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

Author

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

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Cancer, Prevention, Human Genome, Clinical Research, Ovarian Cancer, Women's Health, Orphan Drug, Rare Diseases, 2.1 Biological and endogenous factors, AOCS Group, OPAL Study Group, Medical biotechnology
Abstract

Survival from ovarian cancer depends on the resection status after primary surgery. We performed genome-wide association analyses for resection status of 7705 ovarian cancer patients, including 4954 with high-grade serous carcinoma (HGSOC), to identify variants associated with residual disease. The most significant association with resection status was observed for rs72845444, upstream of MGMT, in HGSOC (p = 3.9 × 10-8). In gene-based analyses, PPP2R5C was the most strongly associated gene in HGSOC after stage adjustment. In an independent set of 378 ovarian tumours from the AGO-OVAR 11 study, variants near MGMT and PPP2R5C correlated with methylation and transcript levels, and PPP2R5C mRNA levels predicted progression-free survival in patients with residual disease. MGMT encodes a DNA repair enzyme, and PPP2R5C encodes the B56γ subunit of the PP2A tumour suppressor. Our results link heritable variation at these two loci with resection status in HGSOC.

Published
2024

2. Clinical parameters affecting survival outcomes in patients with low-grade serous ovarian carcinoma: an international multicentre analysis

Author

May, Taymaa, Bernardini, Marcus, Lheureux, Stephanie, Aben, Katja KH, Bandera, Elisa V, Beckmann, Matthias W, Benitez, Javier, Berchuck, Andrew, Bjørge, Line, Carney, Michael E, Cramer, Daniel W, deFazio, Anna, Dörk, Thilo, Eccles, Diana M, Friedlander, Michael, García, María Jose, Goode, Ellen L, Hein, Alexander, Høgdall, Claus K, Jensen, Allan, Johnatty, Sharon, Kennedy, Catherine J, Kiemeney, Lambertus A, Kjær, Susanne K, Kupryjańczyk, Jolanta, Matsuo, Keitaro, McGuire, Valerie, Modugno, Francesmary, Paddock, Lisa E, Pejovic, Tanja, Phelan, Catherine M, Riggan, Marjorie J, Rodriguez-Antona, Cristina, Rothstein, Joseph H, Sieh, Weiva, Song, Honglin, Terry, Kathryn L, van Altena, Anne M, Vanderstichele, Adriaan, Vergote, Ignace, Thomsen, Liv Cecilie Vestrheim, Webb, Penelope M, Wentzensen, Nicolas, Wilkens, Lynne R, Ziogas, Argyrios, Jiang, Haiyan, and Tone, Alicia

Subjects
Reproductive Medicine, Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Oncology and Carcinogenesis, Ovarian Cancer, Cancer, Clinical Research, Rare Diseases, 6.4 Surgery, Evaluation of treatments and therapeutic interventions, Humans, Female, Middle Aged, Retrospective Studies, Neoplasm Staging, Ovarian Neoplasms, Cystadenocarcinoma, Serous, Kaplan-Meier Estimate, Ovarian Cancer Association and the Australian Ovarian Cancer Study Group, Clinical Sciences, Surgery, Clinical sciences
Abstract

BackgroundWomen with low-grade ovarian serous carcinoma (LGSC) benefit from surgical treatment; however, the role of chemotherapy is controversial. We examined an international database through the Ovarian Cancer Association Consortium to identify factors that affect survival in LGSC.MethodsWe performed a retrospective cohort analysis of patients with LGSC who had had primary surgery and had overall survival data available. We performed univariate and multivariate analyses of progression-free survival and overall survival, and generated Kaplan-Meier survival curves.ResultsOf the 707 patients with LGSC, 680 (96.2%) had available overall survival data. The patients' median age overall was 54 years. Of the 659 patients with International Federation of Obstetrics and Gynecology stage data, 156 (23.7%) had stage I disease, 64 (9.7%) had stage II, 395 (59.9%) had stage III, and 44 (6.7%) had stage IV. Of the 377 patients with surgical data, 200 (53.0%) had no visible residual disease. Of the 361 patients with chemotherapy data, 330 (91.4%) received first-line platinum-based chemotherapy. The median follow-up duration was 5.0 years. The median progression-free survival and overall survival were 43.2 months and 110.4 months, respectively. Multivariate analysis indicated a statistically significant impact of stage and residual disease on progression-free survival and overall survival. Platinum-based chemotherapy was not associated with a survival advantage.ConclusionThis multicentre analysis indicates that complete surgical cytoreduction to no visible residual disease has the most impact on improved survival in LGSC. This finding could immediately inform and change practice.

Published
2023

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

Author

Kang, Eun‐Young, Weir, Ashley, Meagher, Nicola S, Farrington, Kyo, Nelson, Gregg S, Ghatage, Prafull, Lee, Cheng‐Han, Riggan, Marjorie J, Bolithon, Adelyn, Popovic, Gordana, Leung, Betty, Tang, Katrina, Lambie, Neil, Millstein, Joshua, Alsop, Jennifer, Anglesio, Michael S, Ataseven, Beyhan, Barlow, Ellen, Beckmann, Matthias W, Berger, Jessica, Bisinotto, Christiani, Bösmüller, Hans, Boros, Jessica, Brand, Alison H, Brooks‐Wilson, Angela, Brucker, Sara Y, Carney, Michael E, Casablanca, Yovanni, Cazorla‐Jiménez, Alicia, Cohen, Paul A, Conrads, Thomas P, Cook, Linda S, Coulson, Penny, Courtney‐Brooks, Madeleine, Cramer, Daniel W, Crowe, Philip, Cunningham, Julie M, Cybulski, Cezary, Darcy, Kathleen M, El‐Bahrawy, Mona A, Elishaev, Esther, Erber, Ramona, Farrell, Rhonda, Fereday, Sian, Fischer, Anna, García, María J, Gayther, Simon A, Gentry‐Maharaj, Aleksandra, Gilks, C Blake, 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

4. Gene expression profiling of mucinous ovarian tumors and comparison with upper and lower gastrointestinal tumors identifies markers associated with adverse outcomes.

Author

Meagher, Nicola S, Gorringe, Kylie L, Wakefield, Matthew, Bolithon, Adelyn, Pang, Chi Nam Ignatius, Chiu, Derek S, Anglesio, Michael S, Mallitt, Kylie-Ann, Doherty, Jennifer A, Harris, Holly R, Schildkraut, Joellen M, Berchuck, Andrew, Cushing-Haugen, Kara L, Chezar, Ksenia, Chou, Angela, Tan, Adeline, Alsop, Jennifer, Barlow, Ellen, Beckmann, Matthias W, Boros, Jessica, Bowtell, David DL, Group, for the AOCS, Brand, Alison H, Brenton, James D, Campbell, Ian, Cheasley, Dane, Cohen, Joshua, Cybulski, Cezary, Elishaev, Esther, Erber, Ramona, Farrell, Rhonda, Fischer, Anna, Fu, Zhuxuan, Gilks, Blake, Gill, Anthony J, Initiative, for the Australian Pancreatic Genome, Gourley, Charlie, Grube, Marcel, Harnett, Paul R, Hartmann, Arndt, Hettiaratchi, Anusha, Høgdall, Claus K, Huzarski, Tomasz, Jakubowska, Anna, Jimenez-Linan, Mercedes, Kennedy, Catherine J, Kim, Byoung-Gie, Kim, Jae-Weon, Kim, Jae-Hoon, Klett, Kayla, Koziak, Jennifer M, Lai, Tiffany, Laslavic, Angela, Lester, Jenny, Leung, Yee, Li, Na, Liauw, Winston, Lim, Belle WX, Linder, Anna, Lubiński, Jan, Mahale, Sakshi, Mateoiu, Constantina, McInerny, Simone, Menkiszak, Janusz, Minoo, Parham, Mittelstadt, Suzana, Morris, David, Orsulic, Sandra, Park, Sang-Yoon, Pearce, Celeste Leigh, Pearson, John V, Pike, Malcolm C, Quinn, Carmel M, Mohan, Ganendra Raj, Rao, Jianyu, Riggan, Marjorie J, Ruebner, Matthias, Salfinger, Stuart, Scott, Clare L, Shah, Mitul, Steed, Helen, Stewart, Colin JR, Subramanian, Deepak, Sung, Soseul, Tang, Katrina, Timpson, Paul, Ward, Robyn L, Wiedenhoefer, Rebekka, Thorne, Heather, Investigators, for the kConFab, Cohen, Paul A, Crowe, Philip, Fasching, Peter A, Gronwald, Jacek, Hawkins, Nicholas J, Høgdall, Estrid, Huntsman, David G, James, Paul A, Karlan, Beth Y, and Kelemen, Linda E

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Ovarian Cancer, Rare Diseases, Cancer, Digestive Diseases, Genetics, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Female, Humans, Neoplasm Staging, Ovarian Neoplasms, Carcinoma, Ovarian Epithelial, Adenocarcinoma, Mucinous, Prognosis, Gastrointestinal Neoplasms, AOCS Group, Australian Pancreatic Genome Initiative, kConFab Investigators, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

PurposeAdvanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features.Experimental designDiscovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55).ResultsInfiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%).ConclusionsAn infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.

Published
2022

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

Author

Dareng, Eileen O, Tyrer, Jonathan P, Barnes, Daniel R, Jones, Michelle R, Yang, Xin, Aben, Katja KH, Adank, Muriel A, Agata, Simona, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Aravantinos, Gerasimos, Arun, Banu K, Augustinsson, Annelie, Balmaña, Judith, Bandera, Elisa V, Barkardottir, Rosa B, Barrowdale, Daniel, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q, Bjorge, Line, Black, Amanda, Bogdanova, Natalia V, Bonanni, Bernardo, Borg, Ake, Brenton, James D, Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S, Cai, Hui, Caligo, Maria A, Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K, Claes, Kathleen BM, Colonna, Sarah, Cook, Linda S, Couch, Fergus J, Daly, Mary B, Dao, Fanny, Davies, Eleanor, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A, Domchek, Susan M, Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana M, Eliassen, Heather A, Engel, Christoph, Evans, Gareth D, Fasching, Peter A, Flanagan, James M, Fortner, Renée T, Machackova, Eva, Friedman, Eitan, Ganz, Patricia A, Garber, Judy, Gensini, Francesca, Giles, Graham G, Glendon, Gord, Godwin, Andrew K, Goodman, Marc T, Greene, Mark H, Gronwald, Jacek, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hamann, Ute, Hansen, Thomas VO, Harris, Holly R, Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle AT, Høgdall, Estrid, Høgdall, Claus K, Hopper, John L, Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J, Huntsman, David G, Imyanitov, Evgeny N, Isaacs, Claudine, Jakubowska, Anna, James, Paul A, and Janavicius, Ramunas

Subjects
GEMO Study Collaborators, GC-HBOC Study Collaborators, EMBRACE Collaborators, OPAL Study Group, AOCS Group, KConFab Investigators, HEBON Investigators, OCAC Consortium, CIMBA Consortium, Genetics, Clinical Sciences, Genetics & Heredity
Published
2022

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

Author

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

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Women's Health, Infectious Diseases, HIV/AIDS, Cancer, Rare Diseases, Sexually Transmitted Infections, Genetics, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Biomarkers, Tumor, Cell Proliferation, Cystadenocarcinoma, Serous, Female, Humans, Ki-67 Antigen, Minichromosome Maintenance Complex Component 3, Ovarian Neoplasms, RNA, Messenger, Survival Rate, High-grade serous carcinoma, Proliferation, MCM3, Clinical Sciences, Pathology, Clinical sciences
Abstract

Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan-Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81-0.92, p

Published
2022

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

Author

Dareng, Eileen O, Tyrer, Jonathan P, Barnes, Daniel R, Jones, Michelle R, Yang, Xin, Aben, Katja KH, Adank, Muriel A, Agata, Simona, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Aravantinos, Gerasimos, Arun, Banu K, Augustinsson, Annelie, Balmaña, Judith, Bandera, Elisa V, Barkardottir, Rosa B, Barrowdale, Daniel, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q, Bjorge, Line, Black, Amanda, Bogdanova, Natalia V, Bonanni, Bernardo, Borg, Ake, Brenton, James D, Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S, Cai, Hui, Caligo, Maria A, Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J, Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K, Claes, Kathleen BM, Colonna, Sarah, Cook, Linda S, Couch, Fergus J, Daly, Mary B, Dao, Fanny, Davies, Eleanor, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A, Domchek, Susan M, Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana M, Eliassen, Heather A, Engel, Christoph, Evans, Gareth D, Fasching, Peter A, Flanagan, James M, Fortner, Renée T, Machackova, Eva, Friedman, Eitan, Ganz, Patricia A, Garber, Judy, Gensini, Francesca, Giles, Graham G, Glendon, Gord, Godwin, Andrew K, Goodman, Marc T, Greene, Mark H, Gronwald, Jacek, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hamann, Ute, Hansen, Thomas VO, Harris, Holly R, Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle AT, Høgdall, Estrid, Høgdall, Claus K, Hopper, John L, Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J, Huntsman, David G, Imyanitov, Evgeny N, Isaacs, Claudine, Jakubowska, Anna, James, Paul A, and Janavicius, Ramunas

Subjects
Prevention, Cancer, Ovarian Cancer, Rare Diseases, Good Health and Well Being, Bayes Theorem, Breast Neoplasms, Carcinoma, Ovarian Epithelial, Female, Genetic Predisposition to Disease, Humans, Male, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Prospective Studies, Risk Factors, GEMO Study Collaborators, GC-HBOC Study Collaborators, EMBRACE Collaborators, OPAL Study Group, AOCS Group, KConFab Investigators, HEBON Investigators, OCAC Consortium, CIMBA Consortium, Genetics, Clinical Sciences, Genetics & Heredity
Abstract

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

Published
2022

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

Author

Wohlmuth, Christoph, Djedovic, Vladimir, Kjaer, Susanne K, Jensen, Allan, Glasspool, Rosalind, Roxburgh, Patricia, DeFazio, Anna, Johnatty, Sharon E, Webb, Penelope M, Modugno, Francesmary, Lambrechts, Diether, Schildkraut, Joellen M, Berchuck, Andrew, Thomsen, Liv Cecilie Vestrheim, Bjorge, Line, Høgdall, Estrid, Høgdall, Claus K, Goode, Ellen L, Winham, Stacey J, Matsuo, Keitaro, Karlan, Beth Y, Lester, Jenny, Goodman, Marc T, Thompson, Pamela J, Pejovic, Tanja, Riggan, Marjorie J, Lajkosz, Katherine, Tone, Alicia, and May, Taymaa

Subjects
Cancer, Prevention, Clinical Research, Rare Diseases, Ovarian Cancer, ovarian cancer, low-grade serous cancer, CA-125, survival, Oncology and Carcinogenesis
Abstract

ObjectiveStudies on low-grade serous ovarian cancer (LGSC) are limited by a low number of cases. The aim of this study was to define the prognostic significance of age, stage, and CA-125 levels on survival in a multi-institutional cohort of women with pathologically confirmed LGSC.MethodsWomen with LGSC were identified from the collaborative Ovarian Cancer Association Consortium (OCAC). Cases of newly diagnosed primary LGSC were included if peri-operative CA-125 levels were available. Age at diagnosis, FIGO stage, pre- and post-treatment CA-125 levels, residual disease, adjuvant chemotherapy, disease recurrence, and vital status were collected by the participating institutions. Progression-free (PFS) and overall survival (OS) were calculated. Multivariable (MVA) Cox proportional hazard models were used and hazard ratios (HR) calculated.ResultsA total of 176 women with LGSC were included in this study; 82% had stage III/IV disease. The median PFS was 2.3 years and the median OS was 6.4 years. Age at diagnosis was not significantly associated with worse PFS (p = 0.23) or OS (p = 0.3) (HR per year: 0.99; 95%CI, 0.96-1.01 and 0.98; 95%CI 0.95-1.01). FIGO stage III/IV was independently associated with PFS (HR 4.26, 95%CI 1.43-12.73) and OS (HR 1.69, 95%CI 0.56-5.05). Elevated CA-125 (≥35 U/mL) at diagnosis was not significantly associated with worse PFS (p = 0.87) or OS (p = 0.78) in MVA. Elevated CA-125 (≥35 U/mL) after completion of primary treatment was independently associated with worse PFS (HR 2.81, 95%CI 1.36-5.81) and OS (HR 6.62, 95%CI 2.45-17.92). In the MVA, residual disease was independently associated with PFS (0.022), but not OS (0.85).ConclusionAdvanced LGSC was associated with poor long-term prognosis. FIGO stage and abnormal post-treatment CA-125 level are key prognostic factors inversely associated with PFS and OS.Highlights1. Through a multi-center collaborative effort, data from 176 women with low-grade serous ovarian cancer were analyzed. 2. Although low-grade serous ovarian cancer is often considered indolent, the progression-free and overall survival are poor. 3. Elevated post-treatment CA-125 levels are independently associated with poor survival.

Published
2022

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

Author

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

Subjects
Biotechnology, Genetics, Prevention, Cancer, Breast Cancer, Human Genome, Ovarian Cancer, Rare Diseases, 2.1 Biological and endogenous factors
Abstract

Familial, sequencing, and genome-wide association studies (GWASs) and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWASs) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through application of a pleiotropy-guided conditional/conjunction false discovery rate (FDR) approach in the setting of a TWASs. This identified 14 candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR < 0.05 that were >1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. The 22 genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk.

Published
2021

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

Author

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

Subjects
Prevention, Human Genome, Cancer, Biotechnology, Genetics, Breast Cancer, Rare Diseases, Ovarian Cancer, Aetiology, 2.1 Biological and endogenous factors
Abstract

Familial, sequencing, and genome-wide association studies (GWASs) and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWASs) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through application of a pleiotropy-guided conditional/conjunction false discovery rate (FDR) approach in the setting of a TWASs. This identified 14 candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR < 0.05 that were >1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. The 22 genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk.

Published
2021

11. Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers

Author

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

Subjects
Epidemiology, Biomedical and Clinical Sciences, Health Sciences, Oncology and Carcinogenesis, Human Genome, Uterine Cancer, Genetics, Biotechnology, Ovarian Cancer, Prevention, Cancer, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Carcinoma, Ovarian Epithelial, Endometrial Neoplasms, Female, Genome-Wide Association Study, Humans, Ovarian Neoplasms, Quantitative Trait Loci, Risk Factors, OPAL Study Group, AOCS Group, Medical and Health Sciences, Biomedical and clinical sciences, Health sciences
Abstract

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

Published
2021

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

Author

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

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Epidemiology, Health Sciences, Statistics, Mathematical Sciences, Oncology and Carcinogenesis, Aging, Rare Diseases, Human Genome, Cancer, Uterine Cancer, Ovarian Cancer, Prevention, Biotechnology, Aetiology, 2.1 Biological and endogenous factors
Abstract

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

Published
2020

13. 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

14. 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

15. 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
Humans, Ovarian Neoplasms, Genetic Predisposition to Disease, Prognosis, Risk Factors, Cohort Studies, Gene Expression Profiling, Genotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Female, Genome-Wide Association Study, Transcriptome, Carcinogenesis, Carcinoma, Ovarian Epithelial, Polymorphism, Single Nucleotide, Carcinoma, Ovarian Epithelial, Prevention, Genetics, Human Genome, Cancer, Rare Diseases, Ovarian Cancer, 2.1 Biological and endogenous factors, Oncology & Carcinogenesis, 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

16. 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, Ovarian Cancer, Genetics, Women's Health, Prevention, 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

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

Author

Dixon-Suen, Suzanne C, Nagle, Christina M, Thrift, Aaron P, Pharoah, Paul DP, Ewing, Ailith, Pearce, Celeste Leigh, Zheng, Wei, Australian Ovarian Cancer Study Group, Chenevix-Trench, Georgia, Fasching, Peter A, Beckmann, Matthias W, Lambrechts, Diether, Vergote, Ignace, Lambrechts, Sandrina, Van Nieuwenhuysen, Els, Rossing, Mary Anne, Doherty, Jennifer A, Wicklund, Kristine G, Chang-Claude, Jenny, Jung, Audrey Y, Moysich, Kirsten B, Odunsi, Kunle, Goodman, Marc T, Wilkens, Lynne R, Thompson, Pamela J, Shvetsov, Yurii B, Dörk, Thilo, Park-Simon, Tjoung-Won, Hillemanns, Peter, Bogdanova, Natalia, Butzow, Ralf, Nevanlinna, Heli, Pelttari, Liisa M, Leminen, Arto, Modugno, Francesmary, Ness, Roberta B, Edwards, Robert P, Kelley, Joseph L, Heitz, Florian, du Bois, Andreas, Harter, Philipp, Schwaab, Ira, Karlan, Beth Y, Lester, Jenny, Orsulic, Sandra, Rimel, Bobbie J, Kjær, Susanne K, Høgdall, Estrid, Jensen, Allan, Goode, Ellen L, Fridley, Brooke L, Cunningham, Julie M, Winham, Stacey J, Giles, Graham G, Bruinsma, Fiona, Milne, Roger L, Southey, Melissa C, Hildebrandt, Michelle AT, Wu, Xifeng, Lu, Karen H, Liang, Dong, Levine, Douglas A, Bisogna, Maria, Schildkraut, Joellen M, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Bandera, Elisa V, Olson, Sara H, Salvesen, Helga B, Thomsen, Liv Cecilie Vestrheim, Kopperud, Reidun K, Bjorge, Line, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Bruegl, Amanda, Cook, Linda S, Le, Nhu D, Swenerton, Kenneth D, Brooks-Wilson, Angela, Kelemen, Linda E, Lubiński, Jan, Huzarski, Tomasz, Gronwald, Jacek, Menkiszak, Janusz, Wentzensen, Nicolas, Brinton, Louise, Yang, Hannah, Lissowska, Jolanta, Høgdall, Claus K, Lundvall, Lene, Song, Honglin, Tyrer, Jonathan P, Campbell, Ian, Eccles, Diana, Paul, James, Glasspool, Rosalind, Siddiqui, Nadeem, and Whittemore, Alice S

Subjects
Australian Ovarian Cancer Study Group, Ovarian Cancer Association Consortium, Humans, Ovarian Neoplasms, Genetic Predisposition to Disease, Body Height, Risk Factors, Case-Control Studies, Geography, Adolescent, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Young Adult, Mendelian Randomization Analysis, Carcinoma, Ovarian Epithelial, Genetics, Clinical Research, Rare Diseases, Ovarian Cancer, Cancer, Oncology & Carcinogenesis, Oncology and Carcinogenesis, Public Health and Health Services
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

18. 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

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

Author

Ong, Jue-Sheng, Cuellar-Partida, Gabriel, Lu, Yi, Study, Australian Ovarian Cancer, 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, 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
Epidemiology, Health Sciences, Nutrition, Ovarian Cancer, Prevention, Clinical Research, Cancer, Rare Diseases, Carcinoma, Ovarian Epithelial, Female, Genetic Predisposition to Disease, Humans, Mendelian Randomization Analysis, Neoplasms, Glandular and Epithelial, Odds Ratio, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Risk Factors, Vitamin D, Australian Ovarian Cancer Study, Statistics, Public Health and Health Services, Public health
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

20. Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Author

Kar, Siddhartha P, Beesley, Jonathan, Olama, Ali Amin Al, Michailidou, Kyriaki, Tyrer, Jonathan, Kote-Jarai, ZSofia, Lawrenson, Kate, Lindstrom, Sara, Ramus, Susan J, Thompson, Deborah J, Investigators, ABCTB, Kibel, Adam S, Dansonka-Mieszkowska, Agnieszka, Michael, Agnieszka, Dieffenbach, Aida K, Gentry-Maharaj, Aleksandra, Whittemore, Alice S, Wolk, Alicja, Monteiro, Alvaro, Peixoto, Ana, Kierzek, Andrzej, Cox, Angela, Rudolph, Anja, Gonzalez-Neira, Anna, Wu, Anna H, Lindblom, Annika, Swerdlow, Anthony, Study, AOCS Study Group amp Australian Cancer, BioResource, APCB, Ziogas, Argyrios, Ekici, Arif B, Burwinkel, Barbara, Karlan, Beth Y, Nordestgaard, Børge G, Blomqvist, Carl, Phelan, Catherine, McLean, Catriona, Pearce, Celeste Leigh, Vachon, Celine, Cybulski, Cezary, Slavov, Chavdar, Stegmaier, Christa, Maier, Christiane, Ambrosone, Christine B, Høgdall, Claus K, Teerlink, Craig C, Kang, Daehee, Tessier, Daniel C, Schaid, Daniel J, Stram, Daniel O, Cramer, Daniel W, Neal, David E, Eccles, Diana, Flesch-Janys, Dieter, Edwards, Digna R Velez, Wokozorczyk, Dominika, Levine, Douglas A, Yannoukakos, Drakoulis, Sawyer, Elinor J, Bandera, Elisa V, Poole, Elizabeth M, Goode, Ellen L, Khusnutdinova, Elza, Høgdall, Estrid, Song, Fengju, Bruinsma, Fiona, Heitz, Florian, Modugno, Francesmary, Hamdy, Freddie C, Wiklund, Fredrik, Giles, Graham G, Olsson, Håkan, Wildiers, Hans, Ulmer, Hans-Ulrich, Pandha, Hardev, Risch, Harvey A, Darabi, Hatef, Salvesen, Helga B, Nevanlinna, Heli, Gronberg, Henrik, Brenner, Hermann, Brauch, Hiltrud, Anton-Culver, Hoda, Song, Honglin, Lim, Hui-Yi, McNeish, Iain, Campbell, Ian, Vergote, Ignace, Gronwald, Jacek, Lubiński, Jan, Stanford, Janet L, Benítez, Javier, Doherty, Jennifer A, Permuth, Jennifer B, Chang-Claude, Jenny, Donovan, Jenny L, Dennis, Joe, Schildkraut, Joellen M, Schleutker, Johanna, and Hopper, John L

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Breast Cancer, Aging, Urologic Diseases, Prostate Cancer, Ovarian Cancer, Rare Diseases, Human Genome, Cancer, Aetiology, 2.1 Biological and endogenous factors, Breast Neoplasms, Case-Control Studies, Chromosome Mapping, Datasets as Topic, Enhancer Elements, Genetic, Female, Gene Regulatory Networks, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Organ Specificity, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Quantitative Trait Loci, Signal Transduction, ABCTB Investigators, AOCS Study Group & Australian Cancer Study, APCB BioResource, kConFab Investigators, NBCS Investigators, GENICA Network, PRACTICAL consortium, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

UnlabelledBreast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis.SignificanceWe demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.

Published
2016

21. Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types.

Author

Kar, Siddhartha P, Beesley, Jonathan, Amin Al Olama, Ali, Michailidou, Kyriaki, Tyrer, Jonathan, Kote-Jarai, ZSofia, Lawrenson, Kate, Lindstrom, Sara, Ramus, Susan J, Thompson, Deborah J, ABCTB Investigators, Kibel, Adam S, Dansonka-Mieszkowska, Agnieszka, Michael, Agnieszka, Dieffenbach, Aida K, Gentry-Maharaj, Aleksandra, Whittemore, Alice S, Wolk, Alicja, Monteiro, Alvaro, Peixoto, Ana, Kierzek, Andrzej, Cox, Angela, Rudolph, Anja, Gonzalez-Neira, Anna, Wu, Anna H, Lindblom, Annika, Swerdlow, Anthony, AOCS Study Group & Australian Cancer Study (Ovarian Cancer), APCB BioResource, Ziogas, Argyrios, Ekici, Arif B, Burwinkel, Barbara, Karlan, Beth Y, Nordestgaard, Børge G, Blomqvist, Carl, Phelan, Catherine, McLean, Catriona, Pearce, Celeste Leigh, Vachon, Celine, Cybulski, Cezary, Slavov, Chavdar, Stegmaier, Christa, Maier, Christiane, Ambrosone, Christine B, Høgdall, Claus K, Teerlink, Craig C, Kang, Daehee, Tessier, Daniel C, Schaid, Daniel J, Stram, Daniel O, Cramer, Daniel W, Neal, David E, Eccles, Diana, Flesch-Janys, Dieter, Edwards, Digna R Velez, Wokozorczyk, Dominika, Levine, Douglas A, Yannoukakos, Drakoulis, Sawyer, Elinor J, Bandera, Elisa V, Poole, Elizabeth M, Goode, Ellen L, Khusnutdinova, Elza, Høgdall, Estrid, Song, Fengju, Bruinsma, Fiona, Heitz, Florian, Modugno, Francesmary, Hamdy, Freddie C, Wiklund, Fredrik, Giles, Graham G, Olsson, Håkan, Wildiers, Hans, Ulmer, Hans-Ulrich, Pandha, Hardev, Risch, Harvey A, Darabi, Hatef, Salvesen, Helga B, Nevanlinna, Heli, Gronberg, Henrik, Brenner, Hermann, Brauch, Hiltrud, Anton-Culver, Hoda, Song, Honglin, Lim, Hui-Yi, McNeish, Iain, Campbell, Ian, Vergote, Ignace, Gronwald, Jacek, Lubiński, Jan, Stanford, Janet L, Benítez, Javier, Doherty, Jennifer A, Permuth, Jennifer B, Chang-Claude, Jenny, Donovan, Jenny L, Dennis, Joe, Schildkraut, Joellen M, Schleutker, Johanna, and Hopper, John L

Subjects
ABCTB Investigators, AOCS Study Group & Australian Cancer Study, APCB BioResource, kConFab Investigators, NBCS Investigators, GENICA Network, PRACTICAL consortium, Humans, Breast Neoplasms, Ovarian Neoplasms, Prostatic Neoplasms, Genetic Predisposition to Disease, Case-Control Studies, Chromosome Mapping, Signal Transduction, Organ Specificity, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Female, Male, Gene Regulatory Networks, Meta-Analysis as Topic, Enhancer Elements, Genetic, Genome-Wide Association Study, Genetic Loci, Datasets as Topic, Polymorphism, Single Nucleotide, Enhancer Elements, Genetic, Urologic Diseases, Prostate Cancer, Human Genome, Rare Diseases, Genetics, Cancer, Breast Cancer, Aging, Ovarian Cancer, 2.1 Biological and endogenous factors, Oncology and Carcinogenesis
Abstract

UnlabelledBreast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis.SignificanceWe demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.

Published
2016

22. Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk.

Author

Kelemen, Linda E, Terry, Kathryn L, Goodman, Marc T, Webb, Penelope M, Bandera, Elisa V, McGuire, Valerie, Rossing, Mary Anne, Wang, Qinggang, Dicks, Ed, Tyrer, Jonathan P, Song, Honglin, Kupryjanczyk, Jolanta, Dansonka-Mieszkowska, Agnieszka, Plisiecka-Halasa, Joanna, Timorek, Agnieszka, Menon, Usha, Gentry-Maharaj, Aleksandra, Gayther, Simon A, Ramus, Susan J, Narod, Steven A, Risch, Harvey A, McLaughlin, John R, Siddiqui, Nadeem, Glasspool, Rosalind, Paul, James, Carty, Karen, Gronwald, Jacek, Lubiński, Jan, Jakubowska, Anna, Cybulski, Cezary, Kiemeney, Lambertus A, Massuger, Leon FAG, van Altena, Anne M, Aben, Katja KH, Olson, Sara H, Orlow, Irene, Cramer, Daniel W, Levine, Douglas A, Bisogna, Maria, Giles, Graham G, Southey, Melissa C, Bruinsma, Fiona, Kjaer, Susanne K, Høgdall, Estrid, Jensen, Allan, Høgdall, Claus K, Lundvall, Lene, Engelholm, Svend-Aage, Heitz, Florian, du Bois, Andreas, Harter, Philipp, Schwaab, Ira, Butzow, Ralf, Nevanlinna, Heli, Pelttari, Liisa M, Leminen, Arto, Thompson, Pamela J, Lurie, Galina, Wilkens, Lynne R, Lambrechts, Diether, Van Nieuwenhuysen, Els, Lambrechts, Sandrina, Vergote, Ignace, Beesley, Jonathan, AOCS Study Group/ACS Investigators, Fasching, Peter A, Beckmann, Matthias W, Hein, Alexander, Ekici, Arif B, Doherty, Jennifer A, Wu, Anna H, Pearce, Celeste L, Pike, Malcolm C, Stram, Daniel, Chang-Claude, Jenny, Rudolph, Anja, Dörk, Thilo, Dürst, Matthias, Hillemanns, Peter, Runnebaum, Ingo B, Bogdanova, Natalia, Antonenkova, Natalia, Odunsi, Kunle, Edwards, Robert P, Kelley, Joseph L, Modugno, Francesmary, Ness, Roberta B, Karlan, Beth Y, Walsh, Christine, Lester, Jenny, Orsulic, Sandra, Fridley, Brooke L, Vierkant, Robert A, Cunningham, Julie M, Wu, Xifeng, Lu, Karen, Liang, Dong, Hildebrandt, Michelle AT, Weber, Rachel Palmieri, and Iversen, Edwin S

Subjects
AOCS Study Group/ACS Investigators, Humans, Carcinoma, Ovarian Neoplasms, Folic Acid Deficiency, Genetic Predisposition to Disease, Folic Acid, Dihydrouracil Dehydrogenase (NADP), Neoplasm Proteins, Diet, Multivariate Analysis, Risk Factors, Case-Control Studies, Energy Intake, Polymorphism, Single Nucleotide, Dietary Supplements, European Continental Ancestry Group, Female, Genome-Wide Association Study, Global Health, Case-control, Dihydropyrimidine dehydrogenase, Folate, Polymorphism, Serine hydroxymethyltransferase 1, Rare Diseases, Cancer, Ovarian Cancer, Genetics, Nutrition, 2.1 Biological and endogenous factors, Nutrition & Dietetics, Food Science, Food Sciences, Nutrition and Dietetics, Public Health and Health Services
Abstract

ScopeWe reevaluated previously reported associations between variants in pathways of one-carbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake.Methods and resultsOdds ratios (OR) for 446 genetic variants were estimated among 13,410 OC cases and 22,635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 × 10⁻⁵) and rs828054 (OR = 1.06; p = 1 × 10⁻⁴). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 × 10⁻⁶) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1-C transfer, previously reported with OC, suggested lower risk at higher folate (p(interaction) = 0.03-0.006).ConclusionVariation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-by-folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.

Published
2014

23. Consortium analysis of gene and gene–folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk

Author

Kelemen, Linda E, Terry, Kathryn L, Goodman, Marc T, Webb, Penelope M, Bandera, Elisa V, McGuire, Valerie, Rossing, Mary Anne, Wang, Qinggang, Dicks, Ed, Tyrer, Jonathan P, Song, Honglin, Kupryjanczyk, Jolanta, Dansonka‐Mieszkowska, Agnieszka, Plisiecka‐Halasa, Joanna, Timorek, Agnieszka, Menon, Usha, Gentry‐Maharaj, Aleksandra, Gayther, Simon A, Ramus, Susan J, Narod, Steven A, Risch, Harvey A, McLaughlin, John R, Siddiqui, Nadeem, Glasspool, Rosalind, Paul, James, Carty, Karen, Gronwald, Jacek, Lubiński, Jan, Jakubowska, Anna, Cybulski, Cezary, Kiemeney, Lambertus A, Massuger, Leon FAG, van Altena, Anne M, Aben, Katja KH, Olson, Sara H, Orlow, Irene, Cramer, Daniel W, Levine, Douglas A, Bisogna, Maria, Giles, Graham G, Southey, Melissa C, Bruinsma, Fiona, Kjær, Susanne K, Høgdall, Estrid, Jensen, Allan, Høgdall, Claus K, Lundvall, Lene, Engelholm, Svend‐Aage, Heitz, Florian, du Bois, Andreas, Harter, Philipp, Schwaab, Ira, Butzow, Ralf, Nevanlinna, Heli, Pelttari, Liisa M, Leminen, Arto, Thompson, Pamela J, Lurie, Galina, Wilkens, Lynne R, Lambrechts, Diether, Van Nieuwenhuysen, Els, Lambrechts, Sandrina, Vergote, Ignace, Beesley, Jonathan, Investigators, AOCS Study Group ACS, Fasching, Peter A, Beckmann, Matthias W, Hein, Alexander, Ekici, Arif B, Doherty, Jennifer A, Wu, Anna H, Pearce, Celeste L, Pike, Malcolm C, Stram, Daniel, Chang‐Claude, Jenny, Rudolph, Anja, Dörk, Thilo, Dürst, Matthias, Hillemanns, Peter, Runnebaum, Ingo B, Bogdanova, Natalia, Antonenkova, Natalia, Odunsi, Kunle, Edwards, Robert P, Kelley, Joseph L, Modugno, Francesmary, Ness, Roberta B, Karlan, Beth Y, Walsh, Christine, Lester, Jenny, Orsulic, Sandra, Fridley, Brooke L, Vierkant, Robert A, Cunningham, Julie M, Wu, Xifeng, Lu, Karen, Liang, Dong, Hildebrandt, Michelle AT, Weber, Rachel Palmieri, and Iversen, Edwin S

Subjects
Biomedical and Clinical Sciences, Nutrition and Dietetics, Genetics, Cancer, Nutrition, Rare Diseases, Ovarian Cancer, 2.1 Biological and endogenous factors, Aetiology, Carcinoma, Case-Control Studies, Diet, Dietary Supplements, Dihydrouracil Dehydrogenase (NADP), Energy Intake, Female, Folic Acid, Folic Acid Deficiency, Genetic Predisposition to Disease, Genome-Wide Association Study, Global Health, Humans, Multivariate Analysis, Neoplasm Proteins, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Risk Factors, White People, Case-control, Dihydropyrimidine dehydrogenase, Folate, Polymorphism, Serine hydroxymethyltransferase 1, AOCS Study Group/ACS Investigators, Food Sciences, Public Health and Health Services, Food Science, Nutrition & Dietetics, Food sciences, Nutrition and dietetics
Abstract

ScopeWe reevaluated previously reported associations between variants in pathways of one-carbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake.Methods and resultsOdds ratios (OR) for 446 genetic variants were estimated among 13,410 OC cases and 22,635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 × 10⁻⁵) and rs828054 (OR = 1.06; p = 1 × 10⁻⁴). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 × 10⁻⁶) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1-C transfer, previously reported with OC, suggested lower risk at higher folate (p(interaction) = 0.03-0.006).ConclusionVariation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-by-folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.

Published
2014

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

Author

Earp, Madalene A, Kelemen, Linda E, Magliocco, Anthony M, Swenerton, Kenneth D, Chenevix-Trench, Georgia, Australian Cancer Study, Australian Ovarian Cancer Study Group, Lu, Yi, Hein, Alexander, Ekici, Arif B, Beckmann, Matthias W, Fasching, Peter A, Lambrechts, Diether, Despierre, Evelyn, Vergote, Ignace, Lambrechts, Sandrina, Doherty, Jennifer A, Rossing, Mary Anne, Chang-Claude, Jenny, Rudolph, Anja, Friel, Grace, Moysich, Kirsten B, Odunsi, Kunle, Sucheston-Campbell, Lara, Lurie, Galina, Goodman, Marc T, Carney, Michael E, Thompson, Pamela J, Runnebaum, Ingo B, Dürst, Matthias, Hillemanns, Peter, Dörk, Thilo, Antonenkova, Natalia, Bogdanova, Natalia, Leminen, Arto, Nevanlinna, Heli, Pelttari, Liisa M, Butzow, Ralf, Bunker, Clareann H, Modugno, Francesmary, Edwards, Robert P, Ness, Roberta B, du Bois, Andreas, Heitz, Florian, Schwaab, Ira, Harter, Philipp, Karlan, Beth Y, Walsh, Christine, Lester, Jenny, Jensen, Allan, Kjær, Susanne K, Høgdall, Claus K, Høgdall, Estrid, Lundvall, Lene, Sellers, Thomas A, Fridley, Brooke L, Goode, Ellen L, Cunningham, Julie M, Vierkant, Robert A, Giles, Graham G, Baglietto, Laura, Severi, Gianluca, Southey, Melissa C, Liang, Dong, Wu, Xifeng, Lu, Karen, Hildebrandt, Michelle AT, Levine, Douglas A, Bisogna, Maria, Schildkraut, Joellen M, Iversen, Edwin S, Weber, Rachel Palmieri, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Poole, Elizabeth M, Tworoger, Shelley S, Bandera, Elisa V, Chandran, Urmila, Orlow, Irene, Olson, Sara H, Wik, Elisabeth, Salvesen, Helga B, Bjorge, Line, Halle, Mari K, van Altena, Anne M, Aben, Katja KH, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Bean, Yukie T, Cybulski, Cezary, Gronwald, Jacek, Lubinski, Jan, Wentzensen, Nicolas, Brinton, Louise A, Lissowska, Jolanta, Garcia-Closas, Montserrat, Dicks, Ed, and Dennis, Joe

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Prevention, Cancer Genomics, Rare Diseases, Women's Health, Ovarian Cancer, Cancer, Human Genome, 2.1 Biological and endogenous factors, Alleles, Carcinoma, Ovarian Epithelial, DNA, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Quality Control, Australian Cancer Study, Australian Ovarian Cancer Study Group, Ovarian Cancer Association Consortium, Complementary and Alternative Medicine, Paediatrics and Reproductive Medicine, Genetics & Heredity, Reproductive medicine
Abstract

Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P

Published
2014

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

Author

Earp, Madalene A, Kelemen, Linda E, Magliocco, Anthony M, Swenerton, Kenneth D, Chenevix-Trench, Georgia, Australian Cancer Study, Australian Ovarian Cancer Study Group, Lu, Yi, Hein, Alexander, Ekici, Arif B, Beckmann, Matthias W, Fasching, Peter A, Lambrechts, Diether, Despierre, Evelyn, Vergote, Ignace, Lambrechts, Sandrina, Doherty, Jennifer A, Rossing, Mary Anne, Chang-Claude, Jenny, Rudolph, Anja, Friel, Grace, Moysich, Kirsten B, Odunsi, Kunle, Sucheston-Campbell, Lara, Lurie, Galina, Goodman, Marc T, Carney, Michael E, Thompson, Pamela J, Runnebaum, Ingo B, Dürst, Matthias, Hillemanns, Peter, Dörk, Thilo, Antonenkova, Natalia, Bogdanova, Natalia, Leminen, Arto, Nevanlinna, Heli, Pelttari, Liisa M, Butzow, Ralf, Bunker, Clareann H, Modugno, Francesmary, Edwards, Robert P, Ness, Roberta B, du Bois, Andreas, Heitz, Florian, Schwaab, Ira, Harter, Philipp, Karlan, Beth Y, Walsh, Christine, Lester, Jenny, Jensen, Allan, Kjær, Susanne K, Høgdall, Claus K, Høgdall, Estrid, Lundvall, Lene, Sellers, Thomas A, Fridley, Brooke L, Goode, Ellen L, Cunningham, Julie M, Vierkant, Robert A, Giles, Graham G, Baglietto, Laura, Severi, Gianluca, Southey, Melissa C, Liang, Dong, Wu, Xifeng, Lu, Karen, Hildebrandt, Michelle AT, Levine, Douglas A, Bisogna, Maria, Schildkraut, Joellen M, Iversen, Edwin S, Weber, Rachel Palmieri, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Poole, Elizabeth M, Tworoger, Shelley S, Bandera, Elisa V, Chandran, Urmila, Orlow, Irene, Olson, Sara H, Wik, Elisabeth, Salvesen, Helga B, Bjorge, Line, Halle, Mari K, van Altena, Anne M, Aben, Katja KH, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Bean, Yukie T, Cybulski, Cezary, Gronwald, Jacek, Lubinski, Jan, Wentzensen, Nicolas, Brinton, Louise A, Lissowska, Jolanta, Garcia-Closas, Montserrat, Dicks, Ed, and Dennis, Joe

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Rare Diseases, Prevention, Ovarian Cancer, Human Genome, Cancer, 2.1 Biological and endogenous factors, Aetiology, Alleles, Carcinoma, Ovarian Epithelial, DNA, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Quality Control, Australian Cancer Study, Australian Ovarian Cancer Study Group, Ovarian Cancer Association Consortium, Complementary and Alternative Medicine, Paediatrics and Reproductive Medicine, Genetics & Heredity, Reproductive medicine
Abstract

Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P

Published
2014

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

Author

Earp, Madalene A, Kelemen, Linda E, Magliocco, Anthony M, Swenerton, Kenneth D, Chenevix-Trench, Georgia, Australian Cancer Study, Australian Ovarian Cancer Study Group, Lu, Yi, Hein, Alexander, Ekici, Arif B, Beckmann, Matthias W, Fasching, Peter A, Lambrechts, Diether, Despierre, Evelyn, Vergote, Ignace, Lambrechts, Sandrina, Doherty, Jennifer A, Rossing, Mary Anne, Chang-Claude, Jenny, Rudolph, Anja, Friel, Grace, Moysich, Kirsten B, Odunsi, Kunle, Sucheston-Campbell, Lara, Lurie, Galina, Goodman, Marc T, Carney, Michael E, Thompson, Pamela J, Runnebaum, Ingo B, Dürst, Matthias, Hillemanns, Peter, Dörk, Thilo, Antonenkova, Natalia, Bogdanova, Natalia, Leminen, Arto, Nevanlinna, Heli, Pelttari, Liisa M, Butzow, Ralf, Bunker, Clareann H, Modugno, Francesmary, Edwards, Robert P, Ness, Roberta B, du Bois, Andreas, Heitz, Florian, Schwaab, Ira, Harter, Philipp, Karlan, Beth Y, Walsh, Christine, Lester, Jenny, Jensen, Allan, Kjær, Susanne K, Høgdall, Claus K, Høgdall, Estrid, Lundvall, Lene, Sellers, Thomas A, Fridley, Brooke L, Goode, Ellen L, Cunningham, Julie M, Vierkant, Robert A, Giles, Graham G, Baglietto, Laura, Severi, Gianluca, Southey, Melissa C, Liang, Dong, Wu, Xifeng, Lu, Karen, Hildebrandt, Michelle AT, Levine, Douglas A, Bisogna, Maria, Schildkraut, Joellen M, Iversen, Edwin S, Weber, Rachel Palmieri, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Poole, Elizabeth M, Tworoger, Shelley S, Bandera, Elisa V, Chandran, Urmila, Orlow, Irene, Olson, Sara H, Wik, Elisabeth, Salvesen, Helga B, Bjorge, Line, Halle, Mari K, van Altena, Anne M, Aben, Katja KH, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Bean, Yukie T, Cybulski, Cezary, Gronwald, Jacek, Lubinski, Jan, Wentzensen, Nicolas, Brinton, Louise A, Lissowska, Jolanta, Garcia-Closas, Montserrat, Dicks, Ed, and Dennis, Joe

Subjects
Australian Cancer Study, Australian Ovarian Cancer Study Group, Ovarian Cancer Association Consortium, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Genetic Predisposition to Disease, DNA, Polymorphism, Single Nucleotide, Alleles, Quality Control, Female, Genome-Wide Association Study, Carcinoma, Ovarian Epithelial, Neoplasms, Glandular and Epithelial, Polymorphism, Single Nucleotide, Carcinoma, Ovarian Epithelial, Genetics & Heredity, Genetics, Complementary and Alternative Medicine, Paediatrics and Reproductive Medicine
Abstract

Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P

Published
2014

27. 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

28. 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, Prevention, Human Genome, Rare Diseases, Genetics, Cancer, Ovarian Cancer, 2.1 Biological and endogenous factors, Developmental Biology, Biological Sciences, Medical and Health Sciences
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

29. 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

30. 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, Chen, Y Ann, 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, Australian Cancer Study, Australian Ovarian Cancer Study, 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, Consortium of Investigators of Modifiers of BRCA1/2, 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, Kjaer, Susanne Krüger, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Lancaster, Johnathan M, Le, Nhu D, Leminen, Arto, Levine, Douglas A, Liang, Dong, Lim, Boon Kiong, and Lin, Jie

Subjects
Australian Cancer Study, Australian Ovarian Cancer Study, Consortium of Investigators of Modifiers of BRCA1/2, Chromosomes, Human, Pair 17, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Female, Carcinoma, Ovarian Epithelial, Human Genome, Biotechnology, Rare Diseases, Cancer, Genetics, Ovarian Cancer, 2.1 Biological and endogenous factors
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

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