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

Author

Meagher, Nicola S, White, Kami K, Wilkens, Lynne R, Bandera, Elisa V, Berchuck, Andrew, Carney, Michael E, Cramer, Daniel W, Cushing-Haugen, Kara L, Jordan, Susan, Kaufmann, Scott H, Le, Nhu D, Pike, Malcolm C, Riggan, Marjorie, Qin, Bo, Rothstein, Joseph H, Titus, Linda, Winham, Stacey J, Anton-Culver, Hoda, Doherty, Jennifer A, Goode, Ellen L, Pearce, Celeste Leigh, Risch, Harvey A, Webb, Penelope M, Cook, Linda S, Goodman, Marc T, Harris, Holly R, Le Marchand, Loic, McGuire, Valerie, Pharoah, Paul DP, Sarink, Danja, Schildkraut, Joellen M, Sieh, Weiva, Terry, Kathryn L, Thompson, Pamela J, Whittemore, Alice S, Wu, Anna H, Peres, Lauren C, and Merritt, Melissa A

Subjects
Epidemiology, Health Sciences, Ovarian Cancer, Rare Diseases, Cancer, Minority Health, Prevention, Women's Health, Humans, Female, Ovarian Neoplasms, Middle Aged, Carcinoma, Ovarian Epithelial, Risk Factors, Adult, Native Hawaiian or Other Pacific Islander, Case-Control Studies, Aged, Sterilization, Tubal, Parity, Asian, White People, Hispanic or Latino, United States, Contraceptives, Oral, Logistic Models, Smoking, Neoplasms, Glandular and Epithelial, Ethnicity, Odds Ratio, ovarian cancer, risk factors, race, ethnicity, Mathematical Sciences, Medical and Health Sciences
Abstract

Limited estimates exist on risk factors for epithelial ovarian cancer (EOC) in Asian, Hispanic, and Native Hawaiian/Pacific Islander women. Participants in this study included 1734 Asian (n = 785 case and 949 control participants), 266 Native Hawaiian/Pacific Islander (n = 99 case and 167 control participants), 1149 Hispanic (n = 505 case and 644 control participants), and 24 189 White (n = 9981 case and 14 208 control participants) from 11 studies in the Ovarian Cancer Association Consortium. Logistic regression models estimated odds ratios (ORs) and 95% CIs for risk associations by race and ethnicity. Heterogeneity in EOC risk associations by race and ethnicity (P ≤ .02) was observed for oral contraceptive (OC) use, parity, tubal ligation, and smoking. We observed inverse associations with EOC risk for OC use and parity across all groups; associations were strongest in Native Hawaiian/Pacific Islander and Asian women. The inverse association for tubal ligation with risk was most pronounced for Native Hawaiian/Pacific Islander participants (odds ratio (OR) = 0.25; 95% CI, 0.13-0.48) compared with Asian and White participants (OR = 0.68 [95% CI, 0.51-0.90] and OR = 0.78 [95% CI, 0.73-0.85], respectively). Differences in EOC risk factor associations were observed across racial and ethnic groups, which could be due, in part, to varying prevalence of EOC histotypes. Inclusion of greater diversity in future studies is essential to inform prevention strategies. This article is part of a Special Collection on Gynecological Cancers.

Published
2024

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

Author

Saner, Flurina AM, Takahashi, Kazuaki, Budden, Timothy, Pandey, Ahwan, Ariyaratne, Dinuka, Zwimpfer, Tibor A, Meagher, Nicola S, Fereday, Sian, Twomey, Laura, Pishas, Kathleen I, Hoang, Therese, Bolithon, Adelyn, Traficante, Nadia, Group, for the Australian Ovarian Cancer Study, Alsop, Kathryn, Christie, Elizabeth L, Kang, Eun-Young, Nelson, Gregg S, Ghatage, Prafull, Lee, Cheng-Han, Riggan, Marjorie J, Alsop, Jennifer, Beckmann, Matthias W, Boros, Jessica, Brand, Alison H, Brooks-Wilson, Angela, Carney, Michael E, Coulson, Penny, Courtney-Brooks, Madeleine, Cushing-Haugen, Kara L, Cybulski, Cezary, El-Bahrawy, Mona A, Elishaev, Esther, Erber, Ramona, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Gilks, C Blake, Harnett, Paul R, Harris, Holly R, Hartmann, Arndt, Hein, Alexander, Hendley, Joy, Hernandez, Brenda Y, Jakubowska, Anna, Jimenez-Linan, Mercedes, Jones, Michael E, Kaufmann, Scott H, Kennedy, Catherine J, Kluz, Tomasz, Koziak, Jennifer M, Kristjansdottir, Björg, Le, Nhu D, Lener, Marcin, Lester, Jenny, Lubiński, Jan, Mateoiu, Constantina, Orsulic, Sandra, Ruebner, Matthias, Schoemaker, Minouk J, Shah, Mitul, Sharma, Raghwa, Sherman, Mark E, Shvetsov, Yurii B, Soong, T Rinda, Steed, Helen, Sukumvanich, Paniti, Talhouk, Aline, Taylor, Sarah E, Vierkant, Robert A, Wang, Chen, Widschwendter, Martin, Wilkens, Lynne R, Winham, Stacey J, Anglesio, Michael S, Berchuck, Andrew, Brenton, James D, Campbell, Ian, Cook, Linda S, Doherty, Jennifer A, Fasching, Peter A, Fortner, Renée T, Goodman, Marc T, Gronwald, Jacek, Huntsman, David G, Karlan, Beth Y, Kelemen, Linda E, Menon, Usha, Modugno, Francesmary, Pharoah, Paul DP, Schildkraut, Joellen M, Sundfeldt, Karin, Swerdlow, Anthony J, Goode, Ellen L, DeFazio, Anna, Köbel, Martin, Ramus, Susan J, Bowtell, David DL, and Garsed, Dale W

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Genetics, Women's Health, Rare Diseases, Orphan Drug, Cancer Genomics, Ovarian Cancer, Precision Medicine, Human Genome, Cancer, 2.1 Biological and endogenous factors, Humans, Female, Ovarian Neoplasms, BRCA2 Protein, BRCA1 Protein, Cystadenocarcinoma, Serous, Retinoblastoma Binding Proteins, Prognosis, Ubiquitin-Protein Ligases, Neoplasm Grading, Lymphocytes, Tumor-Infiltrating, Middle Aged, Germ-Line Mutation, Gene Expression Regulation, Neoplastic, Aged, Biomarkers, Tumor, CD8-Positive T-Lymphocytes, Australian Ovarian Cancer Study Group, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

PurposeThe purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC).Experimental designRB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 patients with primary HGSC to characterize tumors with concurrent BRCA deficiency and RB1 loss.ResultsRB1 loss was associated with longer OS in HGSC but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1.ConclusionsCo-occurrence of RB1 loss and BRCA deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

Published
2024

5. Breast cancer survivors’ experiences of pet ownership: A qualitative analysis

Author

Currin-McCulloch, Jennifer, Kogan, Lori R., Malone, Amelia, Schwab, Savannah, and Cook, Linda S.

Subjects
breast cancer survivor, pets, guilt, support, stressors
Abstract

Research suggests that the emotional bond shared with a pet can be particularly significant for those with declining physical health, yet little is known about breast cancer survivors’ experiences with pet ownership. The purpose of this study was to explore breast cancer survivors’ pet-related experiences including the benefits, challenges, and unmet needs. Adults (ages 18 and older), diagnosed with stages 0 (in situ)-IV breast cancer and currently the primary owner of at least one dog or cat for at least 6 months were recruited through cancer treatment and support organizations and pet and breast cancer social media outlets. An online, anonymous, cross-sectional, mixed method survey was developed that included seven open-ended prompts to explore the stressors and benefits breast cancer survivors encountered in caring for a pet during cancer treatment and survivorship, as well as their advice for medical providers and other breast cancer survivors. Breast cancer survivors (n = 221) responded to the online survey between July and November 2022. Researchers used the thematic analysis method to analyze salient themes in the data and descriptive statistics to summarize participants’ sociodemographic variables. The seven open-ended prompts resulted in four key themes: my furry reason to keep fighting; seeking quality care resources; my pets are my family; and someone special is waiting for you. Findings from this study suggest practical ways that medical and mental health providers and communities can enhance the well-being of survivors and support the invaluable relationships with their pets.

Published
2023
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6. Lifetime ovulatory years and risk of epithelial ovarian cancer: a multinational pooled analysis

Author

Fu, Zhuxuan, Brooks, Maria Mori, Irvin, Sarah, Jordan, Susan, Aben, Katja KH, Anton-Culver, Hoda, Bandera, Elisa V, Beckmann, Matthias W, Berchuck, Andrew, Brooks-Wilson, Angela, Chang-Claude, Jenny, Cook, Linda S, Cramer, Daniel W, Cushing-Haugen, Kara L, Doherty, Jennifer A, Ekici, Arif B, Fasching, Peter A, Fortner, Renée T, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Giles, Graham G, Goode, Ellen L, Goodman, Marc T, Group, AOCS, Harris, Holly R, Hein, Alexander, Kaaks, Rudolf, Kiemeney, Lambertus A, Köbel, Martin, Kotsopoulos, Joanne, Le, Nhu D, Lee, Alice W, Matsuo, Keitaro, McGuire, Valerie, McLaughlin, John R, Menon, Usha, Milne, Roger L, Moysich, Kirsten B, Pearce, Celeste Leigh, Pike, Malcolm C, Qin, Bo, Ramus, Susan J, Riggan, Marjorie J, Rothstein, Joseph H, Schildkraut, Joellen M, Sieh, Weiva, Sutphen, Rebecca, Terry, Kathryn L, Thompson, Pamela J, Titus, Linda, van Altena, Anne M, White, Emily, Whittemore, Alice S, Wu, Anna H, Zheng, Wei, Ziogas, Argyrios, Taylor, Sarah E, Tang, Lu, Songer, Thomas, Wentzensen, Nicolas, Webb, Penelope M, Risch, Harvey A, and Modugno, Francesmary

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Clinical Research, Cancer, Ovarian Cancer, Prevention, Pregnancy, Humans, Female, Carcinoma, Ovarian Epithelial, Ovarian Neoplasms, Risk Factors, Parity, Contraceptives, Oral, Case-Control Studies, AOCS Group, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundThe role of ovulation in epithelial ovarian cancer (EOC) is supported by the consistent protective effects of parity and oral contraceptive use. Whether these factors protect through anovulation alone remains unclear. We explored the association between lifetime ovulatory years (LOY) and EOC.MethodsLOY was calculated using 12 algorithms. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the association between LOY or LOY components and EOC among 26 204 control participants and 21 267 case patients from 25 studies. To assess whether LOY components act through ovulation suppression alone, we compared beta coefficients obtained from regression models with expected estimates assuming 1 year of ovulation suppression has the same effect regardless of source.ResultsLOY was associated with increased EOC risk (OR per year increase = 1.014, 95% CI = 1.009 to 1.020 to OR per year increase = 1.044, 95% CI = 1.041 to 1.048). Individual LOY components, except age at menarche, also associated with EOC. The estimated model coefficient for oral contraceptive use and pregnancies were 4.45 times and 12- to 15-fold greater than expected, respectively. LOY was associated with high-grade serous, low-grade serous, endometrioid, and clear cell histotypes (ORs per year increase = 1.054, 1.040, 1.065, and 1.098, respectively) but not mucinous tumors. Estimated coefficients of LOY components were close to expected estimates for high-grade serous but larger than expected for low-grade serous, endometrioid, and clear cell histotypes.ConclusionsLOY is positively associated with nonmucinous EOC. Differences between estimated and expected model coefficients for LOY components suggest factors beyond ovulation underlie the associations between LOY components and EOC in general and for non-HGSOC.

Published
2023

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

Author

Köbel, Martin, Kang, Eun‐Young, Weir, Ashley, Rambau, Peter F, Lee, Cheng‐Han, Nelson, Gregg S, Ghatage, Prafull, Meagher, Nicola S, Riggan, Marjorie J, Alsop, Jennifer, Anglesio, Michael S, Beckmann, Matthias W, Bisinotto, Christiani, Boisen, Michelle, Boros, Jessica, Brand, Alison H, Brooks‐Wilson, Angela, Carney, Michael E, Coulson, Penny, Courtney‐Brooks, Madeleine, Cushing‐Haugen, Kara L, Cybulski, Cezary, Deen, Suha, El‐Bahrawy, Mona A, Elishaev, Esther, Erber, Ramona, Fereday, Sian, Group, AOCS, Fischer, Anna, Gayther, Simon A, Barquin‐Garcia, Arantzazu, Gentry‐Maharaj, Aleksandra, Gilks, C Blake, Gronwald, Helena, Grube, Marcel, Harnett, Paul R, Harris, Holly R, Hartkopf, Andreas D, Hartmann, Arndt, Hein, Alexander, Hendley, Joy, Hernandez, Brenda Y, Huang, Yajue, Jakubowska, Anna, Jimenez‐Linan, Mercedes, Jones, Michael E, Kennedy, Catherine J, Kluz, Tomasz, Koziak, Jennifer M, Lesnock, Jaime, Lester, Jenny, Lubiński, Jan, Longacre, Teri A, Lycke, Maria, Mateoiu, Constantina, McCauley, Bryan M, McGuire, Valerie, Ney, Britta, Olawaiye, Alexander, Orsulic, Sandra, Osorio, Ana, Paz‐Ares, Luis, Ramón y Cajal, Teresa, Rothstein, Joseph H, Ruebner, Matthias, Schoemaker, Minouk J, Shah, Mitul, Sharma, Raghwa, Sherman, Mark E, Shvetsov, Yurii B, Singh, Naveena, Steed, Helen, Storr, Sarah J, Talhouk, Aline, Traficante, Nadia, Wang, Chen, Whittemore, Alice S, Widschwendter, Martin, Wilkens, Lynne R, Winham, Stacey J, Benitez, Javier, Berchuck, Andrew, Bowtell, David D, dos Reis, Francisco J Candido, Campbell, Ian, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Fasching, Peter A, Fortner, Renée T, García, María J, Goodman, Marc T, Goode, Ellen L, Gronwald, Jacek, Huntsman, David G, Karlan, Beth Y, Kelemen, Linda E, Kommoss, Stefan, Le, Nhu D, and Martin, Stewart G

Subjects
Reproductive Medicine, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Rare Diseases, Ovarian Cancer, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Humans, Female, Tumor Suppressor Protein p53, Ovarian Neoplasms, Carcinoma, Ovarian Epithelial, Carcinoma, Endometrioid, ovarian cancer, high-grade serous carcinoma, endometrioid, clear cell, TP53, p53, prognosis, AOCS Group, Clinical sciences
Abstract

Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.

Published
2023

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

Author

Kang, Eun‐Young, Weir, Ashley, Meagher, Nicola S, Farrington, Kyo, Nelson, Gregg S, Ghatage, Prafull, Lee, Cheng‐Han, Riggan, Marjorie J, Bolithon, Adelyn, Popovic, Gordana, Leung, Betty, Tang, Katrina, Lambie, Neil, Millstein, Joshua, Alsop, Jennifer, Anglesio, Michael S, Ataseven, Beyhan, Barlow, Ellen, Beckmann, Matthias W, Berger, Jessica, Bisinotto, Christiani, Bösmüller, Hans, Boros, Jessica, Brand, Alison H, Brooks‐Wilson, Angela, Brucker, Sara Y, Carney, Michael E, Casablanca, Yovanni, Cazorla‐Jiménez, Alicia, Cohen, Paul A, Conrads, Thomas P, Cook, Linda S, Coulson, Penny, Courtney‐Brooks, Madeleine, Cramer, Daniel W, Crowe, Philip, Cunningham, Julie M, Cybulski, Cezary, Darcy, Kathleen M, El‐Bahrawy, Mona A, Elishaev, Esther, Erber, Ramona, Farrell, Rhonda, Fereday, Sian, Fischer, Anna, García, María J, Gayther, Simon A, Gentry‐Maharaj, Aleksandra, Gilks, C Blake, Group, AOCS, Grube, Marcel, Harnett, Paul R, Harrington, Shariska Petersen, Harter, Philipp, Hartmann, Arndt, Hecht, Jonathan L, Heikaus, Sebastian, Hein, Alexander, Heitz, Florian, Hendley, Joy, Hernandez, Brenda Y, Polo, Susanna Hernando, Heublein, Sabine, Hirasawa, Akira, Høgdall, Estrid, Høgdall, Claus K, Horlings, Hugo M, Huntsman, David G, Huzarski, Tomasz, Jewell, Andrea, Jimenez‐Linan, Mercedes, Jones, Michael E, Kaufmann, Scott H, Kennedy, Catherine J, Khabele, Dineo, Kommoss, Felix KF, Kruitwagen, Roy FPM, Lambrechts, Diether, Le, Nhu D, Lener, Marcin, Lester, Jenny, Leung, Yee, Linder, Anna, Loverix, Liselore, Lubiński, Jan, Madan, Rashna, Maxwell, G Larry, Modugno, Francesmary, Neuhausen, Susan L, Olawaiye, Alexander, Olbrecht, Siel, Orsulic, Sandra, Palacios, José, Pearce, Celeste Leigh, Pike, Malcolm C, Quinn, Carmel M, Mohan, Ganendra Raj, Rodríguez‐Antona, Cristina, Ruebner, Matthias, and Ryan, Andy

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Clinical Research, Ovarian Cancer, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Female, Humans, Ovarian Neoplasms, Transcription Factors, Carcinoma, RNA, Messenger, Cystadenocarcinoma, Serous, Oncogene Proteins, Cyclin E, CCNE1 amplification, cyclin E1 expression, high-grade serous carcinoma, ovarian cancer, prognosis, AOCS Group, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis, Public health
Abstract

BackgroundCyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC.MethodsWithin the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated.ResultsHigh-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss.ConclusionThis study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

Published
2023

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

Author

Weir, Ashley, Kang, Eun-Young, Meagher, Nicola S, Nelson, Gregg S, Ghatage, Prafull, Lee, Cheng-Han, Riggan, Marjorie J, Gentry-Maharaj, Aleksandra, Ryan, Andy, Singh, Naveena, Widschwendter, Martin, Alsop, Jennifer, Anglesio, Michael S, Beckmann, Matthias W, Berger, Jessica, Bisinotto, Christiani, Boros, Jessica, Brand, Alison H, Brenton, James D, Brooks-Wilson, Angela, Carney, Michael E, Cunningham, Julie M, Cushing-Haugen, Kara L, Cybulski, Cezary, Elishaev, Esther, Erber, Ramona, Fereday, Sian, Fischer, Anna, Paz-Ares, Luis, Gayarre, Javier, Gilks, Blake C, Grube, Marcel, Harnett, Paul R, Harris, Holly R, Hartmann, Arndt, Hein, Alexander, Hendley, Joy, Hernandez, Brenda Y, Heublein, Sabine, Huang, Yajue, Huzarski, Tomasz, Jakubowska, Anna, Jimenez-Linan, Mercedes, Kennedy, Catherine J, Kommoss, Felix KF, Koziak, Jennifer M, Kraemer, Bernhard, Le, Nhu D, Lesnock, Jaime, Lester, Jenny, Lubiński, Jan, Menkiszak, Janusz, Ney, Britta, Olawaiye, Alexander, Orsulic, Sandra, Osorio, Ana, Robles-Díaz, Luis, Ruebner, Matthias, Shah, Mitul, Sharma, Raghwa, Shvetsov, Yurii B, Steed, Helen, Talhouk, Aline, Taylor, Sarah E, Traficante, Nadia, Vierkant, Robert A, Wang, Chen, Wilkens, Lynne R, Winham, Stacey J, Benitez, Javier, Berchuck, Andrew, Bowtell, David D, Candido dos Reis, Francisco J, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Fasching, Peter A, García, María J, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Huntsman, David G, Karlan, Beth Y, Kommoss, Stefan, Modugno, Francesmary, Schildkraut, Joellen M, Sinn, Hans-Peter, Staebler, Annette, Kelemen, Linda E, Ford, Caroline E, Menon, Usha, Pharoah, Paul DP, Köbel, Martin, and Ramus, Susan J

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Ovarian Cancer, Clinical Research, Rare Diseases, Cancer, Aetiology, 2.1 Biological and endogenous factors, Humans, Female, Ovarian Neoplasms, Prognosis, Survival Analysis, RNA, Messenger, Cystadenocarcinoma, Serous, Biomarkers, Tumor, Forkhead Transcription Factors, AOCs group, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundRecently, we showed a >60% difference in 5-year survival for patients with tubo-ovarian high-grade serous carcinoma (HGSC) when stratified by a 101-gene mRNA expression prognostic signature. Given the varied patient outcomes, this study aimed to translate prognostic mRNA markers into protein expression assays by immunohistochemistry and validate their survival association in HGSC.MethodsTwo prognostic genes, FOXJ1 and GMNN, were selected based on high-quality antibodies, correlation with protein expression and variation in immunohistochemical scores in a preliminary cohort (n = 134 and n = 80, respectively). Six thousand four hundred and thirty-four (FOXJ1) and 5470 (GMNN) formalin-fixed, paraffin-embedded ovarian neoplasms (4634 and 4185 HGSC, respectively) represented on tissue microarrays from the Ovarian Tumor Tissue Analysis consortium underwent immunohistochemical staining and scoring, then univariate and multivariate survival analysis.ResultsConsistent with mRNA, FOXJ1 protein expression exhibited a linear, increasing association with improved overall survival in HGSC patients. Women with >50% expression had the most favourable outcomes (HR = 0.78, 95% CI 0.67-0.91, p 35% GMNN expression showed a trend for better outcomes, though this was not significant.ConclusionWe provide foundational evidence for the prognostic value of FOXJ1 in HGSC, validating the prior mRNA-based prognostic association by immunohistochemistry.

Published
2023

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

Author

DeVries, Amber A, Dennis, Joe, Tyrer, Jonathan P, Peng, Pei-Chen, Coetzee, Simon G, Reyes, Alberto L, Plummer, Jasmine T, Davis, Brian D, Chen, Stephanie S, Dezem, Felipe Segato, Aben, Katja KH, Anton-Culver, Hoda, Antonenkova, Natalia N, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Berchuck, Andrew, Bogdanova, Natalia V, Bogdanova-Markov, Nadja, Brenton, James D, Butzow, Ralf, Campbell, Ian, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Dörk, Thilo, Eccles, Diana M, Eliassen, A Heather, Fasching, Peter A, Fortner, Renée T, Giles, Graham G, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Webb, P, DeFazio, A, Friedlander, M, Obermair, A, Grant, P, Nagle, C, Beesley, V, Chevenix-Trench, G, Bowtell, D, Blomfield, P, Brand, A, Davis, A, Leung, Y, Nicklin, J, Quinn, M, Livingstone, K, O'Neill, H, Williams, M, Black, A, Hadley, A, Glasgow, A, Garrett, A, Rao, A, Shannon, C, Steer, C, Allen, D, Neesham, D, Otton, G, Au-Yeung, G, Goss, G, Wain, G, Gard, G, Robertson, G, Lombard, J, Tan, J, McNeilage, J, Power, J, Coward, J, Miller, J, Carter, J, Lamont, J, Wong, KM, Reid, K, Perrin, L, Milishkin, L, Nascimento, M, Buck, M, Bunting, M, Harrison, M, Chetty, N, Hacker, N, McNally, O, Harnett, P, Beale, P, Awad, R, Mohan, R, Farrell, R, McIntosh, R, Rome, R, Sayer, R, Houghton, R, Hogg, R, Land, R, Baron-Hay, S, and Paramasivum, S

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Human Genome, Genetic Testing, Clinical Research, Ovarian Cancer, Rare Diseases, Prevention, Women's Health, Cancer, Genetics, 2.1 Biological and endogenous factors, Female, Humans, Carcinoma, Ovarian Epithelial, Genome-Wide Association Study, Alleles, DNA Copy Number Variations, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Ovarian Neoplasms, OPAL Study Group, AOCS Group, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundKnown risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort.MethodsSingle nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types.ResultsWe identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P

Published
2022

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

Author

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

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

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

Author

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

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

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

Published
2022

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

Author

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

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

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

Published
2021

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

Author

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

Subjects
Oncology & Carcinogenesis, Oncology and Carcinogenesis, Public Health and Health Services
Abstract

BackgroundPTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study.MethodsTumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests.ResultsDownregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value

Published
2020

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

Author

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

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

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

Published
2020

19. 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

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

Author

Yang, Yaohua, Wu, Lang, Shu, Xiang, Lu, Yingchang, Shu, Xiao-Ou, Cai, Qiuyin, Beeghly-Fadiel, Alicia, Li, Bingshan, Ye, Fei, Berchuck, Andrew, Anton-Culver, Hoda, Banerjee, Susana, Benitez, Javier, Bjørge, Line, Brenton, James D, Butzow, Ralf, Campbell, Ian G, Chang-Claude, Jenny, Chen, Kexin, Cook, Linda S, Cramer, Daniel W, deFazio, Anna, Dennis, Joe, Doherty, Jennifer A, Dörk, Thilo, Eccles, Diana M, Edwards, Digna Velez, Fasching, Peter A, Fortner, Renée T, Gayther, Simon A, Giles, Graham G, Glasspool, Rosalind M, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Harris, Holly R, Heitz, Florian, Hildebrandt, Michelle A, Høgdall, Estrid, Høgdall, Claus K, Huntsman, David G, Kar, Siddhartha P, Karlan, Beth Y, Kelemen, Linda E, Kiemeney, Lambertus A, Kjaer, Susanne K, Koushik, Anita, Lambrechts, Diether, Le, Nhu D, Levine, Douglas A, Massuger, Leon F, Matsuo, Keitaro, May, Taymaa, McNeish, Iain A, Menon, Usha, Modugno, Francesmary, Monteiro, Alvaro N, Moorman, Patricia G, Moysich, Kirsten B, Ness, Roberta B, Nevanlinna, Heli, Olsson, Håkan, Onland-Moret, N Charlotte, Park, Sue K, Paul, James, Pearce, Celeste L, Pejovic, Tanja, Phelan, Catherine M, Pike, Malcolm C, Ramus, Susan J, Riboli, Elio, Rodriguez-Antona, Cristina, Romieu, Isabelle, Sandler, Dale P, Schildkraut, Joellen M, Setiawan, Veronica W, Shan, Kang, Siddiqui, Nadeem, Sieh, Weiva, Stampfer, Meir J, Sutphen, Rebecca, Swerdlow, Anthony J, Szafron, Lukasz M, Teo, Soo Hwang, Tworoger, Shelley S, Tyrer, Jonathan P, Webb, Penelope M, Wentzensen, Nicolas, White, Emily, Willett, Walter C, Wolk, Alicja, Woo, Yin Ling, Wu, Anna H, Yan, Li, Yannoukakos, Drakoulis, Chenevix-Trench, Georgia, Sellers, Thomas A, Pharoah, Paul DP, Zheng, Wei, and Long, Jirong

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Biotechnology, Rare Diseases, Ovarian Cancer, Cancer Genomics, Prevention, Women's Health, Cancer, Clinical Research, Human Genome, 2.1 Biological and endogenous factors, Biomarkers, Tumor, Carcinoma, Ovarian Epithelial, Cohort Studies, DNA Methylation, Female, Genetic Predisposition to Disease, Humans, Models, Genetic, Ovarian Neoplasms, Predictive Value of Tests, Risk, White People, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10-7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. SIGNIFICANCE: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.

Published
2019

21. Coffee consumption and risk of endometrial cancer: a pooled analysis of individual participant data in the Epidemiology of Endometrial Cancer Consortium (E2C2)

Author

Crous-Bou, Marta, Du, Mengmeng, Gunter, Marc J, Setiawan, Veronica W, Schouten, Leo J, Shu, Xiao-ou, Wentzensen, Nicolas, Bertrand, Kimberly A, Cook, Linda S, Friedenreich, Christine M, Gapstur, Susan M, Goodman, Marc T, Ibiebele, Torukiri I, La Vecchia, Carlo, Levi, Fabio, Liao, Linda M, Negri, Eva, McCann, Susan E, O’Connell, Kelly, Palmer, Julie R, Patel, Alpa V, Ponte, Jeanette, Reynolds, Peggy, Sacerdote, Carlotta, Sinha, Rashmi, Spurdle, Amanda B, Trabert, Britton, van den Brandt, Piet A, Webb, Penelope M, Petruzella, Stacey, Olson, Sara H, and De Vivo, Immaculata

Published
2022
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23. MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma

Author

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

Published
2022
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24. Early menopause and hormone therapy as determinants for lung health outcomes: a secondary analysis using the PLCO trial.

Author

Xiaochun Gai, Yue Feng, Flores, Tessa M., Huining Kang, Hui Yu, Leslie, Kimberly K., Yiliang Zhu, Doherty, Jennifer A., Yan Guo, Belinsky, Steven A., Cook, Linda S., and Shuguang Leng

Subjects
PREMATURE menopause, HORMONE therapy for menopause, OVARIAN cancer, DNA repair, HORMONE therapy, REPRODUCTIVE technology, FORCED expiratory volume
Published
2024
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26. 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

27. 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

28. 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

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

Author

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

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Prevention, Genetics, Ovarian Cancer, Women's Health, Cancer, 2.1 Biological and endogenous factors, Adolescent, Adult, Aged, Aged, 80 and over, Body Height, Carcinoma, Ovarian Epithelial, Case-Control Studies, Female, Genetic Predisposition to Disease, Geography, Humans, Mendelian Randomization Analysis, Middle Aged, Ovarian Neoplasms, Risk Factors, Young Adult, Australian Ovarian Cancer Study Group, Ovarian Cancer Association Consortium, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundObservational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias.MethodsWe pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted genetic risk score combining 609 single-nucleotide polymorphisms. Study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted height and risk were pooled using random-effects meta-analysis.ResultsGreater genetically predicted height was associated with increased ovarian cancer risk overall (pooled-OR (pOR) = 1.06; 95% CI: 1.01-1.11 per 5 cm increase in height), and separately for invasive (pOR = 1.06; 95% CI: 1.01-1.11) and borderline (pOR = 1.15; 95% CI: 1.02-1.29) tumours.ConclusionsWomen with a genetic propensity to being taller have increased risk of ovarian cancer. This suggests genes influencing height are involved in pathways promoting ovarian carcinogenesis.

Published
2018

30. 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

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

Author

Goode, Ellen L, Block, Matthew S, Kalli, Kimberly R, Vierkant, Robert A, Chen, Wenqian, Fogarty, Zachary C, Gentry-Maharaj, Aleksandra, Tołoczko, Aleksandra, Hein, Alexander, Bouligny, Aliecia L, Jensen, Allan, Osorio, Ana, Hartkopf, Andreas D, Ryan, Andy, Chudecka-Głaz, Anita, Magliocco, Anthony M, Hartmann, Arndt, Jung, Audrey Y, Gao, Bo, Hernandez, Brenda Y, Fridley, Brooke L, McCauley, Bryan M, Kennedy, Catherine J, Wang, Chen, Karpinskyj, Chloe, de Sousa, Christiani B, Tiezzi, Daniel G, Wachter, David L, Herpel, Esther, Taran, Florin Andrei, Modugno, Francesmary, Nelson, Gregg, Lubiński, Jan, Menkiszak, Janusz, Alsop, Jennifer, Lester, Jenny, García-Donas, Jesús, Nation, Jill, Hung, Jillian, Palacios, José, Rothstein, Joseph H, Kelley, Joseph L, de Andrade, Jurandyr M, Robles-Díaz, Luis, Intermaggio, Maria P, Widschwendter, Martin, Beckmann, Matthias W, Ruebner, Matthias, Jimenez-Linan, Mercedes, Singh, Naveena, Oszurek, Oleg, Harnett, Paul R, Rambau, Peter F, Sinn, Peter, Wagner, Philipp, Ghatage, Prafull, Sharma, Raghwa, Edwards, Robert P, Ness, Roberta B, Orsulic, Sandra, Brucker, Sara Y, Johnatty, Sharon E, Longacre, Teri A, Eilber, Ursula, McGuire, Valerie, Sieh, Weiva, Natanzon, Yanina, Li, Zheng, Whittemore, Alice S, deFazio, Anna, Staebler, Annette, Karlan, Beth Y, Gilks, Blake, Bowtell, David D, Høgdall, Estrid, dos Reis, Francisco J Candido, Steed, Helen, Campbell, Ian G, Gronwald, Jacek, Benítez, Javier, Koziak, Jennifer M, Chang-Claude, Jenny, Moysich, Kirsten B, Kelemen, Linda E, Cook, Linda S, Goodman, Marc T, García, María José, Fasching, Peter A, Kommoss, Stefan, Deen, Suha, Kjaer, Susanne K, Menon, Usha, Brenton, James D, Pharoah, Paul DP, Chenevix-Trench, Georgia, Huntsman, David G, Winham, Stacey J, Köbel, Martin, and Ramus, Susan J

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Cancer, Prevention, Vaccine Related, Rare Diseases, Clinical Research, Ovarian Cancer, BRCA2 Protein, CD8 Antigens, Carcinoma, Ovarian Epithelial, Cohort Studies, Cystadenocarcinoma, Serous, Female, Humans, Lymphocytes, Tumor-Infiltrating, Middle Aged, Mutation, Neoplasm Grading, Ovarian Neoplasms, Prospective Studies, Survival Analysis, Treatment Outcome, Ovarian Tumor Tissue Analysis (OTTA) Consortium, Public Health and Health Services, Oncology and carcinogenesis
Abstract

ImportanceCytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors.ObjectiveTo define the prognostic role of CD8+ TILs in epithelial ovarian cancer.Design, setting, and participantsThis was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years.ExposuresFollowing immunohistochemical analysis, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (≥20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines.Main outcomes and measuresOverall survival time.ResultsThe final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (P value for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near-log-linear functional form.Conclusions and relevanceThis study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+ TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer.

Published
2017

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

Author

Ovarian Tumor Tissue Analysis (OTTA) Consortium, Goode, Ellen L, Block, Matthew S, Kalli, Kimberly R, Vierkant, Robert A, Chen, Wenqian, Fogarty, Zachary C, Gentry-Maharaj, Aleksandra, Tołoczko, Aleksandra, Hein, Alexander, Bouligny, Aliecia L, Jensen, Allan, Osorio, Ana, Hartkopf, Andreas, Ryan, Andy, Chudecka-Głaz, Anita, Magliocco, Anthony M, Hartmann, Arndt, Jung, Audrey Y, Gao, Bo, Hernandez, Brenda Y, Fridley, Brooke L, McCauley, Bryan M, Kennedy, Catherine J, Wang, Chen, Karpinskyj, Chloe, de Sousa, Christiani B, Tiezzi, Daniel G, Wachter, David L, Herpel, Esther, Taran, Florin Andrei, Modugno, Francesmary, Nelson, Gregg, Lubiński, Jan, Menkiszak, Janusz, Alsop, Jennifer, Lester, Jenny, García-Donas, Jesús, Nation, Jill, Hung, Jillian, Palacios, José, Rothstein, Joseph H, Kelley, Joseph L, de Andrade, Jurandyr M, Robles-Díaz, Luis, Intermaggio, Maria P, Widschwendter, Martin, Beckmann, Matthias W, Ruebner, Matthias, Jimenez-Linan, Mercedes, Singh, Naveena, Oszurek, Oleg, Harnett, Paul R, Rambau, Peter F, Sinn, Peter, Wagner, Philipp, Ghatage, Prafull, Sharma, Raghwa, Edwards, Robert P, Ness, Roberta B, Orsulic, Sandra, Brucker, Sara Y, Johnatty, Sharon E, Longacre, Teri A, Ursula, Eilber, McGuire, Valerie, Sieh, Weiva, Natanzon, Yanina, Li, Zheng, Whittemore, Alice S, Anna, deFazio, Staebler, Annette, Karlan, Beth Y, Gilks, Blake, Bowtell, David D, Høgdall, Estrid, Candido dos Reis, Francisco J, Steed, Helen, Campbell, Ian G, Gronwald, Jacek, Benítez, Javier, Koziak, Jennifer M, Chang-Claude, Jenny, Moysich, Kirsten B, Kelemen, Linda E, Cook, Linda S, Goodman, Marc T, García, María José, Fasching, Peter A, Kommoss, Stefan, Deen, Suha, Kjaer, Susanne K, Menon, Usha, Brenton, James D, Pharoah, Paul DP, Chenevix-Trench, Georgia, Huntsman, David G, Winham, Stacey J, Köbel, Martin, and Ramus, Susan J

Subjects
Ovarian Tumor Tissue Analysis (OTTA) Consortium, Lymphocytes, Tumor-Infiltrating, Humans, Cystadenocarcinoma, Serous, Ovarian Neoplasms, BRCA2 Protein, Treatment Outcome, Survival Analysis, Cohort Studies, Prospective Studies, Mutation, Middle Aged, Female, Neoplasm Grading, CD8 Antigens, Carcinoma, Ovarian Epithelial, Lymphocytes, Tumor-Infiltrating, Cystadenocarcinoma, Serous, Carcinoma, Ovarian Epithelial, Cancer, Prevention, Ovarian Cancer, Rare Diseases, Vaccine Related, Clinical Research, Oncology and Carcinogenesis, Public Health and Health Services
Abstract

ImportanceCytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors.ObjectiveTo define the prognostic role of CD8+ TILs in epithelial ovarian cancer.Design, setting, and participantsThis was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years.ExposuresFollowing immunohistochemical analysis, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (≥20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines.Main outcomes and measuresOverall survival time.ResultsThe final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (P value for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near-log-linear functional form.Conclusions and relevanceThis study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+ TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer.

Published
2017

33. Hypertension and risk of endometrial cancer: a pooled analysis in the Epidemiology of Endometrial Cancer Consortium (E2C2)

Author

Habeshian, Talar S., primary, Peeri, Noah C., additional, De Vivo, Immaculata, additional, Schouten, Leo J., additional, Shu, Xiao-Ou, additional, Cote, Michele L., additional, Bertrand, Kimberly A., additional, Chen, Yu, additional, Clarke, Megan A., additional, Clendenen, Tess V., additional, Cook, Linda S., additional, Costas, Laura, additional, Dal Maso, Luigino, additional, Freudenheim, Jo L., additional, Friedenreich, Christine M., additional, Gallagher, Grace, additional, Gierach, Gretchen L., additional, Goodman, Marc T., additional, Jordan, Susan J., additional, La Vecchia, Carlo, additional, Lacey, James V., additional, Levi, Fabio, additional, Liao, Linda M., additional, Lipworth, Loren, additional, Lu, Lingeng, additional, Matías-Guiu, Xavier, additional, Moysich, Kirsten B., additional, Mutter, George L., additional, Na, Renhua, additional, Naduparambil, Jeffin, additional, Negri, Eva, additional, O'Connell, Kelli, additional, O'Mara, Tracy A., additional, Onieva Hernández, Irene, additional, Palmer, Julie R., additional, Parazzini, Fabio, additional, Patel, Alpa V., additional, Penney, Kathryn L., additional, Prizment, Anna E., additional, Ricceri, Fulvio, additional, Risch, Harvey A., additional, Sacerdote, Carlotta, additional, Sandin, Sven, additional, Stolzenberg-Solomon, Rachael Z., additional, van den Brandt, Piet A., additional, Webb, Penelope M., additional, Wentzensen, Nicolas, additional, Wijayabahu, Akemi T., additional, Wilkens, Lynne R., additional, Xu, Wanghong, additional, Yu, Herbert, additional, Zeleniuch-Jacquotte, Anne, additional, Zheng, Wei, additional, Du, Mengmeng, additional, and Setiawan, Veronica Wendy., additional

Published
2024
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37. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

Author

Phelan, Catherine M, Kuchenbaecker, Karoline B, Tyrer, Jonathan P, Kar, Siddhartha P, Lawrenson, Kate, Winham, Stacey J, Dennis, Joe, Pirie, Ailith, Riggan, Marjorie J, Chornokur, Ganna, Earp, Madalene A, Lyra, Paulo C, Lee, Janet M, Coetzee, Simon, Beesley, Jonathan, McGuffog, Lesley, Soucy, Penny, Dicks, Ed, Lee, Andrew, Barrowdale, Daniel, Lecarpentier, Julie, Leslie, Goska, Aalfs, Cora M, Aben, Katja KH, Adams, Marcia, Adlard, Julian, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia, AOCS study group, Aravantinos, Gerasimos, Arnold, Norbert, Arun, Banu K, Arver, Brita, Azzollini, Jacopo, Balmaña, Judith, Banerjee, Susana N, Barjhoux, Laure, Barkardottir, Rosa B, Bean, Yukie, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q, Birrer, Michael J, Bjorge, Line, Black, Amanda, Blankstein, Kenneth, Blok, Marinus J, Bodelon, Clara, Bogdanova, Natalia, Bojesen, Anders, Bonanni, Bernardo, Borg, Åke, Bradbury, Angela R, Brenton, James D, Brewer, Carole, Brinton, Louise, Broberg, Per, Brooks-Wilson, Angela, Bruinsma, Fiona, Brunet, Joan, Buecher, Bruno, Butzow, Ralf, Buys, Saundra S, Caldes, Trinidad, Caligo, Maria A, Campbell, Ian, Cannioto, Rikki, Carney, Michael E, Cescon, Terence, Chan, Salina B, Chang-Claude, Jenny, Chanock, Stephen, Chen, Xiao Qing, Chiew, Yoke-Eng, Chiquette, Jocelyne, Chung, Wendy K, Claes, Kathleen BM, Conner, Thomas, Cook, Linda S, Cook, Jackie, Cramer, Daniel W, Cunningham, Julie M, D'Aloisio, Aimee A, Daly, Mary B, Damiola, Francesca, Damirovna, Sakaeva Dina, Dansonka-Mieszkowska, Agnieszka, Dao, Fanny, Davidson, Rosemarie, DeFazio, Anna, Delnatte, Capucine, Doheny, Kimberly F, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer Anne, Domchek, Susan M, and Dorfling, Cecilia M

Subjects
AOCS study group, EMBRACE Study, GEMO Study Collaborators, HEBON Study, KConFab Investigators, OPAL study group, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Genetic Predisposition to Disease, Telomere-Binding Proteins, BRCA1 Protein, BRCA2 Protein, Risk Factors, Genotype, Mutation, Polymorphism, Single Nucleotide, Alleles, Female, Meta-Analysis as Topic, Genome-Wide Association Study, Genetic Loci, Carcinoma, Ovarian Epithelial, Genetics, Cancer, Human Genome, Rare Diseases, Prevention, Ovarian Cancer, Aetiology, 2.1 Biological and endogenous factors, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

Published
2017

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

Author

Kang, Eun Young, Cheasley, Dane, LePage, Cecile, Wakefield, Matthew J., da Cunha Torres, Michelle, Rowley, Simone, Salazar, Carolina, Xing, Zhongyue, Allan, Prue, Bowtell, David D.L., Mes-Masson, Anne-Marie, Provencher, Diane M., Rahimi, Kurosh, Kelemen, Linda E., Fasching, Peter A., Doherty, Jennifer A., Goodman, Marc T., Goode, Ellen L., Deen, Suha, Pharoah, Paul D.P., Brenton, James D., Sieh, Weiva, Mateoiu, Constantina, Sundfeldt, Karin, Cook, Linda S., Le, Nhu D., Anglesio, Michael S., Gilks, C. Blake, Huntsman, David G., Kennedy, Catherine J., Traficante, Nadia, Bowtell, D., Chenevix-Trench, G., Green, A., Webb, P., DeFazio, A., Gertig, D., Traficante, N., Fereday, S., Moore, S., Hung, J., Harrap, K., Sadkowsky, T., Pandeya, N., Malt, M., Mellon, A., Robertson, R., Bergh, T. Vanden, Jones, M., Mackenzie, P., Maidens, J., Nattress, K., Chiew, Y.E., Stenlake, A., Sullivan, H., Alexander, B., Ashover, P., Brown, S., Corrish, T., Green, L., Jackman, L., Ferguson, K., Martin, K., Martyn, A., Ranieri, B., White, J., Jayde, V., Mamers, P., Bowes, L., Galletta, L., Giles, D., Hendley, J., Alsop, K., Schmidt, T., Shirley, H., Ball, C., Young, C., Viduka, S., Tran, Hoa, Bilic, Sanela, Glavinas, Lydia, Brooks, Julia, Stuart-Harris, R., Kirsten, F., Rutovitz, J., Clingan, P., Glasgow, A., Proietto, A., Braye, S., Otton, G., Shannon, J., Bonaventura, T., Stewart, J., Begbie, S., Friedlander, M., Bell, D., Baron-Hay, S., Ferrier, A., Gard, G., Nevell, D., Pavlakis, N., Valmadre, S., Young, B., Camaris, C., Crouch, R., Edwards, L., Hacker, N., Marsden, D., Robertson, G., Beale, P., Beith, J., Carter, J., Dalrymple, C., Houghton, R., Russell, P., Links, M., Grygiel, J., Hill, J., Brand, A., Byth, K., Jaworski, R., Harnett, P., Sharma, R., Wain, G., Ward, B., Papadimos, D., Crandon, A., Cummings, M., Horwood, K., Obermair, A., Perrin, L., Wyld, D., Nicklin, J., Davy, M., Oehler, M.K., Hall, C., Dodd, T., Healy, T., Pittman, K., Henderson, D., Miller, J., Pierdes, J., Blomfield, P., Challis, D., McIntosh, R., Parker, A., Brown, B., Rome, R., Allen, D., Grant, P., Hyde, S., Laurie, R., Robbie, M., Healy, D., Jobling, T., Manolitsas, T., McNealage, J., Rogers, P., Susil, B., Sumithran, E., Simpson, I., Phillips, K., Rischin, D., Fox, S., Johnson, D., Lade, S., Loughrey, M., O'Callaghan, N., Murray, W., Waring, P., Billson, V., Pyman, J., Neesham, D., Quinn, M., Underhill, C., Bell, R., Ng, L.F., Blum, R., Ganju, V., Hammond, I., Leung, Y., McCartney, A., Buck, M., Haviv, I., Purdie, D., Whiteman, D., Zeps, N., DeFazio, Anna, Kaufmann, Scott, Churchman, Michael, Gourley, Charlie, Stephens, Andrew N., Meagher, Nicola S., Ramus, Susan J., Antill, Yoland C., Campbell, Ian, Scott, Clare L., Köbel, Martin, Gorringe, Kylie L., Ryland, Georgina L., Allan, Prue E., Alsop, Kathryn, Ananda, Sumitra, Au-Yeung, George, Böhm, Maret, Brand, Alison, Chenevix-Trench, Georgia, Christie, Michael, Chiew, Yoke-Eng, Dudley, Rhiannon, Fairweather, Nicole, Fereday, Sian, Fox, Stephen B., Hacker, Neville F., Hadley, Alison M., Hendley, Joy, Ho, Gwo-Yaw, Hunter, Sally M., Jobling, Tom W., Kalli, Kimberly R., Kaufmann, Scott H., Le Page, Cecile, McNally, Orla M., McAlpine, Jessica N., Mileshkin, Linda, Pyman, Jan, Samimi, Goli, Sharma, Ragwha, and Campbell, Ian G.

Published
2021
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39. Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions

Author

Data gedreven innovatie, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Circulatory Health, Cardiovasculaire Epi Team 3, 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, Onland-Moret, N. Charlotte, AOCS Group, OPAL Study Group, The Ovarian Cancer Association Consortium (OCAC), Data gedreven innovatie, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Circulatory Health, Cardiovasculaire Epi Team 3, 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, Onland-Moret, N. Charlotte, AOCS Group, OPAL Study Group, and The Ovarian Cancer Association Consortium (OCAC)

Published
2024

40. Mesonephric‐type adenocarcinomas of the ovary: prevalence, diagnostic reproducibility, outcome, and value of PAX2.

Author

Köbel, Martin, Kang, Eun Young, Lee, Sandra, Ogilvie, Travis, Terzic, Tatjana, Wang, Linyuan, Wiebe, Nicholas JP, Al‐Shamma, Zainab, Cook, Linda S, Nelson, Gregg S, Stewart, Colin JR, von Deimling, Andreas, Kommoss, Felix KF, and Lee, Cheng‐Han

Subjects
PROGNOSIS, OVARIAN tumors, EARLY death, ADENOCARCINOMA, CALRETININ
Abstract

Mesonephric‐type (or ‐like) adenocarcinomas (MAs) of the ovary are an uncommon and aggressive histotype. They appear to arise through transdifferentiation from Müllerian lesions creating diagnostic challenges. Thus, we aimed to develop a histologic and immunohistochemical (IHC) approach to optimize the identification of MA over its histologic mimics, such as ovarian endometrioid carcinoma (EC). First, we screened 1,537 ovarian epithelial neoplasms with a four‐marker IHC panel of GATA3, TTF1, ER, and PR followed by a morphological review of EC to identify MA in retrospective cohorts. Interobserver reproducibility for the distinction of MA versus EC was assessed in 66 cases initially without and subsequently with IHC information (four‐marker panel). Expression of PAX2, CD10, and calretinin was evaluated separately, and survival analyses were performed. We identified 23 MAs from which 22 were among 385 cases initially reported as EC (5.7%) and 1 as clear cell carcinoma. The interobserver reproducibility increased from fair to substantial (κ = 0.376–0.727) with the integration of the four‐marker IHC panel. PAX2 was the single most sensitive and specific marker to distinguish MA from EC and could be used as a first‐line marker together with ER/PR and GATA3/TTF1. Patients with MA had significantly increased risk of earlier death from disease (hazard ratio = 3.08; 95% CI, 1.62–5.85; p < 0.0001) compared with patients with EC, when adjusted for age, stage, and p53 status. A diagnosis of MA has prognostic implications for stage I disease, and due to the subtlety of morphological features in some tumors, a low threshold for ancillary testing is recommended. [ABSTRACT FROM AUTHOR]

Published
2024
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42. FIGURE 1 from WNT4 Regulates Cellular Metabolism via Intracellular Activity at the Mitochondria in Breast and Gynecologic Cancers

Author

Sottnik, Joseph L., primary, Shackleford, Madeleine T., primary, Robinson, Sydney K., primary, Villagomez, Fabian R., primary, Bahnassy, Shaymaa, primary, Oesterreich, Steffi, primary, Hu, Junxiao, primary, Madak-Erdogan, Zeynep, primary, Riggins, Rebecca B., primary, Corr, Bradley R., primary, Cook, Linda S., primary, Treviño, Lindsey S., primary, Bitler, Benjamin G., primary, and Sikora, Matthew J., primary

Published
2024
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43. FIGURE 2 from WNT4 Regulates Cellular Metabolism via Intracellular Activity at the Mitochondria in Breast and Gynecologic Cancers

Author

Sottnik, Joseph L., primary, Shackleford, Madeleine T., primary, Robinson, Sydney K., primary, Villagomez, Fabian R., primary, Bahnassy, Shaymaa, primary, Oesterreich, Steffi, primary, Hu, Junxiao, primary, Madak-Erdogan, Zeynep, primary, Riggins, Rebecca B., primary, Corr, Bradley R., primary, Cook, Linda S., primary, Treviño, Lindsey S., primary, Bitler, Benjamin G., primary, and Sikora, Matthew J., primary

Published
2024
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44. FIGURE 4 from WNT4 Regulates Cellular Metabolism via Intracellular Activity at the Mitochondria in Breast and Gynecologic Cancers

Author

Sottnik, Joseph L., primary, Shackleford, Madeleine T., primary, Robinson, Sydney K., primary, Villagomez, Fabian R., primary, Bahnassy, Shaymaa, primary, Oesterreich, Steffi, primary, Hu, Junxiao, primary, Madak-Erdogan, Zeynep, primary, Riggins, Rebecca B., primary, Corr, Bradley R., primary, Cook, Linda S., primary, Treviño, Lindsey S., primary, Bitler, Benjamin G., primary, and Sikora, Matthew J., primary

Published
2024
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45. Supplementary File 7 from WNT4 Regulates Cellular Metabolism via Intracellular Activity at the Mitochondria in Breast and Gynecologic Cancers

Author

Sottnik, Joseph L., primary, Shackleford, Madeleine T., primary, Robinson, Sydney K., primary, Villagomez, Fabian R., primary, Bahnassy, Shaymaa, primary, Oesterreich, Steffi, primary, Hu, Junxiao, primary, Madak-Erdogan, Zeynep, primary, Riggins, Rebecca B., primary, Corr, Bradley R., primary, Cook, Linda S., primary, Treviño, Lindsey S., primary, Bitler, Benjamin G., primary, and Sikora, Matthew J., primary

Published
2024
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46. Supplementary File 5 from WNT4 Regulates Cellular Metabolism via Intracellular Activity at the Mitochondria in Breast and Gynecologic Cancers

Author

Sottnik, Joseph L., primary, Shackleford, Madeleine T., primary, Robinson, Sydney K., primary, Villagomez, Fabian R., primary, Bahnassy, Shaymaa, primary, Oesterreich, Steffi, primary, Hu, Junxiao, primary, Madak-Erdogan, Zeynep, primary, Riggins, Rebecca B., primary, Corr, Bradley R., primary, Cook, Linda S., primary, Treviño, Lindsey S., primary, Bitler, Benjamin G., primary, and Sikora, Matthew J., primary

Published
2024
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47. FIGURE 5 from WNT4 Regulates Cellular Metabolism via Intracellular Activity at the Mitochondria in Breast and Gynecologic Cancers

Author

Sottnik, Joseph L., primary, Shackleford, Madeleine T., primary, Robinson, Sydney K., primary, Villagomez, Fabian R., primary, Bahnassy, Shaymaa, primary, Oesterreich, Steffi, primary, Hu, Junxiao, primary, Madak-Erdogan, Zeynep, primary, Riggins, Rebecca B., primary, Corr, Bradley R., primary, Cook, Linda S., primary, Treviño, Lindsey S., primary, Bitler, Benjamin G., primary, and Sikora, Matthew J., primary

Published
2024
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48. TABLE 1 from WNT4 Regulates Cellular Metabolism via Intracellular Activity at the Mitochondria in Breast and Gynecologic Cancers

Author

Sottnik, Joseph L., primary, Shackleford, Madeleine T., primary, Robinson, Sydney K., primary, Villagomez, Fabian R., primary, Bahnassy, Shaymaa, primary, Oesterreich, Steffi, primary, Hu, Junxiao, primary, Madak-Erdogan, Zeynep, primary, Riggins, Rebecca B., primary, Corr, Bradley R., primary, Cook, Linda S., primary, Treviño, Lindsey S., primary, Bitler, Benjamin G., primary, and Sikora, Matthew J., primary

Published
2024
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49. Data from WNT4 Regulates Cellular Metabolism via Intracellular Activity at the Mitochondria in Breast and Gynecologic Cancers

Author

Sottnik, Joseph L., primary, Shackleford, Madeleine T., primary, Robinson, Sydney K., primary, Villagomez, Fabian R., primary, Bahnassy, Shaymaa, primary, Oesterreich, Steffi, primary, Hu, Junxiao, primary, Madak-Erdogan, Zeynep, primary, Riggins, Rebecca B., primary, Corr, Bradley R., primary, Cook, Linda S., primary, Treviño, Lindsey S., primary, Bitler, Benjamin G., primary, and Sikora, Matthew J., primary

Published
2024
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50. Supplementary File 4 from WNT4 Regulates Cellular Metabolism via Intracellular Activity at the Mitochondria in Breast and Gynecologic Cancers

Author

Sottnik, Joseph L., primary, Shackleford, Madeleine T., primary, Robinson, Sydney K., primary, Villagomez, Fabian R., primary, Bahnassy, Shaymaa, primary, Oesterreich, Steffi, primary, Hu, Junxiao, primary, Madak-Erdogan, Zeynep, primary, Riggins, Rebecca B., primary, Corr, Bradley R., primary, Cook, Linda S., primary, Treviño, Lindsey S., primary, Bitler, Benjamin G., primary, and Sikora, Matthew J., primary

Published
2024
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