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1. Racial and ethnic differences in epithelial ovarian cancer risk: an analysis from the Ovarian Cancer Association Consortium

Author: Meagher, Nicola S, White, Kami K, Wilkens, Lynne R, Bandera, Elisa V, Berchuck, Andrew, Carney, Michael E, Cramer, Daniel W, Cushing-Haugen, Kara L, Jordan, Susan, Kaufmann, Scott H, Le, Nhu D, Pike, Malcolm C, Riggan, Marjorie, Qin, Bo, Rothstein, Joseph H, Titus, Linda, Winham, Stacey J, Anton-Culver, Hoda, Doherty, Jennifer A, Goode, Ellen L, Pearce, Celeste Leigh, Risch, Harvey A, Webb, Penelope M, Cook, Linda S, Goodman, Marc T, Harris, Holly R, Le Marchand, Loic, McGuire, Valerie, Pharoah, Paul DP, Sarink, Danja, Schildkraut, Joellen M, Sieh, Weiva, Terry, Kathryn L, Thompson, Pamela J, Whittemore, Alice S, Wu, Anna H, Peres, Lauren C, and Merritt, Melissa A
Subjects: Epidemiology, Health Sciences, Ovarian Cancer, Rare Diseases, Cancer, Minority Health, Prevention, Women's Health, Humans, Female, Ovarian Neoplasms, Middle Aged, Carcinoma, Ovarian Epithelial, Risk Factors, Adult, Native Hawaiian or Other Pacific Islander, Case-Control Studies, Aged, Sterilization, Tubal, Parity, Asian, White People, Hispanic or Latino, United States, Contraceptives, Oral, Logistic Models, Smoking, Neoplasms, Glandular and Epithelial, Ethnicity, Odds Ratio, ovarian cancer, risk factors, race, ethnicity, Mathematical Sciences, Medical and Health Sciences
Abstract: Limited estimates exist on risk factors for epithelial ovarian cancer (EOC) in Asian, Hispanic, and Native Hawaiian/Pacific Islander women. Participants in this study included 1734 Asian (n = 785 case and 949 control participants), 266 Native Hawaiian/Pacific Islander (n = 99 case and 167 control participants), 1149 Hispanic (n = 505 case and 644 control participants), and 24 189 White (n = 9981 case and 14 208 control participants) from 11 studies in the Ovarian Cancer Association Consortium. Logistic regression models estimated odds ratios (ORs) and 95% CIs for risk associations by race and ethnicity. Heterogeneity in EOC risk associations by race and ethnicity (P ≤ .02) was observed for oral contraceptive (OC) use, parity, tubal ligation, and smoking. We observed inverse associations with EOC risk for OC use and parity across all groups; associations were strongest in Native Hawaiian/Pacific Islander and Asian women. The inverse association for tubal ligation with risk was most pronounced for Native Hawaiian/Pacific Islander participants (odds ratio (OR) = 0.25; 95% CI, 0.13-0.48) compared with Asian and White participants (OR = 0.68 [95% CI, 0.51-0.90] and OR = 0.78 [95% CI, 0.73-0.85], respectively). Differences in EOC risk factor associations were observed across racial and ethnic groups, which could be due, in part, to varying prevalence of EOC histotypes. Inclusion of greater diversity in future studies is essential to inform prevention strategies. This article is part of a Special Collection on Gynecological Cancers.
Published: 2024

2. Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma

Author: Saner, Flurina AM, Takahashi, Kazuaki, Budden, Timothy, Pandey, Ahwan, Ariyaratne, Dinuka, Zwimpfer, Tibor A, Meagher, Nicola S, Fereday, Sian, Twomey, Laura, Pishas, Kathleen I, Hoang, Therese, Bolithon, Adelyn, Traficante, Nadia, Group, for the Australian Ovarian Cancer Study, Alsop, Kathryn, Christie, Elizabeth L, Kang, Eun-Young, Nelson, Gregg S, Ghatage, Prafull, Lee, Cheng-Han, Riggan, Marjorie J, Alsop, Jennifer, Beckmann, Matthias W, Boros, Jessica, Brand, Alison H, Brooks-Wilson, Angela, Carney, Michael E, Coulson, Penny, Courtney-Brooks, Madeleine, Cushing-Haugen, Kara L, Cybulski, Cezary, El-Bahrawy, Mona A, Elishaev, Esther, Erber, Ramona, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Gilks, C Blake, Harnett, Paul R, Harris, Holly R, Hartmann, Arndt, Hein, Alexander, Hendley, Joy, Hernandez, Brenda Y, Jakubowska, Anna, Jimenez-Linan, Mercedes, Jones, Michael E, Kaufmann, Scott H, Kennedy, Catherine J, Kluz, Tomasz, Koziak, Jennifer M, Kristjansdottir, Björg, Le, Nhu D, Lener, Marcin, Lester, Jenny, Lubiński, Jan, Mateoiu, Constantina, Orsulic, Sandra, Ruebner, Matthias, Schoemaker, Minouk J, Shah, Mitul, Sharma, Raghwa, Sherman, Mark E, Shvetsov, Yurii B, Soong, T Rinda, Steed, Helen, Sukumvanich, Paniti, Talhouk, Aline, Taylor, Sarah E, Vierkant, Robert A, Wang, Chen, Widschwendter, Martin, Wilkens, Lynne R, Winham, Stacey J, Anglesio, Michael S, Berchuck, Andrew, Brenton, James D, Campbell, Ian, Cook, Linda S, Doherty, Jennifer A, Fasching, Peter A, Fortner, Renée T, Goodman, Marc T, Gronwald, Jacek, Huntsman, David G, Karlan, Beth Y, Kelemen, Linda E, Menon, Usha, Modugno, Francesmary, Pharoah, Paul DP, Schildkraut, Joellen M, Sundfeldt, Karin, Swerdlow, Anthony J, Goode, Ellen L, DeFazio, Anna, Köbel, Martin, Ramus, Susan J, Bowtell, David DL, and Garsed, Dale W
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Genetics, Women's Health, Rare Diseases, Orphan Drug, Cancer Genomics, Ovarian Cancer, Precision Medicine, Human Genome, Cancer, 2.1 Biological and endogenous factors, Humans, Female, Ovarian Neoplasms, BRCA2 Protein, BRCA1 Protein, Cystadenocarcinoma, Serous, Retinoblastoma Binding Proteins, Prognosis, Ubiquitin-Protein Ligases, Neoplasm Grading, Lymphocytes, Tumor-Infiltrating, Middle Aged, Germ-Line Mutation, Gene Expression Regulation, Neoplastic, Aged, Biomarkers, Tumor, CD8-Positive T-Lymphocytes, Australian Ovarian Cancer Study Group, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract: PurposeThe purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC).Experimental designRB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 patients with primary HGSC to characterize tumors with concurrent BRCA deficiency and RB1 loss.ResultsRB1 loss was associated with longer OS in HGSC but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1.ConclusionsCo-occurrence of RB1 loss and BRCA deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.
Published: 2024

3. Lifetime ovulatory years and risk of epithelial ovarian cancer: a multinational pooled analysis

Author: Fu, Zhuxuan, Brooks, Maria Mori, Irvin, Sarah, Jordan, Susan, Aben, Katja KH, Anton-Culver, Hoda, Bandera, Elisa V, Beckmann, Matthias W, Berchuck, Andrew, Brooks-Wilson, Angela, Chang-Claude, Jenny, Cook, Linda S, Cramer, Daniel W, Cushing-Haugen, Kara L, Doherty, Jennifer A, Ekici, Arif B, Fasching, Peter A, Fortner, Renée T, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Giles, Graham G, Goode, Ellen L, Goodman, Marc T, Group, AOCS, Harris, Holly R, Hein, Alexander, Kaaks, Rudolf, Kiemeney, Lambertus A, Köbel, Martin, Kotsopoulos, Joanne, Le, Nhu D, Lee, Alice W, Matsuo, Keitaro, McGuire, Valerie, McLaughlin, John R, Menon, Usha, Milne, Roger L, Moysich, Kirsten B, Pearce, Celeste Leigh, Pike, Malcolm C, Qin, Bo, Ramus, Susan J, Riggan, Marjorie J, Rothstein, Joseph H, Schildkraut, Joellen M, Sieh, Weiva, Sutphen, Rebecca, Terry, Kathryn L, Thompson, Pamela J, Titus, Linda, van Altena, Anne M, White, Emily, Whittemore, Alice S, Wu, Anna H, Zheng, Wei, Ziogas, Argyrios, Taylor, Sarah E, Tang, Lu, Songer, Thomas, Wentzensen, Nicolas, Webb, Penelope M, Risch, Harvey A, and Modugno, Francesmary
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Clinical Research, Cancer, Ovarian Cancer, Prevention, Pregnancy, Humans, Female, Carcinoma, Ovarian Epithelial, Ovarian Neoplasms, Risk Factors, Parity, Contraceptives, Oral, Case-Control Studies, AOCS Group, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract: BackgroundThe role of ovulation in epithelial ovarian cancer (EOC) is supported by the consistent protective effects of parity and oral contraceptive use. Whether these factors protect through anovulation alone remains unclear. We explored the association between lifetime ovulatory years (LOY) and EOC.MethodsLOY was calculated using 12 algorithms. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the association between LOY or LOY components and EOC among 26 204 control participants and 21 267 case patients from 25 studies. To assess whether LOY components act through ovulation suppression alone, we compared beta coefficients obtained from regression models with expected estimates assuming 1 year of ovulation suppression has the same effect regardless of source.ResultsLOY was associated with increased EOC risk (OR per year increase = 1.014, 95% CI = 1.009 to 1.020 to OR per year increase = 1.044, 95% CI = 1.041 to 1.048). Individual LOY components, except age at menarche, also associated with EOC. The estimated model coefficient for oral contraceptive use and pregnancies were 4.45 times and 12- to 15-fold greater than expected, respectively. LOY was associated with high-grade serous, low-grade serous, endometrioid, and clear cell histotypes (ORs per year increase = 1.054, 1.040, 1.065, and 1.098, respectively) but not mucinous tumors. Estimated coefficients of LOY components were close to expected estimates for high-grade serous but larger than expected for low-grade serous, endometrioid, and clear cell histotypes.ConclusionsLOY is positively associated with nonmucinous EOC. Differences between estimated and expected model coefficients for LOY components suggest factors beyond ovulation underlie the associations between LOY components and EOC in general and for non-HGSOC.
Published: 2023

4. 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, Group, AOCS, Fischer, Anna, Gayther, Simon A, Barquin‐Garcia, Arantzazu, Gentry‐Maharaj, Aleksandra, Gilks, C Blake, Gronwald, Helena, Grube, Marcel, Harnett, Paul R, Harris, Holly R, Hartkopf, Andreas D, Hartmann, Arndt, Hein, Alexander, Hendley, Joy, Hernandez, Brenda Y, Huang, Yajue, Jakubowska, Anna, Jimenez‐Linan, Mercedes, Jones, Michael E, Kennedy, Catherine J, Kluz, Tomasz, Koziak, Jennifer M, Lesnock, Jaime, Lester, Jenny, Lubiński, Jan, Longacre, Teri A, Lycke, Maria, Mateoiu, Constantina, McCauley, Bryan M, McGuire, Valerie, Ney, Britta, Olawaiye, Alexander, Orsulic, Sandra, Osorio, Ana, Paz‐Ares, Luis, Ramón y Cajal, Teresa, Rothstein, Joseph H, Ruebner, Matthias, Schoemaker, Minouk J, Shah, Mitul, Sharma, Raghwa, Sherman, Mark E, Shvetsov, Yurii B, Singh, Naveena, Steed, Helen, Storr, Sarah J, Talhouk, Aline, Traficante, Nadia, Wang, Chen, Whittemore, Alice S, Widschwendter, Martin, Wilkens, Lynne R, Winham, Stacey J, Benitez, Javier, Berchuck, Andrew, Bowtell, David D, dos Reis, Francisco J Candido, Campbell, Ian, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Fasching, Peter A, Fortner, Renée T, García, María J, Goodman, Marc T, Goode, Ellen L, Gronwald, Jacek, Huntsman, David G, Karlan, Beth Y, Kelemen, Linda E, Kommoss, Stefan, Le, Nhu D, and Martin, Stewart G
Subjects: Reproductive Medicine, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Rare Diseases, Ovarian Cancer, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Humans, Female, Tumor Suppressor Protein p53, Ovarian Neoplasms, Carcinoma, Ovarian Epithelial, Carcinoma, Endometrioid, ovarian cancer, high-grade serous carcinoma, endometrioid, clear cell, TP53, p53, prognosis, AOCS Group, Clinical sciences
Abstract: Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.
Published: 2023

5. 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, Group, AOCS, Grube, Marcel, Harnett, Paul R, Harrington, Shariska Petersen, Harter, Philipp, Hartmann, Arndt, Hecht, Jonathan L, Heikaus, Sebastian, Hein, Alexander, Heitz, Florian, Hendley, Joy, Hernandez, Brenda Y, Polo, Susanna Hernando, Heublein, Sabine, Hirasawa, Akira, Høgdall, Estrid, Høgdall, Claus K, Horlings, Hugo M, Huntsman, David G, Huzarski, Tomasz, Jewell, Andrea, Jimenez‐Linan, Mercedes, Jones, Michael E, Kaufmann, Scott H, Kennedy, Catherine J, Khabele, Dineo, Kommoss, Felix KF, Kruitwagen, Roy FPM, Lambrechts, Diether, Le, Nhu D, Lener, Marcin, Lester, Jenny, Leung, Yee, Linder, Anna, Loverix, Liselore, Lubiński, Jan, Madan, Rashna, Maxwell, G Larry, Modugno, Francesmary, Neuhausen, Susan L, Olawaiye, Alexander, Olbrecht, Siel, Orsulic, Sandra, Palacios, José, Pearce, Celeste Leigh, Pike, Malcolm C, Quinn, Carmel M, Mohan, Ganendra Raj, Rodríguez‐Antona, Cristina, Ruebner, Matthias, and Ryan, Andy
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Clinical Research, Ovarian Cancer, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Female, Humans, Ovarian Neoplasms, Transcription Factors, Carcinoma, RNA, Messenger, Cystadenocarcinoma, Serous, Oncogene Proteins, Cyclin E, CCNE1 amplification, cyclin E1 expression, high-grade serous carcinoma, ovarian cancer, prognosis, AOCS Group, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis, Public health
Abstract: BackgroundCyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC.MethodsWithin the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated.ResultsHigh-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss.ConclusionThis study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.
Published: 2023

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

Author: Weir, Ashley, Kang, Eun-Young, Meagher, Nicola S, Nelson, Gregg S, Ghatage, Prafull, Lee, Cheng-Han, Riggan, Marjorie J, Gentry-Maharaj, Aleksandra, Ryan, Andy, Singh, Naveena, Widschwendter, Martin, Alsop, Jennifer, Anglesio, Michael S, Beckmann, Matthias W, Berger, Jessica, Bisinotto, Christiani, Boros, Jessica, Brand, Alison H, Brenton, James D, Brooks-Wilson, Angela, Carney, Michael E, Cunningham, Julie M, Cushing-Haugen, Kara L, Cybulski, Cezary, Elishaev, Esther, Erber, Ramona, Fereday, Sian, Fischer, Anna, Paz-Ares, Luis, Gayarre, Javier, Gilks, Blake C, Grube, Marcel, Harnett, Paul R, Harris, Holly R, Hartmann, Arndt, Hein, Alexander, Hendley, Joy, Hernandez, Brenda Y, Heublein, Sabine, Huang, Yajue, Huzarski, Tomasz, Jakubowska, Anna, Jimenez-Linan, Mercedes, Kennedy, Catherine J, Kommoss, Felix KF, Koziak, Jennifer M, Kraemer, Bernhard, Le, Nhu D, Lesnock, Jaime, Lester, Jenny, Lubiński, Jan, Menkiszak, Janusz, Ney, Britta, Olawaiye, Alexander, Orsulic, Sandra, Osorio, Ana, Robles-Díaz, Luis, Ruebner, Matthias, Shah, Mitul, Sharma, Raghwa, Shvetsov, Yurii B, Steed, Helen, Talhouk, Aline, Taylor, Sarah E, Traficante, Nadia, Vierkant, Robert A, Wang, Chen, Wilkens, Lynne R, Winham, Stacey J, Benitez, Javier, Berchuck, Andrew, Bowtell, David D, Candido dos Reis, Francisco J, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Fasching, Peter A, García, María J, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Huntsman, David G, Karlan, Beth Y, Kommoss, Stefan, Modugno, Francesmary, Schildkraut, Joellen M, Sinn, Hans-Peter, Staebler, Annette, Kelemen, Linda E, Ford, Caroline E, Menon, Usha, Pharoah, Paul DP, Köbel, Martin, and Ramus, Susan J
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Ovarian Cancer, Clinical Research, Rare Diseases, Cancer, Aetiology, 2.1 Biological and endogenous factors, Humans, Female, Ovarian Neoplasms, Prognosis, Survival Analysis, RNA, Messenger, Cystadenocarcinoma, Serous, Biomarkers, Tumor, Forkhead Transcription Factors, AOCs group, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract: BackgroundRecently, we showed a >60% difference in 5-year survival for patients with tubo-ovarian high-grade serous carcinoma (HGSC) when stratified by a 101-gene mRNA expression prognostic signature. Given the varied patient outcomes, this study aimed to translate prognostic mRNA markers into protein expression assays by immunohistochemistry and validate their survival association in HGSC.MethodsTwo prognostic genes, FOXJ1 and GMNN, were selected based on high-quality antibodies, correlation with protein expression and variation in immunohistochemical scores in a preliminary cohort (n = 134 and n = 80, respectively). Six thousand four hundred and thirty-four (FOXJ1) and 5470 (GMNN) formalin-fixed, paraffin-embedded ovarian neoplasms (4634 and 4185 HGSC, respectively) represented on tissue microarrays from the Ovarian Tumor Tissue Analysis consortium underwent immunohistochemical staining and scoring, then univariate and multivariate survival analysis.ResultsConsistent with mRNA, FOXJ1 protein expression exhibited a linear, increasing association with improved overall survival in HGSC patients. Women with >50% expression had the most favourable outcomes (HR = 0.78, 95% CI 0.67-0.91, p 35% GMNN expression showed a trend for better outcomes, though this was not significant.ConclusionWe provide foundational evidence for the prognostic value of FOXJ1 in HGSC, validating the prior mRNA-based prognostic association by immunohistochemistry.
Published: 2023

7. 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, Group, The Australian Ovarian Cancer Study, 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, and Goodman, Marc T
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biotechnology, Human Genome, Ovarian Cancer, Genetics, Prevention, Clinical Research, Rare Diseases, Cancer, 2.1 Biological and endogenous factors, Aetiology, Asian People, Base Sequence, Carcinoma, Ovarian Epithelial, Case-Control Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-wide association study, Asian ancestry, Epithelial ovarian cancer, Enhancer, eQTL, Gene regulation, Australian Ovarian Cancer Study Group, Paediatrics and Reproductive Medicine, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis, Reproductive medicine
Abstract: ObjectiveGenome-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.MethodsGenotyping 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.ResultsAt 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

8. 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: Rare Diseases, Human Genome, Clinical Research, Genetics, Patient Safety, Cancer, Prevention, Ovarian Cancer, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Case-Control Studies, Contraceptives, Oral, Hormonal, Environment, Environmental Exposure, Female, Gene-Environment Interaction, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Risk, ovarian cancer, genetics, additive interaction, G x E, G × E, Oncology and Carcinogenesis, Oncology & Carcinogenesis
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.
Published: 2019

9. Evaluation of vitamin D biosynthesis and pathway target genes reveals UGT2A1/2 and EGFR polymorphisms associated with epithelial ovarian cancer in African American Women

Author: Grant, Delores J, Manichaikul, Ani, Alberg, Anthony J, Bandera, Elisa V, Barnholtz‐Sloan, Jill, Bondy, Melissa, Cote, Michele L, Funkhouser, Ellen, Moorman, Patricia G, Peres, Lauren C, Peters, Edward S, Schwartz, Ann G, Terry, Paul D, Wang, Xin‐Qun, Keku, Temitope O, Hoyo, Cathrine, Berchuck, Andrew, Sandler, Dale P, Taylor, Jack A, O’Brien, Katie M, Edwards, Digna R Velez, Edwards, Todd L, Beeghly‐Fadiel, Alicia, Wentzensen, Nicolas, Pearce, Celeste Leigh, Wu, Anna H, Whittemore, Alice S, McGuire, Valerie, Sieh, Weiva, Rothstein, Joseph H, Modugno, Francesmary, Ness, Roberta, Moysich, Kirsten, Rossing, Mary Anne, Doherty, Jennifer A, Sellers, Thomas A, Permuth‐Way, Jennifer B, Monteiro, Alvaro N, Levine, Douglas A, Setiawan, Veronica Wendy, Haiman, Christopher A, LeMarchand, Loic, Wilkens, Lynne R, Karlan, Beth Y, Menon, Usha, Ramus, Susan, Gayther, Simon, Gentry‐Maharaj, Aleksandra, Terry, Kathryn L, Cramer, Daniel W, Goode, Ellen L, Larson, Melissa C, Kaufmann, Scott H, Cannioto, Rikki, Odunsi, Kunle, Etter, John L, Huang, Ruea‐Yea, Bernardini, Marcus Q, Tone, Alicia A, May, Taymaa, Goodman, Marc T, Thompson, Pamela J, Carney, Michael E, Tworoger, Shelley S, Poole, Elizabeth M, Lambrechts, Diether, Vergote, Ignace, Vanderstichele, Adriaan, Van Nieuwenhuysen, Els, Anton‐Culver, Hoda, Ziogas, Argyrios, Brenton, James D, Bjorge, Line, Salvensen, Helga B, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Bruegl, Amanda, Moffitt, Melissa, Cook, Linda, Le, Nhu D, Brooks‐Wilson, Angela, Kelemen, Linda E, Pharoah, Paul DP, Song, Honglin, Campbell, Ian, Eccles, Diana, DeFazio, Anna, Kennedy, Catherine J, and Schildkraut, Joellen M
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biotechnology, Nutrition, Rare Diseases, Clinical Research, Genetics, Ovarian Cancer, Prevention, Cancer, 2.1 Biological and endogenous factors, Aetiology, Black or African American, Bayes Theorem, Carcinoma, Ovarian Epithelial, ErbB Receptors, Female, Genetic Association Studies, Glucuronosyltransferase, Humans, Logistic Models, Middle Aged, Neoplasm Grading, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Receptors, Calcitriol, Vitamin D, African ancestry risk, genetic association, ovarian cancer, vitamin D pathway, Biochemistry and Cell Biology, Oncology and carcinogenesis
Abstract: An association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom-designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high-grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 1.2 × 10-6 , BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6-3.4, P = 1.6 × 10-5 , BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 2.3 × 10-5 , BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC.
Published: 2019

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

Author: Yang, Yaohua, Wu, Lang, Shu, Xiang, Lu, Yingchang, Shu, Xiao-Ou, Cai, Qiuyin, Beeghly-Fadiel, Alicia, Li, Bingshan, Ye, Fei, Berchuck, Andrew, Anton-Culver, Hoda, Banerjee, Susana, Benitez, Javier, Bjørge, Line, Brenton, James D, Butzow, Ralf, Campbell, Ian G, Chang-Claude, Jenny, Chen, Kexin, Cook, Linda S, Cramer, Daniel W, deFazio, Anna, Dennis, Joe, Doherty, Jennifer A, Dörk, Thilo, Eccles, Diana M, Edwards, Digna Velez, Fasching, Peter A, Fortner, Renée T, Gayther, Simon A, Giles, Graham G, Glasspool, Rosalind M, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Harris, Holly R, Heitz, Florian, Hildebrandt, Michelle A, Høgdall, Estrid, Høgdall, Claus K, Huntsman, David G, Kar, Siddhartha P, Karlan, Beth Y, Kelemen, Linda E, Kiemeney, Lambertus A, Kjaer, Susanne K, Koushik, Anita, Lambrechts, Diether, Le, Nhu D, Levine, Douglas A, Massuger, Leon F, Matsuo, Keitaro, May, Taymaa, McNeish, Iain A, Menon, Usha, Modugno, Francesmary, Monteiro, Alvaro N, Moorman, Patricia G, Moysich, Kirsten B, Ness, Roberta B, Nevanlinna, Heli, Olsson, Håkan, Onland-Moret, N Charlotte, Park, Sue K, Paul, James, Pearce, Celeste L, Pejovic, Tanja, Phelan, Catherine M, Pike, Malcolm C, Ramus, Susan J, Riboli, Elio, Rodriguez-Antona, Cristina, Romieu, Isabelle, Sandler, Dale P, Schildkraut, Joellen M, Setiawan, Veronica W, Shan, Kang, Siddiqui, Nadeem, Sieh, Weiva, Stampfer, Meir J, Sutphen, Rebecca, Swerdlow, Anthony J, Szafron, Lukasz M, Teo, Soo Hwang, Tworoger, Shelley S, Tyrer, Jonathan P, Webb, Penelope M, Wentzensen, Nicolas, White, Emily, Willett, Walter C, Wolk, Alicja, Woo, Yin Ling, Wu, Anna H, Yan, Li, Yannoukakos, Drakoulis, Chenevix-Trench, Georgia, Sellers, Thomas A, Pharoah, Paul DP, Zheng, Wei, and Long, Jirong
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Biotechnology, Rare Diseases, Ovarian Cancer, Cancer Genomics, Prevention, Women's Health, Cancer, Clinical Research, Human Genome, 2.1 Biological and endogenous factors, Biomarkers, Tumor, Carcinoma, Ovarian Epithelial, Cohort Studies, DNA Methylation, Female, Genetic Predisposition to Disease, Humans, Models, Genetic, Ovarian Neoplasms, Predictive Value of Tests, Risk, White People, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract: DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10-7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. SIGNIFICANCE: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.
Published: 2019

11. 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: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Prevention, Human Genome, Ovarian Cancer, Rare Diseases, Cancer, 2.1 Biological and endogenous factors, Aetiology, Carcinogenesis, Carcinoma, Ovarian Epithelial, Cohort Studies, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Prognosis, Quantitative Trait Loci, Risk Factors, Transcriptome, Oncology and Carcinogenesis, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
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

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

Author: Kelemen, Linda E, Earp, Madalene, Fridley, Brooke L, Chenevix-Trench, Georgia, Australian Ovarian Cancer Study Group, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Hein, Alexander, Lambrechts, Diether, Lambrechts, Sandrina, Van Nieuwenhuysen, Els, Vergote, Ignace, Rossing, Mary Anne, Doherty, Jennifer A, Chang-Claude, Jenny, Behrens, Sabine, Moysich, Kirsten B, Cannioto, Rikki, Lele, Shashikant, Odunsi, Kunle, Goodman, Marc T, Shvetsov, Yurii B, Thompson, Pamela J, Wilkens, Lynne R, Dörk, Thilo, Antonenkova, Natalia, Bogdanova, Natalia, Hillemanns, Peter, Runnebaum, Ingo B, du Bois, Andreas, Harter, Philipp, Heitz, Florian, Schwaab, Ira, Butzow, Ralf, Pelttari, Liisa M, Nevanlinna, Heli, Modugno, Francesmary, Edwards, Robert P, Kelley, Joseph L, Ness, Roberta B, Karlan, Beth Y, Lester, Jenny, Orsulic, Sandra, Walsh, Christine, Kjaer, Susanne K, Jensen, Allan, Cunningham, Julie M, Vierkant, Robert A, Giles, Graham G, Bruinsma, Fiona, Southey, Melissa C, Hildebrandt, Michelle AT, Liang, Dong, Lu, Karen, Wu, Xifeng, Sellers, Thomas A, Levine, Douglas A, Schildkraut, Joellen M, Iversen, Edwin S, Terry, Kathryn L, Cramer, Daniel W, Tworoger, Shelley S, Poole, Elizabeth M, Bandera, Elisa V, Olson, Sara H, Orlow, Irene, Vestrheim Thomsen, Liv Cecilie, Bjorge, Line, Krakstad, Camilla, Tangen, Ingvild L, Kiemeney, Lambertus A, Aben, Katja KH, Massuger, Leon FAG, van Altena, Anne M, Pejovic, Tanja, Bean, Yukie, Kellar, Melissa, Cook, Linda S, Le, Nhu D, Brooks-Wilson, Angela, Gronwald, Jacek, Cybulski, Cezary, Jakubowska, Anna, Lubiński, Jan, Wentzensen, Nicolas, Brinton, Louise A, Lissowska, Jolanta, Hogdall, Estrid, Engelholm, Svend Aage, Hogdall, Claus, Lundvall, Lene, Nedergaard, Lotte, Pharoah, Paul DP, Dicks, Ed, Song, Honglin, Tyrer, Jonathan P, McNeish, Iain, Siddiqui, Nadeem, and Carty, Karen
Subjects: Australian Ovarian Cancer Study Group, Ovarian Cancer Association Consortium, Humans, Adenocarcinoma, Mucinous, Ovarian Neoplasms, Hydro-Lyases, Thymidylate Synthase, Proteins, RNA, Antisense, Logistic Models, Odds Ratio, Risk, Case-Control Studies, Signal Transduction, Gene Expression Regulation, Neoplastic, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Middle Aged, Female, Genetic Association Studies, consortia, enolase superfamily member 1, expression quantitative trait locus, genetics, gynecology, ovarian neoplasms, single-nucleotide polymorphism, thymidylate synthase, Ovarian Cancer, Rare Diseases, Biotechnology, Cancer, Digestive Diseases, Genetics, Chemical Physics, Other Chemical Sciences, Other Biological Sciences
Abstract: Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3' gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97⁻1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03⁻1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10-28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.
Published: 2018

13. Assessment of moderate coffee consumption and risk of epithelial ovarian cancer: a Mendelian randomization study

Author: Ong, Jue-Sheng, Hwang, Liang-Dar, Cuellar-Partida, Gabriel, Martin, Nicholas G, Chenevix-Trench, Georgia, Quinn, Michael CJ, Cornelis, Marilyn C, Gharahkhani, Puya, Webb, Penelope M, MacGregor, Stuart, Bryne, Enda, Fasching, Peter A, Hein, Alexander, Burghaus, Stefanie, Beckmann, Matthias W, Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Vanderstichele, Adriaan, Swerdlow, Anthony J, Jones, Michael, Orr, Nicholas, Schoemaker, Minouk, Edwards, Digna Velez, Brenton, James, Benítez, Javier, García, María J, Rodriguez-Antona, Cristina, Rossing, Mary Anne, Fortner, Renée T, Riboli, Elio, Chang-Claude, Jenny, Eilber, Ursula, Wang-Gohrke, Shan, Yannoukakos, Drakoulis, Goodman, Marc T, Bogdanova, Natalia, Dörk, Thilo, Duerst, Matthias, Hillemanns, Peter, Runnebaum, Ingo B, Antonenkova, Natalia, Butzow, Ralf, Nevanlinna, Heli, Pelttari, Liisa M, Edwards, Robert P, Kelley, Joseph L, Modugno, Francesmary, Moysich, Kirsten B, Ness, Roberta B, Cannioto, Rikki, Heitz, Florian, Karlan, Beth, Olsson, Håkan, Kjaer, Susanne K, Jensen, Allan, Giles, Graham G, Bruinsma, Fiona, Hildebrandt, Michelle AT, Liang, Dong, Wu, Xifeng, Le Marchand, Loic, Setiawan, V Wendy, Permuth, Jennifer B, Bisogna, Maria, Dao, Fanny, Levine, Douglas A, Cramer, Daniel W, Terry, Kathryn L, Tworoger, Shelley S, Stampfer, Meir, Willet, Walter, Missmer, Stacey, Bjorge, Line, Kopperud, Reidun K, Bischof, Katharina, Thomsen, Liv Cecilie Vestrheim, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Brooks-Wilson, Angela, Olson, Sara H, McGuire, Valerie, Rothstein, Joseph H, Sieh, Weiva, Whittemore, Alice S, Cook, Linda S, Le, Nhu D, Gilks, C Blake, Gronwald, Jacek, Jakubowska, Anna, Lubiński, Jan, Kluz, Tomasz, Wentzensen, Nicolas, Brinton, Louise, Trabert, Britton, and Lissowska, Jolanta
Subjects: Epidemiology, Health Sciences, Clinical Research, Ovarian Cancer, Nutrition, Rare Diseases, Prevention, Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, Carcinoma, Ovarian Epithelial, Coffee, Female, Humans, Mendelian Randomization Analysis, Odds Ratio, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Risk Factors, Ovarian Cancer Association Consortium, Statistics, Public Health and Health Services, Public health
Abstract: BackgroundCoffee consumption has been shown to be associated with various health outcomes in observational studies. However, evidence for its association with epithelial ovarian cancer (EOC) is inconsistent and it is unclear whether these associations are causal.MethodsWe used single nucleotide polymorphisms associated with (i) coffee and (ii) caffeine consumption to perform Mendelian randomization (MR) on EOC risk. We conducted a two-sample MR using genetic data on 44 062 individuals of European ancestry from the Ovarian Cancer Association Consortium (OCAC), and combined instrumental variable estimates using a Wald-type ratio estimator.ResultsFor all EOC cases, the causal odds ratio (COR) for genetically predicted consumption of one additional cup of coffee per day was 0.92 [95% confidence interval (CI): 0.79, 1.06]. The COR was 0.90 (95% CI: 0.73, 1.10) for high-grade serous EOC. The COR for genetically predicted consumption of an additional 80 mg caffeine was 1.01 (95% CI: 0.92, 1.11) for all EOC cases and 0.90 (95% CI: 0.73, 1.10) for high-grade serous cases.ConclusionsWe found no evidence indicative of a strong association between EOC risk and genetically predicted coffee or caffeine levels. However, our estimates were not statistically inconsistent with earlier observational studies and we were unable to rule out small protective associations.
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: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Prevention, Genetics, Ovarian Cancer, Women's Health, Cancer, 2.1 Biological and endogenous factors, Adolescent, Adult, Aged, Aged, 80 and over, Body Height, Carcinoma, Ovarian Epithelial, Case-Control Studies, Female, Genetic Predisposition to Disease, Geography, Humans, Mendelian Randomization Analysis, Middle Aged, Ovarian Neoplasms, Risk Factors, Young Adult, Australian Ovarian Cancer Study Group, Ovarian Cancer Association Consortium, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
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 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.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. 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, Lim, Boon Kiong, 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, and Runnebaum, Ingo B
Subjects: Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Genetics, Oncology and Carcinogenesis, Biotechnology, Ovarian Cancer, Cancer, Human Genome, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, A Kinase Anchor Proteins, Carcinoma, Ovarian Epithelial, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Monomeric GTP-Binding Proteins, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Rho Guanine Nucleotide Exchange Factors, Risk Factors, General Science & Technology
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

16. 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, and McGuire, Valeria
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Ovarian Cancer, Rare Diseases, Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, Adenocarcinoma, Clear Cell, Adult, Aged, Carcinoma, Ovarian Epithelial, Female, Gene Expression Regulation, Neoplastic, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Middle Aged, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Protein Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Risk Factors, T-Lymphocytes, Regulatory, ovarian cancer, immunosuppression, biomarkers, genetic variation, TGFBR2, TGFBR2, Oncology and carcinogenesis
Abstract: BackgroundRegulatory 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.MethodsIn 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.ResultsThe 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).ConclusionsCommon 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.
Published: 2016

17. Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study.

Author: Ong, Jue-Sheng, Cuellar-Partida, Gabriel, Lu, Yi, Australian Ovarian Cancer Study, Fasching, Peter A, Hein, Alexander, Burghaus, Stefanie, Beckmann, Matthias W, Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Vanderstichele, Adriaan, Anne Doherty, Jennifer, Anne Rossing, Mary, Chang-Claude, Jenny, Eilber, Ursula, Rudolph, Anja, Wang-Gohrke, Shan, Goodman, Marc T, Bogdanova, Natalia, Dörk, Thilo, Dürst, Matthias, Hillemanns, Peter, Runnebaum, Ingo B, Antonenkova, Natalia, Butzow, Ralf, Leminen, Arto, Nevanlinna, Heli, Pelttari, Liisa M, Edwards, Robert P, Kelley, Joseph L, Modugno, Francesmary, Moysich, Kirsten B, Ness, Roberta B, Cannioto, Rikki, Høgdall, Estrid, Høgdall, Claus K, Jensen, Allan, Giles, Graham G, Bruinsma, Fiona, Kjaer, Susanne K, Hildebrandt, Michelle At, Liang, Dong, Lu, Karen H, Wu, Xifeng, Bisogna, Maria, Dao, Fanny, Levine, Douglas A, Cramer, Daniel W, Terry, Kathryn L, Tworoger, Shelley S, Stampfer, Meir, Missmer, Stacey, Bjorge, Line, Salvesen, Helga B, Kopperud, Reidun K, Bischof, Katharina, Aben, Katja Kh, Kiemeney, Lambertus A, Massuger, Leon Fag, Brooks-Wilson, Angela, Olson, Sara H, McGuire, Valerie, Rothstein, Joseph H, Sieh, Weiva, Whittemore, Alice S, Cook, Linda S, Le, Nhu D, Gilks, C Blake, Gronwald, Jacek, Jakubowska, Anna, Lubiński, Jan, Kluz, Tomasz, Song, Honglin, Tyrer, Jonathan P, Wentzensen, Nicolas, Brinton, Louise, Trabert, Britton, Lissowska, Jolanta, McLaughlin, John R, Narod, Steven A, Phelan, Catherine, Anton-Culver, Hoda, Ziogas, Argyrios, Eccles, Diana, Campbell, Ian, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Menon, Usha, Ramus, Susan J, Wu, Anna H, Dansonka-Mieszkowska, Agnieszka, Kupryjanczyk, Jolanta, Timorek, Agnieszka, Szafron, Lukasz, Cunningham, Julie M, Fridley, Brooke L, Winham, Stacey J, Bandera, Elisa V, and Poole, Elizabeth M
Subjects: Australian Ovarian Cancer Study, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Genetic Predisposition to Disease, Vitamin D, Odds Ratio, Risk Factors, Polymorphism, Single Nucleotide, Female, Mendelian Randomization Analysis, Carcinoma, Ovarian Epithelial, Neoplasms, Glandular and Epithelial, Polymorphism, Single Nucleotide, Carcinoma, Ovarian Epithelial, Prevention, Rare Diseases, Nutrition, Clinical Research, Cancer, Ovarian Cancer, Statistics, Public Health and Health Services, Epidemiology
Abstract: BackgroundIn vitro and observational epidemiological studies suggest that vitamin D may play a role in cancer prevention. However, the relationship between vitamin D and ovarian cancer is uncertain, with observational studies generating conflicting findings. A potential limitation of observational studies is inadequate control of confounding. To overcome this problem, we used Mendelian randomization (MR) to evaluate the association between single nucleotide polymorphisms (SNPs) associated with circulating 25-hydroxyvitamin D [25(OH)D] concentration and risk of ovarian cancer.MethodsWe employed SNPs with well-established associations with 25(OH)D concentration as instrumental variables for MR: rs7944926 (DHCR7), rs12794714 (CYP2R1) and rs2282679 (GC). We included 31 719 women of European ancestry (10 065 cases, 21 654 controls) from the Ovarian Cancer Association Consortium, who were genotyped using customized Illumina Infinium iSelect (iCOGS) arrays. A two-sample (summary data) MR approach was used and analyses were performed separately for all ovarian cancer (10 065 cases) and for high-grade serous ovarian cancer (4121 cases).ResultsThe odds ratio for epithelial ovarian cancer risk (10 065 cases) estimated by combining the individual SNP associations using inverse variance weighting was 1.27 (95% confidence interval: 1.06 to 1.51) per 20 nmol/L decrease in 25(OH)D concentration. The estimated odds ratio for high-grade serous epithelial ovarian cancer (4121 cases) was 1.54 (1.19, 2.01).ConclusionsGenetically lowered 25-hydroxyvitamin D concentrations were associated with higher ovarian cancer susceptibility in Europeans. These findings suggest that increasing plasma vitamin D levels may reduce risk of ovarian cancer.
Published: 2016

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

Author: Permuth, Jennifer B, Pirie, Ailith, Chen, Y Ann, Lin, Hui-Yi, Reid, Brett M, Chen, Zhihua, Monteiro, Alvaro, Dennis, Joe, Mendoza-Fandino, Gustavo, Group, AOCS Study, Study, Australian 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, Doherty, Jennifer Anne, 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, Rossing, Mary Anne, 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 Consortium, on behalf of the Ovarian Cancer Association
Subjects: Biological Sciences, Genetics, Rare Diseases, Human Genome, Prevention, Cancer, Ovarian Cancer, 2.1 Biological and endogenous factors, Aetiology, Actins, Biotinidase, Carcinoma, Ovarian Epithelial, Exome, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Keratin-13, Neoplasm Proteins, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Receptor, Melanocortin, Type 2, AOCS Study Group, Australian Cancer Study, Ovarian Cancer Association Consortium, Medical and Health Sciences, Genetics & Heredity
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

19. Assessing the genetic architecture of epithelial ovarian cancer histological subtypes

Author: Cuellar-Partida, Gabriel, Lu, Yi, Dixon, Suzanne C, Australian Ovarian Cancer Study, Fasching, Peter A, Hein, Alexander, Burghaus, Stefanie, Beckmann, Matthias W, Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Vanderstichele, Adriaan, Doherty, Jennifer Anne, Rossing, Mary Anne, Chang-Claude, Jenny, Rudolph, Anja, Wang-Gohrke, Shan, Goodman, Marc T, Bogdanova, Natalia, Dörk, Thilo, Dürst, Matthias, Hillemanns, Peter, Runnebaum, Ingo B, Antonenkova, Natalia, Butzow, Ralf, Leminen, Arto, Nevanlinna, Heli, Pelttari, Liisa M, Edwards, Robert P, Kelley, Joseph L, Modugno, Francesmary, Moysich, Kirsten B, Ness, Roberta B, Cannioto, Rikki, Høgdall, Estrid, Høgdall, Claus, Jensen, Allan, Giles, Graham G, Bruinsma, Fiona, Kjaer, Susanne K, Hildebrandt, Michelle AT, Liang, Dong, Lu, Karen H, Wu, Xifeng, Bisogna, Maria, Dao, Fanny, Levine, Douglas A, Cramer, Daniel W, Terry, Kathryn L, Tworoger, Shelley S, Stampfer, Meir, Missmer, Stacey, Bjorge, Line, Salvesen, Helga B, Kopperud, Reidun K, Bischof, Katharina, Aben, Katja KH, Kiemeney, Lambertus A, Massuger, Leon FAG, Brooks-Wilson, Angela, Olson, Sara H, McGuire, Valerie, Rothstein, Joseph H, Sieh, Weiva, Whittemore, Alice S, Cook, Linda S, Le, Nhu D, Blake Gilks, C, Gronwald, Jacek, Jakubowska, Anna, Lubiński, Jan, Kluz, Tomasz, Song, Honglin, Tyrer, Jonathan P, Wentzensen, Nicolas, Brinton, Louise, Trabert, Britton, Lissowska, Jolanta, McLaughlin, John R, Narod, Steven A, Phelan, Catherine, Anton-Culver, Hoda, Ziogas, Argyrios, Eccles, Diana, Campbell, Ian, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Menon, Usha, Ramus, Susan J, Wu, Anna H, Dansonka-Mieszkowska, Agnieszka, Kupryjanczyk, Jolanta, Timorek, Agnieszka, Szafron, Lukasz, Cunningham, Julie M, Fridley, Brooke L, Winham, Stacey J, Bandera, Elisa V, Poole, Elizabeth M, and Morgan, Terry K
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Obesity, Women's Health, Cancer Genomics, Ovarian Cancer, Cancer, Human Genome, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Carcinoma, Ovarian Epithelial, Female, Genotype, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Pathology, Molecular, Polymorphism, Single Nucleotide, Australian Ovarian Cancer Study, Complementary and Alternative Medicine, Paediatrics and Reproductive Medicine, Genetics & Heredity, Reproductive medicine
Abstract: Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ([Formula: see text] = 8.8 ± 1.1 %), endometrioid ([Formula: see text] = 3.2 ± 1.6 %), clear cell ([Formula: see text] = 6.7 ± 3.3 %) and all EOC ([Formula: see text] = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.
Published: 2016

20. A targeted genetic association study of epithelial ovarian cancer susceptibility

Author: Earp, Madalene, Winham, Stacey J, Larson, Nicholas, Permuth, Jennifer B, Sicotte, Hugues, Chien, Jeremy, Anton-Culver, Hoda, Bandera, Elisa V, Berchuck, Andrew, Cook, Linda S, Cramer, Daniel, Doherty, Jennifer A, Goodman, Marc T, Levine, Douglas A, Monteiro, Alvaro NA, Ness, Roberta B, Pearce, Celeste L, Rossing, Mary Anne, Tworoger, Shelley S, Wentzensen, Nicolas, Bisogna, Maria, Brinton, Louise, Brooks-Wilson, Angela, Carney, Michael E, Cunningham, Julie M, Edwards, Robert P, Fogarty, Zachary C, Iversen, Edwin S, Kraft, Peter, Larson, Melissa C, Le, Nhu D, Lin, Hui-Yi, Lissowska, Jolanta, Modugno, Francesmary, Moysich, Kirsten B, Olson, Sara H, Pike, Malcolm C, Poole, Elizabeth M, Rider, David N, Terry, Kathryn L, Thompson, Pamela J, van den Berg, David, Vierkant, Robert A, Vitonis, Allison F, Wilkens, Lynne R, Wu, Anna H, Yang, Hannah P, Ziogas, Argyrios, Phelan, Catherine M, Schildkraut, Joellen M, Chen, Yian Ann, Sellers, Thomas A, Fridley, Brooke L, and Goode, Ellen L
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Prevention, Cancer, Human Genome, Rare Diseases, Ovarian Cancer, Clinical Research, Genetics, Aetiology, 2.1 Biological and endogenous factors, Biomarkers, Tumor, Carcinoma, Ovarian Epithelial, Case-Control Studies, Female, Gene Expression Profiling, Genetic Association Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Neoplasm Staging, Neoplasms, Glandular and Epithelial, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Prognosis, Risk Factors, ovarian cancer, high-grade serous carcinoma, genetic association, susceptibility loci, NF-kappa B, NF-κB, Oncology and carcinogenesis
Abstract: BackgroundGenome-wide association studies have identified several common susceptibility alleles for epithelial ovarian cancer (EOC). To further understand EOC susceptibility, we examined previously ungenotyped candidate variants, including uncommon variants and those residing within known susceptibility loci.ResultsAt nine of eleven previously published EOC susceptibility regions (2q31, 3q25, 5p15, 8q21, 8q24, 10p12, 17q12, 17q21.31, and 19p13), novel variants were identified that were more strongly associated with risk than previously reported variants. Beyond known susceptibility regions, no variants were found to be associated with EOC risk at genome-wide statistical significance (p
Published: 2016

21. 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, Cancer, Ovarian Cancer, Biological Sciences, Medical and Health Sciences, Developmental Biology
Published: 2016

22. 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: Georgia Chenevix-Trench on behalf of the AOCS management group, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Genetic Predisposition to Disease, Odds Ratio, Risk, Genotype, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, European Continental Ancestry Group, Female, Genome-Wide Association Study, Epithelial-Mesenchymal Transition, Carcinoma, Ovarian Epithelial, epithelial-mesenchymal transition, ovarian cancer, single-nucleotide polymorphisms, Neoplasms, Glandular and Epithelial, Polymorphism, Single Nucleotide, Carcinoma, Ovarian Epithelial, Epidemiology, Public Health and Health Services, Genetics
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

23. Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer

Author: Lawrenson, Kate, Iversen, Edwin S, Tyrer, Jonathan, Weber, Rachel Palmieri, Concannon, Patrick, Hazelett, Dennis J, Li, Qiyuan, Marks, Jeffrey R, Berchuck, Andrew, Lee, Janet M, Aben, Katja KH, Anton-Culver, Hoda, Antonenkova, Natalia, 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, Chenevix-Trench, Georgia, Chen, Ann, Chen, Zhihua, Cook, Linda S, Cramer, Daniel W, Cunningham, Julie M, Cybulski, Cezary, Plisiecka-Halasa, Joanna, Dennis, Joe, Dicks, Ed, Doherty, Jennifer A, Dörk, Thilo, du Bois, Andreas, 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, Gronwald, Jacek, Harter, Philipp, Hasmad, Hanis Nazihah, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Hogdall, Estrid, Hogdall, Claus, Hosono, Satoyo, Jakubowska, Anna, Paul, James, Jensen, Allan, Karlan, Beth Y, Kjaer, Susanne Kruger, Kelemen, Linda E, Kellar, Melissa, Kelley, Joseph L, Kiemeney, Lambertus A, Krakstad, Camilla, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D, Lee, Alice W, Cannioto, Rikki, 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, Iain, Menon, Usha, Modugno, Francesmary, Moysich, Kirsten B, Narod, Steven A, Nedergaard, Lotte, Ness, Roberta B, Azmi, Mat Adenan Noor, Odunsi, Kunle, and Olson, Sara H
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Biotechnology, Cancer, Human Genome, Ovarian Cancer, Prevention, Rare Diseases, Genetic Testing, Genetics, Aetiology, 2.1 Biological and endogenous factors, Carcinoma, Ovarian Epithelial, Case-Control Studies, Checkpoint Kinase 2, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, Australian Cancer Study, Australian Ovarian Cancer Study Group, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract: Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r (2) with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1×10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72×10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r (2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70×10(-8)). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.
Published: 2015

24. Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk.

Author: Kar, Siddhartha P, Tyrer, Jonathan P, Li, Qiyuan, Lawrenson, Kate, Aben, Katja KH, Anton-Culver, Hoda, Antonenkova, Natalia, Chenevix-Trench, Georgia, Australian Cancer Study, Australian Ovarian Cancer Study Group, Baker, Helen, Bandera, Elisa V, Bean, Yukie T, Beckmann, Matthias W, Berchuck, Andrew, Bisogna, Maria, Bjørge, Line, Bogdanova, Natalia, Brinton, Louise, Brooks-Wilson, Angela, Butzow, Ralf, Campbell, Ian, Carty, Karen, Chang-Claude, Jenny, Chen, Yian Ann, Chen, Zhihua, Cook, Linda S, Cramer, Daniel, 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 F, Edwards, Robert P, 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, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Hogdall, Estrid, Hogdall, Claus K, Hosono, Satoyo, Iversen, Edwin S, Jakubowska, Anna, Paul, James, Jensen, Allan, Ji, Bu-Tian, Karlan, Beth Y, Kjaer, Susanne K, Kelemen, Linda E, Kellar, Melissa, Kelley, Joseph, 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, Matsuo, Keitaro, McGuire, Valerie, McLaughlin, John R, McNeish, Iain A, Menon, Usha, Modugno, Francesmary, Moysich, Kirsten B, Narod, Steven A, Nedergaard, Lotte, Ness, Roberta B, Nevanlinna, Heli, Odunsi, Kunle, Olson, Sara H, and Orlow, Irene
Subjects: Australian Cancer Study, Australian Ovarian Cancer Study Group, Humans, Cystadenocarcinoma, Serous, Ovarian Neoplasms, Genetic Predisposition to Disease, Nuclear Proteins, Transcription Factors, DNA, Neoplasm, Morbidity, Risk Factors, Gene Expression Regulation, Neoplastic, Genotype, Female, Genome-Wide Association Study, Global Health, Ovarian Cancer, Biotechnology, Cancer, Genetics, Rare Diseases, Prevention, Human Genome, 2.1 Biological and endogenous factors, Epidemiology, Medical and Health Sciences
Abstract: BackgroundGenome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations.MethodsWe selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls).ResultsGene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network.ConclusionWe identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development.ImpactNetwork analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization.
Published: 2015

25. 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, Cell Line, Tumor, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Genetic Predisposition to Disease, Homeodomain Proteins, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Protein Binding, Quantitative Trait Loci, Female, Nuchal Cord, Genetic Association Studies, Carcinoma, Ovarian Epithelial, Cell Line, Tumor, Neoplasms, Glandular and Epithelial, Gene Expression Regulation, Neoplastic, Carcinoma, Ovarian Epithelial, Rare Diseases, Prevention, Ovarian Cancer, Biotechnology, Human Genome, Cancer, Genetics, 2.1 Biological and endogenous factors
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

26. Genome-wide significant risk associations for mucinous ovarian carcinoma

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, and Moysich, Kirsten B
Subjects: Rare Diseases, Prevention, Ovarian Cancer, Genetics, Cancer, 2.1 Biological and endogenous factors, Aetiology, Adenocarcinoma, Mucinous, Base Sequence, Cell Line, Tumor, Cell Nucleus, Chromosomes, Human, Pair 2, Female, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Green Fluorescent Proteins, Homeodomain Proteins, Humans, Microscopy, Fluorescence, Molecular Sequence Data, Neoplasm Proteins, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Reverse Transcriptase Polymerase Chain Reaction, Risk Factors, Australian Cancer Study, Australian Ovarian Cancer Study Group, Ovarian Cancer Association Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract: Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10(-8)), rs711830 at 2q31.1 (P = 7.5 × 10(-12)) and rs688187 at 19q13.2 (P = 6.8 × 10(-13)). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10(-4), false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.
Published: 2015

27. Cell-type-specific enrichment of risk-associated regulatory elements at ovarian cancer susceptibility loci

Author: Coetzee, Simon G, Shen, Howard C, Hazelett, Dennis J, Lawrenson, Kate, Kuchenbaecker, Karoline, Tyrer, Jonathan, Rhie, Suhn K, Levanon, Keren, Karst, Alison, Drapkin, Ronny, Ramus, Susan J, Consortium, The Consortium of Investigators of Modifiers of BRCA1 2 The Ovarian Cancer Association, Couch, Fergus J, Offit, Kenneth, Chenevix-Trench, Georgia, Monteiro, Alvaro NA, Antoniou, Antonis, Freedman, Matthew, Coetzee, Gerhard A, Pharoah, Paul DP, Noushmehr, Houtan, Gayther, Simon A, Anton-Culver, Hoda, Antonenkova, Natalia, 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, Chen, Ann, 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 F, 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, Kjaer, Susanne Kruger, Kelemen, Linda E, Kellar, Melissa, Kelley, Joseph L, Kiemeney, Lambertus A, Krakstad, Camilla, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D, Lele, Shashi, Leminen, Arto, Lester, Jenny, Levine, Douglas A, Liang, Dong, and Lissowska, Jolanta
Subjects: Biological Sciences, Genetics, Rare Diseases, Prevention, Human Genome, Ovarian Cancer, Biotechnology, Cancer, 2.1 Biological and endogenous factors, Underpinning research, Aetiology, 1.1 Normal biological development and functioning, Chromatin, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Histones, Humans, Organ Specificity, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Regulatory Sequences, Nucleic Acid, Ovarian Cancer Association Consortium, The Consortium of Investigators of Modifiers of BRCA1/2, Ovarian Cancer Association Consortium The Consortium of Investigators of Modifiers of BRCA1/2, Medical and Health Sciences, Genetics & Heredity
Abstract: Understanding the regulatory landscape of the human genome is a central question in complex trait genetics. Most single-nucleotide polymorphisms (SNPs) associated with cancer risk lie in non-protein-coding regions, implicating regulatory DNA elements as functional targets of susceptibility variants. Here, we describe genome-wide annotation of regions of open chromatin and histone modification in fallopian tube and ovarian surface epithelial cells (FTSECs, OSECs), the debated cellular origins of high-grade serous ovarian cancers (HGSOCs) and in endometriosis epithelial cells (EECs), the likely precursor of clear cell ovarian carcinomas (CCOCs). The regulatory architecture of these cell types was compared with normal human mammary epithelial cells and LNCaP prostate cancer cells. We observed similar positional patterns of global enhancer signatures across the three different ovarian cancer precursor cell types, and evidence of tissue-specific regulatory signatures compared to non-gynecological cell types. We found significant enrichment for risk-associated SNPs intersecting regulatory biofeatures at 17 known HGSOC susceptibility loci in FTSECs (P = 3.8 × 10(-30)), OSECs (P = 2.4 × 10(-23)) and HMECs (P = 6.7 × 10(-15)) but not for EECs (P = 0.45) or LNCaP cells (P = 0.88). Hierarchical clustering of risk SNPs conditioned on the six different cell types indicates FTSECs and OSECs are highly related (96% of samples using multi-scale bootstrapping) suggesting both cell types may be precursors of HGSOC. These data represent the first description of regulatory catalogues of normal precursor cells for different ovarian cancer subtypes, and provide unique insights into the tissue specific regulatory variation with respect to the likely functional targets of germline genetic susceptibility variants for ovarian cancer.
Published: 2015

28. Evaluating the ovarian cancer gonadotropin hypothesis: a candidate gene study.

Author: Lee, Alice W, Tyrer, Jonathan P, Doherty, Jennifer A, Stram, Douglas A, Kupryjanczyk, Jolanta, Dansonka-Mieszkowska, Agnieszka, Plisiecka-Halasa, Joanna, Spiewankiewicz, Beata, Myers, Emily J, Australian Cancer Study (Ovarian Cancer), Australian Ovarian Cancer Study Group, Chenevix-Trench, Georgia, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Hein, Alexander, Vergote, Ignace, Van Nieuwenhuysen, Els, Lambrechts, Diether, Wicklund, Kristine G, Eilber, Ursula, Wang-Gohrke, Shan, Chang-Claude, Jenny, Rudolph, Anja, Sucheston-Campbell, Lara, Odunsi, Kunle, Moysich, Kirsten B, Shvetsov, Yurii B, Thompson, Pamela J, Goodman, Marc T, Wilkens, Lynne R, Dörk, Thilo, Hillemanns, Peter, Dürst, Matthias, Runnebaum, Ingo B, Bogdanova, Natalia, Pelttari, Liisa M, Nevanlinna, Heli, Leminen, Arto, Edwards, Robert P, Kelley, Joseph L, Harter, Philipp, Schwaab, Ira, Heitz, Florian, du Bois, Andreas, Orsulic, Sandra, Lester, Jenny, Walsh, Christine, Karlan, Beth Y, Hogdall, Estrid, Kjaer, Susanne K, Jensen, Allan, Vierkant, Robert A, Cunningham, Julie M, Goode, Ellen L, Fridley, Brooke L, Southey, Melissa C, Giles, Graham G, Bruinsma, Fiona, Wu, Xifeng, Hildebrandt, Michelle AT, Lu, Karen, Liang, Dong, Bisogna, Maria, Levine, Douglas A, Weber, Rachel Palmieri, Schildkraut, Joellen M, Iversen, Edwin S, Berchuck, Andrew, Terry, Kathryn L, Cramer, Daniel W, Tworoger, Shelley S, Poole, Elizabeth M, Olson, Sara H, Orlow, Irene, Bandera, Elisa V, Bjorge, Line, Tangen, Ingvild L, Salvesen, Helga B, Krakstad, Camilla, Massuger, Leon FAG, Kiemeney, Lambertus A, Aben, Katja KH, van Altena, Anne M, Bean, Yukie, Pejovic, Tanja, Kellar, Melissa, Le, Nhu D, Cook, Linda S, Kelemen, Linda E, Brooks-Wilson, Angela, Lubinski, Jan, Gronwald, Jacek, Cybulski, Cezary, Jakubowska, Anna, Wentzensen, Nicolas, Brinton, Louise A, Lissowska, Jolanta, Yang, Hannah, and Nedergaard, Lotte
Subjects: Australian Cancer Study, Australian Ovarian Cancer Study Group, Humans, Ovarian Neoplasms, Genetic Predisposition to Disease, Gonadotropins, Genetic Markers, Logistic Models, Risk Factors, Case-Control Studies, Signal Transduction, Genotype, Polymorphism, Single Nucleotide, Female, Genome-Wide Association Study, Biomarkers, Tumor, Gene, Genetic variation, Genetics, Ovarian cancer, Polymorphisms, Polymorphism, Single Nucleotide, Biomarkers, Tumor, Ovarian Cancer, Aging, Prevention, Human Genome, Cancer, Biotechnology, Rare Diseases, 2.1 Biological and endogenous factors, Oncology & Carcinogenesis, Oncology and Carcinogenesis, Paediatrics and Reproductive Medicine
Abstract: ObjectiveOvarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted.MethodsGenetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations.ResultsWe did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p=0.045, mucinous), LHCGR (p=0.046, high-grade serous), GNRH (p=0.041, high-grade serous), and FSHB (p=0.036, overall invasive). There was also suggestive evidence for INHA (p=0.060, overall invasive).ConclusionsOvarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available.
Published: 2015

29. Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk

Author: Chornokur, Ganna, Lin, Hui-Yi, Tyrer, Jonathan P, Lawrenson, Kate, Dennis, Joe, Amankwah, Ernest K, Qu, Xiaotao, Tsai, Ya-Yu, Jim, Heather SL, 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, 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, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Hogdall, Claus K, Hogdall, Estrid, Hosono, Satoyo, Jakubowska, Anna, Jensen, Allan, Ji, Bu-Tian, Karlan, Beth Y, Kelemen, Linda E, Kellar, Mellissa, 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, Iain, Menon, Usha, Milne, Roger L, Modugno, Francesmary, Moysich, Kirsten B, Ness, Roberta B, Nevanlinna, Heli, Eilber, Ursula, Odunsi, Kunle, Olson, Sara H, and Orlow, Irene
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Cancer, Ovarian Cancer, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Black or African American, Alleles, Asian, Biological Transport, Carcinoma, Ovarian Epithelial, Carrier Proteins, Case-Control Studies, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Humans, Neoplasms, Glandular and Epithelial, Odds Ratio, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Risk, Georgia Chenevix-Trench, AOCS management group, General Science & Technology
Abstract: BackgroundDefective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk.MethodsIn total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q
Published: 2015

30. 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: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Health Services and Systems, Health Sciences, Oncology and Carcinogenesis, Cancer, Orphan Drug, Prevention, Sleep Research, Rare Diseases, Ovarian Cancer, Aetiology, 2.1 Biological and endogenous factors, 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.
Published: 2015

31. 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: for AOCS/ACS group, Humans, Ovarian Neoplasms, NF-kappa B, Risk, Case-Control Studies, Signal Transduction, Polymorphism, Single Nucleotide, Female, TNF-Related Apoptosis-Inducing Ligand, Interleukin-1alpha, Genetic Association Studies, Polymorphism, Single Nucleotide, Prevention, Ovarian Cancer, Cancer, Human Genome, Rare Diseases, Genetics, Clinical Research, 2.1 Biological and endogenous factors, Oncology & Carcinogenesis, Oncology and Carcinogenesis
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

32. GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer.

Author: Pharoah, Paul DP, Tsai, Ya-Yu, Ramus, Susan J, Phelan, Catherine M, Goode, Ellen L, Lawrenson, Kate, Buckley, Melissa, Fridley, Brooke L, Tyrer, Jonathan P, Shen, Howard, Weber, Rachel, Karevan, Rod, Larson, Melissa C, Song, Honglin, Tessier, Daniel C, Bacot, François, Vincent, Daniel, Cunningham, Julie M, Dennis, Joe, Dicks, Ed, Australian Cancer Study, Australian Ovarian Cancer Study Group, Aben, Katja K, Anton-Culver, Hoda, Antonenkova, Natalia, Armasu, Sebastian M, Baglietto, Laura, Bandera, Elisa V, Beckmann, Matthias W, Birrer, Michael J, Bloom, Greg, Bogdanova, Natalia, Brenton, James D, Brinton, Louise A, Brooks-Wilson, Angela, Brown, Robert, Butzow, Ralf, Campbell, Ian, Carney, Michael E, Carvalho, Renato S, Chang-Claude, Jenny, Chen, Y Anne, Chen, Zhihua, Chow, Wong-Ho, Cicek, Mine S, Coetzee, Gerhard, Cook, Linda S, Cramer, Daniel W, Cybulski, Cezary, Dansonka-Mieszkowska, Agnieszka, Despierre, Evelyn, Doherty, Jennifer A, Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana, Edwards, Robert, Ekici, Arif B, Fasching, Peter A, Fenstermacher, David, Flanagan, James, Gao, Yu-Tang, Garcia-Closas, Montserrat, Gentry-Maharaj, Aleksandra, Giles, Graham, Gjyshi, Anxhela, Gore, Martin, Gronwald, Jacek, Guo, Qi, Halle, Mari K, Harter, Philipp, Hein, Alexander, Heitz, Florian, Hillemanns, Peter, Hoatlin, Maureen, Høgdall, Estrid, Høgdall, Claus K, Hosono, Satoyo, Jakubowska, Anna, Jensen, Allan, Kalli, Kimberly R, Karlan, Beth Y, Kelemen, Linda E, Kiemeney, Lambertus A, Kjaer, Susanne Krüger, Konecny, Gottfried E, Krakstad, Camilla, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D, Lee, Nathan, Lee, Janet, Leminen, Arto, Lim, Boon Kiong, Lissowska, Jolanta, Lubiński, Jan, Lundvall, Lene, Lurie, Galina, and Massuger, Leon FAG
Subjects: Australian Cancer Study, Australian Ovarian Cancer Study Group, Humans, Cystadenocarcinoma, Serous, Ovarian Neoplasms, Neoplasm Invasiveness, Genetic Predisposition to Disease, Risk Factors, Case-Control Studies, Cooperative Behavior, Genotype, Polymorphism, Single Nucleotide, Female, Meta-Analysis as Topic, Genome-Wide Association Study, Genetic Loci, Gene-Environment Interaction, Cancer, Human Genome, Prevention, Genetics, Rare Diseases, Ovarian Cancer, Aetiology, 2.1 Biological and endogenous factors, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract: Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 × 10(-9)) and 10p12 (rs1243180, P = 1.8 × 10(-8)) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 × 10(-10)). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.
Published: 2013

33. Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer

Author: Shen, Hui, Fridley, Brooke L, Song, Honglin, Lawrenson, Kate, Cunningham, Julie M, Ramus, Susan J, Cicek, Mine S, Tyrer, Jonathan, Stram, Douglas, Larson, Melissa C, Köbel, Martin, Ziogas, Argyrios, Zheng, Wei, Yang, Hannah P, Wu, Anna H, Wozniak, Eva L, Ling Woo, Yin, Winterhoff, Boris, Wik, Elisabeth, Whittemore, Alice S, Wentzensen, Nicolas, Palmieri Weber, Rachel, Vitonis, Allison F, Vincent, Daniel, Vierkant, Robert A, Vergote, Ignace, Van Den Berg, David, Van Altena, Anne M, Tworoger, Shelley S, Thompson, Pamela J, Tessier, Daniel C, Terry, Kathryn L, Teo, Soo-Hwang, Templeman, Claire, Stram, Daniel O, Southey, Melissa C, Sieh, Weiva, Siddiqui, Nadeem, Shvetsov, Yurii B, Shu, Xiao-Ou, Shridhar, Viji, Wang-Gohrke, Shan, Severi, Gianluca, Schwaab, Ira, Salvesen, Helga B, Rzepecka, Iwona K, Runnebaum, Ingo B, Anne Rossing, Mary, Rodriguez-Rodriguez, Lorna, Risch, Harvey A, Renner, Stefan P, Poole, Elizabeth M, Pike, Malcolm C, Phelan, Catherine M, Pelttari, Liisa M, Pejovic, Tanja, Paul, James, Orlow, Irene, Zawiah Omar, Siti, Olson, Sara H, Odunsi, Kunle, Nickels, Stefan, Nevanlinna, Heli, Ness, Roberta B, Narod, Steven A, Nakanishi, Toru, Moysich, Kirsten B, Monteiro, Alvaro NA, Moes-Sosnowska, Joanna, Modugno, Francesmary, Menon, Usha, McLaughlin, John R, McGuire, Valerie, Matsuo, Keitaro, Mat Adenan, Noor Azmi, Massuger, Leon FAG, Lurie, Galina, Lundvall, Lene, Lubiński, Jan, Lissowska, Jolanta, Levine, Douglas A, Leminen, Arto, Lee, Alice W, Le, Nhu D, Lambrechts, Sandrina, Lambrechts, Diether, Kupryjanczyk, Jolanta, Krakstad, Camilla, Konecny, Gottfried E, Krüger Kjaer, Susanne, Kiemeney, Lambertus A, Kelemen, Linda E, Keeney, Gary L, Karlan, Beth Y, Karevan, Rod, Kalli, Kimberly R, Kajiyama, Hiroaki, Ji, Bu-Tian, Jensen, Allan, and Jakubowska, Anna
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Ovarian Cancer, Cancer, Human Genome, Rare Diseases, Prevention, Aetiology, 2.1 Biological and endogenous factors, DNA Methylation, Epigenesis, Genetic, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Hepatocyte Nuclear Factor 1-beta, Humans, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, PRACTICAL Consortium, Australian Ovarian Cancer Study Group, Australian Cancer Study
Abstract: HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 × 10(-10)) and clear cell (rs11651755 OR=0.77, P=1.6 × 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.
Published: 2013

34. Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31

Author: Permuth-Wey, Jennifer, Lawrenson, Kate, Shen, Howard C, Velkova, Aneliya, Tyrer, Jonathan P, Chen, Zhihua, Lin, Hui-Yi, Ann Chen, Y, Tsai, Ya-Yu, Qu, Xiaotao, Ramus, Susan J, Karevan, Rod, Lee, Janet, Lee, Nathan, Larson, Melissa C, Aben, Katja K, Anton-Culver, Hoda, Antonenkova, Natalia, Antoniou, Antonis C, Armasu, Sebastian M, Bacot, François, Baglietto, Laura, Bandera, Elisa V, Barnholtz-Sloan, Jill, Beckmann, Matthias W, Birrer, Michael J, Bloom, Greg, Bogdanova, Natalia, Brinton, Louise A, Brooks-Wilson, Angela, Brown, Robert, Butzow, Ralf, Cai, Qiuyin, Campbell, Ian, Chang-Claude, Jenny, Chanock, Stephen, Chenevix-Trench, Georgia, Cheng, Jin Q, Cicek, Mine S, Coetzee, Gerhard A, Cook, Linda S, Couch, Fergus J, Cramer, Daniel W, Cunningham, Julie M, Dansonka-Mieszkowska, Agnieszka, Despierre, Evelyn, Doherty, Jennifer A, Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Easton, Douglas F, Eccles, Diana, Edwards, Robert, Ekici, Arif B, Fasching, Peter A, Fenstermacher, David A, Flanagan, James M, Garcia-Closas, Montserrat, Gentry-Maharaj, Aleksandra, Giles, Graham G, Glasspool, Rosalind M, Gonzalez-Bosquet, Jesus, Goodman, Marc T, Gore, Martin, Górski, Bohdan, Gronwald, Jacek, Hall, Per, Halle, Mari K, Harter, Philipp, Heitz, Florian, Hillemanns, Peter, Hoatlin, Maureen, Høgdall, Claus K, Høgdall, Estrid, Hosono, Satoyo, Jakubowska, Anna, Jensen, Allan, Jim, Heather, Kalli, Kimberly R, Karlan, Beth Y, Kaye, Stanley B, Kelemen, Linda E, Kiemeney, Lambertus A, Kikkawa, Fumitaka, Konecny, Gottfried E, Krakstad, Camilla, Krüger Kjaer, Susanne, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Lancaster, Johnathan M, Le, Nhu D, Leminen, Arto, Levine, Douglas A, Liang, Dong, Kiong Lim, Boon, Lin, Jie, Lissowska, Jolanta, Lu, Karen H, and Lubiński, Jan
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Rare Diseases, Biotechnology, Ovarian Cancer, Cancer, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Carcinoma, Ovarian Epithelial, Chromosomes, Human, Pair 17, Female, Genetic Predisposition to Disease, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Australian Cancer Study, Australian Ovarian Cancer Study, Consortium of Investigators of Modifiers of BRCA1/2
Abstract: Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3' untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio=1.12, P=10(-8)) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10(-10)). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes.
Published: 2013

35. 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, Australian Cancer Study, Ovarian Cancer Association Consortium, Ovary, Tumor Cells, Cultured, Chromosomes, Human, Pair 19, Humans, Adenocarcinoma, Clear Cell, Adenocarcinoma, Mucinous, Cystadenocarcinoma, Serous, Ovarian Neoplasms, Endometrial Neoplasms, Genetic Predisposition to Disease, Adaptor Proteins, Signal Transducing, Oligonucleotide Array Sequence Analysis, Case-Control Studies, Gene Expression Profiling, Genotype, Polymorphism, Single Nucleotide, Genome, Human, Middle Aged, Female, Genome-Wide Association Study, Biomarkers, Tumor, Tumor Cells, Cultured, Chromosomes, Human, Pair 19, Adenocarcinoma, Clear Cell, Mucinous, Cystadenocarcinoma, Serous, Adaptor Proteins, Signal Transducing, Polymorphism, Single Nucleotide, Genome, Biomarkers, Tumor, Cancer, Human Genome, Genetics, Ovarian Cancer, Orphan Drug, Rare Diseases, 2.1 Biological and endogenous factors, Developmental Biology, Medical and Health Sciences, Biological Sciences
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

36. 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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37. 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

38. Occupational exposure and ovarian cancer risk

Author: Le, Nhu D., Leung, Andy, Brooks-Wilson, Angela, Gallagher, Richard P., Swenerton, Kenneth D., Demers, Paul A., and Cook, Linda S.
Published: 2014

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

Author: Southey, Melissa C, Goldgar, David E, Winqvist, Robert, Pylkäs, Katri, Couch, Fergus, Tischkowitz, Marc, Foulkes, William D, Dennis, Joe, Michailidou, Kyriaki, van Rensburg, Elizabeth J, Heikkinen, Tuomas, Nevanlinna, Heli, Hopper, John L, Dörk, Thilo, Claes, Kathleen Bm, Reis-Filho, Jorge, Teo, Zhi Ling, Radice, Paolo, Catucci, Irene, Peterlongo, Paolo, Tsimiklis, Helen, Odefrey, Fabrice A, Dowty, James G, Schmidt, Marjanka K, Broeks, Annegien, Hogervorst, Frans B, Verhoef, Senno, Carpenter, Jane, Clarke, Christine, Scott, Rodney J, Fasching, Peter A, Haeberle, Lothar, Ekici, Arif B, Beckmann, Matthias W, Peto, Julian, Dos-Santos-Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Bolla, Manjeet K, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Marme, Federik, Burwinkel, Barbara, Yang, Rongxi, Guénel, Pascal, Truong, Thérèse, Menegaux, Florence, Sanchez, Marie, Bojesen, Stig, Nielsen, Sune F, Flyger, Henrik, Benitez, Javier, Zamora, M Pilar, Perez, Jose Ignacio Arias, Menéndez, Primitiva, Anton-Culver, Hoda, Neuhausen, Susan, Ziogas, Argyrios, Clarke, Christina A, Brenner, Hermann, Arndt, Volker, Stegmaier, Christa, Brauch, Hiltrud, Brüning, Thomas, Ko, Yon-Dschun, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Bogdanova, Natalia V, Antonenkova, Natalia N, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, Spurdle, Amanda B, Investigators, kConFab, Australian Ovarian Cancer Study Group, Wauters, Els, Smeets, Dominiek, Beuselinck, Benoit, Floris, Giuseppe, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Olson, Janet E, Vachon, Celine, Pankratz, Vernon S, McLean, Catriona, Haiman, Christopher A, Henderson, Brian E, Schumacher, Fredrick, Le Marchand, Loic, Kristensen, Vessela, Alnæs, Grethe Grenaker, Zheng, Wei, Hunter, David J, Lindstrom, Sara, Hankinson, Susan E, Kraft, Peter, Andrulis, Irene, Knight, Julia A, Glendon, Gord, Mulligan, Anna Marie, Jukkola-Vuorinen, Arja, Grip, Mervi, Kauppila, Saila, Devilee, Peter, Tollenaar, Robert AEM, Seynaeve, Caroline, Hollestelle, Antoinette, Garcia-Closas, Montserrat, Figueroa, Jonine, Chanock, Stephen J, Lissowska, Jolanta, Czene, Kamila, Darabi, Hatef, Eriksson, Mikael, Eccles, Diana M, Rafiq, Sajjad, Tapper, William J, Gerty, Sue M, Hooning, Maartje J, Martens, John WM, Collée, J Margriet, Tilanus-Linthorst, Madeleine, Hall, Per, Li, Jingmei, Brand, Judith S, Humphreys, Keith, Cox, Angela, Reed, Malcolm WR, Luccarini, Craig, Baynes, Caroline, Dunning, Alison M, Hamann, Ute, Torres, Diana, Ulmer, Hans Ulrich, Rüdiger, Thomas, Jakubowska, Anna, Lubinski, Jan, Jaworska, Katarzyna, Durda, Katarzyna, Slager, Susan, Toland, Amanda E, Ambrosone, Christine B, Yannoukakos, Drakoulis, Swerdlow, Anthony, Ashworth, Alan, Orr, Nick, Jones, Michael, González-Neira, Anna, Pita, Guillermo, Alonso, M Rosario, Álvarez, Nuria, Herrero, Daniel, Tessier, Daniel C, Vincent, Daniel, Bacot, Francois, Simard, Jacques, Dumont, Martine, Soucy, Penny, Eeles, Rosalind, Muir, Kenneth, Wiklund, Fredrik, Gronberg, Henrik, Schleutker, Johanna, Nordestgaard, Børge G, Weischer, Maren, Travis, Ruth C, Neal, David, Donovan, Jenny L, Hamdy, Freddie C, Khaw, Kay-Tee, Stanford, Janet L, Blot, William J, Thibodeau, Stephen, Schaid, Daniel J, Kelley, Joseph L, Maier, Christiane, Kibel, Adam S, Cybulski, Cezary, Cannon-Albright, Lisa, Butterbach, Katja, Park, Jong, Kaneva, Radka, Batra, Jyotsna, Teixeira, Manuel R, Kote-Jarai, Zsofia, Olama, Ali Amin Al, Benlloch, Sara, Renner, Stefan P, Hartmann, Arndt, Hein, Alexander, Ruebner, Matthias, Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Lambretchs, Sandrina, Doherty, Jennifer A, Rossing, Mary Anne, Nickels, Stefan, Eilber, Ursula, Wang-Gohrke, Shan, Odunsi, Kunle, Sucheston-Campbell, Lara E, Friel, Grace, Lurie, Galina, Killeen, Jeffrey L, Wilkens, Lynne R, Goodman, Marc T, Runnebaum, Ingo, Hillemanns, Peter A, Pelttari, Liisa M, Butzow, Ralf, Modugno, Francesmary, Edwards, Robert P, Ness, Roberta B, Moysich, Kirsten B, du Bois, Andreas, Heitz, Florian, Harter, Philipp, Kommoss, Stefan, Karlan, Beth Y, Walsh, Christine, Lester, Jenny, Jensen, Allan, Kjaer, Susanne Krüger, Høgdall, Estrid, Peissel, Bernard, Bonanni, Bernardo, Bernard, Loris, Goode, Ellen L, Fridley, Brooke L, Vierkant, Robert A, Cunningham, Julie M, Larson, Melissa C, Fogarty, Zachary C, Kalli, Kimberly R, Liang, Dong, Lu, Karen H, Hildebrandt, Michelle AT, Wu, Xifeng, Levine, Douglas A, Dao, Fanny, Bisogna, Maria, Berchuck, Andrew, Iversen, Edwin S, Marks, Jeffrey R, Akushevich, Lucy, Cramer, Daniel W, Schildkraut, Joellen, Terry, Kathryn L, Poole, Elizabeth M, Stampfer, Meir, Tworoger, Shelley S, Bandera, Elisa V, Orlow, Irene, Olson, Sara H, Bjorge, Line, Salvesen, Helga B, van Altena, Anne M, Aben, Katja KH, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Bean, Yukie, Brooks-Wilson, Angela, Kelemen, Linda E, Cook, Linda S, Le, Nhu D, Górski, Bohdan, Gronwald, Jacek, Menkiszak, Janusz, Høgdall, Claus K, Lundvall, Lene, Nedergaard, Lotte, Engelholm, Svend Aage, Dicks, Ed, Tyrer, Jonathan, Campbell, Ian, McNeish, Iain, Paul, James, Siddiqui, Nadeem, Glasspool, Rosalind, Whittemore, Alice S, Rothstein, Joseph H, McGuire, Valerie, Sieh, Weiva, Cai, Hui, Shu, Xiao-Ou, Teten, Rachel T, Sutphen, Rebecca, McLaughlin, John R, Narod, Steven A, Phelan, Catherine M, Monteiro, Alvaro N, Fenstermacher, David, Lin, Hui-Yi, Permuth, Jennifer B, Sellers, Thomas A, Chen, Y Ann, Tsai, Ya-Yu, Chen, Zhihua, Gentry-Maharaj, Aleksandra, Gayther, Simon A, Ramus, Susan J, Menon, Usha, Wu, Anna H, Pearce, Celeste L, Van Den Berg, David, Pike, Malcolm C, Dansonka-Mieszkowska, Agnieszka, Plisiecka-Halasa, Joanna, Moes-Sosnowska, Joanna, Kupryjanczyk, Jolanta, Pharoah, Paul Dp, Song, Honglin, Winship, Ingrid, Chenevix-Trench, Georgia, Giles, Graham G, Tavtigian, Sean V, Easton, Doug F, Milne, Roger L, Clinical Genetics, Neurology, Medical Oncology, Surgery, Erasmus MC other, Clinicum, Department of Obstetrics and Gynecology, Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Department of Oncology, Department of Pathology, HUS Gynecology and Obstetrics, Tischkowitz, Marc [0000-0002-7880-0628], Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Khaw, Kay-Tee [0000-0002-8802-2903], Amin Al Olama, Ali [0000-0002-7178-3431], Dicks, Ed [0000-0002-0617-0401], Tyrer, Jonathan [0000-0003-3724-4757], Pharoah, Paul [0000-0001-8494-732X], Song, Honglin [0000-0001-5076-7371], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Oncology, Male, Ataxia Telangiectasia Mutated Proteins, prostate-cancer, Prostate cancer, 0302 clinical medicine, brca1, Medizinische Fakultät, Medicine and Health Sciences, skin and connective tissue diseases, Genetics (clinical), Ovarian Neoplasms, education.field_of_study, brca2-interacting protein, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], 1184 Genetics, developmental biology, physiology, Nuclear Proteins, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, PROSTATE-CANCER, Cancer: prostate, Multicenter Study, ovarian-cancer, Centre for Surgical Research, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, ovary [Cancer], Female, Fanconi Anemia Complementation Group N Protein, metaanalysis, Risk, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Population, 3122 Cancers, cancer predisposition, Breast Neoplasms, OVARIAN-CANCER, BRCA2-INTERACTING PROTEIN, Cancer: ovary, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, prostate [Cancer], medicine, Cancer Genetics, Genetics, Journal Article, breast [Cancer], BREAST-CANCER, Humans, Genetic Predisposition to Disease, ddc:610, education, gene, CHEK2, FAMILY REGISTRY, METAANALYSIS, breast-cancer, Genetic Association Studies, business.industry, MUTATIONS, Cancer: breast, Tumor Suppressor Proteins, Case-control study, Cancer, Prostatic Neoplasms, medicine.disease, BRCA1, mutations, GENE, susceptibility loci, Checkpoint Kinase 2, 030104 developmental biology, Relative risk, Case-Control Studies, Mutation, family registry, Ovarian cancer, business
Abstract: Background: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.Methods: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant.Results: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10−8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants.Conclusions: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
Published: 2016

40. 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 K.H., 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 A.T., 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 F.A.G., 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: ovarian cancer, immunosuppression, biomarkers, genetic variation, TGFBR2
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 (p = 0.001) and clear cell EOC. Gene associations with histotypes at< 0.05 included:(p = 0.005 and = 0.008, serous and high-grade serous, respectively), (p = 0.035, endometrioid and mucinous), (p = 0.03, mucinous), (p = 0.022, clear cell), (p = 0.021 endometrioid) and (p = 0.017 and = 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.
Published: 2016
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41. No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer

Author: Hollestelle, Antoinette, van der Baan, Frederieke H., Berchuck, Andrew, Johnatty, Sharon E., Aben, Katja K., Agnarsson, Bjarni A., Aittomäki, Kristiina, Alducci, Elisa, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Antoniou, Antonis C., Apicella, Carmel, Arndt, Volker, Arnold, Norbert, Arun, Banu K., Arver, Brita, Ashworth, Alan, Baglietto, Laura, Balleine, Rosemary, Bandera, Elisa V., Barrowdale, Daniel, Bean, Yukie T., Beckmann, Lars, Beckmann, Matthias W., Benitez, Javier, Berger, Andreas, Berger, Raanan, Beuselinck, Benoit, Bisogna, Maria, Bjorge, Line, Blomqvist, Carl, Bogdanova, Natalia V., Bojesen, Anders, Bojesen, Stig E., Bolla, Manjeet K., Bonanni, Bernardo, Brand, Judith S., Brauch, Hiltrud, Brenner, Hermann, Brinton, Louise, Brooks-Wilson, Angela, Bruinsma, Fiona, Brunet, Joan, Brüning, Thomas, Budzilowska, Agnieszka, Bunker, Clareann H., Burwinkel, Barbara, Butzow, Ralf, Buys, Saundra S., Caligo, Maria A., Campbell, Ian, Carter, Jonathan, Chang-Claude, Jenny, Chanock, Stephen J., Claes, Kathleen B.M., Collée, J. Margriet, Cook, Linda S., Couch, Fergus J., Cox, Angela, Cramer, Daniel William, Cross, Simon S., Cunningham, Julie M., Cybulski, Cezary, Czene, Kamila, Damiola, Francesca, Dansonka-Mieszkowska, Agnieszka, Darabi, Hatef, de la Hoya, Miguel, deFazio, Anna, Dennis, Joseph, Devilee, Peter, Dicks, Ed M., Diez, Orland, Doherty, Jennifer A., Domchek, Susan M., Dorfling, Cecilia M., Dörk, Thilo, Silva, Isabel Dos Santos, du Bois, Andreas, Dumont, Martine, Dunning, Alison M., Duran, Mercedes, Easton, Douglas F., Eccles, Diana, Edwards, Robert P., Ehrencrona, Hans, Ejlertsen, Bent, Ekici, Arif B., Ellis, Steve D., Engel, Christoph, Eriksson, Mikael, Fasching, Peter A., Feliubadalo, Lidia, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Fontaine, Annette, Fortuzzi, Stefano, Fostira, Florentia, Fridley, Brooke L., Friebel, Tara, Friedman, Eitan, Friel, Grace, Frost, Debra, Garber, Judy Ellen, García-Closas, Montserrat, Gayther, Simon A., Gentry-Maharaj, Aleksandra, Gerdes, Anne-Marie, Giles, Graham G., Glasspool, Rosalind, Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Gore, Martin, Greene, Mark H., Grip, Mervi, Gronwald, Jacek, Gschwantler Kaulich, Daphne, Guénel, Pascal, Guzman, Starr R., Haeberle, Lothar, Haiman, Christopher A., Hall, Per, Halverson, Sandra L., Hamann, Ute, Hansen, Thomas V.O., Harter, Philipp, Hartikainen, Jaana M., Healey, Sue, Hein, Alexander, Heitz, Florian, Henderson, Brian E., Herzog, Josef, T Hildebrandt, Michelle A., Høgdall, Claus K., Høgdall, Estrid, Hogervorst, Frans B.L., Hopper, John L., Humphreys, Keith, Huzarski, Tomasz, Imyanitov, Evgeny N., Isaacs, Claudine, Jakubowska, Anna, Janavicius, Ramunas, Jaworska, Katarzyna, Jensen, Allan, Jensen, Uffe Birk, Johnson, Nichola, Jukkola-Vuorinen, Arja, Kabisch, Maria, Karlan, Beth Y., Kataja, Vesa, Kauff, Noah, Kelemen, Linda E., Kerin, Michael J., Kiemeney, Lambertus A., Kjaer, Susanne K., Knight, Julia A., Knol-Bout, Jacoba P., Konstantopoulou, Irene, Kosma, Veli-Matti, Krakstad, Camilla, Kristensen, Vessela, Kuchenbaecker, Karoline B., Kupryjanczyk, Jolanta, Laitman, Yael, Lambrechts, Diether, Lambrechts, Sandrina, Larson, Melissa C., Lasa, Adriana, Laurent-Puig, Pierre, Lazaro, Conxi, Le, Nhu D., Le Marchand, Loic, Leminen, Arto, Lester, Jenny, Levine, Douglas A., Li, Jingmei, Liang, Dong, Lindblom, Annika, Lindor, Noralane, Lissowska, Jolanta, Long, Jirong, Lu, Karen H., Lubinski, Jan, Lundvall, Lene, Lurie, Galina, Mai, Phuong L., Mannermaa, Arto, Margolin, Sara, Mariette, Frederique, Marme, Frederik, Martens, John W.M., Massuger, Leon F.A.G., Maugard, Christine, Mazoyer, Sylvie, McGuffog, Lesley, McGuire, Valerie, McLean, Catriona, McNeish, Iain, Meindl, Alfons, Menegaux, Florence, Menéndez, Primitiva, Menkiszak, Janusz, Menon, Usha, Mensenkamp, Arjen R., Miller, Nicola, Milne, Roger L., Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Müller, Heiko, Mulligan, Anna Marie, Muranen, Taru A., Narod, Steven A., Nathanson, Katherine L., Ness, Roberta B., Neuhausen, Susan L., Nevanlinna, Heli, Neven, Patrick, Nielsen, Finn C., Nielsen, Sune F., Nordestgaard, Børge G., Nussbaum, Robert L., Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I., Olson, Janet E., Olson, Sara H., Oosterwijk, Jan C., Orlow, Irene, Orr, Nick, Orsulic, Sandra, Osorio, Ana, Ottini, Laura, Paul, James, Pearce, Celeste L., Pedersen, Inge Sokilde, Peissel, Bernard, Pejovic, Tanja, Pelttari, Liisa M., Perkins, Jo, Permuth-Wey, Jenny, Peterlongo, Paolo, Peto, Julian, Phelan, Catherine M., Phillips, Kelly-Anne, Piedmonte, Marion, Pike, Malcolm C., Platte, Radka, Plisiecka-Halasa, Joanna, Poole, Elizabeth M., Poppe, Bruce, Pylkäs, Katri, Radice, Paolo, Ramus, Susan J., Rebbeck, Timothy R, Reed, Malcolm W.R., Rennert, Gad, Risch, Harvey A., Robson, Mark, Rodriguez, Gustavo C., Romero, Atocha, Rossing, Mary Anne, Rothstein, Joseph H., Rudolph, Anja, Runnebaum, Ingo, Salani, Ritu, Salvesen, Helga B., Sawyer, Elinor J., Schildkraut, Joellen M., Schmidt, Marjanka K., Schmutzler, Rita K., Schneeweiss, Andreas, Schoemaker, Minouk J., Schrauder, Michael G., Schumacher, Fredrick, Schwaab, Ira, Scuvera, Giulietta, Sellers, Thomas A., Severi, Gianluca, Seynaeve, Caroline M., Shah, Mitul, Shrubsole, Martha, Siddiqui, Nadeem, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sinilnikova, Olga M., Smeets, Dominiek, Sohn, Christof, Soller, Maria, Song, Honglin, Soucy, Penny, Southey, Melissa C., Stegmaier, Christa, Stoppa-Lyonnet, Dominique, Sucheston, Lara, Swerdlow, Anthony, Tangen, Ingvild L., Tea, Muy-Kheng, Teixeira, Manuel R., Terry, Kathryn Lynne, Terry, Mary Beth, Thomassen, Mads, Thompson, Pamela J., Tihomirova, Laima, Tischkowitz, Marc, Toland, Amanda Ewart, Tollenaar, Rob A.E.M., Tomlinson, Ian, Torres, Diana, Truong, Thérèse, Tsimiklis, Helen, Tung, Nadine Muskatel, Tworoger, Shelley Slate, Tyrer, Jonathan P., Vachon, Celine M., Van, Laura J., van Altena, Anne M., Van Asperen, C.J., van den Berg, David, van den Ouweland, Ans M.W., van Doorn, Helena C., Van Nieuwenhuysen, Els, van Rensburg, Elizabeth J., Vergote, Ignace, Verhoef, Senno, Vierkant, Robert A., Vijai, Joseph, Vitonis, Allison F., von Wachenfeldt, Anna, Walsh, Christine, Wang, Qin, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weischer, Maren, Weitzel, Jeffrey N., Weltens, Caroline, Wentzensen, Nicolas, Whittemore, Alice S., Wilkens, Lynne R., Winqvist, Robert, Wu, Anna H., Wu, Xifeng, Yang, Hannah P., Zaffaroni, Daniela, Pilar Zamora, M., Zheng, Wei, Ziogas, Argyrios, Chenevix-Trench, Georgia, Pharoah, Paul D.P., Rookus, Matti A., Hooning, Maartje J., and Goode, Ellen L.
Subjects: KRAS variant, Breast cancer, Ovarian cancer, Genetic association, Clinical outcome
Abstract: OBJECTIVE: Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. METHODS: Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). RESULTS: We found no association with risk of ovarian cancer (OR=0.99, 95% CI 0.94-1.04, p=0.74) or breast cancer (OR=0.98, 95% CI 0.94-1.01, p=0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR=1.09, 95% CI 0.97-1.23, p=0.14, breast cancer HR=1.04, 95% CI 0.97-1.12, p=0.27; BRCA2, ovarian cancer HR=0.89, 95% CI 0.71-1.13, p=0.34, breast cancer HR=1.06, 95% CI 0.94-1.19, p=0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR=0.94, 95% CI 0.83-1.07, p=0.38), breast cancer (HR=0.96, 95% CI 0.87-1.06, p=0.38), and all other previously-reported associations. CONCLUSIONS: rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers., Other Research Unit
Published: 2016
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42. 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 K. H., 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 William, 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 A. T., 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 F. A. G., 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, Weber, Rachel Palmieri, Paul, James, Pearce, Celeste L., Pejovic, Tanja, Pelttari, Liisa M., Permuth-Wey, Jennifer, Pike, Malcolm C., Poole, Elizabeth M., Risch, Harvey A., Rosen, Barry, Rossing, Mary Anne, Rothstein, Joseph H., Rudolph, Anja, Runnebaum, Ingo B., Rzepecka, Iwona K., Salvesen, Helga B., Schernhammer, Eva S, Schwaab, Ira, Shu, Xiao-Ou, Shvetsov, Yurii B., Siddiqui, Nadeem, Sieh, Weiva, Song, Honglin, Southey, Melissa C., Spiewankiewicz, Beata, Sucheston-Campbell, Lara, Teo, Soo-Hwang, Terry, Kathryn Lynne, Thompson, Pamela J., Thomsen, Lotte, Tangen, Ingvild L., Tworoger, Shelley Slate, van Altena, Anne M., Vierkant, Robert A., 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, Kelemen, Linda E., Berchuck, Andrew, Schildkraut, Joellen M., Ramus, Susan J., Goode, Ellen L., Monteiro, Alvaro N. A., Gayther, Simon A., Narod, Steven A., Pharoah, Paul D. P., Sellers, Thomas A., and Phelan, Catherine M.
Subjects: ovarian cancer, epithelial-mesenchymal transition, single nucleotide polymorphisms
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 <0.05 and a false discovery rate (FDR) <0.2 were considered statistically significant. In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (odds ratio (OR) = 1.16, 95% CI = 1.07-1.25, P = 0.0003, FDR = 0.19), whereas F8 rs7053448 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), F8 rs7058826 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), and CAPN13 rs1983383 (OR = 0.79, 95% CI = 0.69-0.90, P = 0.0005, FDR = 0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC., Other Research Unit
Published: 2015
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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. 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.

45. Profiling the immune landscape in mucinous ovarian carcinoma.

Author: Meagher, Nicola S., Hamilton, Phineas, Milne, Katy, Thornton, Shelby, Harris, Bronwyn, Weir, Ashley, Alsop, Jennifer, Bisinoto, Christiani, Brenton, James D., Brooks-Wilson, Angela, Chiu, Derek S., Cushing-Haugen, Kara L., Fereday, Sian, Garsed, Dale W., Gayther, Simon A., Gentry-Maharaj, Aleksandra, Gilks, Blake, Jimenez-Linan, Mercedes, Kennedy, Catherine J., and Le, Nhu D.
Subjects: *MUCINOUS adenocarcinoma, *REGULATORY T cells, *OVARIAN cancer, *PLASMA cells, *T cells, *IMMUNE checkpoint inhibitors, *IPILIMUMAB, *SCURFIN (Protein)
Abstract: Mucinous ovarian carcinoma (MOC) is a rare histotype of ovarian cancer, with low response rates to standard chemotherapy, and very poor survival for patients diagnosed at advanced stage. There is a limited understanding of the MOC immune landscape, and consequently whether immune checkpoint inhibitors could be considered for a subset of patients. We performed multicolor immunohistochemistry (IHC) and immunofluorescence (IF) on tissue microarrays in a cohort of 126 MOC patients. Cell densities were calculated in the epithelial and stromal components for tumor-associated macrophages (CD68+/PD-L1+, CD68+/PD-L1-), T cells (CD3+/CD8-, CD3+/CD8+), putative T-regulatory cells (Tregs, FOXP3+), B cells (CD20+/CD79A+), plasma cells (CD20-/CD79a+), and PD-L1+ and PD-1+ cells, and compared these values with clinical factors. Univariate and multivariable Cox Proportional Hazards assessed overall survival. Unsupervised k-means clustering identified patient subsets with common patterns of immune cell infiltration. Mean densities of PD1+ cells, PD-L1- macrophages, CD4+ and CD8+ T cells, and FOXP3+ Tregs were higher in the stroma compared to the epithelium. Tumors from advanced (Stage III/IV) MOC had greater epithelial infiltration of PD-L1- macrophages, and fewer PD-L1+ macrophages compared with Stage I/II cancers (p = 0.004 and p = 0.014 respectively). Patients with high epithelial density of FOXP3+ cells, CD8+/FOXP3+ cells, or PD-L1- macrophages, had poorer survival, and high epithelial CD79a + plasma cells conferred better survival, all upon univariate analysis only. Clustering showed that most MOC (86%) had an immune depleted (cold) phenotype, with only a small proportion (11/76,14%) considered immune inflamed (hot) based on T cell and PD-L1 infiltrates. In summary, MOCs are mostly immunogenically 'cold', suggesting they may have limited response to current immunotherapies. • High stage compared to low stage MOC have features suggestive of a more immunosuppressive environment. • High epithelial FOXP3+ T-regulatory cells associated with poorer overall survival, possibly inhibiting the immune response. • Most mucinous ovarian carcinomas are immunogenically 'cold' and tailored immune therapy approaches would be required. [ABSTRACT FROM AUTHOR]
Published: 2023
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46. Adult lifetime alcohol consumption and invasive epithelial ovarian cancer risk in a population-based case–control study.

Author: Cook, Linda S., Leung, Andy C.Y., Swenerton, Kenneth, Gallagher, Richard P., Magliocco, Anthony, Steed, Helen, Koebel, Martin, Nation, Jill, Eshragh, Sima, Brooks-Wilson, Angela, and Le, Nhu D.
Subjects: *ALCOHOL drinking, *EPITHELIAL cells, *OVARIAN cancer, *MEDICAL research, *META-analysis, *CANCER risk factors
Abstract: Objective Meta-analyses report a null association between recent alcohol consumption and ovarian cancer risk. However, because few studies investigated different types of alcohol over adult ages, we investigated adult lifetime and type (beer, wine, spirits) of consumption and risk. Methods Consumption after age 20 years was ascertained in 1144 invasive epithelial ovarian cancer cases and 2513 controls in a population-based case–control study (Alberta and British Columbia, Canada, 2001–2012). Non-drinkers consumed any types of alcohol < 12 times per year on average. Logistic regression was use to estimate adjusted odds ratios [aOR] and 95% confidence intervals [CIs]. Results Wine consumption was associated with a risk reduction (aOR = 0.67, 95% CI: 0.50–0.88) relative to non-drinkers, but not beer (aOR = 1.06, 95% CI: 0.71–1.58) or spirits (aOR = 0.98, 95% CI: 0.69–1.39). The reduced risk was stronger for exclusive red wine drinkers (aOR = 0.44, 95% CI: 0.19–0.92) than white wine drinkers (aOR = 0.79, 95% CI: 0.46–1.34), although most women drank both types of wine. Risk decreased with increasing cumulative consumption of any wine (P-trend < 0.05) and was evident for the serous histotype. Wine consumption initiated prior to age 50 was associated with a risk reduction (e.g., at 40–49 years, aOR = 0.58, 95% CI: 0.42–0.78), but not drinking initiated after 50 years of age. For any type, level, or age at initiation of alcohol consumption, we found no increased risks. Conclusions For the moderate consumption in this study, higher levels of wine consumption were generally associated with risk reductions; reductions may be stronger for red wine. Our results suggest that alcohol consumption that is guideline concordant will not increase epithelial ovarian cancer risk. [ABSTRACT FROM AUTHOR]
Published: 2016
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