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1. Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions

Author: Dareng, Eileen O., Coetzee, Simon G., Tyrer, Jonathan P., Peng, Pei-Chen, Rosenow, Will, Chen, Stephanie, Davis, Brian D., Dezem, Felipe Segato, Seo, Ji-Heui, Nameki, Robbin, Reyes, Alberto L., Aben, Katja K.H., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Bandera, Elisa V., Beane Freeman, Laura E., Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia V., Bolton, Kelly L., Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Cai, Hui, Campbell, Ian, Cannioto, Rikki, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chenevix-Trench, Georgia, Chiew, Yoke-Eng, Cook, Linda S., DeFazio, Anna, Dennis, Joe, Doherty, Jennifer A., Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana M., Ene, Gabrielle, Fasching, Peter A., Flanagan, James M., Fortner, Renée T., Fostira, Florentia, Gentry-Maharaj, Aleksandra, Giles, Graham G., Goodman, Marc T., Gronwald, Jacek, Haiman, Christopher A., Håkansson, Niclas, Heitz, Florian, Hildebrandt, Michelle A.T., Høgdall, Estrid, Høgdall, Claus K., Huang, Ruea-Yea, Jensen, Allan, Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony N., Kelemen, Linda E., Kennedy, Catherine J., Khusnutdinova, Elza K., Kiemeney, Lambertus A., Kjaer, Susanne K., Kupryjanczyk, Jolanta, Labrie, Marilyne, Lambrechts, Diether, Larson, Melissa C., Le, Nhu D., Lester, Jenny, Li, Lian, Lubiński, Jan, Lush, Michael, Marks, Jeffrey R., Matsuo, Keitaro, May, Taymaa, McLaughlin, John R., McNeish, Iain A., Menon, Usha, Missmer, Stacey, Modugno, Francesmary, Moffitt, Melissa, Monteiro, Alvaro N., Moysich, Kirsten B., Narod, Steven A., Nguyen-Dumont, Tu, Odunsi, Kunle, Olsson, Håkan, Onland-Moret, N. Charlotte, Park, Sue K., Pejovic, Tanja, Permuth, Jennifer B., Piskorz, Anna, Prokofyeva, Darya, Riggan, Marjorie J., Risch, Harvey A., Rodríguez-Antona, Cristina, Rossing, Mary Anne, Sandler, Dale P., Setiawan, V. Wendy, Shan, Kang, Song, Honglin, Southey, Melissa C., Steed, Helen, Sutphen, Rebecca, Swerdlow, Anthony J., Teo, Soo Hwang, Terry, Kathryn L., Thompson, Pamela J., Vestrheim Thomsen, Liv Cecilie, Titus, Linda, Trabert, Britton, Travis, Ruth, Tworoger, Shelley S., Valen, Ellen, Van Nieuwenhuysen, Els, Edwards, Digna Velez, Vierkant, Robert A., Webb, Penelope M., Weinberg, Clarice R., Weise, Rayna Matsuno, Wentzensen, Nicolas, White, Emily, Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zeinomar, Nur, Zheng, Wei, Ziogas, Argyrios, Berchuck, Andrew, Goode, Ellen L., Huntsman, David G., Pearce, Celeste L., Ramus, Susan J., Sellers, Thomas A., Freedman, Matthew L., Lawrenson, Kate, Schildkraut, Joellen M., Hazelett, Dennis, Plummer, Jasmine T., Kar, Siddhartha, Jones, Michelle R., Pharoah, Paul D.P., and Gayther, Simon A.
Published: 2024
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2. High pre-diagnosis inflammation-related risk score associated with decreased ovarian cancer survival

Author: Brieger, Katharine K, Phung, Minh Tung, Mukherjee, Bhramar, Bakulski, Kelly M, Anton-Culver, Hoda, Bandera, Elisa V, Bowtell, David DL, Cramer, Daniel W, DeFazio, Anna, Doherty, Jennifer A, Fereday, Sian, Fortner, Renée Turzanski, Gentry-Maharaj, Aleksandra, Goode, Ellen L, Goodman, Marc T, Harris, Holly R, Matsuo, Keitaro, Menon, Usha, Modugno, Francesmary, Moysich, Kirsten B, Qin, Bo, Ramus, Susan J, Risch, Harvey A, Rossing, Mary Anne, Schildkraut, Joellen M, Trabert, Britton, Vierkant, Robert A, Winham, Stacey J, Wentzensen, Nicolas, Wu, Anna H, Ziogas, Argyrios, Khoja, Lilah, Cho, Kathleen R, McLean, Karen, Richardson, Jean, Grout, Bronwyn, Chase, Anne, Deurloo, Cindy McKinnon, Odunsi, Kunle, Nelson, Brad H, Brenton, James D, Terry, Kathryn L, Pharoah, Paul DP, Berchuck, Andrew, Hanley, Gillian E, Webb, Penelope M, Pike, Malcolm C, and Pearce, Celeste Leigh
Subjects: Epidemiology, Biomedical and Clinical Sciences, Health Sciences, Tobacco Smoke and Health, Prevention, Ovarian Cancer, Tobacco, Cancer, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Aged, Carcinoma, Ovarian Epithelial, Female, Health Behavior, Humans, Inflammation, Middle Aged, Ovarian Neoplasms, Proportional Hazards Models, Risk Assessment, Ovarian Cancer Association Consortium, Medical and Health Sciences, Biomedical and clinical sciences, Health sciences
Abstract: BackgroundThere is suggestive evidence that inflammation is related to ovarian cancer survival. However, more research is needed to identify inflammation-related factors that are associated with ovarian cancer survival and to determine their combined effects.MethodsThis analysis used pooled data on 8,147 women with invasive epithelial ovarian cancer from the Ovarian Cancer Association Consortium. The prediagnosis inflammation-related exposures of interest included alcohol use; aspirin use; other nonsteroidal anti-inflammatory drug use; body mass index; environmental tobacco smoke exposure; history of pelvic inflammatory disease, polycystic ovarian syndrome, and endometriosis; menopausal hormone therapy use; physical inactivity; smoking status; and talc use. Using Cox proportional hazards models, the relationship between each exposure and survival was assessed in 50% of the data. A weighted inflammation-related risk score (IRRS) was developed, and its association with survival was assessed using Cox proportional hazards models in the remaining 50% of the data.ResultsThere was a statistically significant trend of increasing risk of death per quartile of the IRRS [HR = 1.09; 95% confidence interval (CI), 1.03-1.14]. Women in the upper quartile of the IRRS had a 31% higher death rate compared with the lowest quartile (95% CI, 1.11-1.54).ConclusionsA higher prediagnosis IRRS was associated with an increased mortality risk after an ovarian cancer diagnosis. Further investigation is warranted to evaluate whether postdiagnosis exposures are also associated with survival.ImpactGiven that pre- and postdiagnosis exposures are often correlated and many are modifiable, our study results can ultimately motivate the development of behavioral recommendations to enhance survival among patients with ovarian cancer.
Published: 2022

3. Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer

Author: Song, Honglin, Dicks, Ed M, Tyrer, Jonathan, Intermaggio, Maria, Chenevix-Trench, Georgia, Bowtell, David D, Traficante, Nadia, Group, AOCS, Brenton, James, Goranova, Teodora, Hosking, Karen, Piskorz, Anna, van Oudenhove, Elke, Doherty, Jen, Harris, Holly R, Rossing, Mary Anne, Duerst, Matthias, Dork, Thilo, Bogdanova, Natalia V, Modugno, Francesmary, Moysich, Kirsten, Odunsi, Kunle, Ness, Roberta, Karlan, Beth Y, Lester, Jenny, Jensen, Allan, Kjaer, Susanne Krüger, Høgdall, Estrid, Campbell, Ian G, Lázaro, Conxi, Pujara, Miguel Angel, Cunningham, Julie, Vierkant, Robert, Winham, Stacey J, Hildebrandt, Michelle, Huff, Chad, Li, Donghui, Wu, Xifeng, Yu, Yao, Permuth, Jennifer B, Levine, Douglas A, Schildkraut, Joellen M, Riggan, Marjorie J, Berchuck, Andrew, Webb, Penelope M, Group, OPAL Study, Cybulski, Cezary, Gronwald, Jacek, Jakubowska, Anna, Lubinski, Jan, Alsop, Jennifer, Harrington, Patricia, Chan, Isaac, Menon, Usha, Pearce, Celeste L, Wu, Anna H, de Fazio, Anna, Kennedy, Catherine J, Goode, Ellen, Ramus, Susan, Gayther, Simon, and Pharoah, Paul
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Orphan Drug, Ovarian Cancer, Prevention, Clinical Research, Rare Diseases, Cancer, 2.1 Biological and endogenous factors, Aetiology, Case-Control Studies, Fanconi Anemia Complementation Group N Protein, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Ovarian Neoplasms, Risk Assessment, cancer, endocrine, genetic epidemiology, cancer: endocrine, Medical and Health Sciences, Genetics & Heredity, Clinical sciences
Abstract: PurposeThe known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes.MethodsWe sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics.ResultsThe ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive.ConclusionsWe have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.
Published: 2021

4. Expanding Our Understanding of Ovarian Cancer Risk: The Role of Incomplete Pregnancies

Author: Lee, Alice W, Rosenzweig, Stacey, Wiensch, Ashley, Group, the Australian Ovarian Cancer Study, Ramus, Susan J, Menon, Usha, Gentry-Maharaj, Aleksandra, Ziogas, Argyrios, Anton-Culver, Hoda, Whittemore, Alice S, Sieh, Weiva, Rothstein, Joseph H, McGuire, Valerie, Wentzensen, Nicolas, Bandera, Elisa V, Qin, Bo, Terry, Kathryn L, Cramer, Daniel W, Titus, Linda, Schildkraut, Joellen M, Berchuck, Andrew, Goode, Ellen L, Kjaer, Susanne K, Jensen, Allan, Jordan, Susan J, Ness, Roberta B, Modugno, Francesmary, Moysich, Kirsten, Thompson, Pamela J, Goodman, Marc T, Carney, Michael E, Chang-Claude, Jenny, Rossing, Mary Anne, Harris, Holly R, Doherty, Jennifer Anne, Risch, Harvey A, Khoja, Lilah, Alimujiang, Aliya, Phung, Minh Tung, Brieger, Katharine, Mukherjee, Bhramar, Pharoah, Paul DP, Wu, Anna H, Pike, Malcolm C, Webb, Penelope M, and Pearce, Celeste Leigh
Subjects: Rare Diseases, Prevention, Cancer, Ovarian Cancer, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Abortion, Induced, Abortion, Spontaneous, Carcinoma, Ovarian Epithelial, Case-Control Studies, Female, Humans, Ovarian Neoplasms, Parity, Pregnancy, Risk, United Kingdom, United States, Australian Ovarian Cancer Study Group, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract: BackgroundParity is associated with decreased risk of invasive ovarian cancer; however, the relationship between incomplete pregnancies and invasive ovarian cancer risk is unclear. This relationship was examined using 15 case-control studies from the Ovarian Cancer Association Consortium (OCAC). Histotype-specific associations, which have not been examined previously with large sample sizes, were also evaluated.MethodsA pooled analysis of 10 470 invasive epithelial ovarian cancer cases and 16 942 controls was conducted. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between incomplete pregnancies and invasive epithelial ovarian cancer were estimated using logistic regression. All models were conditioned on OCAC study, race and ethnicity, age, and education level and adjusted for number of complete pregnancies, oral contraceptive use, and history of breastfeeding. The same approach was used for histotype-specific analyses.ResultsEver having an incomplete pregnancy was associated with a 16% reduction in ovarian cancer risk (OR = 0.84, 95% CI = 0.79 to 0.89). There was a trend of decreasing risk with increasing number of incomplete pregnancies (2-sided Ptrend < .001). An inverse association was observed for all major histotypes; it was strongest for clear cell ovarian cancer.ConclusionsIncomplete pregnancies are associated with a reduced risk of invasive epithelial ovarian cancer. Pregnancy, including incomplete pregnancy, was associated with a greater reduction in risk of clear cell ovarian cancer, but the result was broadly consistent across histotypes. Future work should focus on understanding the mechanisms underlying this reduced risk.
Published: 2021

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

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

6. Population based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high grade serous ovarian cancer

Author: Song, Honglin, Dicks, Ed, Tyrer, Jonathan P, Intermaggio, Maria, Chenevix-Trench, Georgia, Bowtell, David D, Traficante, Nadia, Group, AOCS, Brenton, James D, Goranova, Teodora, Hosking, Karen, Piskorz, Anna, Van Oudenhove, Elke, Doherty, Jennifer Anne, Harris, Holly R, Rossing, Mary Anne, Dürst, Matthias, Dörk, Thilo, Bogdanova, Natalia V, Modugno, Francesmary, Moysich, Kirsten B, Odunsi, Kunle, Ness, Roberta B, Karlan, Beth Y, Lester, Jenny, Jensen, Allan, Kjaer, Susanne K, Høgdall, Estrid, Campbell, Ian, Lazaro, Conxi, Pujana, Miquel Angel, Cunningham, Julie M, Vierkant, Robert A, Winham, Stacey J, Hildebrandt, Michelle AT, Huff, Chad, Li, Donghui, Wu, Xifeng, Yu, Yao, Permuth, Jennifer B, Levine, Douglas A, Schildkraut, Joellen M, Riggan, Marjorie J, Berchuck, Andrew, Webb, Penelope M, Group, OPAL Study, Cybulski, Cezary, Gronwald, Jacek, Jakubowska, Anna, Lubiński, Jan, Alsop, Jennifer, Harrington, Patricia A, Chan, Isaac, Menon, Usha, Pearce, Celeste L, Wu, Anna H, de Fazio, Anna, Kennedy, Catherine J, Goode, Ellen L, Ramus, Susan J, Gayther, Simon A, and Pharoah, Paul DP
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Health Sciences, Oncology and Carcinogenesis, Orphan Drug, Clinical Research, Human Genome, Rare Diseases, Ovarian Cancer, Cancer, Prevention, 2.1 Biological and endogenous factors, Aetiology
Abstract: Abstract: Purpose: The known EOC susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes. Methods: We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases verses controls were further examined in an independent set of 14,146 EOC cases and 28,661 controls from the ovarian cancer association consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics. Results: The odds ratios (OR) associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 – 5.68; P = 0.00068), 1.99 for POLK (95% CI 1.15 – 3.43; P = 0.014), and 4.07 for SLX4 (95% CI 1.34-12.4; P = 0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 −1.00, P=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive. Conclusions: We have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.
Published: 2019

7. Association between genetically predicted polycystic ovary syndrome and ovarian cancer: a Mendelian randomization study

Author: Harris, Holly R, Cushing-Haugen, Kara L, Webb, Penelope M, Nagle, Christina M, Jordan, Susan J, Group, Australian Ovarian Cancer Study, Risch, Harvey A, Rossing, Mary Anne, Doherty, Jennifer A, Goodman, Marc T, Modugno, Francesmary, Ness, Roberta B, Moysich, Kirsten B, Kjær, Susanne K, Høgdall, Estrid, Jensen, Allan, Schildkraut, Joellen M, Berchuck, Andrew, Cramer, Daniel W, Bandera, Elisa V, Rodriguez, Lorna, Wentzensen, Nicolas, Kotsopoulos, Joanne, Narod, Steven A, McLaughlin, John R, Anton-Culver, Hoda, Ziogas, Argyrios, Pearce, Celeste L, Wu, Anna H, Lindström, Sara, and Terry, Kathryn L
Subjects: Epidemiology, Health Sciences, Ovarian Cancer, Prevention, Genetics, Clinical Research, Infertility, Cancer, Contraception/Reproduction, Rare Diseases, Reproductive health and childbirth, Good Health and Well Being, Adenocarcinoma, Clear Cell, Adenocarcinoma, Mucinous, Carcinoma, Endometrioid, Female, Humans, Mendelian Randomization Analysis, Neoplasms, Cystic, Mucinous, and Serous, Ovarian Neoplasms, Polycystic Ovary Syndrome, Polycystic ovary syndrome, ovarian cancer, histotype, Mendelian randomization, Australian Ovarian Cancer Study Group, Statistics, Public Health and Health Services, Public health
Abstract: BackgroundPolycystic ovary syndrome (PCOS) is a complex endocrine disorder with an estimated prevalence of 4-21% in reproductive aged women. Recently, the Ovarian Cancer Association Consortium (OCAC) reported a decreased risk of invasive ovarian cancer among women with self-reported PCOS. However, given the limitations of self-reported PCOS, the validity of these observed associations remains uncertain. Therefore, we sought to use Mendelian randomization with genetic markers as a proxy for PCOS, to examine the association between PCOS and ovarian cancer.MethodsUtilizing 14 single nucleotide polymorphisms (SNPs) previously associated with PCOS we assessed the association between genetically predicted PCOS and ovarian cancer risk, overall and by histotype, using summary statistics from a previously conducted genome-wide association study (GWAS) of ovarian cancer among European ancestry women within the OCAC (22 406 with invasive disease, 3103 with borderline disease and 40 941 controls).ResultsAn inverse association was observed between genetically predicted PCOS and invasive ovarian cancer risk: odds ratio (OR)=0.92 [95% confidence interval (CI)=0.85-0.99; P = 0.03]. When results were examined by histotype, the strongest inverse association was observed between genetically predicted PCOS and endometrioid tumors (OR = 0.77; 95% CI = 0.65-0.92; P = 0.003). Adjustment for individual-level body mass index, oral contraceptive use and parity did not materially change the associations.ConclusionOur study provides evidence for a relationship between PCOS and reduced ovarian cancer risk, overall and among specific histotypes of invasive ovarian cancer. These results lend support to our previous observational study results. Future studies are needed to understand mechanisms underlying this association.
Published: 2019

8. A comprehensive gene–environment interaction analysis in Ovarian Cancer using genome‐wide significant common variants

Author: Kim, Sehee, Wang, Miao, Tyrer, Jonathan P, Jensen, Allan, Wiensch, Ashley, Liu, Gang, Lee, Alice W, Ness, Roberta B, Salvatore, Maxwell, Tworoger, Shelley S, Whittemore, Alice S, Anton‐Culver, Hoda, Sieh, Weiva, Olson, Sara H, Berchuck, Andrew, Goode, Ellen L, Goodman, Marc T, Doherty, Jennifer Anne, Chenevix‐Trench, Georgia, Rossing, Mary Anne, Webb, Penelope M, Giles, Graham G, Terry, Kathryn L, Ziogas, Argyrios, Fortner, Renée T, Menon, Usha, Gayther, Simon A, Wu, Anna H, Song, Honglin, Brooks‐Wilson, Angela, Bandera, Elisa V, Cook, Linda S, Cramer, Daniel W, Milne, Roger L, Winham, Stacey J, Kjaer, Susanne K, Modugno, Francesmary, Thompson, Pamela J, Chang‐Claude, Jenny, Harris, Holly R, Schildkraut, Joellen M, Le, Nhu D, Wentzensen, Nico, Trabert, Britton, Høgdall, Estrid, Huntsman, David, Pike, Malcolm C, Pharoah, Paul DP, Pearce, Celeste Leigh, and Mukherjee, Bhramar
Subjects: Rare Diseases, Human Genome, Clinical Research, Genetics, Patient Safety, Cancer, Prevention, Ovarian Cancer, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Case-Control Studies, Contraceptives, Oral, Hormonal, Environment, Environmental Exposure, Female, Gene-Environment Interaction, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Risk, ovarian cancer, genetics, additive interaction, G x E, G × E, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract: As a follow-up to genome-wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well-known ovarian cancer risk factors and their interactions with 28 genome-wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case-control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 × 10-4 ). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI = 0.46-0.60) compared to 0.71 (95%CI = 0.66-0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1-5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene-environment analysis in ovarian cancer.
Published: 2019

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

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

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

Author: Rambau, Peter F, Vierkant, Robert A, Intermaggio, Maria P, Kelemen, Linda E, Goodman, Marc T, Herpel, Esther, Pharoah, Paul D, Kommoss, Stefan, Jimenez-Linan, Mercedes, Karlan, Beth Y, Gentry-Maharaj, Aleksandra, Menon, Usha, Polo, Susanna Hernando, Candido Dos Reis, Francisco J, Doherty, Jennifer Anne, Gayther, Simon A, Sharma, Raghwa, Larson, Melissa C, Harnett, Paul R, Hatfield, Emma, de Andrade, Jurandyr M, Nelson, Gregg S, Steed, Helen, Schildkraut, Joellen M, Carney, Micheal E, Høgdall, Estrid, Whittemore, Alice S, Widschwendter, Martin, Kennedy, Catherine J, Wang, Frances, Wang, Qin, Wang, Chen, Armasu, Sebastian M, Daley, Frances, Coulson, Penny, Jones, Micheal E, Anglesio, Micheal S, Chow, Christine, de Fazio, Anna, García-Closas, Montserrat, Brucker, Sara Y, Cybulski, Cezary, Harris, Holly R, Hartkopf, Andreas D, Huzarski, Tomasz, Jensen, Allan, Lubiński, Jan, Oszurek, Oleg, Benitez, Javier, Mina, Fady, Staebler, Annette, Taran, Florin Andrei, Pasternak, Jana, Talhouk, Aline, Rossing, Mary Anne, Hendley, Joy, AOCS Group, Edwards, Robert P, Fereday, Sian, Modugno, Francesmary, Ness, Roberta B, Sieh, Weiva, El-Bahrawy, Mona A, Winham, Stacey J, Lester, Jenny, Kjaer, Susanne K, Gronwald, Jacek, Sinn, Peter, Fasching, Peter A, Chang-Claude, Jenny, Moysich, Kirsten B, Bowtell, David D, Hernandez, Brenda Y, Luk, Hugh, Behrens, Sabine, Shah, Mitul, Jung, Audrey, Ghatage, Prafull, Alsop, Jennifer, Alsop, Kathryn, García-Donas, Jesús, Thompson, Pamela J, Swerdlow, Anthony J, Karpinskyj, Chloe, Cazorla-Jiménez, Alicia, García, María J, Deen, Susha, Wilkens, Lynne R, Palacios, José, Berchuck, Andrew, Koziak, Jennifer M, Brenton, James D, Cook, Linda S, Goode, Ellen L, Huntsman, David G, Ramus, Susan J, and Köbel, Martin
Subjects: AOCS Group, Ovary, Humans, Adenocarcinoma, Mucinous, Cystadenocarcinoma, Serous, Ovarian Neoplasms, Prognosis, Immunohistochemistry, Survival Rate, Adult, Aged, Middle Aged, Female, Cyclin-Dependent Kinase Inhibitor p16, RT-QPCR, immunocytochemistry, ovary, Adenocarcinoma, Mucinous, Cystadenocarcinoma, Serous, Cancer, Genetics, Ovarian Cancer, Rare Diseases, 2.1 Biological and endogenous factors
Abstract: We aimed to validate the prognostic association of p16 expression in ovarian high-grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical-grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis-associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47-2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30-2.75, p = 0.004), while absence was associated with shorter OS in low-grade serous carcinomas (HR: 2.95, 95% CI 1.61-5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype-specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low-grade serous carcinoma justifies CDK4 inhibition.
Published: 2018

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

Author: Dareng, Eileen O., Tyrer, Jonathan P., Barnes, Daniel R., Jones, Michelle R., Yang, Xin, Aben, Katja K. H., Adank, Muriel A., Agata, Simona, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Arun, Banu K., Augustinsson, Annelie, Balmaña, Judith, Bandera, Elisa V., Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia V., Bonanni, Bernardo, Borg, Ake, Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S., Cai, Hui, Caligo, Maria A., Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K., Claes, Kathleen B. M., Colonna, Sarah, 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 V. O., Harris, Holly R., Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle A. T., Høgdall, Estrid, Høgdall, Claus K., Hopper, John L., Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J., Huntsman, David G., Imyanitov, Evgeny N., Isaacs, Claudine, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th., John, Esther M., Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony, Kelemen, Linda E., Khusnutdinova, Elza, Kiemeney, Lambertus A., Kim, Byoung-Gie, Kjaer, Susanne K., Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W., Kwong, Ava, Lambrechts, Diether, Larson, Melissa C., Lazaro, Conxi, Le, Nhu D., Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Levine, Douglas A., Li, Lian, Li, Jingmei, Loud, Jennifer T., Lu, Karen H., Lubiński, Jan, Mai, Phuong L., Manoukian, Siranoush, Marks, Jeffrey R., Matsuno, Rayna Kim, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R., McNeish, Iain A., Mebirouk, Noura, Menon, Usha, Miller, Austin, Milne, Roger L., Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Munro, Elizabeth, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nielsen, Henriette Roed, Nielsen, Finn C., Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo I., Olson, Sara H., Olsson, Håkan, Osorio, Ana, Papi, Laura, Park, Sue K., Parsons, Michael T., Pathak, Harsha, Pedersen, Inge Sokilde, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B., Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J., Risch, Harvey A., Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P., Santamariña, Marta, Soucy, Penny, Schmutzler, Rita K., Setiawan, V. Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sokolenko, Anna P., Song, Honglin, Southey, Melissa C., Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J., Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Terry, Kathryn L., Terry, Mary Beth, Thomassen, Mads, Thompson, Pamela J., Thomsen, Liv Cecilie Vestrheim, Thull, Darcy L., Tischkowitz, Marc, Titus, Linda, Toland, Amanda E., Torres, Diana, Trabert, Britton, Travis, Ruth, Tung, Nadine, Tworoger, Shelley S., Valen, Ellen, van Altena, Anne M., van der Hout, Annemieke H., Van Nieuwenhuysen, Els, van Rensburg, Elizabeth J., Vega, Ana, Edwards, Digna Velez, Vierkant, Robert A., Wang, Frances, Wappenschmidt, Barbara, Webb, Penelope M., Weinberg, Clarice R., Weitzel, Jeffrey N., Wentzensen, Nicolas, White, Emily, Whittemore, Alice S., Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zavaglia, Katia M., Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Kleibl, Zdenek, Easton, Douglas, Lawrenson, Kate, DeFazio, Anna, Sellers, Thomas A., Ramus, Susan J., Pearce, Celeste L., Monteiro, Alvaro N., Cunningham, Julie, Goode, Ellen L., Schildkraut, Joellen M., Berchuck, Andrew, Chenevix-Trench, Georgia, Gayther, Simon A., Antoniou, Antonis C., and Pharoah, Paul D. P.
Published: 2022
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12. rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology.

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

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

Author: Ong, Jue-Sheng, Hwang, Liang-Dar, Cuellar-Partida, Gabriel, Martin, Nicholas G, Chenevix-Trench, Georgia, Quinn, Michael CJ, Cornelis, Marilyn C, Gharahkhani, Puya, Webb, Penelope M, MacGregor, Stuart, Bryne, Enda, Fasching, Peter A, Hein, Alexander, Burghaus, Stefanie, Beckmann, Matthias W, Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Vanderstichele, Adriaan, Swerdlow, Anthony J, Jones, Michael, Orr, Nicholas, Schoemaker, Minouk, Edwards, Digna Velez, Brenton, James, Benítez, Javier, García, María J, Rodriguez-Antona, Cristina, Rossing, Mary Anne, Fortner, Renée T, Riboli, Elio, Chang-Claude, Jenny, Eilber, Ursula, Wang-Gohrke, Shan, Yannoukakos, Drakoulis, Goodman, Marc T, Bogdanova, Natalia, Dörk, Thilo, Duerst, Matthias, Hillemanns, Peter, Runnebaum, Ingo B, Antonenkova, Natalia, Butzow, Ralf, Nevanlinna, Heli, Pelttari, Liisa M, Edwards, Robert P, Kelley, Joseph L, Modugno, Francesmary, Moysich, Kirsten B, Ness, Roberta B, Cannioto, Rikki, Heitz, Florian, Karlan, Beth, Olsson, Håkan, Kjaer, Susanne K, Jensen, Allan, Giles, Graham G, Bruinsma, Fiona, Hildebrandt, Michelle AT, Liang, Dong, Wu, Xifeng, Le Marchand, Loic, Setiawan, V Wendy, Permuth, Jennifer B, Bisogna, Maria, Dao, Fanny, Levine, Douglas A, Cramer, Daniel W, Terry, Kathryn L, Tworoger, Shelley S, Stampfer, Meir, Willet, Walter, Missmer, Stacey, Bjorge, Line, Kopperud, Reidun K, Bischof, Katharina, Thomsen, Liv Cecilie Vestrheim, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Brooks-Wilson, Angela, Olson, Sara H, McGuire, Valerie, Rothstein, Joseph H, Sieh, Weiva, Whittemore, Alice S, Cook, Linda S, Le, Nhu D, Gilks, C Blake, Gronwald, Jacek, Jakubowska, Anna, Lubiński, Jan, Kluz, Tomasz, Wentzensen, Nicolas, Brinton, Louise, Trabert, Britton, and Lissowska, Jolanta
Subjects: Epidemiology, Health Sciences, Clinical Research, Ovarian Cancer, Nutrition, Rare Diseases, Prevention, Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, Carcinoma, Ovarian Epithelial, Coffee, Female, Humans, Mendelian Randomization Analysis, Odds Ratio, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Risk Factors, Ovarian Cancer Association Consortium, Statistics, Public Health and Health Services, Public health
Abstract: BackgroundCoffee consumption has been shown to be associated with various health outcomes in observational studies. However, evidence for its association with epithelial ovarian cancer (EOC) is inconsistent and it is unclear whether these associations are causal.MethodsWe used single nucleotide polymorphisms associated with (i) coffee and (ii) caffeine consumption to perform Mendelian randomization (MR) on EOC risk. We conducted a two-sample MR using genetic data on 44 062 individuals of European ancestry from the Ovarian Cancer Association Consortium (OCAC), and combined instrumental variable estimates using a Wald-type ratio estimator.ResultsFor all EOC cases, the causal odds ratio (COR) for genetically predicted consumption of one additional cup of coffee per day was 0.92 [95% confidence interval (CI): 0.79, 1.06]. The COR was 0.90 (95% CI: 0.73, 1.10) for high-grade serous EOC. The COR for genetically predicted consumption of an additional 80 mg caffeine was 1.01 (95% CI: 0.92, 1.11) for all EOC cases and 0.90 (95% CI: 0.73, 1.10) for high-grade serous cases.ConclusionsWe found no evidence indicative of a strong association between EOC risk and genetically predicted coffee or caffeine levels. However, our estimates were not statistically inconsistent with earlier observational studies and we were unable to rule out small protective associations.
Published: 2018

14. Racial/ethnic differences in the epidemiology of ovarian cancer: a pooled analysis of 12 case-control studies

Author: Peres, Lauren C, Risch, Harvey, Terry, Kathryn L, Webb, Penelope M, Goodman, Marc T, Wu, Anna H, Alberg, Anthony J, Bandera, Elisa V, Barnholtz-Sloan, Jill, Bondy, Melissa L, Cote, Michele L, Funkhouser, Ellen, Moorman, Patricia G, Peters, Edward S, Schwartz, Ann G, Terry, Paul D, Manichaikul, Ani, Abbott, Sarah E, Camacho, Fabian, Jordan, Susan J, Nagle, Christina M, Group, Australian Ovarian Cancer Study, Rossing, Mary Anne, Doherty, Jennifer A, Modugno, Francesmary, Moysich, Kirsten, Ness, Roberta, Berchuck, Andrew, Cook, Linda, Le, Nhu, Brooks-Wilson, Angela, Sieh, Weiva, Whittemore, Alice, McGuire, Valerie, Rothstein, Joseph, Anton-Culver, Hoda, Ziogas, Argyrios, Pearce, Celeste L, Tseng, Chiuchen, Pike, Malcom, Schildkraut, Joellen M, and Consortium, the African American Cancer Epidemiology Study and the Ovarian Cancer Association
Subjects: Epidemiology, Health Sciences, Clinical Research, Ovarian Cancer, Cancer, Rare Diseases, Prevention, Adolescent, Adult, Aged, Aged, 80 and over, Carcinoma, Ovarian Epithelial, Case-Control Studies, Ethnicity, Female, Humans, Incidence, Middle Aged, Multivariate Analysis, Ovarian Neoplasms, Parity, Pregnancy, Prevalence, Probability, Risk Factors, United States, Young Adult, Australian Ovarian Cancer Study Group, African American Cancer Epidemiology Study and the Ovarian Cancer Association Consortium, Statistics, Public Health and Health Services, Public health
Abstract: BackgroundOvarian cancer incidence differs substantially by race/ethnicity, but the reasons for this are not well understood. Data were pooled from the African American Cancer Epidemiology Study (AACES) and 11 case-control studies in the Ovarian Cancer Association Consortium (OCAC) to examine racial/ethnic differences in epidemiological characteristics with suspected involvement in epithelial ovarian cancer (EOC) aetiology.MethodsWe used multivariable logistic regression to estimate associations for 17 reproductive, hormonal and lifestyle characteristics and EOC risk by race/ethnicity among 10 924 women with invasive EOC (8918 Non-Hispanic Whites, 433 Hispanics, 911 Blacks, 662 Asian/Pacific Islanders) and 16 150 controls (13 619 Non-Hispanic Whites, 533 Hispanics, 1233 Blacks, 765 Asian/Pacific Islanders). Likelihood ratio tests were used to evaluate heterogeneity in the risk factor associations by race/ethnicity.ResultsWe observed statistically significant racial/ethnic heterogeneity for hysterectomy and EOC risk (P = 0.008), where the largest odds ratio (OR) was observed in Black women [OR = 1.64, 95% confidence interval (CI) = 1.34-2.02] compared with other racial/ethnic groups. Although not statistically significant, the associations for parity, first-degree family history of ovarian or breast cancer, and endometriosis varied by race/ethnicity. Asian/Pacific Islanders had the greatest magnitude of association for parity (≥3 births: OR = 0.38, 95% CI = 0.28-0.54), and Black women had the largest ORs for family history (OR = 1.77, 95% CI = 1.42-2.21) and endometriosis (OR = 2.42, 95% CI = 1.65-3.55).ConclusionsAlthough racial/ethnic heterogeneity was observed for hysterectomy, our findings support the validity of EOC risk factors across all racial/ethnic groups, and further suggest that any racial/ethnic population with a higher prevalence of a modifiable risk factor should be targeted to disseminate information about prevention.
Published: 2018

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

Author: Dixon-Suen, Suzanne C, Nagle, Christina M, Thrift, Aaron P, Pharoah, Paul DP, Ewing, Ailith, Pearce, Celeste Leigh, Zheng, Wei, Australian Ovarian Cancer Study Group, Chenevix-Trench, Georgia, Fasching, Peter A, Beckmann, Matthias W, Lambrechts, Diether, Vergote, Ignace, Lambrechts, Sandrina, Van Nieuwenhuysen, Els, Rossing, Mary Anne, Doherty, Jennifer A, Wicklund, Kristine G, Chang-Claude, Jenny, Jung, Audrey Y, Moysich, Kirsten B, Odunsi, Kunle, Goodman, Marc T, Wilkens, Lynne R, Thompson, Pamela J, Shvetsov, Yurii B, Dörk, Thilo, Park-Simon, Tjoung-Won, Hillemanns, Peter, Bogdanova, Natalia, Butzow, Ralf, Nevanlinna, Heli, Pelttari, Liisa M, Leminen, Arto, Modugno, Francesmary, Ness, Roberta B, Edwards, Robert P, Kelley, Joseph L, Heitz, Florian, du Bois, Andreas, Harter, Philipp, Schwaab, Ira, Karlan, Beth Y, Lester, Jenny, Orsulic, Sandra, Rimel, Bobbie J, Kjær, Susanne K, Høgdall, Estrid, Jensen, Allan, Goode, Ellen L, Fridley, Brooke L, Cunningham, Julie M, Winham, Stacey J, Giles, Graham G, Bruinsma, Fiona, Milne, Roger L, Southey, Melissa C, Hildebrandt, Michelle AT, Wu, Xifeng, Lu, Karen H, Liang, Dong, Levine, Douglas A, Bisogna, Maria, Schildkraut, Joellen M, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Bandera, Elisa V, Olson, Sara H, Salvesen, Helga B, Thomsen, Liv Cecilie Vestrheim, Kopperud, Reidun K, Bjorge, Line, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Bruegl, Amanda, Cook, Linda S, Le, Nhu D, Swenerton, Kenneth D, Brooks-Wilson, Angela, Kelemen, Linda E, Lubiński, Jan, Huzarski, Tomasz, Gronwald, Jacek, Menkiszak, Janusz, Wentzensen, Nicolas, Brinton, Louise, Yang, Hannah, Lissowska, Jolanta, Høgdall, Claus K, Lundvall, Lene, Song, Honglin, Tyrer, Jonathan P, Campbell, Ian, Eccles, Diana, Paul, James, Glasspool, Rosalind, Siddiqui, Nadeem, and Whittemore, Alice S
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Women's Health, Cancer, Ovarian Cancer, Prevention, Rare Diseases, 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

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

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

17. Robust Tests for Additive Gene-Environment Interaction in Case-Control Studies Using Gene-Environment Independence

Author: Liu, Gang, Mukherjee, Bhramar, Lee, Seunggeun, Lee, Alice W, Wu, Anna H, Bandera, Elisa V, Jensen, Allan, Rossing, Mary Anne, Moysich, Kirsten B, Chang-Claude, Jenny, Doherty, Jennifer A, Gentry-Maharaj, Aleksandra, Kiemeney, Lambertus, Gayther, Simon A, Modugno, Francesmary, Massuger, Leon, Goode, Ellen L, Fridley, Brooke L, Terry, Kathryn L, Cramer, Daniel W, Ramus, Susan J, Anton-Culver, Hoda, Ziogas, Argyrios, Tyrer, Jonathan P, Schildkraut, Joellen M, Kjaer, Susanne K, Webb, Penelope M, Ness, Roberta B, Menon, Usha, Berchuck, Andrew, Pharoah, Paul D, Risch, Harvey, Pearce, Celeste Leigh, and Consortium, for the Ovarian Cancer Association
Subjects: Epidemiology, Health Sciences, Genetics, Bayes Theorem, Bias, Case-Control Studies, Computer Simulation, Epidemiologic Research Design, Gene-Environment Interaction, Humans, Regression Analysis, Retrospective Studies, bias-variance tradeoff, effect modification, empirical Bayes estimation, genetic risk score, relative excess risk, shrinkage, Ovarian Cancer Association Consortium, Mathematical Sciences, Medical and Health Sciences
Abstract: There have been recent proposals advocating the use of additive gene-environment interaction instead of the widely used multiplicative scale, as a more relevant public health measure. Using gene-environment independence enhances statistical power for testing multiplicative interaction in case-control studies. However, under departure from this assumption, substantial bias in the estimates and inflated type I error in the corresponding tests can occur. In this paper, we extend the empirical Bayes (EB) approach previously developed for multiplicative interaction, which trades off between bias and efficiency in a data-adaptive way, to the additive scale. An EB estimator of the relative excess risk due to interaction is derived, and the corresponding Wald test is proposed with a general regression setting under a retrospective likelihood framework. We study the impact of gene-environment association on the resultant test with case-control data. Our simulation studies suggest that the EB approach uses the gene-environment independence assumption in a data-adaptive way and provides a gain in power compared with the standard logistic regression analysis and better control of type I error when compared with the analysis assuming gene-environment independence. We illustrate the methods with data from the Ovarian Cancer Association Consortium.
Published: 2018

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

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

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

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

20. RE: "RISK PREDICTION FOR EPITHELIAL OVARIAN CANCER IN 11 UNITED STATES-BASED CASE-CONTROL STUDIES: INCORPORATION OF EPIDEMIOLOGIC RISK FACTORS AND 17 CONFIRMED GENETIC LOCI".

Author: Clyde, Merlise A, Weber, Rachel Palmieri, Iversen, Edwin S, Poole, Elizabeth M, Doherty, Jennifer A, Goodman, Marc T, Ness, Roberta B, Risch, Harvey A, Rossing, Mary Anne, Terry, Kathryn L, Wentzensen, Nicolas, Whittemore, Alice S, Anton-Culver, Hoda, Bandera, Elisa V, Berchuck, Andrew, Carney, Michael E, Cramer, Daniel W, Cunningham, Julie M, Cushing-Haugen, Kara L, Edwards, Robert P, Fridley, Brooke L, Goode, Ellen L, Lurie, Galina, McGuire, Valerie, Modugno, Francesmary, Moysich, Kirsten B, Olson, Sara H, Pearce, Celeste Leigh, Pike, Malcolm C, Rothstein, Joseph H, Sellers, Thomas A, Sieh, Weiva, Stram, Daniel, Thompson, Pamela J, Vierkant, RobertA, Wicklund, KristineG, Wu, Anna H, Ziogas, Argyrios, Pharoah, Paul D, Tworoger, Shelley S, Schildkraut, Joellen M, and Consortium, Ovarian Canc Assoc
Subjects: Epidemiology, Medical and Health Sciences, Mathematical Sciences
Published: 2017

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

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

22. History of hypertension, heart disease, and diabetes and ovarian cancer patient survival: evidence from the ovarian cancer association consortium

Author: Minlikeeva, Albina N, Freudenheim, Jo L, Cannioto, Rikki A, Szender, J Brian, Eng, Kevin H, Modugno, Francesmary, Ness, Roberta B, LaMonte, Michael J, Friel, Grace, Segal, Brahm H, Odunsi, Kunle, Mayor, Paul, Zsiros, Emese, Schmalfeldt, Barbara, Klapdor, Rüdiger, Dӧrk, Thilo, Hillemanns, Peter, Kelemen, Linda E, Kӧbel, Martin, Steed, Helen, de Fazio, Anna, on behalf of the Australian Ovarian Cancer Study Group, Jordan, Susan J, Nagle, Christina M, Risch, Harvey A, Rossing, Mary Anne, Doherty, Jennifer A, Goodman, Marc T, Edwards, Robert, Matsuo, Keitaro, Mizuno, Mika, Karlan, Beth Y, Kjær, Susanne K, Høgdall, Estrid, Jensen, Allan, Schildkraut, Joellen M, Terry, Kathryn L, Cramer, Daniel W, Bandera, Elisa V, Paddock, Lisa E, Kiemeney, Lambertus A, Massuger, Leon F, Kupryjanczyk, Jolanta, Berchuck, Andrew, Chang-Claude, Jenny, Diergaarde, Brenda, Webb, Penelope M, Moysich, Kirsten B, and on behalf of the Ovarian Cancer Association Consortium
Subjects: Epidemiology, Biomedical and Clinical Sciences, Health Sciences, Oncology and Carcinogenesis, Clinical Research, Cancer, Diabetes, Ovarian Cancer, Rare Diseases, Genetics, Cardiovascular, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Good Health and Well Being, Adrenergic beta-Antagonists, Adult, Aged, Diabetes Mellitus, Disease-Free Survival, Female, Heart Diseases, Humans, Hypertension, Hypoglycemic Agents, Insulin, Middle Aged, Ovarian Neoplasms, Risk, Survival Rate, Ovarian cancer prognosis, Medications, Mortality, Beta blockers, Australian Ovarian Cancer Study Group, Ovarian Cancer Association Consortium, Public Health and Health Services, Oncology and carcinogenesis
Abstract: PurposeSurvival following ovarian cancer diagnosis is generally low; understanding factors related to prognosis could be important to optimize treatment. The role of previously diagnosed comorbidities and use of medications for those conditions in relation to prognosis for ovarian cancer patients has not been studied extensively, particularly according to histological subtype.MethodsUsing pooled data from fifteen studies participating in the Ovarian Cancer Association Consortium, we examined the associations between history of hypertension, heart disease, diabetes, and medications taken for these conditions and overall survival (OS) and progression-free survival (PFS) among patients diagnosed with invasive epithelial ovarian carcinoma. We used Cox proportional hazards regression models adjusted for age and stage to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) overall and within strata of histological subtypes.ResultsHistory of diabetes was associated with increased risk of mortality (n = 7,674; HR = 1.12; 95% CI = 1.01-1.25). No significant mortality associations were observed for hypertension (n = 6,482; HR = 0.95; 95% CI = 0.88-1.02) or heart disease (n = 4,252; HR = 1.05; 95% CI = 0.87-1.27). No association of these comorbidities was found with PFS in the overall study population. However, among patients with endometrioid tumors, hypertension was associated with lower risk of progression (n = 339, HR = 0.54; 95% CI = 0.35-0.84). Comorbidity was not associated with OS or PFS for any of the other histological subtypes. Ever use of beta blockers, oral antidiabetic medications, and insulin was associated with increased mortality, HR = 1.20; 95% CI = 1.03-1.40, HR = 1.28; 95% CI = 1.05-1.55, and HR = 1.63; 95% CI = 1.20-2.20, respectively. Ever use of diuretics was inversely associated with mortality, HR = 0.71; 95% CI = 0.53-0.94.ConclusionsHistories of hypertension, diabetes, and use of diuretics, beta blockers, insulin, and oral antidiabetic medications may influence the survival of ovarian cancer patients. Understanding mechanisms for these observations could provide insight regarding treatment.
Published: 2017

23. Use of common analgesic medications and ovarian cancer survival: results from a pooled analysis in the Ovarian Cancer Association Consortium

Author: Dixon, Suzanne C, Nagle, Christina M, Wentzensen, Nicolas, Trabert, Britton, Beeghly-Fadiel, Alicia, Schildkraut, Joellen M, Moysich, Kirsten B, deFazio, Anna, Risch, Harvey A, Rossing, Mary Anne, Doherty, Jennifer A, Wicklund, Kristine G, Goodman, Marc T, Modugno, Francesmary, Ness, Roberta B, Edwards, Robert P, Jensen, Allan, Kjær, Susanne K, Høgdall, Estrid, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Poole, Elizabeth M, Bandera, Elisa V, Paddock, Lisa E, Anton-Culver, Hoda, Ziogas, Argyrios, Menon, Usha, Gayther, Simon A, Ramus, Susan J, Gentry-Maharaj, Aleksandra, Pearce, Celeste Leigh, Wu, Anna H, Pike, Malcolm C, and Webb, Penelope M
Subjects: Clinical Research, Cancer, Ovarian Cancer, Rare Diseases, Acetaminophen, Adult, Aged, Analgesics, Anti-Inflammatory Agents, Non-Steroidal, Anticarcinogenic Agents, Aspirin, Disease-Free Survival, Female, Humans, Middle Aged, Ovarian Neoplasms, Proportional Hazards Models, Risk Factors, ovarian cancer, aspirin, nonsteroidal anti-inflammatory drugs, NSAID, paracetamol, acetaminophen, pooled analysis, survival, Australian Ovarian Cancer Study Group, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract: BackgroundNonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with improved survival in some cancers, but evidence for ovarian cancer is limited.MethodsPooling individual-level data from 12 Ovarian Cancer Association Consortium studies, we evaluated the association between self-reported, pre-diagnosis use of common analgesics and overall/progression-free/disease-specific survival among 7694 women with invasive epithelial ovarian cancer (4273 deaths).ResultsRegular analgesic use (at least once per week) was not associated with overall survival (pooled hazard ratios, pHRs (95% confidence intervals): aspirin 0.96 (0.88-1.04); non-aspirin NSAIDs 0.97 (0.89-1.05); acetaminophen 1.01 (0.93-1.10)), nor with progression-free/disease-specific survival. There was however a survival advantage for users of any NSAIDs in studies clearly defining non-use as less than once per week (pHR=0.89 (0.82-0.98)).ConclusionsAlthough this study did not show a clear association between analgesic use and ovarian cancer survival, further investigation with clearer definitions of use and information about post-diagnosis use is warranted.
Published: 2017

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

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

25. Pelvic Inflammatory Disease and the Risk of Ovarian Cancer and Borderline Ovarian Tumors: A Pooled Analysis of 13 Case-Control Studies

Author: Rasmussen, Christina B, Kjaer, Susanne K, Albieri, Vanna, Bandera, Elisa V, Doherty, Jennifer A, Høgdall, Estrid, Webb, Penelope M, Jordan, Susan J, Rossing, Mary Anne, Wicklund, Kristine G, Goodman, Marc T, Modugno, Francesmary, Moysich, Kirsten B, Ness, Roberta B, Edwards, Robert P, Schildkraut, Joellen M, Berchuck, Andrew, Olson, Sara H, Kiemeney, Lambertus A, Massuger, Leon FAG, Narod, Steven A, Phelan, Catherine M, Anton-Culver, Hoda, Ziogas, Argyrios, Wu, Anna H, Pearce, Celeste L, Risch, Harvey A, Jensen, Allan, and Consortium, on behalf of the Ovarian Cancer Association
Subjects: Epidemiology, Health Sciences, Rare Diseases, Clinical Research, Human Genome, Prevention, Ovarian Cancer, Genetics, Cancer, Carcinoma, Ovarian Epithelial, Case-Control Studies, Comorbidity, Contraceptives, Oral, Hormonal, Family Health, Female, Genetic Predisposition to Disease, Hormone Replacement Therapy, Humans, Hysterectomy, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Pelvic Inflammatory Disease, Protective Factors, Reproductive History, Risk Factors, Sterilization, Tubal, Talc, inflammation, neoplasms, histological type, ovarian neoplasms, pelvic inflammatory disease, risk factors, on behalf of the Ovarian Cancer Association Consortium, neoplasms, histological type, Mathematical Sciences, Medical and Health Sciences
Abstract: Inflammation has been implicated in ovarian carcinogenesis. However, studies investigating the association between pelvic inflammatory disease (PID) and ovarian cancer risk are few and inconsistent. We investigated the association between PID and the risk of epithelial ovarian cancer according to tumor behavior and histotype. We pooled data from 13 case-control studies, conducted between 1989 and 2009, from the Ovarian Cancer Association Consortium (OCAC), including 9,162 women with ovarian cancers, 2,354 women with borderline tumors, and 14,736 control participants. Study-specific odds ratios were estimated and subsequently combined into a pooled odds ratio using a random-effects model. A history of PID was associated with an increased risk of borderline tumors (pooled odds ratio (pOR) = 1.32, 95% confidence interval (CI): 1.10, 1.58). Women with at least 2 episodes of PID had a 2-fold increased risk of borderline tumors (pOR = 2.14, 95% CI: 1.08, 4.24). No association was observed between PID and ovarian cancer risk overall (pOR = 0.99, 95% CI: 0.83, 1.19); however, a statistically nonsignificantly increased risk of low-grade serous tumors (pOR = 1.48, 95% CI: 0.92, 2.38) was noted. In conclusion, PID was associated with an increased risk of borderline ovarian tumors, particularly among women who had had multiple episodes of PID. Although our results indicated a histotype-specific association with PID, the association of PID with ovarian cancer risk is still somewhat uncertain and requires further investigation.
Published: 2017

26. Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: results from a large-scale collaboration

Author: Permuth, Jennifer B, Reid, Brett, Earp, Madalene, Chen, Y Ann, Monteiro, Alvaro NA, Chen, Zhihua, Group, AOCS Study, Chenevix-Trench, Georgia, Fasching, Peter A, Beckmann, Matthias W, Lambrechts, Diether, Vanderstichele, Adriaan, Van Niewenhuyse, Els, Vergote, Ignace, Rossing, Mary Anne, Doherty, Jennifer Anne, Chang-Claude, Jenny, Moysich, Kirsten, Odunsi, Kunle, Goodman, Marc T, Shvetsov, Yurii B, Wilkens, Lynne R, Thompson, Pamela J, Dörk, Thilo, Bogdanova, Natalia, Butzow, Ralf, Nevanlinna, Heli, Pelttari, Liisa, Leminen, Arto, Modugno, Francesmary, Edwards, Robert P, Ness, Roberta B, Kelley, Joseph, Heitz, Florian, Karlan, Beth, Lester, Jenny, Kjaer, Susanne K, Jensen, Allan, Giles, Graham, Hildebrandt, Michelle, Liang, Dong, Lu, Karen H, Wu, Xifeng, Levine, Douglas A, Bisogna, Maria, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Tworoger, Shelley S, Poole, Elizabeth M, Bandera, Elisa V, Fridley, Brooke, Cunningham, Julie, Winham, Stacey J, Olson, Sara H, Orlow, Irene, Bjorge, Line, Kiemeney, Lambertus A, Massuger, Leon, Pejovic, Tanja, Moffitt, Melissa, Le, Nhu, Cook, Linda S, Brooks-Wilson, Angela, Kelemen, Linda E, Gronwald, Jacek, Lubinski, Jan, Wentzensen, Nicolas, Brinton, Louise A, Lissowska, Jolanta, Yang, Hanna, Hogdall, Estrid, Hogdall, Claus, Lundvall, Lene, Pharoah, Paul DP, Song, Honglin, Campbell, Ian, Eccles, Diana, McNeish, Iain, Whittemore, Alice, McGuire, Valerie, Sieh, Weiva, Rothstein, Joseph, Phelan, Catherine M, Risch, Harvey, Narod, Steven, McLaughlin, John, Anton-Culver, Hoda, Ziogas, Argyrios, Menon, Usha, Gayther, Simon, Ramus, Susan J, Gentry-Maharaj, Aleksandra, Pearce, Celeste Leigh, Wu, Anna H, Kupryjanczyk, Jolanta, Dansonka-Mieszkowska, Agnieszka, Schildkraut, Joellen M, Cheng, Jin Q, and Goode, Ellen L
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Ovarian Cancer, Cancer, Genetics, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Animals, Disease Susceptibility, Female, Genetic Variation, Humans, Middle Aged, Ovarian Neoplasms, Polymorphism, Single Nucleotide, RNA Editing, polymorphisms, RNA editing, ovarian cancer risk, AOCS Study Group, Oncology and carcinogenesis
Abstract: RNA editing in mammals is a form of post-transcriptional modification in which adenosine is converted to inosine by the adenosine deaminases acting on RNA (ADAR) family of enzymes. Based on evidence of altered ADAR expression in epithelial ovarian cancers (EOC), we hypothesized that single nucleotide polymorphisms (SNPs) in ADAR genes modify EOC susceptibility, potentially by altering ovarian tissue gene expression. Using directly genotyped and imputed data from 10,891 invasive EOC cases and 21,693 controls, we evaluated the associations of 5,303 SNPs in ADAD1, ADAR, ADAR2, ADAR3, and SND1. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), with adjustment for European ancestry. We conducted gene-level analyses using the Admixture Maximum Likelihood (AML) test and the Sequence-Kernel Association test for common and rare variants (SKAT-CR). Association analysis revealed top risk-associated SNP rs77027562 (OR (95% CI)= 1.39 (1.17-1.64), P=1.0x10-4) in ADAR3 and rs185455523 in SND1 (OR (95% CI)= 0.68 (0.56-0.83), P=2.0x10-4). When restricting to serous histology (n=6,500), the magnitude of association strengthened for rs185455523 (OR=0.60, P=1.0x10-4). Gene-level analyses revealed that variation in ADAR was associated (P
Published: 2016

27. Risk Prediction for Epithelial Ovarian Cancer in 11 United States–Based Case-Control Studies: Incorporation of Epidemiologic Risk Factors and 17 Confirmed Genetic Loci

Author: Clyde, Merlise A, Weber, Rachel Palmieri, Iversen, Edwin S, Poole, Elizabeth M, Doherty, Jennifer A, Goodman, Marc T, Ness, Roberta B, Risch, Harvey A, Rossing, Mary Anne, Terry, Kathryn L, Wentzensen, Nicolas, Whittemore, Alice S, Anton-Culver, Hoda, Bandera, Elisa V, Berchuck, Andrew, Carney, Michael E, Cramer, Daniel W, Cunningham, Julie M, Cushing-Haugen, Kara L, Edwards, Robert P, Fridley, Brooke L, Goode, Ellen L, Lurie, Galina, McGuire, Valerie, Modugno, Francesmary, Moysich, Kirsten B, Olson, Sara H, Pearce, Celeste Leigh, Pike, Malcolm C, Rothstein, Joseph H, Sellers, Thomas A, Sieh, Weiva, Stram, Daniel, Thompson, Pamela J, Vierkant, Robert A, Wicklund, Kristine G, Wu, Anna H, Ziogas, Argyrios, Tworoger, Shelley S, and Schildkraut, Joellen M
Subjects: Epidemiology, Health Sciences, Ovarian Cancer, Rare Diseases, Prevention, Cancer, Adult, Aged, Area Under Curve, Carcinoma, Ovarian Epithelial, Case-Control Studies, Female, Genetic Loci, Genetic Predisposition to Disease, Humans, Logistic Models, Middle Aged, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, United States, genetic risk polymorphisms, model evaluation, ovarian cancer, risk model, on behalf of the Ovarian Cancer Association Consortium, Mathematical Sciences, Medical and Health Sciences
Abstract: Previously developed models for predicting absolute risk of invasive epithelial ovarian cancer have included a limited number of risk factors and have had low discriminatory power (area under the receiver operating characteristic curve (AUC) < 0.60). Because of this, we developed and internally validated a relative risk prediction model that incorporates 17 established epidemiologic risk factors and 17 genome-wide significant single nucleotide polymorphisms (SNPs) using data from 11 case-control studies in the United States (5,793 cases; 9,512 controls) from the Ovarian Cancer Association Consortium (data accrued from 1992 to 2010). We developed a hierarchical logistic regression model for predicting case-control status that included imputation of missing data. We randomly divided the data into an 80% training sample and used the remaining 20% for model evaluation. The AUC for the full model was 0.664. A reduced model without SNPs performed similarly (AUC = 0.649). Both models performed better than a baseline model that included age and study site only (AUC = 0.563). The best predictive power was obtained in the full model among women younger than 50 years of age (AUC = 0.714); however, the addition of SNPs increased the AUC the most for women older than 50 years of age (AUC = 0.638 vs. 0.616). Adapting this improved model to estimate absolute risk and evaluating it in prospective data sets is warranted.
Published: 2016

28. 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

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

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

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

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

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

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

32. The association between socioeconomic status and tumour stage at diagnosis of ovarian cancer: A pooled analysis of 18 case-control studies

Author: Præstegaard, Camilla, Kjaer, Susanne K, Nielsen, Thor SS, Jensen, Signe M, Webb, Penelope M, Nagle, Christina M, Høgdall, Estrid, Risch, Harvey A, Rossing, Mary Anne, Doherty, Jennifer A, Wicklund, Kristine G, Goodman, Marc T, Modugno, Francesmary, Moysich, Kirsten, Ness, Roberta B, Edwards, Robert P, Goode, Ellen L, Winham, Stacey J, Fridley, Brooke L, Cramer, Daniel W, Terry, Kathryn L, Schildkraut, Joellen M, Berchuck, Andrew, Bandera, Elisa V, Paddock, Lisa, Kiemeney, Lambertus A, Massuger, Leon F, Wentzensen, Nicolas, Pharoah, Paul, Song, Honglin, Whittemore, Alice S, McGuire, Valerie, Sieh, Weiva, Rothstein, Joseph, Anton-Culver, Hoda, Ziogas, Argyrios, Menon, Usha, Gayther, Simon A, Ramus, Susan J, Gentry-Maharaj, Aleksandra, Wu, Anna H, Pearce, Celeste L, Pike, Malcolm C, Lee, Alice W, Chang-Claude, Jenny, Jensen, Allan, and Consortium, Ovarian Cancer Association
Subjects: Biomedical and Clinical Sciences, Epidemiology, Health Services and Systems, Health Sciences, Oncology and Carcinogenesis, Cancer, Ovarian Cancer, Tobacco Smoke and Health, Rare Diseases, Tobacco, Prevention, Aged, Carcinoma, Ovarian Epithelial, Case-Control Studies, Delayed Diagnosis, Female, Humans, Logistic Models, Middle Aged, Neoplasms, Glandular and Epithelial, Odds Ratio, Ovarian Neoplasms, Social Class, Ovarian cancer, Pooled analysis, Socioeconomic status, Tumour stage, Ovarian Cancer Association Consortium, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract: PurposeSocioeconomic status (SES) is a known predictor of survival for several cancers and it has been suggested that SES differences affecting tumour stage at diagnosis may be the most important explanatory factor for this. However, only a limited number of studies have investigated SES differences in tumour stage at diagnosis of ovarian cancer. In a pooled analysis, we investigated whether SES as represented by level of education is predictive for advanced tumour stage at diagnosis of ovarian cancer, overall and by histotype. The effect of cigarette smoking and body mass index (BMI) on the association was also evaluated.MethodsFrom 18 case-control studies, we obtained information on 10,601 women diagnosed with epithelial ovarian cancer. Study specific odds ratios (ORs) with corresponding 95% confidence intervals (CI) were obtained from logistic regression models and combined into a pooled odds ratio (pOR) using a random effects model.ResultsOverall, women who completed ≤high school had an increased risk of advanced tumour stage at diagnosis compared with women who completed >high school (pOR 1.15; 95% CI 1.03-1.28). The risk estimates for the different histotypes of ovarian cancer resembled that observed for ovarian cancers combined but did not reach statistical significance. Our results were unchanged when we included BMI and cigarette smoking.ConclusionLower level of education was associated with an increased risk of advanced tumour stage at diagnosis of ovarian cancer. The observed socioeconomic difference in stage at diagnosis of ovarian cancer calls for further studies on how to reduce this diagnostic delay.
Published: 2016

33. Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer

Author: Winham, Stacey J, Pirie, Ailith, Chen, Yian Ann, Larson, Melissa C, Fogarty, Zachary C, Earp, Madalene A, Anton-Culver, Hoda, Bandera, Elisa V, Cramer, Daniel, Doherty, Jennifer A, Goodman, Marc T, Gronwald, Jacek, Karlan, Beth Y, Kjaer, Susanne K, Levine, Douglas A, Menon, Usha, Ness, Roberta B, Pearce, Celeste L, Pejovic, Tanja, Rossing, Mary Anne, Wentzensen, Nicolas, Bean, Yukie T, Bisogna, Maria, Brinton, Louise A, Carney, Michael E, Cunningham, Julie M, Cybulski, Cezary, deFazio, Anna, Dicks, Ed M, Edwards, Robert P, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Gore, Martin, Iversen, Edwin S, Jensen, Allan, Johnatty, Sharon E, Lester, Jenny, Lin, Hui-Yi, Lissowska, Jolanta, Lubinski, Jan, Menkiszak, Janusz, Modugno, Francesmary, Moysich, Kirsten B, Orlow, Irene, Pike, Malcolm C, Ramus, Susan J, Song, Honglin, Terry, Kathryn L, Thompson, Pamela J, Tyrer, Jonathan P, van den Berg, David J, Vierkant, Robert A, Vitonis, Allison F, Walsh, Christine, Wilkens, Lynne R, Wu, Anna H, Yang, Hannah, Ziogas, Argyrios, Berchuck, Andrew, Group, Georgia Chenevix-Trench on behalf of Australian Ovarian Cancer Study, Schildkraut, Joellen M, Permuth-Wey, Jennifer, Phelan, Catherine M, Pharoah, Paul DP, Fridley, Brooke L, Sellers, Thomas A, and Goode, Ellen L
Subjects: Epidemiology, Biomedical and Clinical Sciences, Health Sciences, Oncology and Carcinogenesis, Cancer, Genetics, Prevention, Clinical Research, Human Genome, Rare Diseases, Ovarian Cancer, 2.1 Biological and endogenous factors, Aetiology, Exome, Female, Genotype, Humans, Middle Aged, Ovarian Neoplasms, Survival Rate, Australian Ovarian Cancer Study Group, Medical and Health Sciences, Biomedical and clinical sciences, Health sciences
Abstract: BackgroundWhile numerous susceptibility loci for epithelial ovarian cancer (EOC) have been identified, few associations have been reported with overall survival. In the absence of common prognostic genetic markers, we hypothesize that rare coding variants may be associated with overall EOC survival and assessed their contribution in two exome-based genotyping projects of the Ovarian Cancer Association Consortium (OCAC).MethodsThe primary patient set (Set 1) included 14 independent EOC studies (4,293 patients) and 227,892 variants, and a secondary patient set (Set 2) included six additional EOC studies (1,744 patients) and 114,620 variants. Because power to detect rare variants individually is reduced, gene-level tests were conducted. Sets were analyzed separately at individual variants and by gene, and then combined with meta-analyses (73,203 variants and 13,163 genes overlapped).ResultsNo individual variant reached genome-wide statistical significance. A SNP previously implicated to be associated with EOC risk and, to a lesser extent, survival, rs8170, showed the strongest evidence of association with survival and similar effect size estimates across sets (Pmeta = 1.1E-6, HRSet1 = 1.17, HRSet2 = 1.14). Rare variants in ATG2B, an autophagy gene important for apoptosis, were significantly associated with survival after multiple testing correction (Pmeta = 1.1E-6; Pcorrected = 0.01).ConclusionsCommon variant rs8170 and rare variants in ATG2B may be associated with EOC overall survival, although further study is needed.ImpactThis study represents the first exome-wide association study of EOC survival to include rare variant analyses, and suggests that complementary single variant and gene-level analyses in large studies are needed to identify rare variants that warrant follow-up study. Cancer Epidemiol Biomarkers Prev; 25(3); 446-54. ©2016 AACR.
Published: 2016

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

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

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

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

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

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

37. 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 K. H., Adank, Muriel A., Agata, Simona, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Arun, Banu K., Augustinsson, Annelie, Balmaña, Judith, Bandera, Elisa V., Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia V., Bonanni, Bernardo, Borg, Ake, Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S., Cai, Hui, Caligo, Maria A., Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K., Claes, Kathleen B. M., Colonna, Sarah, 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 V. O., Harris, Holly R., Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle A. T., Høgdall, Estrid, Høgdall, Claus K., Hopper, John L., Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J., Huntsman, David G., Imyanitov, Evgeny N., Isaacs, Claudine, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th., John, Esther M., Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony, Kelemen, Linda E., Khusnutdinova, Elza, Kiemeney, Lambertus A., Kim, Byoung-Gie, Kjaer, Susanne K., Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W., Kwong, Ava, Lambrechts, Diether, Larson, Melissa C., Lazaro, Conxi, Le, Nhu D., Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Levine, Douglas A., Li, Lian, Li, Jingmei, Loud, Jennifer T., Lu, Karen H., Lubiński, Jan, Mai, Phuong L., Manoukian, Siranoush, Marks, Jeffrey R., Matsuno, Rayna Kim, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R., McNeish, Iain A., Mebirouk, Noura, Menon, Usha, Miller, Austin, Milne, Roger L., Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Munro, Elizabeth, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nielsen, Henriette Roed, Nielsen, Finn C., Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo I., Olson, Sara H., Olsson, Håkan, Osorio, Ana, Papi, Laura, Park, Sue K., Parsons, Michael T., Pathak, Harsha, Pedersen, Inge Sokilde, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B., Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J., Risch, Harvey A., Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P., Santamariña, Marta, Soucy, Penny, Schmutzler, Rita K., Setiawan, V. Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sokolenko, Anna P., Song, Honglin, Southey, Melissa C., Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J., Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Terry, Kathryn L., Terry, Mary Beth, Thomassen, Mads, Thompson, Pamela J., Thomsen, Liv Cecilie Vestrheim, Thull, Darcy L., Tischkowitz, Marc, Titus, Linda, Toland, Amanda E., Torres, Diana, Trabert, Britton, Travis, Ruth, Tung, Nadine, Tworoger, Shelley S., Valen, Ellen, van Altena, Anne M., van der Hout, Annemieke H., Van Nieuwenhuysen, Els, van Rensburg, Elizabeth J., Vega, Ana, Edwards, Digna Velez, Vierkant, Robert A., Wang, Frances, Wappenschmidt, Barbara, Webb, Penelope M., Weinberg, Clarice R., Weitzel, Jeffrey N., Wentzensen, Nicolas, White, Emily, Whittemore, Alice S., Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zavaglia, Katia M., Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Kleibl, Zdenek, Easton, Douglas, Lawrenson, Kate, DeFazio, Anna, Sellers, Thomas A., Ramus, Susan J., Pearce, Celeste L., Monteiro, Alvaro N., Cunningham, Julie, Goode, Ellen L., Schildkraut, Joellen M., Berchuck, Andrew, Chenevix-Trench, Georgia, Gayther, Simon A., Antoniou, Antonis C., and Pharoah, Paul D. P.
Published: 2022
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38. Joint exposure to smoking, excessive weight, and physical inactivity and survival of ovarian cancer patients, evidence from the Ovarian Cancer Association Consortium

Author: Minlikeeva, Albina N., Cannioto, Rikki, Jensen, Allan, Kjaer, Susanne K., Jordan, Susan J., Diergaarde, Brenda, Szender, J. Brian, Odunsi, Kunle, Almohanna, Hani, Mayor, Paul, Starbuck, Kirsten, Zsiros, Emese, Bandera, Elisa V., Cramer, Daniel W., Doherty, Jennifer A., DeFazio, Anna, Edwards, Robert, Goode, Ellen L., Goodman, Marc T., Høgdall, Estrid, Matsuo, Keitary, Mizuno, Mika, Nagle, Christina M., Ness, Roberta B., Paddock, Lisa E., Pearce, Celeste L., Risch, Harvey A., Rossing, Mary Anne, Terry, Kathryn L., Wu, Anna H., Modugno, Francesmary, Webb, Penelope M., and Moysich, Kirsten B.
Published: 2019

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

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

40. 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

41. Variation in NF-κB Signaling Pathways and Survival in Invasive Epithelial Ovarian Cancer

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

42. 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

43. Large-Scale Evaluation of Common Variation in Regulatory T Cell–Related Genes and Ovarian Cancer Outcome

Author: Charbonneau, Bridget, Moysich, Kirsten B, Kalli, Kimberly R, Oberg, Ann L, Vierkant, Robert A, Fogarty, Zachary C, Block, Matthew S, Maurer, Matthew J, Goergen, Krista M, Fridley, Brooke L, Cunningham, Julie M, Rider, David N, Preston, Claudia, Hartmann, Lynn C, Lawrenson, Kate, Wang, Chen, Tyrer, Jonathan, Song, Honglin, deFazio, Anna, Johnatty, Sharon E, Doherty, Jennifer A, Phelan, Catherine M, Sellers, Thomas A, Ramirez, Starr M, Vitonis, Allison F, Terry, Kathryn L, Van Den Berg, David, Pike, Malcolm C, Wu, Anna H, Berchuck, Andrew, Gentry-Maharaj, Aleksandra, Ramus, Susan J, Diergaarde, Brenda, Shen, Howard, Jensen, Allan, Menkiszak, Janusz, Cybulski, Cezary, Lubiński, Jan, Ziogas, Argyrios, Rothstein, Joseph H, McGuire, Valerie, Sieh, Weiva, Lester, Jenny, Walsh, Christine, Vergote, Ignace, Lambrechts, Sandrina, Despierre, Evelyn, Garcia-Closas, Montserrat, Yang, Hannah, Brinton, Louise A, Spiewankiewicz, Beata, Rzepecka, Iwona K, Dansonka-Mieszkowska, Agnieszka, Seibold, Petra, Rudolph, Anja, Paddock, Lisa E, Orlow, Irene, Lundvall, Lene, Olson, Sara H, Hogdall, Claus K, Schwaab, Ira, du Bois, Andreas, Harter, Philipp, Flanagan, James M, Brown, Robert, Paul, James, Ekici, Arif B, Beckmann, Matthias W, Hein, Alexander, Eccles, Diana, Lurie, Galina, Hays, Laura E, Bean, Yukie T, Pejovic, Tanja, Goodman, Marc T, Campbell, Ian, Fasching, Peter A, Konecny, Gottfried, Kaye, Stanley B, Heitz, Florian, Hogdall, Estrid, Bandera, Elisa V, Chang-Claude, Jenny, Kupryjanczyk, Jolanta, Wentzensen, Nicolas, Lambrechts, Diether, Karlan, Beth Y, Whittemore, Alice S, Culver, Hoda Anton, Gronwald, Jacek, Levine, Douglas A, Kjaer, Susanne K, Menon, Usha, Schildkraut, Joellen M, Pearce, Celeste Leigh, Cramer, Daniel W, Rossing, Mary Anne, Chenevix-Trench, Georgia, group, for the AOCS, and ACS
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Cancer, Genetics, Clinical Research, Ovarian Cancer, Rare Diseases, Women's Health, 2.1 Biological and endogenous factors, Female, Gene Expression, Gene Expression Profiling, Genetic Predisposition to Disease, Genetic Variation, Germ-Line Mutation, Humans, Interleukin-2 Receptor alpha Subunit, Neoplasm Grading, Neoplasm Invasiveness, Ovarian Neoplasms, Patient Outcome Assessment, Polymorphism, Single Nucleotide, Prognosis, T-Lymphocytes, Regulatory, AOCS group, ACS, Pharmacology and Pharmaceutical Sciences, Oncology and carcinogenesis
Abstract: The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22-1.64; P = 5.7 × 10(-6)], rs791587 (HR, 1.36; 95% CI, 1.17-1.57; P = 6.2 × 10(-5)), rs2476491 (HR, = 1.40; 95% CI, 1.19-1.64; P = 5.6 × 10(-5)), and rs10795763 (HR, 1.35; 95% CI, 1.17-1.57; P = 7.9 × 10(-5)), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54-0.82; P = 9.3 × 10(-5)) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer.
Published: 2014

44. Histotype classification of ovarian carcinoma: A comparison of approaches

Author: Peres, Lauren C., Cushing-Haugen, Kara L., Anglesio, Michael, Wicklund, Kristine, Bentley, Rex, Berchuck, Andrew, Kelemen, Linda E., Nazeran, Tayyebeh M., Gilks, C. Blake, Harris, Holly R., Huntsman, David G., Schildkraut, Joellen M., Rossing, Mary Anne, Köbel, Martin, and Doherty, Jennifer A.
Published: 2018
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45. Aspirin, Nonaspirin Nonsteroidal Anti-inflammatory Drug, and Acetaminophen Use and Risk of Invasive Epithelial Ovarian Cancer: A Pooled Analysis in the Ovarian Cancer Association Consortium

Author: Trabert, Britton, Ness, Roberta B, Lo-Ciganic, Wei-Hsuan, Murphy, Megan A, Goode, Ellen L, Poole, Elizabeth M, Brinton, Louise A, Webb, Penelope M, Nagle, Christina M, Jordan, Susan J, Group, the Australian Cancer Study Australian Ovarian Cancer Study, Risch, Harvey A, Rossing, Mary Anne, Doherty, Jennifer A, Goodman, Marc T, Lurie, Galina, Kjær, Susanne K, Hogdall, Estrid, Jensen, Allan, Cramer, Daniel W, Terry, Kathryn L, Vitonis, Allison, Bandera, Elisa V, Olson, Sara, King, Melony G, Chandran, Urmila, Anton-Culver, Hoda, Ziogas, Argyrios, Menon, Usha, Gayther, Simon A, Ramus, Susan J, Gentry-Maharaj, Aleksandra, Wu, Anna H, Pearce, Celeste Leigh, Pike, Malcolm C, Berchuck, Andrew, Schildkraut, Joellen M, Wentzensen, Nicolas, and Consortium, on behalf of the Ovarian Cancer Association
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Prevention, Cancer, Ovarian Cancer, Clinical Research, Aging, Rare Diseases, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Acetaminophen, Anti-Inflammatory Agents, Non-Steroidal, Anticarcinogenic Agents, Aspirin, Australia, Carcinoma, Ovarian Epithelial, Case-Control Studies, Data Collection, Denmark, Drug Administration Schedule, Female, Humans, Incidence, Logistic Models, Neoplasms, Glandular and Epithelial, Odds Ratio, Ovarian Neoplasms, Protective Agents, Risk, United Kingdom, United States, Australian Ovarian Cancer Study Group, Australian Cancer Study, Ovarian Cancer Association Consortium, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract: BackgroundRegular aspirin use is associated with reduced risk of several malignancies. Epidemiologic studies analyzing aspirin, nonaspirin nonsteroidal anti-inflammatory drug (NSAID), and acetaminophen use and ovarian cancer risk have been inconclusive.MethodsWe analyzed pooled data from 12 population-based case-control studies of ovarian cancer, including 7776 case patients and 11843 control subjects accrued between 1992 and 2007. Odds ratios (ORs) for associations of medication use with invasive epithelial ovarian cancer were estimated in individual studies using logistic regression and combined using random effects meta-analysis. Associations between frequency, dose, and duration of analgesic use and risk of ovarian cancer were also assessed. All statistical tests were two-sided.ResultsAspirin use was associated with a reduced risk of ovarian cancer (OR = 0.91; 95% confidence interval [CI] = 0.84 to 0.99). Results were similar but not statistically significant for nonaspirin NSAIDs, and there was no association with acetaminophen. In seven studies with frequency data, the reduced risk was strongest among daily aspirin users (OR = 0.80; 95% CI = 0.67 to 0.96). In three studies with dose information, the reduced risk was strongest among users of low dose (
Published: 2014

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

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

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

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

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

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

49. Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies.

Author: Pearce, Celeste Leigh, Templeman, Claire, Rossing, Mary Anne, Lee, Alice, Near, Aimee M, Webb, Penelope M, Nagle, Christina M, Doherty, Jennifer A, Cushing-Haugen, Kara L, Wicklund, Kristine G, Chang-Claude, Jenny, Hein, Rebecca, Lurie, Galina, Wilkens, Lynne R, Carney, Michael E, Goodman, Marc T, Moysich, Kirsten, Kjaer, Susanne K, Hogdall, Estrid, Jensen, Allan, Goode, Ellen L, Fridley, Brooke L, Larson, Melissa C, Schildkraut, Joellen M, Palmieri, Rachel T, Cramer, Daniel W, Terry, Kathryn L, Vitonis, Allison F, Titus, Linda J, Ziogas, Argyrios, Brewster, Wendy, Anton-Culver, Hoda, Gentry-Maharaj, Alexandra, Ramus, Susan J, Anderson, A Rebecca, Brueggmann, Doerthe, Fasching, Peter A, Gayther, Simon A, Huntsman, David G, Menon, Usha, Ness, Roberta B, Pike, Malcolm C, Risch, Harvey, Wu, Anna H, Berchuck, Andrew, and Ovarian Cancer Association Consortium
Subjects: Ovarian Cancer Association Consortium, Humans, Ovarian Neoplasms, Neoplasm Invasiveness, Endometriosis, Neoplasm Staging, Risk Factors, Case-Control Studies, Aged, Aged, 80 and over, Middle Aged, Ethnic Groups, Female, Cancer, Ovarian Cancer, Rare Diseases, Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract: BackgroundEndometriosis is a risk factor for epithelial ovarian cancer; however, whether this risk extends to all invasive histological subtypes or borderline tumours is not clear. We undertook an international collaborative study to assess the association between endometriosis and histological subtypes of ovarian cancer.MethodsData from 13 ovarian cancer case-control studies, which were part of the Ovarian Cancer Association Consortium, were pooled and logistic regression analyses were undertaken to assess the association between self-reported endometriosis and risk of ovarian cancer. Analyses of invasive cases were done with respect to histological subtypes, grade, and stage, and analyses of borderline tumours by histological subtype. Age, ethnic origin, study site, parity, and duration of oral contraceptive use were included in all analytical models.Findings13 226 controls and 7911 women with invasive ovarian cancer were included in this analysis. 818 and 738, respectively, reported a history of endometriosis. 1907 women with borderline ovarian cancer were also included in the analysis, and 168 of these reported a history of endometriosis. Self-reported endometriosis was associated with a significantly increased risk of clear-cell (136 [20·2%] of 674 cases vs 818 [6·2%] of 13 226 controls, odds ratio 3·05, 95% CI 2·43-3·84, p
Published: 2012

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

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

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