, Sundfeldt, Karin, Sutphen, Rebecca, Swerdlow, Anthony J, Tajara, Eloiza H, Tangen, Catherine M, Tardon, Adonina, Taylor, Jack A, Teare, M Dawn, Teixeira, Manuel R, Terry, Mary Beth, Terry, Kathryn L, Thibodeau, Stephen N, Thomassen, Mads, Bjørge, Line, Tischkowitz, Marc, Toland, Amanda E, Torres, Diana, Townsend, Paul A, Travis, Ruth C, Tung, Nadine, Tworoger, Shelley S, Ulrich, Cornelia M, Usmani, Nawaid, Vachon, Celine M, Van Nieuwenhuysen, Els, Vega, Ana, Aguado-Barrera, Miguel Elías, Wang, Qin, Webb, Penelope M, Weinberg, Clarice R, Weinstein, Stephanie, Weissler, Mark C, Weitzel, Jeffrey N, West, Catharine ML, White, Emily, Whittemore, Alice S, Wichmann, H-Erich, Wiklund, Fredrik, Winqvist, Robert, Wolk, Alicja, Woll, Penella, Woods, Michael, Wu, Anna H, Wu, Xifeng, Yannoukakos, Drakoulis, Zheng, Wei, Zienolddiny, Shanbeh, Ziogas, Argyrios, Zorn, Kristin K, Lane, Jacqueline M, Saxena, Richa, Thomas, Duncan, Hung, Rayjean J, Diergaarde, Brenda, McKay, James, Peters, Ulrike, Hsu, Li, García-Closas, Montserrat, Eeles, Rosalind A, Chenevix-Trench, Georgia, Brennan, Paul J, Haiman, Christopher A, Simard, Jacques, Easton, Douglas F, Gruber, Stephen B, Pharoah, Paul DP, Price, Alkes L, Pasaniuc, Bogdan, Amos, Christopher I, Kraft, Peter, and Lindström, Sara
Subjects: Male, Ovarian Neoplasms, Lung Neoplasms, Mental Disorders, Smoking, Inheritance Patterns, Prostatic Neoplasms, Breast Neoplasms, Polymorphism, Single Nucleotide, White People, 3. Good health, Neoplasm Proteins, Phenotype, Head and Neck Neoplasms, Case-Control Studies, Humans, Female, Genetic Predisposition to Disease, Colorectal Neoplasms, Genome-Wide Association Study
Abstract: Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

50. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

Author: Hampras, Shalaka S, Sucheston-Campbell, Lara E, Cannioto, Rikki, Chang-Claude, Jenny, Modugno, Francesmary, Dörk, Thilo, Hillemanns, Peter, Preus, Leah, Knutson, Keith L, Wallace, Paul K, Hong, Chi-Chen, Friel, Grace, Davis, Warren, Nesline, Mary, Pearce, Celeste L, Kelemen, Linda E, Goodman, Marc T, Bandera, Elisa V, Terry, Kathryn L, Schoof, Nils, Eng, Kevin H, Clay, Alyssa, Singh, Prashant K, Joseph, Janine M, Aben, Katja KH, Anton-Culver, Hoda, Antonenkova, Natalia, Baker, Helen, Bean, Yukie, Beckmann, Matthias W, Bisogna, Maria, Bjorge, Line, Bogdanova, Natalia, Brinton, Louise A, Brooks-Wilson, Angela, Bruinsma, Fiona, Butzow, Ralf, Campbell, Ian G, Carty, Karen, Cook, Linda S, Cramer, Daniel W, Cybulski, Cezary, Dansonka-Mieszkowska, Agnieszka, Dennis, Joe, Despierre, Evelyn, Dicks, Ed, Doherty, Jennifer A, Du Bois, Andreas, Dürst, Matthias, Easton, Doug, Eccles, Diana, Edwards, Robert P, Ekici, Arif B, Fasching, Peter A, Fridley, Brooke L, Gao, Yu-Tang, Gentry-Maharaj, Aleksandra, Giles, Graham G, Glasspool, Rosalind, Gronwald, Jacek, Harrington, Patricia, Harter, Philipp, Hasmad, Hanis Nazihah, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hogdall, Claus, Hogdall, Estrid, Hosono, Satoyo, Iversen, Edwin S, Jakubowska, Anna, Jensen, Allan, Ji, Bu-Tian, Karlan, Beth Y, Kellar, Melissa, Kelley, Joseph L, Kiemeney, Lambertus A, Klapdor, Rüdiger, Kolomeyevskaya, Nonna, Krakstad, Camilla, Kjaer, Susanne K, Kruszka, Bridget, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D, Lee, Alice W, Lele, Shashikant, Leminen, Arto, Lester, Jenny, Levine, Douglas A, Liang, Dong, Lissowska, Jolanta, Liu, Song, Lu, Karen, Lubinski, Jan, Lundvall, Lene, Massuger, Leon FAG, Matsuo, Keitaro, McGuire, Valeria, McLaughlin, John R, McNeish, Ian, Menon, Usha, Moes-Sosnowska, Joanna, Narod, Steven A, Nedergaard, Lotte, Nevanlinna, Heli, Nickels, Stefan, Olson, Sara H, Orlow, Irene, Weber, Rachel Palmieri, Paul, James, Pejovic, Tanja, Pelttari, Liisa M, Perkins, Barbara, Permuth-Wey, Jenny, Pike, Malcolm C, Plisiecka-Halasa, Joanna, Poole, Elizabeth M, Risch, Harvey A, Rossing, Mary Anne, Rothstein, Joseph H, Rudolph, Anja, Runnebaum, Ingo B, Rzepecka, Iwona K, Salvesen, Helga B, Schernhammer, Eva, Schmitt, Kristina, Schwaab, Ira, Shu, Xiao-Ou, Shvetsov, Yurii B, Siddiqui, Nadeem, Sieh, Weiva, Song, Honglin, Southey, Melissa C, Tangen, Ingvild L, Teo, Soo-Hwang, Thompson, Pamela J, Timorek, Agnieszka, Tsai, Ya-Yu, Tworoger, Shelley S, Tyrer, Jonathan, Van Altena, Anna M, Vergote, Ignace, Vierkant, Robert A, Walsh, Christine, Wang-Gohrke, Shan, Wentzensen, Nicolas, Whittemore, Alice S, Wicklund, Kristine G, Wilkens, Lynne R, Wu, Anna H, Wu, Xifeng, Woo, Yin-Ling, Yang, Hannah, Zheng, Wei, Ziogas, Argyrios, Gayther, Simon A, Ramus, Susan J, Sellers, Thomas A, Schildkraut, Joellen M, Phelan, Catherine M, Berchuck, Andrew, Chenevix-Trench, Georgia, Cunningham, Julie M, Pharoah, Paul P, Ness, Roberta B, Odunsi, Kunle, Goode, Ellen L, and Moysich, Kirsten B
Subjects: Adult, Ovarian Neoplasms, immunosuppression, endocrine system diseases, Genotype, biomarkers, Middle Aged, Protein-Serine-Threonine Kinases, Polymorphism, Single Nucleotide, T-Lymphocytes, Regulatory, female genital diseases and pregnancy complications, 3. Good health, TGFBR2, Gene Expression Regulation, Neoplastic, ovarian cancer, Gene Frequency, Risk Factors, genetic variation, Humans, Female, Genetic Predisposition to Disease, Neoplasms, Glandular and Epithelial, Receptors, Transforming Growth Factor beta, Adenocarcinoma, Clear Cell, Aged
Abstract: BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid ( p = 0.082) and clear cell ( p = 0.083), with the most significant gene level association seen with TGFBR2 ( p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 ( p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA ( p = 0.035, endometrioid and mucinous), LGALS1 ( p = 0.03, mucinous), STAT5B ( p = 0.022, clear cell), TGFBR1 ( p = 0.021 endometrioid) and TGFBR2 ( p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

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