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

Author

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

Subjects
ovarian cancer, high‐grade serous carcinoma, endometrioid, clear cell, TP53, p53, Pathology, RB1-214
Abstract

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

Author

Delores J. Grant, Ani Manichaikul, Anthony J. Alberg, Elisa V. Bandera, Jill Barnholtz‐Sloan, Melissa Bondy, Michele L. Cote, Ellen Funkhouser, Patricia G. Moorman, Lauren C. Peres, Edward S. Peters, Ann G. Schwartz, Paul D. Terry, Xin‐Qun Wang, Temitope O. Keku, Cathrine Hoyo, Andrew Berchuck, Dale P. Sandler, Jack A. Taylor, Katie M. O’Brien, Digna R. Velez Edwards, Todd L. Edwards, Alicia Beeghly‐Fadiel, Nicolas Wentzensen, Celeste Leigh Pearce, Anna H. Wu, Alice S. Whittemore, Valerie McGuire, Weiva Sieh, Joseph H. Rothstein, Francesmary Modugno, Roberta Ness, Kirsten Moysich, Mary Anne Rossing, Jennifer A. Doherty, Thomas A. Sellers, Jennifer B. Permuth‐Way, Alvaro N. Monteiro, Douglas A. Levine, Veronica Wendy Setiawan, Christopher A. Haiman, Loic LeMarchand, Lynne R. Wilkens, Beth Y. Karlan, Usha Menon, Susan Ramus, Simon Gayther, Aleksandra Gentry‐Maharaj, Kathryn L. Terry, Daniel W. Cramer, Ellen L. Goode, Melissa C. Larson, Scott H. Kaufmann, Rikki Cannioto, Kunle Odunsi, John L. Etter, Ruea‐Yea Huang, Marcus Q. Bernardini, Alicia A. Tone, Taymaa May, Marc T. Goodman, Pamela J. Thompson, Michael E. Carney, Shelley S. Tworoger, Elizabeth M. Poole, Diether Lambrechts, Ignace Vergote, Adriaan Vanderstichele, Els Van Nieuwenhuysen, Hoda Anton‐Culver, Argyrios Ziogas, James D. Brenton, Line Bjorge, Helga B. Salvensen, Lambertus A. Kiemeney, Leon F. A. G. Massuger, Tanja Pejovic, Amanda Bruegl, Melissa Moffitt, Linda Cook, Nhu D. Le, Angela Brooks‐Wilson, Linda E. Kelemen, Paul D.P. Pharoah, Honglin Song, Ian Campbell, Diana Eccles, Anna DeFazio, Catherine J. Kennedy, and Joellen M. Schildkraut

Subjects
African ancestry risk, genetic association, ovarian cancer, vitamin D pathway, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract An association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom‐designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high‐grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2‐1.7, P = 1.2 × 10−6, BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6‐3.4, P = 1.6 × 10−5, BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2‐1.7, P = 2.3 × 10−5, BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC.

Published
2019
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3. CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma

Author

Eun-Young, Kang, Ashley, Weir, Nicola S, Meagher, Kyo, Farrington, Gregg S, Nelson, Prafull, Ghatage, Cheng-Han, Lee, Marjorie J, Riggan, Adelyn, Bolithon, Gordana, Popovic, Betty, Leung, Katrina, Tang, Neil, Lambie, Joshua, Millstein, Jennifer, Alsop, Michael S, Anglesio, Beyhan, Ataseven, Ellen, Barlow, Matthias W, Beckmann, Jessica, Berger, Christiani, Bisinotto, Hans, Bösmüller, Jessica, Boros, Alison H, Brand, Angela, Brooks-Wilson, Sara Y, Brucker, Michael E, Carney, Yovanni, Casablanca, Alicia, Cazorla-Jiménez, Paul A, Cohen, Thomas P, Conrads, Linda S, Cook, Penny, Coulson, Madeleine, Courtney-Brooks, Daniel W, Cramer, Philip, Crowe, Julie M, Cunningham, Cezary, Cybulski, Kathleen M, Darcy, Mona A, El-Bahrawy, Esther, Elishaev, Ramona, Erber, Rhonda, Farrell, Sian, Fereday, Anna, Fischer, María J, García, Simon A, Gayther, Aleksandra, Gentry-Maharaj, C Blake, Gilks, Marcel, Grube, Paul R, Harnett, Shariska Petersen, Harrington, Philipp, Harter, Arndt, Hartmann, Jonathan L, Hecht, Sebastian, Heikaus, Alexander, Hein, Florian, Heitz, Joy, Hendley, Brenda Y, Hernandez, Susanna Hernando, Polo, Sabine, Heublein, Akira, Hirasawa, Estrid, Høgdall, Claus K, Høgdall, Hugo M, Horlings, David G, Huntsman, Tomasz, Huzarski, Andrea, Jewell, Mercedes, Jimenez-Linan, Michael E, Jones, Scott H, Kaufmann, Catherine J, Kennedy, Dineo, Khabele, Felix K F, Kommoss, Roy F P M, Kruitwagen, Diether, Lambrechts, Nhu D, Le, Marcin, Lener, Jenny, Lester, Yee, Leung, Anna, Linder, Liselore, Loverix, Jan, Lubiński, Rashna, Madan, G Larry, Maxwell, Francesmary, Modugno, Susan L, Neuhausen, Alexander, Olawaiye, Siel, Olbrecht, Sandra, Orsulic, José, Palacios, Celeste Leigh, Pearce, Malcolm C, Pike, Carmel M, Quinn, Ganendra Raj, Mohan, Cristina, Rodríguez-Antona, Matthias, Ruebner, Andy, Ryan, Stuart G, Salfinger, Naoko, Sasamoto, Joellen M, Schildkraut, Minouk J, Schoemaker, Mitul, Shah, Raghwa, Sharma, Yurii B, Shvetsov, Naveena, Singh, Gabe S, Sonke, Linda, Steele, Colin J R, Stewart, Karin, Sundfeldt, Anthony J, Swerdlow, Aline, Talhouk, Adeline, Tan, Sarah E, Taylor, Kathryn L, Terry, Aleksandra, Tołoczko, Nadia, Traficante, Koen K, Van de Vijver, Maaike A, van der Aa, Toon, Van Gorp, Els, Van Nieuwenhuysen, Lilian, van-Wagensveld, Ignace, Vergote, Robert A, Vierkant, Chen, Wang, Lynne R, Wilkens, Stacey J, Winham, Anna H, Wu, Javier, Benitez, Andrew, Berchuck, Francisco J, Candido Dos Reis, Anna, DeFazio, Peter A, Fasching, Ellen L, Goode, Marc T, Goodman, Jacek, Gronwald, Beth Y, Karlan, Stefan, Kommoss, Usha, Menon, Hans-Peter, Sinn, Annette, Staebler, James D, Brenton, David D, Bowtell, Paul D P, Pharoah, Susan J, Ramus, Martin, Köbel, MUMC+: MA Obstetrie Gynaecologie (3), MUMC+: Vrouw Moeder en Kind Centrum (3), Obstetrie & Gynaecologie, MUMC+: MA Arts Assistenten Obstetrie Gynaecologie (6), RS: GROW - R2 - Basic and Translational Cancer Biology, and AOCS Group

Subjects
Cancer Research, ovarian cancer, Oncology, high-grade serous carcinoma, Human medicine, prognosis, CCNE1 amplification, cyclin E1 expression
Abstract

BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC. ispartof: CANCER vol:129 issue:5 pages:697-713 ispartof: location:United States status: published

Published
2023

4. A fight-and-flight for life: A rare case of advanced cervical cancer in pregnancy

Author

Jennifer W.H. Wong, Meryl M. Sperling, Scott A. Harvey, Jeffrey L. Killeen, and Michael E. Carney

Subjects
Cervical cancer, Chemotherapy, Hypertension, Multidisciplinary, Pregnancy, Gynecology and obstetrics, RG1-991, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background: Advanced cervical cancer during pregnancy is an extremely rare event. We describe a case of at least stage IIIB cervical squamous cell carcinoma during pregnancy. This may possibly represent the longest gestation from time of diagnosis to delivery in a case of advanced cervical cancer, with potentially the most advanced gestational age at delivery and a relatively favorable outcome in the current literature.Case: A 29-year-old female at 20 0/7 weeks of gestation with at least stage IIIB squamous cell carcinoma of the cervix flew from Micronesia to Hawaii for oncologic treatment. After consultation with gynecologic oncology and maternal-fetal medicine, she opted to continue the pregnancy and began neoadjuvant chemotherapy with carboplatin and paclitaxel. At 33 2/7 weeks of gestation, she was admitted for preterm prelabor rupture of membranes and immediately underwent a cesarean delivery for heavy vaginal bleeding. Postpartum, she underwent cisplatin chemotherapy with concurrent radiation therapy. After 6 cycles of chemotherapy, the patient’s cancer had progressed to the point that hospice was recommended. She died 11 months after initial presentation. Conclusion: Advanced cervical cancer during pregnancy requires individualized treatment, shared decision making, and a multidisciplinary team approach. If the pregnancy is continued, antepartum chemotherapy should be strongly considered. Maternal prognoses tend to be poor, but neonatal outcomes appear to be favorable.

Published
2020
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5. Increased FOXJ1 protein expression is associated with improved overall survival in high-grade serous ovarian carcinoma: an Ovarian Tumor Tissue Analysis Consortium Study

Author

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

Subjects
Cancer Research, Oncology
Abstract

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

Published
2022

6. Figure S3 from Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer

Author

Ellen L. Goode, Thomas A. Sellers, Brooke L. Fridley, Paul D.P. Pharoah, Catherine M. Phelan, Jennifer Permuth-Wey, Joellen M. Schildkraut, Andrew Berchuck, Argyrios Ziogas, Hannah Yang, Anna H. Wu, Lynne R. Wilkens, Christine Walsh, Allison F. Vitonis, Robert A. Vierkant, David J. van den Berg, Jonathan P. Tyrer, Pamela J. Thompson, Kathryn L. Terry, Honglin Song, Susan J. Ramus, Malcolm C. Pike, Irene Orlow, Kirsten B. Moysich, Francesmary Modugno, Janusz Menkiszak, Jan Lubinski, Jolanta Lissowska, Hui-Yi Lin, Jenny Lester, Sharon E. Johnatty, Allan Jensen, Edwin S. Iversen, Martin Gore, Aleksandra Gentry-Maharaj, Simon A. Gayther, Robert P. Edwards, Ed M. Dicks, Anna deFazio, Cezary Cybulski, Julie M. Cunningham, Michael E. Carney, Louise A. Brinton, Maria Bisogna, Yukie T. Bean, Nicolas Wentzensen, Mary Anne Rossing, Tanja Pejovic, Celeste L. Pearce, Roberta B. Ness, Usha Menon, Douglas A. Levine, Susanne K. Kjaer, Beth Y. Karlan, Jacek Gronwald, Marc T. Goodman, Jennifer A. Doherty, Daniel Cramer, Elisa V. Bandera, Hoda Anton-Culver, Madalene A. Earp, Zachary C. Fogarty, Melissa C. Larson, Yian Ann Chen, Ailith Pirie, and Stacey J. Winham

Abstract

Supplemental Figure S 3

Published
2023

7. Supplementary Figures 1-5, Tables 1-8 from Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium

Author

Georgia Chenevix-Trench, Penelope M. Webb, Anna deFazio, Ellen L. Goode, Paul D.P. Pharoah, Stuart MacGregor, Andrew Berchuck, Yoke-Eng Chiew, Catherine Kennedy, Thomas Sellers, Rosalind Glasspool, Nadeem Siddiqui, Karen Carty, James Paul, Ian McNeish, Lene Lundvall, Claus Høgdall, Yukie Bean, Tanja Pejovic, Irene Orlow, Elisa V. Bandera, Daniel W. Cramer, Kathryn L. Terry, Edwin S. Iversen, Joellen M. Schildkraut, Robert A. Vierkant, Julie M. Cunningham, Brooke L. Fridley, Susanne Kruger Kjaer, Allan Jensen, Estrid Høgdall, Zachary C. Fogarty, Melissa C. Larson, Madalene Earp, Stacey J. Winham, Sandra Orsulic, Jenny Lester, Christine Walsh, Beth Y. Karlan, Peter Hillemanns, Jacobus Pisterer, Philipp Harter, Ira Schwaab, Andreas du Bois, Florian Heitz, Pamela J. Thompson, Michael E. Carney, Lynne R. Wilkens, Marc T. Goodman, Beata Spiewankiewicz, Iwona K. Rzepecka, Agnieszka Dansonka-Mieszkowska, Jolanta Kupryjanczyk, Anna H. Wu, Daniel O. Stram, Malcolm C. Pike, Celeste L. Pearce, Susan J. Ramus, Usha Menon, Aleksandra Gentry-Maharaj, Simon A. Gayther, Argyrios Ziogas, Hoda Anton-Culver, Rebecca Sutphen, Joseph H. Rothstein, Valerie McGuire, Alice S. Whittemore, Weiva Sieh, Diana Eccles, Ian Campbell, Valerie Rhenius, Honglin Song, Nicolas Wentzensen, Jolanta Lissowska, Louise Brinton, Cezary Cybulski, Anna Jakubowska, Jan Lubiński, Jacek Gronwald, Leon F.A.G. Massuger, Lambertus A. Kiemeney, Douglas A. Levine, Kirsten B. Moysich, Roberta B. Ness, Francesmary Modugno, Jenny Chang-Claude, Jennifer A. Doherty, Mary Anne Rossing, Sandrina Lambrechts, Ignace Vergote, Els Van Nieuwenhuysen, Diether Lambrechts, Matthias W. Beckmann, Arif B. Ekici, Alexander Hein, Peter A. Fasching, Bo Gao, Yi Lu, Jonathan Beesley, Siddhartha Kar, Jonathan P. Tyrer, and Sharon E. Johnatty

Abstract

Supplementary Figures 1-5, Tables 1-8. Supplementary Figure 1: Overview of the analytic approach. Supplementary Figure 2: QQ plots of SNPs with MAF ≥0.02 and imputation r2 ≥0.9 associated with Overall Survival in A. Supplementary Figure 3: ‘All OCAC’ histology-adjusted analysis. Supplementary Figure 4: Forest plots of promising SNPs. Supplementary Figure 5: KM-Plotter graphs of significant associations with outcome. Supplementary Table 1: All studies (OCAC & TCGA) eligible for analyses according to first-line chemotherapy. Supplementary Table 2: Description of individual OCAC studies included in the secondary 'all OCAC' analysis. Supplementary Table 3a: Overall Survival estimates for selected SNPs (MAF ≥0.02) comparing iCOGS imputed (r2 ≥0.3) and iPLEX genotyped samples. Supplementary Table 3b: Progression-free Survival estimates for selected SNPs (MAF ≥0.02) comparing iCOGS imputed (r2 ≥0.3) and iPLEX genotyped samples. Supplementary Table 4: SNPs with imputation r2 ≥0.9, EAF ≥0.02 and p ≤ 1E-05 for at least one of four outcomes analyzed in cases selected according to first-line chemotherapy. Supplementary Table 5: Meta-analysis of largest possible sample (TCGA, non-overlapping iCOGS and iplex genotyped) for selected promising SNPs analyzed in cases selected according to first-line chemotherapy. Supplementary Table 6: Significant association between protein-coding genes within 1Mb of promising SNPs and ovarian cancer outcomes. Supplementary Table 7: SNPs with imputation r-sq≥0.9 and p ≤ 1E-05 for Overall Survival in histology-adj 'all OCAC' analysis. Supplementary Table 8: iCOGS estimates for SNPs previously identified to be associated with response to chemotherapy as reported in the aNHGRI GWAS catalog.

Published
2023

8. Data from Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer

Author

Ellen L. Goode, Thomas A. Sellers, Brooke L. Fridley, Paul D.P. Pharoah, Catherine M. Phelan, Jennifer Permuth-Wey, Joellen M. Schildkraut, Andrew Berchuck, Argyrios Ziogas, Hannah Yang, Anna H. Wu, Lynne R. Wilkens, Christine Walsh, Allison F. Vitonis, Robert A. Vierkant, David J. van den Berg, Jonathan P. Tyrer, Pamela J. Thompson, Kathryn L. Terry, Honglin Song, Susan J. Ramus, Malcolm C. Pike, Irene Orlow, Kirsten B. Moysich, Francesmary Modugno, Janusz Menkiszak, Jan Lubinski, Jolanta Lissowska, Hui-Yi Lin, Jenny Lester, Sharon E. Johnatty, Allan Jensen, Edwin S. Iversen, Martin Gore, Aleksandra Gentry-Maharaj, Simon A. Gayther, Robert P. Edwards, Ed M. Dicks, Anna deFazio, Cezary Cybulski, Julie M. Cunningham, Michael E. Carney, Louise A. Brinton, Maria Bisogna, Yukie T. Bean, Nicolas Wentzensen, Mary Anne Rossing, Tanja Pejovic, Celeste L. Pearce, Roberta B. Ness, Usha Menon, Douglas A. Levine, Susanne K. Kjaer, Beth Y. Karlan, Jacek Gronwald, Marc T. Goodman, Jennifer A. Doherty, Daniel Cramer, Elisa V. Bandera, Hoda Anton-Culver, Madalene A. Earp, Zachary C. Fogarty, Melissa C. Larson, Yian Ann Chen, Ailith Pirie, and Stacey J. Winham

Abstract

Background: While numerous susceptibility loci for epithelial ovarian cancer (EOC) have been identified, few associations have been reported with overall survival. In the absence of common prognostic genetic markers, we hypothesize that rare coding variants may be associated with overall EOC survival and assessed their contribution in two exome-based genotyping projects of the Ovarian Cancer Association Consortium (OCAC).Methods: The primary patient set (Set 1) included 14 independent EOC studies (4,293 patients) and 227,892 variants, and a secondary patient set (Set 2) included six additional EOC studies (1,744 patients) and 114,620 variants. Because power to detect rare variants individually is reduced, gene-level tests were conducted. Sets were analyzed separately at individual variants and by gene, and then combined with meta-analyses (73,203 variants and 13,163 genes overlapped).Results: No individual variant reached genome-wide statistical significance. A SNP previously implicated to be associated with EOC risk and, to a lesser extent, survival, rs8170, showed the strongest evidence of association with survival and similar effect size estimates across sets (Pmeta = 1.1E−6, HRSet1 = 1.17, HRSet2 = 1.14). Rare variants in ATG2B, an autophagy gene important for apoptosis, were significantly associated with survival after multiple testing correction (Pmeta = 1.1E−6; Pcorrected = 0.01).Conclusions: Common variant rs8170 and rare variants in ATG2B may be associated with EOC overall survival, although further study is needed.Impact: This study represents the first exome-wide association study of EOC survival to include rare variant analyses, and suggests that complementary single variant and gene-level analyses in large studies are needed to identify rare variants that warrant follow-up study. Cancer Epidemiol Biomarkers Prev; 25(3); 446–54. ©2016 AACR.

Published
2023

9. Data from Genetic Variation in TYMS in the One-Carbon Transfer Pathway Is Associated with Ovarian Carcinoma Types in the Ovarian Cancer Association Consortium

Author

Ellen L. Goode, Thomas A. Sellers, Joellen M. Schildkraut, Anna H. Wu, Lynne R. Wilkens, Alice S. Whittemore, Shan Wang-Gohrke, Robert A. Vierkant, David Van Den Berg, Shelley S. Tworoger, Daniel O. Stram, Honglin Song, Susan J. Ramus, Paul D.P. Pharoah, Celeste L. Pearce, Rachel T. Palmieri, Roberta B. Ness, Kirsten Moysich, Patricia G. Moorman, Usha Menon, Galina Lurie, Susanne Krüger Kjær, Estrid Høgdall, Aleksandra Gentry-Maharaj, Simon A. Gayther, Margaret A. Gates, Brooke L. Fridley, Zachary S. Fredericksen, Douglas F. Easton, Jennifer A. Doherty, Richard A. DiCioccio, Julie M. Cunningham, Daniel W. Cramer, Georgia Chenevix-Trench, Jenny Chang-Claude, Michael E. Carney, Sony Brar, Andrew Berchuck, Jonathan Beesley, Hoda Anton-Culver, Martin Köbel, Penelope M. Webb, Mary Anne Rossing, Valerie McGuire, Marc T. Goodman, and Linda E. Kelemen

Abstract

Background: We previously reported the risks of ovarian carcinoma for common polymorphisms in one-carbon transfer genes. We sought to replicate associations for DPYD rs1801265, DNMT3A rs13420827, MTHFD1 rs1950902, MTHFS rs17284990, and TYMS rs495139 with risk of ovarian carcinoma overall and to use the large sample of assembled cases to investigate associations by histologic type.Methods: Associations were evaluated in the Ovarian Cancer Association Consortium, including 16 studies of 5,593 epithelial ovarian carcinoma cases and 9,962 controls of white non-Hispanic origin. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for age and study site.Results: The five polymorphisms were not associated with ovarian carcinoma overall (Ptrend > 0.13); however, associations for the minor allele at TYMS rs495139 were observed for carcinomas of mucinous type (OR, 1.19; 95% CI, 1.03-1.39; P = 0.02), clear cell type (OR, 0.86; 95% CI, 0.75-0.99; P = 0.04), and endometrioid type (OR, 0.90; 95% CI, 0.81-0.99; P = 0.04; Pheterogeneity = 0.001). Restriction to low-grade mucinous carcinomas further strengthened the association for the mucinous type (OR, 1.32; 95% CI, 1.07-1.62; P = 0.01). TYMS rs495139 was not associated with serous type (OR, 1.06; 95% CI, 1.00-1.13; P = 0.05).Conclusions: TYMS rs495139 may be associated with a differential risk of ovarian carcinoma types, indicating the importance of accurate histopathologic classification.Impact: Biomarkers that distinguish ovarian carcinoma types are few, and TYMS rs495139 may provide a novel clue to type etiology. Cancer Epidemiol Biomarkers Prev; 19(7); 1822–30. ©2010 AACR.

Published
2023

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

Author

Georgia Chenevix-Trench, Penelope M. Webb, Anna deFazio, Ellen L. Goode, Paul D.P. Pharoah, Stuart MacGregor, Andrew Berchuck, Yoke-Eng Chiew, Catherine Kennedy, Thomas Sellers, Rosalind Glasspool, Nadeem Siddiqui, Karen Carty, James Paul, Ian McNeish, Lene Lundvall, Claus Høgdall, Yukie Bean, Tanja Pejovic, Irene Orlow, Elisa V. Bandera, Daniel W. Cramer, Kathryn L. Terry, Edwin S. Iversen, Joellen M. Schildkraut, Robert A. Vierkant, Julie M. Cunningham, Brooke L. Fridley, Susanne Kruger Kjaer, Allan Jensen, Estrid Høgdall, Zachary C. Fogarty, Melissa C. Larson, Madalene Earp, Stacey J. Winham, Sandra Orsulic, Jenny Lester, Christine Walsh, Beth Y. Karlan, Peter Hillemanns, Jacobus Pisterer, Philipp Harter, Ira Schwaab, Andreas du Bois, Florian Heitz, Pamela J. Thompson, Michael E. Carney, Lynne R. Wilkens, Marc T. Goodman, Beata Spiewankiewicz, Iwona K. Rzepecka, Agnieszka Dansonka-Mieszkowska, Jolanta Kupryjanczyk, Anna H. Wu, Daniel O. Stram, Malcolm C. Pike, Celeste L. Pearce, Susan J. Ramus, Usha Menon, Aleksandra Gentry-Maharaj, Simon A. Gayther, Argyrios Ziogas, Hoda Anton-Culver, Rebecca Sutphen, Joseph H. Rothstein, Valerie McGuire, Alice S. Whittemore, Weiva Sieh, Diana Eccles, Ian Campbell, Valerie Rhenius, Honglin Song, Nicolas Wentzensen, Jolanta Lissowska, Louise Brinton, Cezary Cybulski, Anna Jakubowska, Jan Lubiński, Jacek Gronwald, Leon F.A.G. Massuger, Lambertus A. Kiemeney, Douglas A. Levine, Kirsten B. Moysich, Roberta B. Ness, Francesmary Modugno, Jenny Chang-Claude, Jennifer A. Doherty, Mary Anne Rossing, Sandrina Lambrechts, Ignace Vergote, Els Van Nieuwenhuysen, Diether Lambrechts, Matthias W. Beckmann, Arif B. Ekici, Alexander Hein, Peter A. Fasching, Bo Gao, Yi Lu, Jonathan Beesley, Siddhartha Kar, Jonathan P. Tyrer, and Sharon E. Johnatty

Abstract

Purpose: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome.Experimental Design: We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis.Results: Five SNPs were significantly associated (P ≤ 1.0 × 10−5) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23), and rs6674079 (1q22), were located in long noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P ≤ 7.1 × 10−6). ENCODE ChIP-seq data at 1q22 for normal ovary show evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression and high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA ≤6 × 10−3).Conclusions: We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies. Clin Cancer Res; 21(23); 5264–76. ©2015 AACR.

Published
2023

11. Supplemental Tables from Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer

Author

Ellen L. Goode, Thomas A. Sellers, Brooke L. Fridley, Paul D.P. Pharoah, Catherine M. Phelan, Jennifer Permuth-Wey, Joellen M. Schildkraut, Andrew Berchuck, Argyrios Ziogas, Hannah Yang, Anna H. Wu, Lynne R. Wilkens, Christine Walsh, Allison F. Vitonis, Robert A. Vierkant, David J. van den Berg, Jonathan P. Tyrer, Pamela J. Thompson, Kathryn L. Terry, Honglin Song, Susan J. Ramus, Malcolm C. Pike, Irene Orlow, Kirsten B. Moysich, Francesmary Modugno, Janusz Menkiszak, Jan Lubinski, Jolanta Lissowska, Hui-Yi Lin, Jenny Lester, Sharon E. Johnatty, Allan Jensen, Edwin S. Iversen, Martin Gore, Aleksandra Gentry-Maharaj, Simon A. Gayther, Robert P. Edwards, Ed M. Dicks, Anna deFazio, Cezary Cybulski, Julie M. Cunningham, Michael E. Carney, Louise A. Brinton, Maria Bisogna, Yukie T. Bean, Nicolas Wentzensen, Mary Anne Rossing, Tanja Pejovic, Celeste L. Pearce, Roberta B. Ness, Usha Menon, Douglas A. Levine, Susanne K. Kjaer, Beth Y. Karlan, Jacek Gronwald, Marc T. Goodman, Jennifer A. Doherty, Daniel Cramer, Elisa V. Bandera, Hoda Anton-Culver, Madalene A. Earp, Zachary C. Fogarty, Melissa C. Larson, Yian Ann Chen, Ailith Pirie, and Stacey J. Winham

Abstract

Supplemental Table S1: Number of invasive EOC patients by study site. Supplemental Table S2: Results of Set 1 single variant analysis, for variants with P

Published
2023

12. Supplementary Tables 1-2 from Genetic Variation in TYMS in the One-Carbon Transfer Pathway Is Associated with Ovarian Carcinoma Types in the Ovarian Cancer Association Consortium

Author

Ellen L. Goode, Thomas A. Sellers, Joellen M. Schildkraut, Anna H. Wu, Lynne R. Wilkens, Alice S. Whittemore, Shan Wang-Gohrke, Robert A. Vierkant, David Van Den Berg, Shelley S. Tworoger, Daniel O. Stram, Honglin Song, Susan J. Ramus, Paul D.P. Pharoah, Celeste L. Pearce, Rachel T. Palmieri, Roberta B. Ness, Kirsten Moysich, Patricia G. Moorman, Usha Menon, Galina Lurie, Susanne Krüger Kjær, Estrid Høgdall, Aleksandra Gentry-Maharaj, Simon A. Gayther, Margaret A. Gates, Brooke L. Fridley, Zachary S. Fredericksen, Douglas F. Easton, Jennifer A. Doherty, Richard A. DiCioccio, Julie M. Cunningham, Daniel W. Cramer, Georgia Chenevix-Trench, Jenny Chang-Claude, Michael E. Carney, Sony Brar, Andrew Berchuck, Jonathan Beesley, Hoda Anton-Culver, Martin Köbel, Penelope M. Webb, Mary Anne Rossing, Valerie McGuire, Marc T. Goodman, and Linda E. Kelemen

Abstract

Supplementary Tables 1-2 from Genetic Variation in TYMS in the One-Carbon Transfer Pathway Is Associated with Ovarian Carcinoma Types in the Ovarian Cancer Association Consortium

Published
2023

13. Supplemental Figure Legends from Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer

Author

Ellen L. Goode, Thomas A. Sellers, Brooke L. Fridley, Paul D.P. Pharoah, Catherine M. Phelan, Jennifer Permuth-Wey, Joellen M. Schildkraut, Andrew Berchuck, Argyrios Ziogas, Hannah Yang, Anna H. Wu, Lynne R. Wilkens, Christine Walsh, Allison F. Vitonis, Robert A. Vierkant, David J. van den Berg, Jonathan P. Tyrer, Pamela J. Thompson, Kathryn L. Terry, Honglin Song, Susan J. Ramus, Malcolm C. Pike, Irene Orlow, Kirsten B. Moysich, Francesmary Modugno, Janusz Menkiszak, Jan Lubinski, Jolanta Lissowska, Hui-Yi Lin, Jenny Lester, Sharon E. Johnatty, Allan Jensen, Edwin S. Iversen, Martin Gore, Aleksandra Gentry-Maharaj, Simon A. Gayther, Robert P. Edwards, Ed M. Dicks, Anna deFazio, Cezary Cybulski, Julie M. Cunningham, Michael E. Carney, Louise A. Brinton, Maria Bisogna, Yukie T. Bean, Nicolas Wentzensen, Mary Anne Rossing, Tanja Pejovic, Celeste L. Pearce, Roberta B. Ness, Usha Menon, Douglas A. Levine, Susanne K. Kjaer, Beth Y. Karlan, Jacek Gronwald, Marc T. Goodman, Jennifer A. Doherty, Daniel Cramer, Elisa V. Bandera, Hoda Anton-Culver, Madalene A. Earp, Zachary C. Fogarty, Melissa C. Larson, Yian Ann Chen, Ailith Pirie, and Stacey J. Winham

Abstract

Supplemental Figure Legends

Published
2023

14. Supplementary Table 4 from Single Nucleotide Polymorphisms in the TP53 Region and Susceptibility to Invasive Epithelial Ovarian Cancer

Author

Montserrat Garcia-Closas, Mark Sherman, Stephen Chanock, Brian Calingaert, Shelley S. Tworoger, Susan E. Hankinson, Daniel W. Cramer, Kathryn L. Terry, Argyrios Ziogas, Hoda Anton-Culver, Lydia Quaye, Valerie McGuire, Alice S. Whittemore, Paul D.P. Pharoah, Honglin Song, Douglas F. Easton, Claus Hogdall, Jan Blaakaer, Estrid Hogdall, Susanne Krüger Kjaer, Ian Jacobs, Susan J. Ramus, Simon A. Gayther, Pamela J. Thompson, Michael E. Carney, Galina Lurie, Marc T. Goodman, Rebecca Anderson, Christopher K. Elund, David Conti, David Van Den Berg, Anna H. Wu, Leigh Pearce, Thomas A. Sellers, Rebecca Sutphen, Catherine Phelan, Xiaoqing Chen, Jonathan Beesley, Penelope M. Webb, Georgia Chenevix-Trench, David N. Rider, Robert A. Vierkant, Julie M. Cunningham, Beata Peplonska, Louise Brinton, Jolanta Lissowska, Jeffrey R. Marks, Andrew Berchuck, Patricia G. Moorman, Edwin S. Iversen, Merlise A. Clyde, Ellen L. Goode, and Joellen M. Schildkraut

Abstract

Supplementary Table 4 from Single Nucleotide Polymorphisms in the TP53 Region and Susceptibility to Invasive Epithelial Ovarian Cancer

Published
2023

15. Data from Tagging Single Nucleotide Polymorphisms in Cell Cycle Control Genes and Susceptibility to Invasive Epithelial Ovarian Cancer

Author

Paul D.P. Pharoah, Andrew Berchuck, Georgia Chenevix-Trench, C. Leigh Pearce, Joellen Schildkraut, Bruce A.J. Ponder, Ian Jacobs, Douglas F. Easton, Beata Peplonska, Jolanta Lissowska, Louise Brinton, Montserrat Garcia-Closas, Jeffrey R. Marks, Edwin S. Iversen, Malcolm C. Pike, Anna H. Wu, Thomas A. Sellers, Julie M. Cunningham, Fergus J. Couch, Ellen L. Goode, Kirsten B. Moysich, Robert P. Edwards, Roberta B. Ness, Francesmary Modugno, Michael E. Carney, Galina Lurie, Marc T. Goodman, David C. Whiteman, Adele C. Green, Jonathan Beesley, Penelope M. Webb, Valerie McGuire, Richard DiCioccio, Jan Blaeker, Claus Hogdall, Estrid Hogdall, Danielle Shadforth, Jonathan Tyrer, Lydia Quaye, Alice S. Whittemore, Susan Krüger Kjaer, Susan J. Ramus, Honglin Song, and Simon A. Gayther

Abstract

High-risk susceptibility genes explain CCND1, CCND2, CCND3, CCNE1, CDK2, CDK4, CDK6, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, and CDKN2D—and risk of invasive epithelial ovarian cancer. We used a two-stage, multicenter, case-control study. In stage 1, 88 SNPs that tag common variation in these genes were genotyped in three studies from the United Kingdom, United States, and Denmark (∼1,500 cases and 2,500 controls). Genotype frequencies in cases and controls were compared using logistic regression. In stage 2, eight other studies from Australia, Poland, and the United States (∼2,000 cases and ∼3,200 controls) were genotyped for the five most significant SNPs from stage 1. No SNP was significant in the stage 2 data alone. Using the combined stages 1 and 2 data set, CDKN2A rs3731257 and CDKN1B rs2066827 were associated with disease risk (unadjusted P trend = 0.008 and 0.036, respectively), but these were not significant after adjusting for multiple testing. Carrying the minor allele of these SNPs was found to be associated with reduced risk [OR, 0.91 (0.85–0.98) for rs3731257; and OR, 0.93 (0.87–0.995) for rs2066827]. In conclusion, we have found evidence that a single tagged SNP in both the CDKN2A and CDKN1B genes may be associated with reduced ovarian cancer risk. This study highlights the need for multicenter collaborations for genetic association studies. [Cancer Res 2007;67(7):3027–35]

Published
2023

16. Supplementary Figure 1 from Single Nucleotide Polymorphisms in the TP53 Region and Susceptibility to Invasive Epithelial Ovarian Cancer

Author

Montserrat Garcia-Closas, Mark Sherman, Stephen Chanock, Brian Calingaert, Shelley S. Tworoger, Susan E. Hankinson, Daniel W. Cramer, Kathryn L. Terry, Argyrios Ziogas, Hoda Anton-Culver, Lydia Quaye, Valerie McGuire, Alice S. Whittemore, Paul D.P. Pharoah, Honglin Song, Douglas F. Easton, Claus Hogdall, Jan Blaakaer, Estrid Hogdall, Susanne Krüger Kjaer, Ian Jacobs, Susan J. Ramus, Simon A. Gayther, Pamela J. Thompson, Michael E. Carney, Galina Lurie, Marc T. Goodman, Rebecca Anderson, Christopher K. Elund, David Conti, David Van Den Berg, Anna H. Wu, Leigh Pearce, Thomas A. Sellers, Rebecca Sutphen, Catherine Phelan, Xiaoqing Chen, Jonathan Beesley, Penelope M. Webb, Georgia Chenevix-Trench, David N. Rider, Robert A. Vierkant, Julie M. Cunningham, Beata Peplonska, Louise Brinton, Jolanta Lissowska, Jeffrey R. Marks, Andrew Berchuck, Patricia G. Moorman, Edwin S. Iversen, Merlise A. Clyde, Ellen L. Goode, and Joellen M. Schildkraut

Abstract

Supplementary Figure 1 from Single Nucleotide Polymorphisms in the TP53 Region and Susceptibility to Invasive Epithelial Ovarian Cancer

Published
2023

17. Supplementary Tables 1-4 from Tagging Single Nucleotide Polymorphisms in Cell Cycle Control Genes and Susceptibility to Invasive Epithelial Ovarian Cancer

Author

Paul D.P. Pharoah, Andrew Berchuck, Georgia Chenevix-Trench, C. Leigh Pearce, Joellen Schildkraut, Bruce A.J. Ponder, Ian Jacobs, Douglas F. Easton, Beata Peplonska, Jolanta Lissowska, Louise Brinton, Montserrat Garcia-Closas, Jeffrey R. Marks, Edwin S. Iversen, Malcolm C. Pike, Anna H. Wu, Thomas A. Sellers, Julie M. Cunningham, Fergus J. Couch, Ellen L. Goode, Kirsten B. Moysich, Robert P. Edwards, Roberta B. Ness, Francesmary Modugno, Michael E. Carney, Galina Lurie, Marc T. Goodman, David C. Whiteman, Adele C. Green, Jonathan Beesley, Penelope M. Webb, Valerie McGuire, Richard DiCioccio, Jan Blaeker, Claus Hogdall, Estrid Hogdall, Danielle Shadforth, Jonathan Tyrer, Lydia Quaye, Alice S. Whittemore, Susan Krüger Kjaer, Susan J. Ramus, Honglin Song, and Simon A. Gayther

Abstract

Supplementary Tables 1-4 from Tagging Single Nucleotide Polymorphisms in Cell Cycle Control Genes and Susceptibility to Invasive Epithelial Ovarian Cancer

Published
2023

18. Supplementary Table 2 from Single Nucleotide Polymorphisms in the TP53 Region and Susceptibility to Invasive Epithelial Ovarian Cancer

Author

Montserrat Garcia-Closas, Mark Sherman, Stephen Chanock, Brian Calingaert, Shelley S. Tworoger, Susan E. Hankinson, Daniel W. Cramer, Kathryn L. Terry, Argyrios Ziogas, Hoda Anton-Culver, Lydia Quaye, Valerie McGuire, Alice S. Whittemore, Paul D.P. Pharoah, Honglin Song, Douglas F. Easton, Claus Hogdall, Jan Blaakaer, Estrid Hogdall, Susanne Krüger Kjaer, Ian Jacobs, Susan J. Ramus, Simon A. Gayther, Pamela J. Thompson, Michael E. Carney, Galina Lurie, Marc T. Goodman, Rebecca Anderson, Christopher K. Elund, David Conti, David Van Den Berg, Anna H. Wu, Leigh Pearce, Thomas A. Sellers, Rebecca Sutphen, Catherine Phelan, Xiaoqing Chen, Jonathan Beesley, Penelope M. Webb, Georgia Chenevix-Trench, David N. Rider, Robert A. Vierkant, Julie M. Cunningham, Beata Peplonska, Louise Brinton, Jolanta Lissowska, Jeffrey R. Marks, Andrew Berchuck, Patricia G. Moorman, Edwin S. Iversen, Merlise A. Clyde, Ellen L. Goode, and Joellen M. Schildkraut

Abstract

Supplementary Table 2 from Single Nucleotide Polymorphisms in the TP53 Region and Susceptibility to Invasive Epithelial Ovarian Cancer

Published
2023

19. Supplementary Table 3 from Single Nucleotide Polymorphisms in the TP53 Region and Susceptibility to Invasive Epithelial Ovarian Cancer

Author

Montserrat Garcia-Closas, Mark Sherman, Stephen Chanock, Brian Calingaert, Shelley S. Tworoger, Susan E. Hankinson, Daniel W. Cramer, Kathryn L. Terry, Argyrios Ziogas, Hoda Anton-Culver, Lydia Quaye, Valerie McGuire, Alice S. Whittemore, Paul D.P. Pharoah, Honglin Song, Douglas F. Easton, Claus Hogdall, Jan Blaakaer, Estrid Hogdall, Susanne Krüger Kjaer, Ian Jacobs, Susan J. Ramus, Simon A. Gayther, Pamela J. Thompson, Michael E. Carney, Galina Lurie, Marc T. Goodman, Rebecca Anderson, Christopher K. Elund, David Conti, David Van Den Berg, Anna H. Wu, Leigh Pearce, Thomas A. Sellers, Rebecca Sutphen, Catherine Phelan, Xiaoqing Chen, Jonathan Beesley, Penelope M. Webb, Georgia Chenevix-Trench, David N. Rider, Robert A. Vierkant, Julie M. Cunningham, Beata Peplonska, Louise Brinton, Jolanta Lissowska, Jeffrey R. Marks, Andrew Berchuck, Patricia G. Moorman, Edwin S. Iversen, Merlise A. Clyde, Ellen L. Goode, and Joellen M. Schildkraut

Abstract

Supplementary Table 3 from Single Nucleotide Polymorphisms in the TP53 Region and Susceptibility to Invasive Epithelial Ovarian Cancer

Published
2023

20. Supplementary Figure 2 from Single Nucleotide Polymorphisms in the TP53 Region and Susceptibility to Invasive Epithelial Ovarian Cancer

Author

Montserrat Garcia-Closas, Mark Sherman, Stephen Chanock, Brian Calingaert, Shelley S. Tworoger, Susan E. Hankinson, Daniel W. Cramer, Kathryn L. Terry, Argyrios Ziogas, Hoda Anton-Culver, Lydia Quaye, Valerie McGuire, Alice S. Whittemore, Paul D.P. Pharoah, Honglin Song, Douglas F. Easton, Claus Hogdall, Jan Blaakaer, Estrid Hogdall, Susanne Krüger Kjaer, Ian Jacobs, Susan J. Ramus, Simon A. Gayther, Pamela J. Thompson, Michael E. Carney, Galina Lurie, Marc T. Goodman, Rebecca Anderson, Christopher K. Elund, David Conti, David Van Den Berg, Anna H. Wu, Leigh Pearce, Thomas A. Sellers, Rebecca Sutphen, Catherine Phelan, Xiaoqing Chen, Jonathan Beesley, Penelope M. Webb, Georgia Chenevix-Trench, David N. Rider, Robert A. Vierkant, Julie M. Cunningham, Beata Peplonska, Louise Brinton, Jolanta Lissowska, Jeffrey R. Marks, Andrew Berchuck, Patricia G. Moorman, Edwin S. Iversen, Merlise A. Clyde, Ellen L. Goode, and Joellen M. Schildkraut

Abstract

Supplementary Figure 2 from Single Nucleotide Polymorphisms in the TP53 Region and Susceptibility to Invasive Epithelial Ovarian Cancer

Published
2023

21. Data from Single Nucleotide Polymorphisms in the TP53 Region and Susceptibility to Invasive Epithelial Ovarian Cancer

Author

Montserrat Garcia-Closas, Mark Sherman, Stephen Chanock, Brian Calingaert, Shelley S. Tworoger, Susan E. Hankinson, Daniel W. Cramer, Kathryn L. Terry, Argyrios Ziogas, Hoda Anton-Culver, Lydia Quaye, Valerie McGuire, Alice S. Whittemore, Paul D.P. Pharoah, Honglin Song, Douglas F. Easton, Claus Hogdall, Jan Blaakaer, Estrid Hogdall, Susanne Krüger Kjaer, Ian Jacobs, Susan J. Ramus, Simon A. Gayther, Pamela J. Thompson, Michael E. Carney, Galina Lurie, Marc T. Goodman, Rebecca Anderson, Christopher K. Elund, David Conti, David Van Den Berg, Anna H. Wu, Leigh Pearce, Thomas A. Sellers, Rebecca Sutphen, Catherine Phelan, Xiaoqing Chen, Jonathan Beesley, Penelope M. Webb, Georgia Chenevix-Trench, David N. Rider, Robert A. Vierkant, Julie M. Cunningham, Beata Peplonska, Louise Brinton, Jolanta Lissowska, Jeffrey R. Marks, Andrew Berchuck, Patricia G. Moorman, Edwin S. Iversen, Merlise A. Clyde, Ellen L. Goode, and Joellen M. Schildkraut

Abstract

The p53 protein is critical for multiple cellular functions including cell growth and DNA repair. We assessed whether polymorphisms in the region encoding TP53 were associated with risk of invasive ovarian cancer. The study population includes a total of 5,206 invasive ovarian cancer cases (2,829 of which were serous) and 8,790 controls from 13 case-control or nested case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Three of the studies performed independent discovery investigations involving genotyping of up to 23 single nucleotide polymorphisms (SNP) in the TP53 region. Significant findings from this discovery phase were followed up for replication in the other OCAC studies. Mixed effects logistic regression was used to generate posterior median per allele odds ratios (OR), 95% probability intervals (PI), and Bayes factors (BF) for genotype associations. Five SNPs showed significant associations with risk in one or more of the discovery investigations and were followed up by OCAC. Mixed effects analysis confirmed associations with serous invasive cancers for two correlated (r2 = 0.62) SNPs: rs2287498 (median per allele OR, 1.30; 95% PI, 1.07–1.57) and rs12951053 (median per allele OR, 1.19; 95% PI, 1.01–1.38). Analyses of other histologic subtypes suggested similar associations with endometrioid but not with mucinous or clear cell cancers. This large study provides statistical evidence for a small increase in risk of ovarian cancer associated with common variants in the TP53 region. [Cancer Res 2009;69(6):2349–57]

Published
2023

22. Supplementary Table 1 from Single Nucleotide Polymorphisms in the TP53 Region and Susceptibility to Invasive Epithelial Ovarian Cancer

Author

Montserrat Garcia-Closas, Mark Sherman, Stephen Chanock, Brian Calingaert, Shelley S. Tworoger, Susan E. Hankinson, Daniel W. Cramer, Kathryn L. Terry, Argyrios Ziogas, Hoda Anton-Culver, Lydia Quaye, Valerie McGuire, Alice S. Whittemore, Paul D.P. Pharoah, Honglin Song, Douglas F. Easton, Claus Hogdall, Jan Blaakaer, Estrid Hogdall, Susanne Krüger Kjaer, Ian Jacobs, Susan J. Ramus, Simon A. Gayther, Pamela J. Thompson, Michael E. Carney, Galina Lurie, Marc T. Goodman, Rebecca Anderson, Christopher K. Elund, David Conti, David Van Den Berg, Anna H. Wu, Leigh Pearce, Thomas A. Sellers, Rebecca Sutphen, Catherine Phelan, Xiaoqing Chen, Jonathan Beesley, Penelope M. Webb, Georgia Chenevix-Trench, David N. Rider, Robert A. Vierkant, Julie M. Cunningham, Beata Peplonska, Louise Brinton, Jolanta Lissowska, Jeffrey R. Marks, Andrew Berchuck, Patricia G. Moorman, Edwin S. Iversen, Merlise A. Clyde, Ellen L. Goode, and Joellen M. Schildkraut

Abstract

Supplementary Table 1 from Single Nucleotide Polymorphisms in the TP53 Region and Susceptibility to Invasive Epithelial Ovarian Cancer

Published
2023

23. Two Cases of Mesonephric-like Carcinoma Arising From Endometriosis: Case Report and Review of the Literature

Author

Connie Shinru, Chang, Michael E, Carney, and Jeffrey L, Killeen

Subjects
Obstetrics and Gynecology, Pathology and Forensic Medicine
Abstract

Endometriosis is a common condition in reproductive age women that is defined as the presence of endometrial tissue (epithelial and/or stromal) outside the uterine corpus. While not a premalignant lesion, it is a condition with a potential for malignancy, especially in the ovaries. Notable endometriosis-associated neoplasms include clear cell carcinoma and endometrioid adenocarcinoma of the ovaries. There have been recent reports of mesonephric-like adenocarcinoma (MLA) of the ovary, a very rare neoplasm with similar morphologic and immunophenotypic characteristics as mesonephric adenocarcinoma, however, without an association with mesonephric remnants. Some of these cases have been associated with endometriosis. Here, we describe 2 cases of MLA arising directly from endometriosis. In both cases, there was evidence of endometriosis contiguous with the tumor and invasion from other sources was excluded. The immunophenotypes of both tumors were typical of mesonephric adenocarcinoma except PAX-8 was strongly positive suggesting a Mullerian origin. Molecular testing on one of the cases revealed KRAS and P53 mutations. We review published findings of MLA and associated endometriosis. This report describes the sixth and seventh reported cases of MLA associated with endometriosis and the first reported cases of MLA arising directly from endometriosis and associated with other forms of epithelial proliferation within endometriosis. These 2 cases provide potential evidence that MLA should be considered an endometriosis-associated neoplasms.

Published
2022

24. Validated biomarker assays confirm that <scp>ARID1A</scp> loss is confounded with <scp>MMR</scp> deficiency, <scp> CD8 + TIL </scp> infiltration, and provides no independent prognostic value in endometriosis‐associated ovarian carcinomas

Author

Karolin Heinze, Tayyebeh M Nazeran, Sandra Lee, Pauline Krämer, Evan S Cairns, Derek S Chiu, Samuel CY Leung, Eun Young Kang, Nicola S Meagher, Catherine J Kennedy, Jessica Boros, Friedrich Kommoss, Hans‐Walter Vollert, Florian Heitz, Andreas Bois, Philipp Harter, Marcel Grube, Bernhard Kraemer, Annette Staebler, Felix KF Kommoss, Sabine Heublein, Hans‐Peter Sinn, Naveena Singh, Angela Laslavic, Esther Elishaev, Alex Olawaiye, Kirsten Moysich, Francesmary Modugno, Raghwa Sharma, Alison H Brand, Paul R Harnett, Anna DeFazio, Renée T Fortner, Jan Lubinski, Marcin Lener, Aleksandra Tołoczko‐Grabarek, Cezary Cybulski, Helena Gronwald, Jacek Gronwald, Penny Coulson, Mona A El‐Bahrawy, Michael E Jones, Minouk J Schoemaker, Anthony J Swerdlow, Kylie L Gorringe, Ian Campbell, Linda Cook, Simon A Gayther, Michael E Carney, Yurii B Shvetsov, Brenda Y Hernandez, Lynne R Wilkens, Marc T Goodman, Constantina Mateoiu, Anna Linder, Karin Sundfeldt, Linda E Kelemen, Aleksandra Gentry‐Maharaj, Martin Widschwendter, Usha Menon, Kelly L Bolton, Jennifer Alsop, Mitul Shah, Mercedes Jimenez‐Linan, Paul DP Pharoah, James D Brenton, Kara L Cushing‐Haugen, Holly R Harris, Jennifer A Doherty, Blake Gilks, Prafull Ghatage, David G Huntsman, Gregg S Nelson, Anna V Tinker, Cheng‐Han Lee, Ellen L Goode, Brad H Nelson, Susan J Ramus, Stefan Kommoss, Aline Talhouk, Martin Köbel, and Michael S Anglesio

Subjects
Ovarian Neoplasms, Canada, Brain Neoplasms, Carcinoma, Endometriosis, Nuclear Proteins, CD8-Positive T-Lymphocytes, Prognosis, Article, Pathology and Forensic Medicine, DNA-Binding Proteins, Neoplastic Syndromes, Hereditary, Mutation, Biomarkers, Tumor, Humans, Female, Colorectal Neoplasms, Carcinoma, Endometrioid, Transcription Factors
Abstract

ARID1A (BAF250a) is a component of the SWI/SNF chromatin modifying complex, plays an important tumour suppressor role, and is considered prognostic in several malignancies. However, in ovarian carcinomas there are contradictory reports on its relationship to outcome, immune response, and correlation with clinicopathological features. We assembled a series of 1,623 endometriosis-associated ovarian carcinomas, including 1,078 endometrioid (ENOC) and 545 clear cell (CCOC) ovarian carcinomas through combining resources of the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Canadian Ovarian Unified Experimental Resource (COEUR), local, and collaborative networks. Validated immunohistochemical surrogate assays for ARID1A mutations were applied to all samples. We investigated associations between ARID1A loss/mutation, clinical features, outcome, CD8+ tumour-infiltrating lymphocytes (CD8+ TIL), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOC and 25% of ENOC. We found no associations between ARID1A loss and outcomes, stage, age, or CD8+ TIL status in CCOC. Similarly, we found no association with outcome or stage in endometrioid cases. In ENOC, ARID1A loss was more prevalent in younger patients (p=0.012), and associated with MMRd (p

Published
2022

25. Identification of a Locus Near ULK1 Associated With Progression-Free Survival in Ovarian Cancer

Author

Stacey L. Edwards, Francesmary Modugno, Michael E. Carney, Jonathan Tyrer, Klaus Bauman, Jue-Sheng Ong, Tanja Pejovic, Rosalind Glasspool, Matthias Dürst, Bryan M. McCauley, Javier Benitez, Andreas du Bois, Ann-Marie Patch, Karen McCue, Florian Heitz, Diether Lambrechts, Paul D.P. Pharoah, Beth Y. Karlan, David G. Huntsman, Matthias W. Beckmann, Wei Shi, Penelope M. Webb, Michelle M.M. Woo, Kathryn L. Terry, Georgia Chenevix-Trench, Puya Gharahkhani, Melissa C. Larson, Kirsten B. Moysich, Estrid Høgdall, Sian Fereday, Julie M. Cunningham, Joellen M. Schildkraut, Andrew Civitarese, Jenny Lester, Peter A. Fasching, Ellen L. Goode, Stuart MacGregor, Jonathan Beesley, Allan Jensen, Michael Friedlander, Claus Høgdall, Stacey J. Winham, Yi Lu, Marc T. Goodman, Thilo Dörk, Dylan M. Glubb, Sharon E. Johnatty, Digna R. Velez Edwards, Tracy A. O'Mara, Melissa Moffitt, Taymaa May, Marjorie J. Riggan, Andrew Berchuck, Jacobus Pfisterer, Bo Gao, María Josefa Mosteiro García, Samantha Hinsley, Alicia Beeghly-Fadiel, Ignace Vergote, Michael C.J. Quinn, Sebastian M. Armasu, Anna deFazio, Line Bjørge, Daniel W. Cramer, Gabrielle Ene, Catherine J. Kennedy, and Susanne K. Kjaer

Subjects
EXPRESSION, Oncology, medicine.medical_specialty, SUSCEPTIBILITY LOCI, endocrine system diseases, Epidemiology, Single-nucleotide polymorphism, Locus (genetics), Genome-wide association study, LIKELIHOOD, chemistry.chemical_compound, Internal medicine, KINASE, Medicine, Progression-free survival, POLYMORPHISMS, METAANALYSIS, Public, Environmental & Occupational Health, OUTCOMES, Science & Technology, business.industry, CONSORTIUM, Cancer, medicine.disease, Carboplatin, 3. Good health, SEROUS OVARIAN, chemistry, Genetic marker, AUTOPHAGY, business, Ovarian cancer, Life Sciences & Biomedicine
Abstract

Background: Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance. Methods: We carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy. Results: We found seven SNPs at 12q24.33 associated with PFS (P < 5 × 10–8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15–1.34; P = 1.47 × 10–8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro. Conclusions: The locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association. Impact: This finding provides insight into genetic markers associated with EOC outcome and potential treatment options. See related commentary by Peres and Monteiro, p. 1604

Published
2021

26. Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE)

Author

Sven Mahner, Robertson Mackenzie, Aline Talhouk, Linda E. Kelemen, Gottfried E. Konecny, Jennifer Alsop, Rosalind Glasspool, Chiu-Chen Tseng, Joy Hendley, Dennis J. Slamon, Jennifer A. Doherty, Andrew Berchuck, Anna H. Wu, Anna M. Piskorz, Chen Wang, Cristina Rodríguez-Antona, D.G.H. de Silva, Valerie Rhenius, Peter A. Fasching, Stacey J. Winham, Gary L. Keeney, Teodora Goranova, Joshy George, Jan Lubinski, Michelle J. Henderson, Rex C. Bentley, Jenny Lester, Sabine Behrens, Joellen M. Schildkraut, Michael E. Carney, Timothy Budden, David G. Huntsman, Oleg Oszurek, Michael S. Anglesio, Jacek Gronwald, Ruby Yun-Ju Huang, Martin Köbel, Javier Benitez, Martin Widschwendter, Melissa C. Larson, Raghwa Sharma, Clara Bodelon, Usha Menon, Janusz Menkiszak, Blake Gilks, María Josefa Mosteiro García, Jesús García-Donas, Wafaa Elatre, Scott H. Kaufmann, Paul Haluska, Pamela J. Thompson, Boris Winterhoff, Susan J. Ramus, Louise A. Brinton, Simon A. Gayther, Mary Anne Rossing, Georgia Chenevix-Trench, Hugh Luk, Jolanta Lissowska, Marc T. Goodman, Billy Chen, Beth Y. Karlan, Naveena Singh, Sian Fereday, Mark E. Sherman, Ana Osorio, Lynne R. Wilkens, Maria P. Intermaggio, Brenda Y. Hernandez, Britton Trabert, Esther Herpel, Mercedes Jimenez-Linan, Janine Senz, Geyi Liu, Celeste Leigh Pearce, Samuel C Y Leong, Iain A. McNeish, Isabelle Ray-Coquard, Susana Banerjee, Malcolm C. Pike, Liz-Anne Lewsley, Helen Steed, Honglin Song, Samantha Hinsley, David D.L. Bowtell, James D. Brenton, Holly R. Harris, Tuan Zea Tan, Cezary Cybulski, Alicia Beeghly-Fadiel, A. Toloczko, Nikilyn Nevins, Robert S. Brown, Darren Ennis, Stephanie Chen, Euan A. Stronach, José Palacios, Sandra Orsulic, Anna deFazio, Geoff Macintyre, Kara L. Cushing-Haugen, Mila Volchek, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Ellen L. Goode, Paul D.P. Pharoah, Hanwei Sudderuddin, Stefan Kommoss, Derek S. Chiu, Huei San Leong, Peter Sinn, Catherine J. Kennedy, Chloe Karpinskyj, Alison Brand, Amy Lum, Veronica Chow, Nicolas Wentzensen, Tayyebeh M. Nazeran, Nadia Traficante, Dustin Johnson, Yoke-Eng Chiew, Casey S. Greene, Jennifer M Koziak, Renée T. Fortner, Imperial College Healthcare NHS Trust- BRC Funding, Cancer Research UK, Ovarian Cancer Action, Talhouk, Aline [0000-0001-7760-410X], George, Joshy [0000-0001-8510-8229], Wang, Chen [0000-0003-2638-3081], Tan, Tuan Zea [0000-0001-6624-1593], Behrens, Sabine [0000-0002-9714-104X], Bodelon, Clara [0000-0002-6578-2678], Brinton, Louise [0000-0003-3853-8562], Fortner, Renée T [0000-0002-1426-8505], García-Donas, Jesús [0000-0001-7731-3601], Gentry-Maharaj, Aleksandra [0000-0001-7270-9762], Glasspool, Rosalind [0000-0002-5000-1680], Greene, Casey S [0000-0001-8713-9213], Harris, Holly R [0000-0002-2572-6727], Kaufmann, Scott H [0000-0002-4900-7145], Kennedy, Catherine J [0000-0002-4465-5784], Köbel, Martin [0000-0002-6615-2037], Koziak, Jennifer M [0000-0001-5830-0397], Lissowska, Jolanta [0000-0003-2695-5799], McNeish, Iain A [0000-0002-9387-7586], Menkiszak, Janusz [0000-0001-8279-7196], Hinsley, Samantha [0000-0001-6903-4688], Pike, Malcolm C [0000-0003-4891-1199], Rodriguez-Antona, Cristina [0000-0001-8750-7338], Sinn, Peter [0000-0003-2836-6699], Trabert, Britton [0000-0002-1539-6090], Widschwendter, Martin [0000-0002-7778-8380], Winham, Stacey J [0000-0002-8492-9102], Brenton, James D [0000-0002-5738-6683], Brown, Robert [0000-0001-7960-5755], Chang-Claude, Jenny [0000-0001-8919-1971], deFazio, Anna [0000-0003-0057-4744], Fasching, Peter A [0000-0003-4885-8471], Kelemen, Linda E [0000-0003-4362-9784], Menon, Usha [0000-0003-3708-1732], Pharoah, Paul DP [0000-0001-8494-732X], Ramus, Susan J [0000-0003-0005-7798], Doherty, Jennifer A [0000-0002-1454-8187], Anglesio, Michael S [0000-0003-1639-5003], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Neoplasm, Residual, Bevacizumab, 03 medical and health sciences, Ovarian tumor, Lymphocytes, Tumor-Infiltrating, 0302 clinical medicine, Ovarian carcinoma, Internal medicine, medicine, Humans, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, Stage (cooking), Aged, Ovarian Neoplasms, business.industry, Cystadenoma, Serous, Cancer, Middle Aged, Precision medicine, Omics, medicine.disease, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Serous fluid, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, Neoplasm Grading, Transcriptome, business, Algorithms, medicine.drug
Abstract

Purpose: Gene expression–based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features. Experimental Design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting. Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations. Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications. See related commentary by McMullen et al., p. 5271

Published
2020

27. Estrogen Plus Progestin Hormone Therapy and Ovarian Cancer

Author

Francesmary Modugno, Bhramar Mukherjee, Celeste Leigh Pearce, Mary Anne Rossing, Aliya Alimujiang, Susanne K. Kjaer, Marc T. Goodman, Penelope M. Webb, Kara L. Cushing-Haugen, Lynda D. Roman, Kathryn L. Terry, Anna H. Wu, Michael E. Carney, Andrew Berchuck, Kirstin B. Moysich, Holly R. Harris, Jennifer A. Doherty, David G. Huntsman, Estrid Høgdall, Alice W. Lee, Malcolm C. Pike, Pamela J. Thompson, Galina Lurie, Daniel O. Stram, Roberta B. Ness, Elisa V. Bandera, Allan Jensen, Daniel W. Cramer, and Ashley Wiensch

Subjects
Oncology, medicine.medical_specialty, endocrine system diseases, Epidemiology, medicine.drug_class, medicine.medical_treatment, Population, Risk Assessment, 01 natural sciences, Article, 010104 statistics & probability, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, 030212 general & internal medicine, 0101 mathematics, Risk factor, education, Ovarian Neoplasms, education.field_of_study, business.industry, Endometrial cancer, Estrogen Replacement Therapy, medicine.disease, Estrogen, Case-Control Studies, Hormonal therapy, Female, Hormone therapy, Ovarian cancer, business, Progestin, hormones, hormone substitutes, and hormone antagonists
Abstract

Background Menopausal estrogen-alone therapy is a risk factor for endometrial and ovarian cancers. When a progestin is included with the estrogen daily (continuous estrogen-progestin combined therapy), there is no increased risk of endometrial cancer. However, the effect of continuous estrogen-progestin combined therapy on risk of ovarian cancer is less clear. Methods We pooled primary data from five population-based case-control studies in the Ovarian Cancer Association Consortium, including 1509 postmenopausal ovarian cancer cases and 2295 postmenopausal controls. Information on previous menopausal hormonal therapy use, as well as ovarian cancer risk factors, was collected using in-person interviews. Logistic regression was used to assess the association between use of continuous estrogen-progestin combined therapy and risk of ovarian cancer by duration and recency of use and disease histotype. Results Ever postmenopausal use of continuous estrogen-progestin combined therapy was not associated with increased risk of ovarian cancer overall (OR = 0.85, 95% CI = 0.72, 1.0). A decreased risk was observed for mucinous ovarian cancer (OR = 0.40, 95% CI = 0.18, 0.91). The other main ovarian cancer histotypes did not show an association (endometrioid: OR = 0.86, 95% CI = 0.57, 1.3, clear cell: OR = 0.68, 95% CI = 0.40, 1.2; serous: OR = 0.98, 95% CI = 0.80, 1.2). Conclusions Given that estrogen-alone therapy has been shown to be associated with increased risk of ovarian cancer, these findings are consistent with the hypothesis that adding a progestin each day ameliorates the carcinogenic effects of estrogen on the cells of origin for all histotypes of ovarian cancer.

Published
2020

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

Author

Yongyong Shi, Ji Yeob Choi, Emily Adler, Beth Y. Karlan, Kate Lawrenson, Sue Park, Simon A. Gayther, Christopher I. Amos, Ellen L. Goode, Keitaro Matsuo, Paul D.P. Pharoah, Noor Azmi Mat Adenan, Xiao-Ou Shu, Weihua Jia, Rosario I. Corona, Kang Shan, Soo-Hwang Teo, Yin L. Woo, Kexin Chen, Jennifer A. Doherty, Felipe Segato, Simon G. Coetzee, Gang J. Jin, Marcos A. S. Fonseca, Dennis J. Hazelett, Pamela J. Thompson, Wei Zheng, Thomas A. Sellers, Byoung-Gie Kim, L Yan, Andrew Berchuck, Weiva Sieh, Michael E. Carney, Qingyi Wei, Fengju Song, Boyoung Park, Siddhartha Kar, Georgia Chenevix-Trench, Houtan Noushmehr, Lian Li, Catherine M. Phelan, Boon K. Lim, Juyeon Lee, Norma Rodriguez-Malave, Celeste Leigh Pearce, Marc T. Goodman, Jonathan Tyrer, Nhu D. Le, Ji-Hei Seo, Lynne R. Wilkens, Mika Mizuno, and Matthew L. Freedman

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, endocrine system diseases, Quantitative Trait Loci, Single-nucleotide polymorphism, Genome-wide association study, Carcinoma, Ovarian Epithelial, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Asian People, Internal medicine, Humans, Medicine, Genetic Predisposition to Disease, Genotyping, Genetic association, Base Sequence, business.industry, Case-control study, Obstetrics and Gynecology, Odds ratio, female genital diseases and pregnancy complications, 3. Good health, 030104 developmental biology, Case-Control Studies, 030220 oncology & carcinogenesis, Expression quantitative trait loci, Female, business, NEOPLASIAS OVARIANAS, Imputation (genetics), Genome-Wide Association Study
Abstract

OBJECTIVE. Genome-wide association studies (GWASs) for epithelial ovarian cancer (EOC) have focused largely on populations of European ancestry. We aimed to identify common germline variants associated with EOC risk in Asian women. METHODS. Genotyping was performed as part of the OncoArray project. Samples with >60% Asian ancestry were included in the analysis. Genotyping was performed on 533,631 SNPs in 3238 Asian subjects diagnosed with invasive or borderline EOC and 4083 unaffected controls. After imputation, genotypes were available for 11,595,112 SNPs to identify associations. RESULTS. At chromosome 6p25.2, SNP rs7748275 was associated with risk of serous EOC (odds ratio [OR] = 1.34, P = 8.7 × 10(−9)) and high-grade serous EOC (HGSOC) (OR = 1.34, P = 4.3 × 10(−9)). SNP rs6902488 at 6p25.2 (r(2) = 0.97 with rs7748275) lies in an active enhancer and is predicted to impact binding of STAT3, P300 and ELF1. We identified additional risk loci with low Bayesian false discovery probability (BFDP) scores, indicating they are likely to be true risk associations (BFDP

Published
2019

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

Author

Francesmary Modugno, Minh Tung Phung, Bhramar Mukherjee, Jennifer A. Doherty, Paul D.P. Pharoah, Weiva Sieh, Penelope M. Webb, Usha Menon, Linda Titus, Valerie McGuire, Alice W. Lee, Malcolm C. Pike, Harvey A. Risch, Hoda Anton-Culver, Mary Anne Rossing, Susan J. Jordan, Katharine Brieger, Ashley Wiensch, Joellen M. Schildkraut, Holly R. Harris, Marc T. Goodman, Kirsten B. Moysich, Roberta B. Ness, Pamela J. Thompson, Joseph H. Rothstein, Argyrios Ziogas, Lilah Khoja, Nicolas Wentzensen, Allan Jensen, Bo Qin, Alice S. Whittemore, Anna H. Wu, Stacey Rosenzweig, Celeste Leigh Pearce, Susan J. Ramus, Susanne K. Kjaer, Aliya Alimujiang, Kathryn L. Terry, Daniel W. Cramer, Michael E. Carney, Andrew Berchuck, Elisa V. Bandera, Ellen L. Goode, Aleksandra Gentry-Maharaj, and Jenny Chang-Claude

Subjects
Risk, Cancer Research, medicine.medical_specialty, Reduced risk, Carcinoma, Ovarian Epithelial, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Medicine, Humans, Epithelial ovarian cancer, 030212 general & internal medicine, Gynecology, Ovarian Neoplasms, business.industry, Abortion, Induced, Odds ratio, Articles, medicine.disease, United Kingdom, United States, Large sample, Abortion, Spontaneous, Parity, Contraceptive use, Pooled analysis, Oncology, 030220 oncology & carcinogenesis, Case-Control Studies, Female, business, Ovarian cancer
Abstract

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

Published
2021

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

Author

Ana Osorio, Fiona Bruinsma, Andrew J. Li, Janine Senz, Stacey J. Winham, Michael E. Carney, Deborah J. Thompson, Xifeng Wu, Susan J. Ramus, Alicia A. Tone, Robert P. Edwards, Chu Chen, Daniel D. Buchanan, Rüdiger Klapdor, Diether Lambrechts, Anthony N. Karnezis, Ralf Bützow, Graham G. Giles, Jolanta Kupryjanczyk, James D. Brenton, Pamela J. Thompson, Joseph L. Kelley, Hui Cai, Dylan M. Glubb, Peter Hillemanns, Veronica Wendy Setiawan, Reidun K. Kopperud, Francesmary Modugno, Rodney J. Scott, Karen H. Lu, Andreas du Bois, Weiva Sieh, Clara Bodelon, Katharina Bischof, Sarah E. Ferguson, Ignace Vergote, Todd L. Edwards, Nadeem Siddiqui, Jennifer A. Doherty, Celeste Leigh Pearce, David G. Huntsman, Håkan Olsson, Ailith Ewing, Tjoung-Won Park-Simon, Harvey A. Risch, Taymaa May, Soo Hwang Teo, Elizabeth G. Holliday, Penelope M. Webb, Lukasz Michael Szafron, Alexander Hein, Martin Köbel, Marjorie J. Riggan, Madhuri Koti, Ahmad Alsulimani, Matthias W. Beckmann, Heli Nevanlinna, Domenico Palli, Melissa C. Larson, Emily White, Ingo B. Runnebaum, Robert A. Vierkant, Elza Khusnutdinova, Jolanta Lissowska, Andrew Berchuck, Rosalind Glasspool, Drakoulis Yannoukakos, Alison M. Dunning, Rosario Tumino, Mia M. Gaudet, Alice S. Whittemore, Anna Jakubowska, Marcus Q. Bernardini, Jennifer B. Permuth, Kunle Odunsi, Aleksandra Gentry-Maharaj, Florentia Fostira, Philipp Harter, Rebecca Sutphen, Sandra Orsulic, Beata Spiewankiewicz, Susanne K. Kjaer, Jessica N. McAlpine, Valerie McGuire, Julie M. Cunningham, Jeffrey Killeen, Christine M. Friedenreich, Estrid Høgdall, George Fountzilas, Michelle A.T. Hildebrandt, Katja K.H. Aben, Tomasz Huzarski, Frédéric Amant, Zhaoming Wang, James M. Flanagan, Timothy R. Rebbeck, Joseph H. Rothstein, Clemens Liebrich, Immaculata De Vivo, Linda Titus, Anna deFazio, Jan Gawełko, Irene Konstantopoulou, Adriaan Vanderstichele, Stephen J. Chanock, Jenny Lester, Amanda B. Spurdle, Allan Jensen, Claus Høgdall, Daniela Annibali, Amalia Mattiello, Peter Kraft, Loic Le Marchand, Line Bjørge, Marina Bermisheva, Agnieszka Podgorska, John Attia, Tracy A. O'Mara, Shashikant Lele, Thomas A. Sellers, Bo Gao, Holly R. Harris, Shan Wang-Gohrke, Lingeng Lu, Louise A. Brinton, Alessandra Macciotta, Digna R. Velez Edwards, Peter A. Fasching, Marc T. Goodman, Linda S. Cook, Constance Turman, Jacek Gronwald, Liv Cecilie Vestrheim Thomsen, Matthias Dürst, Kirsten B. Moysich, Usha Menon, Dong Liang, Arif B. Ekici, Bozena Konopka, Aurelio Barricarte, Thilo Dörk, Stefanie Burghaus, Michael Jones, Loren Lipworth, Zhihua Chen, Xiaoqing Chen, Alison Brand, Iain A. McNeish, Tanja Pejovic, Florian Heitz, Beth Y. Karlan, Anthony J. Swerdlow, Anna H. Wu, Obstetrics and Gynaecology, CCA - Cancer biology and immunology, and Amsterdam Reproduction & Development (AR&D)

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Epidemiology, Quantitative Trait Loci, Genome-wide association study, Biology, Carcinoma, Ovarian Epithelial, Genetic correlation, 03 medical and health sciences, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, Uterine cancer, Risk Factors, Internal medicine, medicine, Humans, Genetic association, Ovarian Neoplasms, Endometrial cancer, Cancer, medicine.disease, 3. Good health, Endometrial Neoplasms, 030104 developmental biology, 030220 oncology & carcinogenesis, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Human genome, Female, Ovarian cancer, Genome-Wide Association Study
Abstract

Background: Accumulating 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. Methods: Using 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. Results: Genetic 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 (PBonferroni < 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. Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis. Impact: Our 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

31. Identification of a Locus Near

Author

Michael C J, Quinn, Karen, McCue, Wei, Shi, Sharon E, Johnatty, Jonathan, Beesley, Andrew, Civitarese, Tracy A, O'Mara, Dylan M, Glubb, Jonathan P, Tyrer, Sebastian M, Armasu, Jue-Sheng, Ong, Puya, Gharahkhani, Yi, Lu, Bo, Gao, Ann-Marie, Patch, Peter A, Fasching, Matthias W, Beckmann, Diether, Lambrechts, Ignace, Vergote, Digna R, Velez Edwards, Alicia, Beeghly-Fadiel, Javier, Benitez, Maria J, Garcia, Marc T, Goodman, Thilo, Dörk, Matthias, Dürst, Francesmary, Modugno, Kirsten, Moysich, Andreas, du Bois, Jacobus, Pfisterer, Klaus, Bauman, Beth Y, Karlan, Jenny, Lester, Julie M, Cunningham, Melissa C, Larson, Bryan M, McCauley, Susanne K, Kjaer, Allan, Jensen, Claus K, Hogdall, Estrid, Hogdall, Joellen M, Schildkraut, Marjorie J, Riggan, Andrew, Berchuck, Daniel W, Cramer, Kathryn L, Terry, Line, Bjorge, Penelope M, Webb, Michael, Friedlander, Tanja, Pejovic, Melissa, Moffitt, Rosalind, Glasspool, Taymaa, May, Gabrielle E V, Ene, David G, Huntsman, Michelle, Woo, Michael E, Carney, Samantha, Hinsley, Florian, Heitz, Sian, Fereday, Catherine J, Kennedy, Stacey L, Edwards, Stacey J, Winham, Anna, deFazio, Paul D P, Pharoah, Ellen L, Goode, Stuart, MacGregor, and Georgia, Chenevix-Trench

Subjects
Ovarian Neoplasms, Gene Knockout Techniques, Biomarkers, Tumor, Intracellular Signaling Peptides and Proteins, Autophagy-Related Protein-1 Homolog, Humans, Female, Carcinoma, Ovarian Epithelial, Polymorphism, Single Nucleotide, Progression-Free Survival, Genome-Wide Association Study
Abstract

Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance.We carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy.We found seven SNPs at 12q24.33 associated with PFS (The locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer.This finding provides insight into genetic markers associated with EOC outcome and potential treatment options.

Published
2020

32. Combining genome-wide studies of breast, prostate, ovarian and endometrial cancers maps cross-cancer susceptibility loci and identifies new genetic associations

Author

Rosalind A. Eeles, Anne van Altena, Rüdiger Klapdor, Rayjean J. Hung, Graham G. Giles, Ingo B. Runnebaum, Stacey J. Winham, Alicia Beeghly-Fadiel, Michelle A.T. Hildebrandt, Ruea-Yea Huang, Amanda B. Spurdle, Ahmad Alsulimani, Robert Winqvist, Robert J. Hamilton, Clare Turnbull, James M. Flanagan, Jan Gawełko, Kenneth Muir, Peter Kraft, Joseph Vijai, Anna Jakubowska, Paul D.P. Pharoah, Stephen J. Chanock, Ailith Ewing, Mary B. Daly, Artitaya Lophatananon, Arvids Irmejs, Hiltrud Brauch, Paolo Radice, Camilla Krakstad, Liher Imaz, Lambertus A. Kiemeney, Clara Bodelon, Nadeem Siddiqui, Alvaro N.A. Monteiro, Bozena Konopka, Taymaa May, Herbert Yu, Stefanie Burghaus, Michael E. Carney, Siddhartha Kar, Beata Spiewankiewicz, Fernando Moreno Antón, Andreas du Bois, Sune F. Nielsen, Ian Tomlinson, Elza Khusnutdinova, Paolo Peterlongo, Zhihua Chen, Deborah J. Thompson, Agnieszka Podgorski, Päivi Kannisto, Andrew Berchuck, Jenny Chang-Claude, Susan J. Ramus, Florian Heitz, Nawaid Usmani, Tracy A. O'Mara, Joellen M. Schildkraut, Jennifer Permuth, Beth Y. Karlan, Ignace Vergote, Douglas F. Easton, Sara Lindstroem, Agnieszka Mieszkowska, Kirsten B. Moysich, Ana Vega-Gliemmo, Simon A. Gayther, Arif B. Ekici, Lukasz Szafron, Kunle Odunsi, Marjanka K. Schmidt, Harvey A. Risch, Linda J. Titus, Weiva Sieh, Robert A. Vierkant, Davor Lessel, Line Bjørge, Allan Jensen, Wei Zheng, Holly R. Harris, Petra Kleiblova, Peter A. Fasching, Jonathan Tyrer, Iwona K. Rzepecka, Georgia Chenevix-Trench, Tjoung-Won Park-Simon, Susanne K. Kjaer, Esther M. John, Daniele Campa, Veronica Wendy Setiawan, Martin Koebel, Cheryl L. Thompson, Håkan Olsson, Dylan M. Glubb, Peter Hillemanns, and Kate Lawrenson

Subjects
Oncology, medicine.medical_specialty, Endometrial cancer, Cancer susceptibility, Susceptibility gene, Effective sample size, Biology, medicine.disease, Genome, medicine.anatomical_structure, Prostate, Internal medicine, medicine, Genetic association
Abstract

We report a meta-analysis of breast, prostate, ovarian, and endometrial cancer genome-wide association data (effective sample size: 237,483 cases/317,006 controls). This identified 465 independent lead variants (P−8) across 192 genomic regions. Four lead variants were >1Mb from previously identified risk loci for the four cancers and an additional 23 lead variant-cancer associations were novel for one of the cancers. Bayesian models supported pleiotropic effects involving at least two cancers at 222/465 lead variants in 118/192 regions. Gene-level association analysis identified 13 shared susceptibility genes (P−6) in 13 regions not previously implicated in any of the four cancers and not uncovered by our variant-level meta-analysis. Several lead variants had opposite effects across cancers, including a cluster of such variants in the TP53 pathway. Fifty-four lead variants were associated with blood cell traits and suggested genetic overlaps with clonal hematopoiesis. Our study highlights the remarkable pervasiveness of pleiotropy across hormone-related cancers, further illuminating their shared genetic and mechanistic origins at variant- and gene-level resolution.

Published
2020

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

Author

Clara Bodelon, Anna H. Wu, V. Wendy Setiawan, Jenny Lester, Adriaan Vanderstichele, Daniela Annibali, Michael E. Carney, Jennifer A. Doherty, Shashikant Lele, Jacek Gronwald, Matthias W. Beckmann, George Fountzilas, Christine M. Friedenreich, Heli Nevanlinna, Immaculata De Vivo, Jolanta Lissowska, Soo Hwang Teo, Ahmad Alsulimani, Daniel D. Buchanan, Rosalind Glasspool, Domenico Palli, Madhuri Koti, Katja K.H. Aben, Tanja Pejovic, Linda S. Cook, Line Bjørge, Mia M. Gaudet, Anna Jakubowska, Tomasz Huzarski, Florian Heitz, Beth Y. Karlan, Andreas du Bois, Linda J. Titus, Joseph L. Kelley, Andrew Berchuck, Aleksandra Gentry-Maharaj, Florentia Fostira, Weiva Sieh, Anthony J. Swerdlow, Celeste Leigh Pearce, Constance Turman, Zhaoming Wang, Ignace Vergote, Dylan M. Glubb, Peter Hillemanns, Chu Chen, Tjoung-Won Park-Simon, Andrew J. Li, Susanne K. Kjaer, Jan Gawełko, Stephen J. Chanock, Tracy A. O'Mara, Elizabeth G. Holliday, Jessica N. McAlpine, Ailith Ewing, Amalia Mattiello, Pamela J. Thompson, Xifeng Wu, Alicia A. Tone, Ana Osorio, Fiona Bruinsma, Digna R. Velez Edwards, Janine Senz, Francesmary Modugno, Michael Jones, Sandra Orsulic, Xiaoqing Chen, Todd L. Edwards, Aurelio Barricarte, Hui Cai, Loren Lipworth, David G. Huntsman, Zhihua Chen, Alison M. Dunning, Julie M. Cunningham, Rosario Tumino, Melissa C. Larson, Ralf Bützow, Alison Brand, Allan Jensen, Marina Bermisheva, Reidun K. Kopperud, Beata Spiewankiewicz, Timothy R. Rebbeck, Bozena Konopka, Matthias Dürst, Thomas A. Sellers, Penelope M. Webb, Claus Høgdall, Anthony N. Karnezis, Håkan Olsson, Liv Cecilie Vestrheim Thomsen, Rodney J. Scott, Iain A. McNeish, Arif B. Ekici, Valerie McGuire, Lukasz Szafron, Harvey A. Risch, Bo Gao, Louise A. Brinton, Alessandra Macciotta, Anna deFazio, Rüdiger Klapdor, Graham G. Giles, Usha Menon, Marc T. Goodman, Robert P. Edwards, Robert A. Vierkant, Dong Liang, Shan Wang-Gohrke, Lingeng Lu, Kirsten B. Moysich, Holly R. Harris, Deborah J. Thompson, Jennifer B. Permuth, Alexander Hein, Thilo Dörk, Elza Khusnutdinova, Stefanie Burghaus, Irene Konstantopoulou, Stacey J. Winham, Susan J. Ramus, Agnieszka Podgorska, Rebecca Sutphen, Michelle A.T. Hildebrandt, Jolanta Kupryjanczyk, Ingo B. Runnebaum, James D. Brenton, Karen H. Lu, Katharina Bischof, Nadeem Siddiqui, Drakoulis Yannoukakos, Estrid Høgdall, John Attia, Clemens Liebrich, Loic Le Marchand, Emily White, Amanda B. Spurdle, Peter Kraft, Alice S. Whittemore, Kunle Odunsi, Sarah E. Ferguson, Taymaa May, Marjorie J. Riggan, Philipp Harter, Jeffrey Killeen, James M. Flanagan, Frédéric Amant, Marcus Q. Bernardini, Joseph H. Rothstein, Martin Köbel, Peter A. Fasching, and Diether Lambrechts

Subjects
Oncology, 0303 health sciences, medicine.medical_specialty, business.industry, Endometrial cancer, Genome-wide association study, medicine.disease, Genetic correlation, 3. Good health, 03 medical and health sciences, Serous fluid, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, Epidemiology, medicine, Epithelial ovarian cancer, business, Clear cell, 030304 developmental biology, Genetic association
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
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34. Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium

Author

Scott H. Kaufmann, Daniel Guimarães Tiezzi, Valerie Rhenius, Gary L. Keeney, Alexander Hein, Dominique-Laurent Couturier, Florin Andrei Taran, Robert Edwards, Aline Talhouk, Stacey J. Winham, Christiani Bisinoto de Sousa, Nadja Pejovic, Andreas D. Hartkopf, Ramona Erber, Brenda Y. Hernandez, Jenny Lester, Teri A. Longacre, Anna L. Paterson, Peter Sinn, Robin Crawford, Lene Lundvall, Hugh Luk, Roberta B. Ness, Adekunle Odunsi, Suha Deen, Javier Benitez, Alice S. Whittemore, Anna Fischer, Anthony N. Karnezis, Christine Chow, Ana Osorio, Ellen L. Goode, Stefan Kommoss, Angela Brooks-Wilson, Linda E. Kelemen, Tanja Pejovic, Simon A. Gayther, Peter A. Fasching, Beth Y. Karlan, Jurandyr Moreira de Andrade, Samuel Leung, David D.L. Bowtell, James D. Brenton, Aleksandra Vrvilo, Marc T. Goodman, Paul D.P. Pharoah, Sara Y. Brucker, Honglin Song, Jennifer M Koziak, Robert A. Vierkant, Naveena Singh, Valerie McGuire, Chloe Karpinskyj, Mercedes Jimenez-Linan, Aleksandra Gentry-Maharaj, Anna deFazio, Jenny Chang-Claude, Linda S. Cook, Francesmary Modugno, Filipe C. Martins, Estrid Høgdall, Prafull Ghatage, Marie Lyne Alcaraz, Susan J. Ramus, Annette Staebler, Jennifer Alsop, David G. Huntsman, Joseph H. Rothstein, Tayyebeh M. Nazeran, Cristina Rodríguez-Antona, Luis Robles-Díaz, Bryan M. McCauley, María Jesús Gómez García, Michael E. Carney, Michael S. Anglesio, Yurii B. Shvetsov, Claus Høgdall, Sian Fereday, Martin Köbel, Maria P. Intermaggio, Sandra Orsulic, Luis Paz-Ares, Mary Anne Brett, Weiva Sieh, Matthias W. Beckmann, Helen Steed, Arndt Hartmann, Michael Schneider, Lynne R. Wilkens, Esther Herpel, Jacek Gronwald, Francisco José Candido dos Reis, Nhu D. Le, Gregg Nelson, Kirsten B. Moysich, Nadia Traficante, Usha Menon, Candido Dos Reis, Francisco J [0000-0001-5758-5917], Brenton, James D [0000-0002-5738-6683], Apollo - University of Cambridge Repository, Candido dos Reis, Francisco J. [0000-0001-5758-5917], and Brenton, James D. [0000-0002-5738-6683]

Subjects
Oncology, Cancer Research, 692/4028/67/1517/1709, Carcinoma, Ovarian Epithelial, Clear Cell, Androgen, ESTUDOS PROSPECTIVOS, Cohort Studies, Gene Knockout Techniques, 0302 clinical medicine, Ovarian carcinoma, Ovarian Epithelial, Receptors, Prospective Studies, Progesterone, Cancer, Ovarian Neoplasms, 0303 health sciences, Tumor, Molecular medicine, biology, Hazard ratio, article, Age Factors, Middle Aged, Ovarian Cancer, Serous fluid, Receptors, Estrogen, Receptors, Androgen, 030220 oncology & carcinogenesis, Public Health and Health Services, Biomarker (medicine), Female, Receptors, Progesterone, medicine.medical_specialty, Oncology and Carcinogenesis, Down-Regulation, Adenocarcinoma, 03 medical and health sciences, Rare Diseases, Ovarian cancer, Internal medicine, Progesterone receptor, medicine, Biomarkers, Tumor, PTEN, Humans, Oncology & Carcinogenesis, 030304 developmental biology, Neoplasm Staging, business.industry, Tumor Suppressor Proteins, Carcinoma, PTEN Phosphohydrolase, medicine.disease, Estrogen, 692/4017, Androgen receptor, Tissue Array Analysis, biology.protein, business, Biomarkers, Adenocarcinoma, Clear Cell
Abstract

Background PTEN 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. Methods Tumours 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. Results Downregulation 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 p value = 0.019) and associated with higher CD8 counts (p value = 0.0016). Conclusions PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.

Published
2020
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35. A Case of Human Papilloma Virus 31- and 68-Associated Metastatic Squamous Cell Carcinoma of the Cervix in a Healthy 28-Year-Old Woman

Author

Jennifer W.H. Wong, Michael E. Carney, Charlie Wang, Jeffrey Killeen, and Aya Sultan

Subjects
Cervical cancer, Human papilloma virus, medicine.medical_specialty, Pathology, business.industry, Cell, Obstetrics and Gynecology, Mean age, medicine.disease, Malignancy, Surgery, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, medicine, Basal cell, 030212 general & internal medicine, Presentation (obstetrics), business, Cervix
Abstract

Background: Cervical cancer is often a slowly progressing malignancy that presents in women with a mean age of 51. This case is a highly unusual presentation of metastatic squamous cell ca...

Published
2018

36. A Case of High-Grade Endometrial Stromal Sarcoma with Concurrent Pregnancy

Author

Tiffany S. Lai, Chanel Casamina, Jeffrey Killeen, Michael E. Carney, Jennifer W.H. Wong, and Kacie R. Fox

Subjects
medicine.medical_specialty, Pregnancy, Pathology, 030219 obstetrics & reproductive medicine, Endometrial stromal sarcoma, Stromal cell, business.industry, Obstetrics and Gynecology, medicine.disease, Surgery, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, medicine, Endometrial stromal tumor, business, Uterine Neoplasm
Abstract

Background: High-grade endometrial stromal sarcomas (HGESS) are very rare uterine tumors, and HGESS during pregnancy is exceedingly rare. This is the first-ever published case of a uterine...

Published
2018

37. Ovarian cancer risk, ALDH2 polymorphism and alcohol drinking: Asian data from the Ovarian Cancer Association Consortium

Author

M. C. Pike, Yong-Bing Xiang, Kathryn L. Terry, Georgia Chenevix-Trench, Anna H. Wu, Jennifer A. Doherty, Hui Cai, Marc T. Goodman, Penelope M. Webb, Pamela J. Thompson, Tomotaka Ugai, Linda E. Kelemen, Keitaro Matsuo, David Van Den Berg, Mary Anne Rossing, Yu-Tang Gao, Joellen M. Schildkraut, Andrew Berchuck, Xiao-Ou Shu, Mika Mizuno, Daniel W. Cramer, Celeste Leigh Pearce, Kristine G. Wicklund, Michael E. Carney, Jue-Sheng Ong, and Lynne R. Wilkens

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, endocrine system diseases, Alcohol Drinking, Polymorphism, Single Nucleotide, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Asian People, Internal medicine, Genotype, medicine, Odds Ratio, Humans, Genetic Predisposition to Disease, Genetic Association Studies, Genetic association, ALDH2, Ovarian Neoplasms, Asian, business.industry, Aldehyde Dehydrogenase, Mitochondrial, Confounding, Epidemiology and Prevention, General Medicine, Odds ratio, Original Articles, medicine.disease, Adenocarcinoma, Mucinous, 3. Good health, 030104 developmental biology, ovarian cancer, Logistic Models, 030220 oncology & carcinogenesis, Adenocarcinoma, Original Article, Female, pooled analysis, business, Ovarian cancer, Cohort study, drinking habit
Abstract

The aldehyde dehydrogenase 2 (ALDH2) polymorphism rs671 (Glu504Lys) causes ALDH2 inactivation and adverse acetaldehyde exposure among Asians, but little is known of the association between alcohol consumption and rs671 and ovarian cancer (OvCa) in Asians. We conducted a pooled analysis of Asian ancestry participants in the Ovarian Cancer Association Consortium. We included seven case-control studies and one cohort study comprising 460 invasive OvCa cases, 37 borderline mucinous OvCa and 1274 controls of Asian descent with information on recent alcohol consumption. Pooled odds ratios (OR) with 95% confidence intervals (CI) for OvCa risk associated with alcohol consumption, rs671 and their interaction were estimated using logistic regression models adjusted for potential confounders. No significant association was observed for daily alcohol intake with invasive OvCa (OR comparing any consumption to none = 0.83; 95% CI = 0.58-1.18) or with individual histotypes. A significant decreased risk was seen for carriers of one or both Lys alleles of rs671 for invasive mucinous OvCa (OR = 0.44; 95% CI = 0.20-0.97) and for invasive and borderline mucinous tumors combined (OR = 0.48; 95% CI = 0.26-0.89). No significant interaction was observed between alcohol consumption and rs671 genotypes. In conclusion, self-reported alcohol consumption at the quantities estimated was not associated with OvCa risk among Asians. Because the rs671 Lys allele causes ALDH2 inactivation leading to increased acetaldehyde exposure, the observed inverse genetic association with mucinous ovarian cancer is inferred to mean that alcohol intake may be a risk factor for this histotype. This association will require replication in a larger sample.

Published
2018

38. The obesity-associated polymorphisms FTO rs9939609 and MC4R rs17782313 and endometrial cancer risk in non-Hispanic white women.

Author

Galina Lurie, Mia M Gaudet, Amanda B Spurdle, Michael E Carney, Lynne R Wilkens, Hannah P Yang, Noel S Weiss, Penelope M Webb, Pamela J Thompson, Keith Terada, Veronica Wendy Setiawan, Timothy R Rebbeck, Jennifer Prescott, Irene Orlow, Tracy O'Mara, Sara H Olson, Steven A Narod, Rayna K Matsuno, Jolanta Lissowska, Xiaolin Liang, Douglas A Levine, Loic Le Marchand, Laurence N Kolonel, Brian E Henderson, Montserrat Garcia-Closas, Jennifer Anne Doherty, Immaculata De Vivo, Chu Chen, Louise A Brinton, Mohammad R Akbari, Australian National Endometrial Cancer Study Group, Epidemiology of Endometrial Cancer Consortium (E2C2), and Marc T Goodman

Subjects
Medicine, Science
Abstract

Overweight and obesity are strongly associated with endometrial cancer. Several independent genome-wide association studies recently identified two common polymorphisms, FTO rs9939609 and MC4R rs17782313, that are linked to increased body weight and obesity. We examined the association of FTO rs9939609 and MC4R rs17782313 with endometrial cancer risk in a pooled analysis of nine case-control studies within the Epidemiology of Endometrial Cancer Consortium (E2C2). This analysis included 3601 non-Hispanic white women with histologically-confirmed endometrial carcinoma and 5275 frequency-matched controls. Unconditional logistic regression models were used to assess the relation of FTO rs9939609 and MC4R rs17782313 genotypes to the risk of endometrial cancer. Among control women, both the FTO rs9939609 A and MC4R rs17782313 C alleles were associated with a 16% increased risk of being overweight (p = 0.001 and p = 0.004, respectively). In case-control analyses, carriers of the FTO rs9939609 AA genotype were at increased risk of endometrial carcinoma compared to women with the TT genotype [odds ratio (OR) = 1.17; 95% confidence interval (CI): 1.03-1.32, p = 0.01]. However, this association was no longer apparent after adjusting for body mass index (BMI), suggesting mediation of the gene-disease effect through body weight. The MC4R rs17782313 polymorphism was not related to endometrial cancer risk (per allele OR = 0.98; 95% CI: 0.91-1.06; p = 0.68). FTO rs9939609 is a susceptibility marker for white non-Hispanic women at higher risk of endometrial cancer. Although FTO rs9939609 alone might have limited clinical or public health significance for identifying women at high risk for endometrial cancer beyond that of excess body weight, further investigation of obesity-related genetic markers might help to identify the pathways that influence endometrial carcinogenesis.

Published
2011
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39. Estrogen receptor beta rs1271572 polymorphism and invasive ovarian carcinoma risk: pooled analysis within the Ovarian Cancer Association Consortium.

Author

Galina Lurie, Lynne R Wilkens, Pamela J Thompson, Yurii B Shvetsov, Rayna K Matsuno, Michael E Carney, Rachel T Palmieri, Anna H Wu, Malcolm C Pike, Celeste L Pearce, Usha Menon, Aleksandra Gentry-Maharaj, Simon A Gayther, Susan J Ramus, Alice S Whittemore, Valerie McGuire, Weiva Sieh, Paul D P Pharoah, Honglin Song, Jacek Gronwald, Anna Jakubowska, Cezary Cybulski, Jan Lubinski, Joellen M Schildkraut, Andrew Berchuck, Susanne Krüger Kjær, Estrid Høgdall, Peter A Fasching, Matthias W Beckmann, Arif B Ekici, Alexander Hein, Georgia Chenevix-Trench, Penelope M Webb, Jonathan Beesley, Australian Ovarian Cancer Study Group, Australian Cancer Study Group, Marc T Goodman, and Ovarian Cancer Association Consortium

Subjects
Medicine, Science
Abstract

The association of ovarian carcinoma risk with the polymorphism rs1271572 in the estrogen receptor beta (ESR2) gene was examined in 4946 women with primary invasive ovarian carcinoma and 6582 controls in a pooled analysis of ten case-control studies within the Ovarian Cancer Association Consortium (OCAC). All participants were non-Hispanic white women. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression adjusted for site and age. Women with the TT genotype were at increased risk of ovarian carcinoma compared to carriers of the G allele (OR = 1.10; 95%; CI: 1.01-1.21; p = 0.04); the OR was 1.09 (CI: 0.99-1.20; p = 0.07) after excluding data from the center (Hawaii) that nominated this SNP for OCAC genotyping A stronger association of rs1271572 TT versus GT/GG with risk was observed among women aged ≤50 years versus older women (OR = 1.35; CI: 1.12-1.62; p = 0.002; p for interaction = 0.02) that remained statistically significant after excluding Hawaii data (OR = 1.34; CI: 1.11-1.61; p = 0.009). No heterogeneity of the association was observed by study, menopausal status, gravidity, parity, use of contraceptive or menopausal hormones, tumor histological type, or stage at diagnosis. This pooled analysis suggests that rs1271572 might influence the risk of ovarian cancer, in particular among younger women.

Published
2011
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40. A combination of the immunohistochemical markers CK7 and SATB2 is highly sensitive and specific for distinguishing primary ovarian mucinous tumors from colorectal and appendiceal metastases

Author

Christine Chow, Hugh Luk, Jennifer Alsop, Aleksandra Tołoczko-Grabarek, Qin Wang, Nicola S. Meagher, Janusz Menkiszak, Stacey J. Winham, Jan Lubinski, Bonnie Zhang, Simon A. Gayther, Gary L. Keeney, Rhonda Farrell, Tomasz Kluz, Constantina Mateoiu, Mona El-Bahrawy, Raghwa Sharma, Montserrat Garcia-Closas, Adeline Tan, Brenda Y. Hernandez, Minouk J. Schoemaker, Maria P. Intermaggio, Marc T. Goodman, Robert A. Vierkant, Björg Kristjansdottir, Chloe Karpinskyj, Penny Coulson, Parham Minoo, Kylie L. Gorringe, Aline Talhouk, Oliver F. Bathe, Anthony J. Swerdlow, Michael E. Carney, James D. Brenton, Robert P. Edwards, John Lewis Etter, Kirsten B. Moysich, Colin J.R. Stewart, Jennifer M Koziak, Mercedes Jimenez-Linan, Yee Leung, Kunle Odunsi, Peter F Rambau, Sabine Behrens, Linda S. Cook, Michael S. Anglesio, Lynne R. Wilkens, Karin Sundfeldt, Esther Herpel, Martin Köbel, Sanela Bilic, Jacek Gronwald, Paul R. Harnett, Helen Steed, Katrina Tang, Susan J. Ramus, Paul A. Cohen, Xianyong Gui, Frances Daley, Ellen L. Goode, Anna deFazio, Ian G. Campbell, Paul D.P. Pharoah, Peter Sinn, Paul Klonowski, Yanina Natanzon, Linyuan Wang, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Catherine J. Kennedy, Roberta B. Ness, Linda E. Kelemen, Oleg Oszurek, Usha Menon, Mitul Shah, Martin Widschwendter, Melissa C. Larson, Gregory Robertson, Francesmary Modugno, David G. Huntsman, Audrey Y. Jung, and Neil Lambie

Subjects
0301 basic medicine, Male, Pathology, 0302 clinical medicine, Medicine, Neoplasm Metastasis, 11 Medical and Health Sciences, Ovarian Neoplasms, Tissue microarray, SERIES, Adenocarcinoma, Mucinous, Immunohistochemistry, Appendiceal Neoplasms, 030220 oncology & carcinogenesis, Cohort, SURVIVAL, Adenocarcinoma, Female, Colorectal Neoplasms, Life Sciences & Biomedicine, NEOPLASMS, EXPRESSION, medicine.medical_specialty, CARCINOMA, CANCERS, Sensitivity and Specificity, Article, Pathology and Forensic Medicine, Diagnosis, Differential, 03 medical and health sciences, DISTINCTION, Carcinoma, Biomarkers, Tumor, Humans, Science & Technology, business.industry, Keratin-7, Histology, ADENOCARCINOMA, PROFILES, Matrix Attachment Region Binding Proteins, medicine.disease, 030104 developmental biology, CDX2, Keratin 7, business, PAX8, Transcription Factors
Abstract

Primary ovarian mucinous tumors can be difficult to distinguish from metastatic gastrointestinal neoplasms by histology alone. The expected immunoprofile of a suspected metastatic lower gastrointestinal tumor is CK7-/CK20+/CDX2+/PAX8-. This study assesses the addition of a novel marker SATB2, to improve the diagnostic algorithm. A test cohort included 155 ovarian mucinous tumors (105 carcinomas and 50 borderline tumors) and 230 primary lower gastrointestinal neoplasms (123 colorectal adenocarcinomas and 107 appendiceal neoplasms). All cases were assessed for SATB2, PAX8 CK7, CK20, and CDX2 expression on tissue microarrays. Expression was scored in a 3-tier system as absent, focal (1-50% of tumor cells) and diffuse ( >50% of tumor cells) and then categorized into either absent/present or nondiffuse/diffuse. SATB2 and PAX8 expression was further evaluated in ovarian tumors from an international cohort of 2876 patients (expansion cohort, including 159 mucinous carcinomas and 46 borderline mucinous tumors). The highest accuracy of an individual marker in distinguishing lower gastrointestinal from ovarian mucinous tumors was CK7 (91.7%, nondiffuse/diffuse cut-off) followed by SATB2 (88.8%, present/absent cut-off). The most effective combination was CK7 and SATB2 with accuracy of 95.3% using the 3-tier interpretation, absent/focal/diffuse. This combination outperformed the standard clinical set of CK7, CK20 and CDX2 (87.5%). Re-evaluation of outlier cases confirmed ovarian origin for all but one case. The accuracy of SATB2 was confirmed in the expansion cohort (91.5%). SATB2 expression was also detected in 15% of ovarian endometrioid carcinoma but less than 5% of other ovarian histotypes. A simple two marker combination of CK7 and SATB2 can distinguish lower gastrointestinal from ovarian primary mucinous tumors with greater than 95% accuracy. PAX8 and CDX2 have value as second-line markers. The utility of CK20 in this setting is low and this warrants replacement of this marker with SATB2 in clinical practice.

Published
2019

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

Author

Argyrios Ziogas, Scott H. Kaufmann, Helga B. Salvensen, Mary Anne Rossing, Amanda S. Bruegl, Douglas A. Levine, Jack A. Taylor, Lauren C. Peres, Ellen Funkhouser, Simon A. Gayther, Ignace Vergote, Paul D.P. Pharoah, Lambertus A. Kiemeney, Francesmary Modugno, Linda E. Kelemen, Todd L. Edwards, Hoda Anton-Culver, Elisa V. Bandera, Aleksandra Gentry-Maharaj, Cathrine Hoyo, Christopher A. Haiman, Weiva Sieh, Els Van Nieuwenhuysen, Alvaro N.A. Monteiro, Alicia Beeghly-Fadiel, Ani Manichaikul, Delores J. Grant, Melissa Moffitt, Taymaa May, Anna H. Wu, Honglin Song, Ellen L. Goode, Melissa C. Larson, Andrew Berchuck, Line Bjørge, Diana Eccles, Diether Lambrechts, Patricia G. Moorman, Ann G. Schwartz, Veronica Wendy Setiawan, Alicia A. Tone, Valerie McGuire, Anthony J. Alberg, Michele L. Cote, Anna deFazio, Pamela J. Thompson, Nhu D. Le, Marcus Q. Bernardini, Shelley S. Tworoger, Ian G. Campbell, Xin-Qun Wang, Alice S. Whittemore, Marc T. Goodman, Kunle Odunsi, Dale P. Sandler, Joellen M. Schildkraut, Kirsten B. Moysich, Kathryn L. Terry, Michael E. Carney, Thomas A. Sellers, Paul D. Terry, Joseph H. Rothstein, Jill S. Barnholtz-Sloan, John Lewis Etter, Catherine J. Kennedy, Roberta B. Ness, Celeste Leigh Pearce, Katie M. O'Brien, Lynne R. Wilkens, Tanja Pejovic, Beth Y. Karlan, Digna R. Velez Edwards, Jennifer B. Permuth-Way, Leon F.A.G. Massuger, Angela Brooks-Wilson, Loic LeMarchand, Elizabeth M. Poole, Rikki Cannioto, Susan J. Ramus, Edward S. Peters, Nicolas Wentzensen, Temitope O. Keku, Daniel W. Cramer, Jennifer A. Doherty, Ruea Yea Huang, James D. Brenton, Adriaan Vanderstichele, Linda S. Cook, Melissa L. Bondy, Usha Menon, Brenton, James [0000-0002-5738-6683], Pharoah, Paul [0000-0001-8494-732X], Song, Honglin [0000-0001-5076-7371], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, genetic association, Single-nucleotide polymorphism, Carcinoma, Ovarian Epithelial, Polymorphism, Single Nucleotide, lcsh:RC254-282, Calcitriol receptor, 03 medical and health sciences, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, Internal medicine, Humans, Medicine, SNP, Radiology, Nuclear Medicine and imaging, Glucuronosyltransferase, Vitamin D, Allele, Genotyping, Genetic Association Studies, Original Research, Genetic association, Ovarian Neoplasms, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], business.industry, Bayes Theorem, Odds ratio, Middle Aged, African ancestry risk, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Black or African American, ErbB Receptors, Logistic Models, ovarian cancer, vitamin D pathway, 030104 developmental biology, 030220 oncology & carcinogenesis, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Receptors, Calcitriol, Female, Neoplasm Grading, business, Cancer Prevention, Imputation (genetics)
Abstract

An association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom-designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high-grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 1.2 × 10-6 , BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6-3.4, P = 1.6 × 10-5 , BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 2.3 × 10-5 , BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC. ispartof: CANCER MEDICINE vol:8 issue:5 pages:2503-2513 ispartof: location:United States status: published

Published
2019

42. A phase III study comparing single-agent olaparib or the combination of cediranib and olaparib to standard platinum-based chemotherapy in recurrent platinum-sensitive ovarian cancer

Author

Michael A. Bookman, David Paul Michelin, Elise C. Kohn, Carolyn Y. Muller, Steven E. Waggoner, Austin Miller, Melissa A. Geller, David Bender, William P. Tew, Stacy D. D'Andre, Keiichi Fujiwara, Angeles Alvarez Secord, Elizabeth M. Swisher, Katherine M. Moxley, Joyce F. Liu, N.G. Cloven, Richard G. Moore, Michael E. Carney, Ursula A. Matulonis, and Mark F. Brady

Subjects
Oncology, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, chemistry.chemical_element, Olaparib, Cediranib, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, otorhinolaryngologic diseases, medicine, In patient, Single agent, Chemotherapy, business.industry, medicine.disease, chemistry, 030220 oncology & carcinogenesis, Platinum sensitive, business, Ovarian cancer, Platinum, 030215 immunology, medicine.drug
Abstract

6003 Background: Combination cediranib (C) and olaparib (O) improved progression-free survival (PFS) in patients (pts) with relapsed platinum (plat)-sensitive high-grade ovarian cancer (ovca) compared to O alone in a Phase 2 trial (NCT01116648). We conducted this randomized, open-label Phase 3 trial (NCT02446600) to assess whether combination C+O, or O alone, was superior to standard of care (SOC) plat-based therapy in relapsed plat-sensitive ovca. Methods: Eligible pts had recurrent plat-sensitive [ > 6-month plat-free interval (PFI)] high-grade serous or endometrioid, or BRCA-related, ovca. One prior non-plat therapy and unlimited prior plat-therapies were allowed; prior anti-angiogenics in the recurrent setting or prior PARP inhibitor were exclusions. Pts were randomized 1:1:1 to SOC (carboplatin/paclitaxel; carboplatin/gemcitabine; or carboplatin/liposomal doxorubicin), O (300mg twice daily), or C+O (C 30mg daily + O 200mg twice daily). Randomization was stratified by g BRCA status, PFI (6-12 vs > 12 months), and prior anti-angiogenic therapy. Target sample size was 549 pts; primary analysis occurred 2 years after the last pt enrolled. The primary endpoint was PFS. Type 1 error = 0.025 was controlled by a gatekeeping hierarchy that assessed C+O vs SOC, then O alone vs SOC, and finally C+O vs O. All maintenance therapy was prohibited. Results: Between 4FEB2016 and 13NOV2017, 565 pts enrolled (187 SOC, 189 O, 189 C+O), and 528 pts initiated treatment (166 SOC, 183 O, 179 C+O). 23.7% of patients had g BRCAmut. Median follow-up was 29.1 months. 53 pts on SOC initiated non-protocol therapy (predominantly PARP inhibitor maintenance) before disease progression. The hazard ratio (HR) for PFS was 0.856 (95% CI 0.66-1.11, p = 0.08, 1-tail) between C+O and SOC and 1.20 (95% CI 0.93-1.54) between O and SOC, with median PFS of 10.3, 8.2, and 10.4 months for SOC, O, and C+O, respectively. Response rates were 71.3% (SOC), 52.4% (O), and 69.4% (C+O). In gBRCA pts, HR for PFS was 0.55 (95% CI 0.73-1.30) for C+O vs SOC, and 0.63 (95% CI 0.37-1.07) for O vs SOC. In non-g BRCA pts, HR for these comparisons was 0.97 (95% CI 0.73-1.30) and 1.41 (1.07-1.86). No OS differences between arms were observed at 44% events. Pts receiving C+O (vs SOC) had more frequent Grade 3 or higher gastrointestinal (30.1% vs 8.4%), hypertension (31.7% vs 1.8%), and fatigue events (17.5% vs 1.8%). Conclusion: C+O demonstrated similar activity to SOC in relapsed plat-sensitive ovca but did not meet the primary endpoint of improved PFS. Clinical trial information: NCT02446600.

Published
2020

43. A fight-and-flight for life: A rare case of advanced cervical cancer in pregnancy

Author

Jeffrey Killeen, Scott A. Harvey, Jennifer W.H. Wong, Meryl M. Sperling, and Michael E. Carney

Subjects
medicine.medical_specialty, medicine.medical_treatment, Case Report, Gynecologic oncology, SCC, squamous cell carcinoma, lcsh:Gynecology and obstetrics, lcsh:RC254-282, PET, positron emission tomography, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Chemotherapy, Medicine, Rupture of membranes, Vaginal bleeding, Cervix, lcsh:RG1-991, Cervical cancer, Multidisciplinary, 030219 obstetrics & reproductive medicine, business.industry, Obstetrics, Obstetrics and Gynecology, Cancer, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, CT, computed tomography, Radiation therapy, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Hypertension, medicine.symptom, business
Abstract

Highlights • Advanced cervical cancer during pregnancy requires shared decision making and a multidisciplinary team approach. • If the pregnancy is continued, antepartum chemotherapy should be strongly considered. • Maternal prognoses tend to be poor, but neonatal outcomes appear to be favorable., Background Advanced cervical cancer during pregnancy is an extremely rare event. We describe a case of at least stage IIIB cervical squamous cell carcinoma during pregnancy. This may possibly represent the longest gestation from time of diagnosis to delivery in a case of advanced cervical cancer, with potentially the most advanced gestational age at delivery and a relatively favorable outcome in the current literature. Case: A 29-year-old female at 20 0/7 weeks of gestation with at least stage IIIB squamous cell carcinoma of the cervix flew from Micronesia to Hawaii for oncologic treatment. After consultation with gynecologic oncology and maternal-fetal medicine, she opted to continue the pregnancy and began neoadjuvant chemotherapy with carboplatin and paclitaxel. At 33 2/7 weeks of gestation, she was admitted for preterm prelabor rupture of membranes and immediately underwent a cesarean delivery for heavy vaginal bleeding. Postpartum, she underwent cisplatin chemotherapy with concurrent radiation therapy. After 6 cycles of chemotherapy, the patient’s cancer had progressed to the point that hospice was recommended. She died 11 months after initial presentation. Conclusion Advanced cervical cancer during pregnancy requires individualized treatment, shared decision making, and a multidisciplinary team approach. If the pregnancy is continued, antepartum chemotherapy should be strongly considered. Maternal prognoses tend to be poor, but neonatal outcomes appear to be favorable.

Published
2020

44. Low-Volume Lymph Node Metastases in Endometrial Carcinoma

Author

Keith Y. Terada, Lani K. Clinton, Pamela Tauchi-Nishi, Michael E. Carney, David Shimizu, and Jordan Kondo

Subjects
Adult, medicine.medical_specialty, Sentinel lymph node, Hysterectomy, 03 medical and health sciences, 0302 clinical medicine, Robotic Surgical Procedures, Biopsy, Carcinoma, medicine, Humans, Lymph node, Aged, Neoplasm Staging, Retrospective Studies, Aged, 80 and over, 030219 obstetrics & reproductive medicine, medicine.diagnostic_test, business.industry, Sentinel Lymph Node Biopsy, Endometrial cancer, Obstetrics and Gynecology, Middle Aged, medicine.disease, Endometrial Neoplasms, Isolated Tumor Cells, Dissection, medicine.anatomical_structure, Oncology, Neoplasm Micrometastasis, 030220 oncology & carcinogenesis, Lymphatic Metastasis, Female, Lymph, Radiology, Lymph Nodes, business
Abstract

ObjectiveThe aim of this study was to determine the histopathologic characteristics of patients with endometrial carcinoma with low-volume metastases (micrometastases and isolated tumor cells) compared with macrometastases.MethodsWe performed a retrospective review of patients with endometrial carcinoma.ResultsAmong 350 robotic-assisted hysterectomies for endometrial cancer, 187 (53%) underwent attempted sentinel lymph node (SLN) biopsy. At least 1 SLN was detected in 185, a 99% overall detection rate; 108 (58%) also had non-SLNs removed. Among 91 patients with SLNs and non-SLNs from the ipsilateral hemipelvis, both were negative in 74 (81%) and positive in 7 (8%), and 10 (11%) had a positive SLN with negative non-SLNs. Among 17 patients with SLNs and non-SLNs from the contralateral hemipelvis, both were negative in 12 (71%), both were positive in 3 (18%), and 2 patients (12%) had negative SLNs with contralateral positive non-SLNs. Among 79 patients with only a SLN dissection, 4 (5%) were positive; among 69 patients with only a non-SLN dissection, 14 (20%) had positive lymph nodes. Among 24 patients with metastatic SLNs, 9 (38%) had isolated tumor cells, 3 (13%) had micrometastases, and 12 (50%) had macrometastases. Among the 40 total patients with metastatic lymph nodes, low-volume metastases represented the largest metastatic deposit in one third of patients, all of which had SLN dissection. All 12 with low-volume metastases had endometrioid histology compared with less than half (46%) of those with macrometastases (P < 0.01). Grade 1 carcinoma was present in 7 (58%) of the patients with low-volume metastases compared with 4 (14%) of those with macrometastases (P < 0.01) Furthermore, significantly more patients with low-volume metastases versus macrometastases had less than 50% myometrial invasion (67% vs 4%, P < 0.001).ConclusionsLow-volume disease was present in one third of patients with nodal metastases, the largest metastatic deposit only in patients who had SLN dissection; these patients were significantly more likely to have grade 1 endometrioid carcinoma with less than 50% myometrial invasion, traditional “low-risk” features.

Published
2017

45. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

Author

Eitan Friedman, Mattias Van Heetvelde, Jennifer B. Permuth, Joseph Vijai, Patricia A. Ganz, Jennifer A. Doherty, Argyrios Ziogas, Bernard Peissel, Edwin S. Iversen, Angela Brooks-Wilson, Ingo B. Runnebaum, Amanda B. Spurdle, Heli Nevanlinna, Kenneth Offit, Laura Papi, Georgia Chenevix-Trench, Saundra S. Buys, Martin Köbel, Fabienne Lesueur, Elizabeth W. Pugh, Joe Dennis, Sylvie Mazoyer, Diana Eccles, Shirley Hodgson, Jolanta Lissowska, Judy Garber, Pascal Pujol, Kristin K. Zorn, Orland Diez, Marcia Adams, Thomas Conner, Renée T. Fortner, Tjoung-Won Park-Simon, Vanesa García-Barberán, Kerstin Rhiem, Norbert Arnold, Karoline Kuchenbaecker, Susan M. Domchek, María Josefa Mosteiro García, Matthias W. Beckmann, Alex Henderson, Melissa C. Larson, Jane Romm, Anja Rudolph, Steven A. Narod, Mats Jernetz, Jolanta Kupryjanczyk, Natalia Bogdanova, Jacob Musinsky, Helga B. Salvesen, Jonathan Beesley, Paolo Peterlongo, Arif B. Ekici, Clarice R. Weinberg, Marion Piedmonte, Christian F. Singer, Robert L. Nussbaum, Katja K.H. Aben, Michael J. Birrer, Juul T. Wijnen, Elizabeth M. Poole, Phuong L. Mai, David J. Hunter, Tanja Pejovic, Athanassios Vratimos, Barbara Wappenschmidt, Nicolas Wentzensen, Marcus Q. Bernardini, Leigha Senter, Terence Cescon, Daniel W. Cramer, Silvia Tognazzo, Drakoulis Yannoukakos, Jacopo Azzollini, Ignace Vergote, Karen H. Lu, Gustavo C. Rodriguez, Julian Adlard, Tomasz Huzarski, Mark H. Greene, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Paulo C Lyra, Usha Menon, Ralf Bützow, Siddhartha Kar, Manuel R. Teixeira, Conxi Lázaro, Agnieszka Dansonka-Mieszkowska, Aleksandra Gentry-Maharaj, Zsofia K. Stadler, Melissa C. Southey, Ramunas Janavicius, Douglas F. Easton, Digna R. Velez Edwards, Jocelyne Chiquette, Karin Kast, Jonathan Tyrer, Georg Pfeiler, Tara M. Friebel, Bruno Buecher, Goska Leslie, Jackie Cook, Catherine M. Phelan, Steve Ellis, Estrid Høgdall, Beth Y. Karlan, Anthony J. Swerdlow, Sarah E. Ferguson, Rosalind Glasspool, Frans B. L. Hogervorst, Lotte Nedergaard, Britton Trabert, Jack A. Taylor, Irene L. Andrulis, Paolo Radice, Dennis J. Hazelett, Mads Thomassen, Dong Liang, Joseph H. Rothstein, Loren Lipworth, Melissa A. Merritt, Ana Vega, Petra H.M. Peeters, Claus Høgdall, Anna M. Piskorz, Bernardo Bonanni, Janet M. Lee, Malcolm C. Pike, Clemens Liebrich, Zachary C. Fogarty, Bent Ejlertsen, Yuan Chun Ding, Dieter Niederacher, Michael E. Carney, Dominique Stoppa-Lyonnet, Nadine Tung, Curtis Olswold, Ana Osorio, Fiona Bruinsma, Christine Walsh, Fabienne Prieur, Lara E. Sucheston-Campbell, Stephen B. Gruber, Maartje J. Hooning, George Fountzilas, Amanda Black, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Angela R. Bradbury, Helene Holland, Ruth C. Travis, Susana Banerjee, Penelope M. Webb, Brooke L. Fridley, Clara Bodelon, Mary Anne Rossing, Yen Y. Tan, Rosa B. Barkardottir, Jong Won Lee, Stephen J. Chanock, Bruce Poppe, Sandra Fert Ferrer, Melissa Moffitt, Taymaa May, Gustavo Mendoza-Fandiño, Christopher A. Haiman, Alicia Beeghly-Fadiel, Rebecca Sutphen, Michelle A.T. Hildebrandt, Lambertus A. Kiemeney, Thilo Dörk, Douglas A. Levine, Gerasimos Aravantinos, Celeste Leigh Pearce, Sue K. Park, David Van Den Berg, Louise Izatt, Hannah P. Yang, Graham G. Giles, Linda S. Cook, John R. McLaughlin, Nick Orr, Weiva Sieh, Raymonda Varon-Mateeva, Marco Montagna, Honglin Song, Laura Ottini, Ruea-Yea Huang, Joanna Moes-Sosnowska, Anders Bojesen, David M. O'Malley, Andrew K. Godwin, Lucy Side, Sung-Won Kim, Lukasz Szafron, Christoph Engel, Harvey A. Risch, Alexander Hein, Penny Soucy, Elza Khusnutdinova, Ana Peixoto, Arto Leminen, Cora M. Aalfs, Matthias Dürst, Mary B. Daly, Patricia Rice, Nadeem Siddiqui, Dale P. Sandler, Ava Kwong, Madalene Earp, Marjorie J. Riggan, Inge Søkilde Pedersen, Susanne K. Kjaer, Mercedes Durán, Joellen M. Schildkraut, James D. Brenton, D. Gareth Evans, Liisa M. Pelttari, Kimberly F. Doheny, Karen Hosking, Miquel Angel Pujana, Salina B. Chan, Joan Brunet, Trinidad Caldés, Rosemarie Davidson, Jessica N. McAlpine, Jenny Lester, Niclas Håkansson, Kai-ren Ong, Ros Eeles, Francesmary Modugno, Martin Gore, Loic Le Marchand, Robert A. Vierkant, Wendy K. Chung, Christopher I. Amos, N. Charlotte Onland-Moret, Brita Arver, Marc Tischkowitz, Craig Luccarini, Daniel Barrowdale, Laima Tihomirova, Louise A. Brinton, Fergus J. Couch, Alfons Meindl, Nerea Larrañaga, Cristina Rodríguez-Antona, Alice S. Whittemore, Johanna I. Kiiski, Todd L. Edwards, Eric Hahnen, Grzegorz Sukiennicki, Els Van Nieuwenhuysen, Elizabeth J. van Rensburg, Michael Jones, Åke Borg, Edith Olah, Ute Hamann, Liv Cecilie Vestrheim Thomsen, Xiaoqing Chen, Ganna Chornokur, Minouk J. Schoemaker, Marc T. Goodman, Fanny Dao, Andrea Gehrig, Hagay Sobol, Nhu D. Le, Esther M. John, Adriaan Vanderstichele, Antonia Trichopoulou, Kunle Odunsi, Yukie Bean, David G. Huntsman, Lidia Pezzani, V. Wendy Setiawan, Marinus J. Blok, Yael Laitman, Mary Porteous, Patricia Harrington, Samantha Poblete, Shashikant Lele, Anne M. van Altena, Mingajeva Elvira, Lene Lundvall, Dominique Leroux, Annemarie H. van der Hout, Darya Prokofyeva, Debra Frost, Yoke-Eng Chiew, Gad Rennert, Stacey J. Winham, Muy-Kheng Tea, Kirsten B. Moysich, Angel Izquierdo, Anna H. Wu, Christine Rappaport-Fuerhauser, Peter Hillemanns, Rob B. van der Luijt, Gord Glendon, Jan Lubinński, Csilla Szabo, Gillian Mitchell, Andrea L. Richardson, Mark E. Robson, Roger L. Milne, Thomas Hansen, Francesca Damiola, Tameka Shelford, Natalia Antonenkova, Julie Lecarpentier, Paul A. James, Claudine Isaacs, Gianluca Severi, Maria A. Caligo, Teodora Goranova, Kate Lawrenson, Sandra Orsulic, Priyanka Sharma, Holly R. Harris, Peter A. Fasching, Christian Sutter, Torben A Kruse, Line Bjørge, Lesley McGuffog, Leon F.A.G. Massuger, Lynne R. Wilkens, Reidun K. Kopperud, Jillian Hung, Iain A. McNeish, Hanne Meijers-Heijboer, Uffe Birk Jensen, Diether Lambrechts, Johanna Rantala, Kelly-Anne Phillips, Michelle M.M. Woo, Kathryn L. Terry, Kathleen Claes, Ellen L. Goode, Olufunmilayo I. Olopade, Darcy L. Thull, Ailith Pirie, Sharon E. Johnatty, Soo Hwang Teo, Aimee A D'Aloisio, Evgeny N. Imyanitov, Domenico Palli, Andrew Berchuck, Banu Arun, Florentia Fostira, Jan Hauke, Jenny Chang-Claude, Pamela J. Thompson, Peter J. Hulick, Per Broberg, Arjen R. Mensenkamp, Xifeng Wu, Alicia A. Tone, Jacques Simard, Ursula Eilber, Jacek Gronwald, Kenneth Blankstein, James M. Flanagan, Alvaro N.A. Monteiro, Timea Pocza, Rita K. Schmutzler, Jeffrey N. Weitzel, Simon A. Gayther, William D. Foulkes, Valerie McGuire, Katherine L. Nathanson, Kevin H. Eng, Anna deFazio, Ian G. Campbell, Capucine Delnatte, Shan Wang-Gohrke, Jenna Lilyquist, Matti A. Rookus, Sakaeva Dina Damirovna, Laure Dossus, Simon G. Coetzee, Catherine J. Kennedy, Roberta B. Ness, James Paul, Andrew Lee, Linda E. Kelemen, Judith Balmaña, Anne-Marie Gerdes, Laure Barjhoux, Håkan Olsson, Lisa Walker, Doris Steinemann, Cecilia M. Dorfling, Julie M. Cunningham, Shelley S. Tworoger, Allan Jensen, Thomas A. Sellers, Javier Benitez, Anthony N. Karnezis, Hoda Anton-Culver, Carole Brewer, Siranoush Manoukian, Dorothea Wand, Ed Dicks, Antonis C. Antoniou, Amanda E. Toland, Anna Marie Mulligan, Päivi Kannisto, Rikki Cannioto, Bernd Dworniczak, Susan J. Ramus, Anna V. Tinker, Epidemiology and Data Science, Amsterdam Reproduction & Development (AR&D), CCA - Cancer biology and immunology, Amsterdam Neuroscience - Complex Trait Genetics, Human genetics, MUMC+: DA KG Lab Centraal Lab (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Government of Canada, Cancer Research Foundation, Canadian Institutes of Health Research, National Institutes of Health (US), Fonds de Recherche du Québec, Ministry of Health and Welfare (South Korea), Associazione Italiana per la Ricerca sul Cancro, Deutsche Krebshilfe, Genome Canada, Medical Oncology, Clinical Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, Centre Léon Bérard [Lyon], Service de Génétique Oncologique, Institut Curie [Paris], CRLCC René Gauducheau, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Centre Hospitalier Métropole Savoie [Chambéry], CHU Grenoble, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Etienne, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), Université Paris-Saclay, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Tyrer, Jonathan [0000-0003-3724-4757], Dennis, Joe [0000-0003-4591-1214], Dicks, Ed [0000-0002-0617-0401], Lee, Andrew [0000-0003-0677-0252], Leslie, Goska [0000-0001-5756-6222], Brenton, James [0000-0002-5738-6683], Song, Honglin [0000-0001-5076-7371], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, endocrine system diseases, Epidemiology, Càncer d'ovari, Genome-wide association study, Carcinoma, Ovarian Epithelial, Genome-wide association studies, susceptibility, Risk Factors, Genotype, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Medicine and Health Sciences, Neoplasms, Glandular and Epithelial, POPULATION, Genetics & Heredity, Genetics, Ovarian Neoplasms, RISK, education.field_of_study, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], cancer, ovary, BRCA1 Protein, COMMON VARIANTS, 11 Medical And Health Sciences, ASSOCIATION, female genital diseases and pregnancy complications, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, Serous fluid, ovarian cancer, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Life Sciences & Biomedicine, epithelial ovarian cancer, BRCA1, BRCA2, Population, Telomere-Binding Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Meta-Analysis as Topic, CLEAR-CELL CARCINOMA, Ovarian cancer, medicine, Journal Article, Humans, BREAST-CANCER, Genetic Predisposition to Disease, Allele, education, Genotyping, Alleles, METAANALYSIS, BRCA2 Protein, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, MUTATIONS, ENDOMETRIOSIS, Biology and Life Sciences, 06 Biological Sciences, medicine.disease, 030104 developmental biology, Genetic Loci, Mutation, TELOMERE LENGTH, Cancer research, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Developmental Biology, Genome-Wide Association Study
Abstract

The OCAC OncoArray genotyping project: et al., 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., The OCAC OncoArray genotyping project was funded through grants from the US National Institutes of Health (CA1X01HG007491-01 (C.I.A.), U19-CA148112 (T.A.S.), R01-CA149429 (C.M.P.) and R01-CA058598 (M.T.G.)); Canadian Institutes of Health Research (MOP-86727 (L.E.K.)); and the Ovarian Cancer Research Fund (A.B.). Funding for the CIMBA OncoArray genotyping was provided by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l’Économie, de la Science et de l’Innovation du Québec through Génome Québec, the Quebec Breast Cancer Foundation for the PERSPECTIVE project, the US National Institutes of Health (CA1X01HG007491-01 (C.I.A.)), the Odense University Hospital Research Foundation (M.T.), the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1420190 (S.K.P.)), the Italian Association for Cancer Research (IG16933 (L.O.)) and German Cancer Aid (110837 (R.K.S.).

Published
2017

46. Genital Powder Use and Risk of Ovarian Cancer: A Pooled Analysis of 8,525 Cases and 9,859 Controls

Author

Malcolm C. Pike, Jennifer A. Doherty, Weiva Sieh, Galina Lurie, Lucy Akushevich, Kirsten B. Moysich, Wei-Hsuan Lo-Ciganic, Mary Anne Rossing, Harvey A. Risch, Stalo Karageorgi, Andrew Berchuck, Celeste Leigh Pearce, Christina M. Nagle, Kathryn L. Terry, Melissa A. Merritt, Kara L. Cushing-Haugen, Penelope M. Webb, Pamela J. Thompson, Yurii B. Shvetsov, Joellen M. Schildkraut, Michael E. Carney, Rachel Palmieri Weber, Roberta B. Ness, and Marc T. Goodman

Subjects
Cancer Research, medicine.medical_specialty, Population, Gastroenterology, Article, Internal medicine, Odds Ratio, Humans, Medicine, education, Ovarian Neoplasms, Gynecology, education.field_of_study, business.industry, Confounding, Case-control study, Odds ratio, Middle Aged, Prognosis, medicine.disease, Confidence interval, Serous fluid, Oncology, Talc, Case-Control Studies, Meta-analysis, Female, Powders, business, Ovarian cancer
Abstract

Genital powder use has been associated with risk of epithelial ovarian cancer in some, but not all, epidemiologic investigations, possibly reflecting the carcinogenic effects of talc particles found in most of these products. Whether risk increases with number of genital powder applications and for all histologic types of ovarian cancer also remains uncertain. Therefore, we estimated the association between self-reported genital powder use and epithelial ovarian cancer risk in eight population-based case–control studies. Individual data from each study were collected and harmonized. Lifetime number of genital powder applications was estimated from duration and frequency of use. Pooled ORs were calculated using conditional logistic regression matched on study and age and adjusted for potential confounders. Subtype-specific risks were estimated according to tumor behavior and histology. 8,525 cases and 9,859 controls were included in the analyses. Genital powder use was associated with a modest increased risk of epithelial ovarian cancer [OR, 1.24; 95% confidence interval (CI), 1.15–1.33] relative to women who never used powder. Risk was elevated for invasive serous (OR, 1.20; 95% CI, 1.09–1.32), endometrioid (OR, 1.22; 95% CI, 1.04–1.43), and clear cell (OR, 1.24; 95% CI, 1.01–1.52) tumors, and for borderline serous tumors (OR, 1.46; 95% CI, 1.24–1.72). Among genital powder users, we observed no significant trend (P = 0.17) in risk with increasing number of lifetime applications (assessed in quartiles). We noted no increase in risk among women who only reported nongenital powder use. In summary, genital powder use is a modifiable exposure associated with small-to-moderate increases in risk of most histologic subtypes of epithelial ovarian cancer. Cancer Prev Res; 6(8); 811–21. ©2013 AACR.

Published
2013

47. Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study

Author

Kirsten B. Moysich, Michael E. Carney, Aleksandra Gentry-Maharaj, Susan J. Ramus, Georgia Chenevix-Trench, Carl Morrison, Julie M. Cunningham, Andre E. Kim, Anna V. Tinker, Shashikant Lele, Jennifer Alsop, Allan Jensen, Weiva Sieh, Teri A. Longacre, C. Blake Gilks, Susanne K. Kjaer, Joshy George, Usha Menon, Suha Deen, Michael S. Anglesio, Paul D.P. Pharoah, Rayna K. Matsuno, Estrid Høgdall, Montserrat Garcia-Closas, Leah M Prentice, Marie Mack, Martin Köbel, Jolanta Lissowska, Brooke L. Fridley, Lynne R. Wilkens, Lara Sucheston, Galina Lurie, Kristy Driver, Valerie McGuire, Pamela J. Thompson, Barry P. Rosen, Marcus Q. Bernardini, Christine Chow, Simon A. Gayther, Wiam Bshara, Anna deFazio, Eva Wozniak, Ellen L. Goode, Gary L. Keeney, David D.L. Bowtell, James D. Brenton, Robert A. Vierkant, Louise A. Brinton, Blaise Clarke, Kimberly R. Kalli, Marc T. Goodman, Nicolas Wentzensen, Sian Fereday, Joseph H. Rothstein, Elizabeth Benjamin, Sharon E. Johnatty, Amit M. Oza, Hannah P. Yang, Alice S. Whittemore, Kunle Odunsi, Claus Høgdall, Laura Galletta, David G. Huntsman, Mark E. Sherman, Helen Mackay, Jason Madore, and Mercedes Jimenez-Linan

Subjects
Oncology, medicine.medical_specialty, endocrine system diseases, Serous carcinoma, Immunoenzyme Techniques, 03 medical and health sciences, Ovarian tumor, 0302 clinical medicine, Internal medicine, Biomarkers, Tumor, medicine, Humans, Mucinous carcinoma, Neoplasm Invasiveness, Neoplasm Staging, 030304 developmental biology, Ovarian Neoplasms, 0303 health sciences, Tissue microarray, business.industry, Ovary, Cancer, Middle Aged, Prognosis, medicine.disease, Adenocarcinoma, Mucinous, female genital diseases and pregnancy complications, Cystadenocarcinoma, Serous, 3. Good health, Survival Rate, Serous fluid, Receptors, Estrogen, Tissue Array Analysis, Case-Control Studies, 030220 oncology & carcinogenesis, Adenocarcinoma, Female, Neoplasm Grading, Receptors, Progesterone, business, Ovarian cancer, Carcinoma, Endometrioid, Adenocarcinoma, Clear Cell, Follow-Up Studies
Abstract

Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated with subtype-specific survival.12 studies participating in the Ovarian Tumor Tissue Analysis consortium contributed tissue microarray sections and clinical data to our study. Participants included in our analysis had been diagnosed with invasive serous, mucinous, endometrioid, or clear-cell carcinomas of the ovary. For a patient to be eligible, tissue microarrays, clinical follow-up data, age at diagnosis, and tumour grade and stage had to be available. Clinical data were obtained from medical records, cancer registries, death certificates, pathology reports, and review of histological slides. PR and ER statuses were assessed by central immunohistochemistry analysis done by masked pathologists. PR and ER staining was defined as negative (1% tumour cell nuclei), weak (1 to50%), or strong (≥50%). Associations with disease-specific survival were assessed.2933 women with invasive epithelial ovarian cancer were included: 1742 with high-grade serous carcinoma, 110 with low-grade serous carcinoma, 207 with mucinous carcinoma, 484 with endometrioid carcinoma, and 390 with clear-cell carcinoma. PR expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p0·0001) and high-grade serous carcinoma (log-rank p=0·0006), and ER expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p0·0001). We recorded no significant associations for mucinous, clear-cell, or low-grade serous carcinoma. Positive hormone-receptor expression (weak or strong staining for PR or ER, or both) was associated with significantly improved disease-specific survival in endometrioid carcinoma compared with negative hormone-receptor expression, independent of study site, age, stage, and grade (hazard ratio 0·33, 95% CI 0·21-0·51; p0·0001). Strong PR expression was independently associated with improved disease-specific survival in high-grade serous carcinoma (0·71, 0·55-0·91; p=0·0080), but weak PR expression was not (1·02, 0·89-1·18; p=0·74).PR and ER are prognostic biomarkers for endometrioid and high-grade serous ovarian cancers. Clinical trials, stratified by subtype and biomarker status, are needed to establish whether hormone-receptor status predicts response to endocrine treatment, and whether it could guide personalised treatment for ovarian cancer.Carraresi Foundation and others.

Published
2013

48. Integrated genomic characterization of endometrial carcinoma

Author

Ding Li, Esther Elishaev, Linda Dao, Juok Cho, Alexei Protopopov, Heather Schmidt, Tod D. Casasent, Bobbie S. Gostout, P.J. DiSaia, Jacqueline E. Schein, J. Todd Auman, Jay Bowen, S. Onur Sumer, Beth Y. Karlan, Gordon Saksena, Prachi Kothiyal, Robert E. Pyatt, Theodore C. Goldstein, Lisle E. Mose, Paul J. Goodfellow, Brenda Ayala, Nilsa C. Ramirez, Thomas Barr, Payal Sipahimalani, Gordon B. Mills, Rebecca Carlsen, Linda Van Le, Andy Chu, Peter W. Laird, Russell Broaddus, Helga B. Salvesen, Sam Ng, Cyriac Kandoth, Christopher Adams, Yiling Lu, Donghui Tan, Peter White, Lori Boice, Saianand Balu, Daniel DiCara, Robert A. Holt, Christopher C. Benz, Shi Yan, Joel S. Parker, Jessica Frick, Adrian Ally, Boris Winterhoff, Pamela M. Pollock, Patrick Plettner, Ethan Cerami, Angela Tam, Katherine A. Hoadley, Melissa Hart-Kothari, Robert C. Onofrio, John N. Weinstein, Sheila Reynolds, David Haussler, Kristian Cibulskis, Charles M. Perou, Timothy J. Triche, Rehan Akbani, Jeff Roach, Michael Mayo, Ranabir Guin, W. Kimryn Rathmell, Carmen Helsel, Junyuan Wu, Will Mallard, Nandita Barnabas, Todd Pihl, Ruibin Xi, Nianxiang Zhang, David Mallery, Douglas A. Levine, Aaron D. Black, David I. Heiman, Sugy Kodeeswaran, Lynda Chin, Guoyan Liu, Mark E. Borowsky, Daniel J. Weisenberger, Yuexin Liu, Hailei Zhang, Kenna R. Mills Shaw, Anna K. Unruh, Andrew Berchuck, Michael Button, Noreen Dhalla, Bryan Hernandez, Rayna K. Matsuno, David G. Mutch, Chen Wang, Teresa R. Tabler, Yaron S.N. Butterfield, Jeff Gentry, Stuart R. Jefferys, Thomas Grossman, Kelley Kneile, Fanny Dao, Scot Waring, Barbara Tabak, Eric E. Snyder, Eric S. Lander, Richard A. Moore, David J. Dooling, David Van Den Berg, Jiabin Tang, Piotr A. Mieczkowski, Victoria Blanc, Wei Zhang, Inanc Birol, Harkness Kuck, Mathew G. Soloway, Johanna Gardner, Gary Witkin, Sahil Seth, Heidi J. Sofia, B. Arman Aksoy, Nikolaus Schultz, Marco A. Marra, Andrew D. Cherniack, D L Rotin, Anders Jacobsen, Erik Zmuda, Candace Carter, Christina Yau, Stephen C. Benz, Alexander A. Green, Michael D. Topal, Jean MacKenzie, Elena Nemirovich-Danchenko, Nicholas J. Petrelli, Dana Nicholson, Eve Shinbrot, Han Liang, Rameen Beroukhim, Charlenia Berry-Green, Kristin G. Ardlie, Joan Pontius, David Pot, Ari B. Kahn, Marc T. Goodman, Yevgeniy Antipin, Christopher Szeto, Jianhua Zhang, Ilya Shmulevich, Lori Huelsenbeck-Dill, Steven J.M. Jones, Carrie Sougnez, Kristen M. Leraas, Pei Lin, Robert A. Soslow, Erin Curley, Leigh B. Thorne, Hye Jung E. Chun, Michael S. Lawrence, Michelle O'Laughlin, Moiz S. Bootwalla, Lixing Yang, Mark A. Jensen, Rajiv Dhir, David A. Wheeler, C. Blake Gilks, Jianjiong Gao, Lisa Wise, Giovanni Ciriello, Joelle Kalicki-Veizer, Shaowu Meng, Mei Huang, Elaine R. Mardis, Faina Bogomolniy, Kai Ye, Jenny Lester, Lihua Zou, Hollie A. Harper, Robert Edwards, Ronglai Shen, Xiaojia Ren, Nils Weinhold, Harshad S. Mahadeshwar, Sandra Orsulic, Tom Bodenheimer, Zhenlin Ju, Chris Wakefield, Scott Frazer, John M. S. Bartlett, Gideon Dresdner, Hui Shen, Deepak Srinivasan, Aaron Hobensack, Cynthia McAllister, Marc Ladanyi, Tanja Davidsen, Lucinda Fulton, Michael D. McLellan, Richard K. Wilson, Zeng Dong, Olga Potapova, Sean C. Dowdy, Rui Jing, Kristin K. Zorn, Robert S. Fulton, Matti Annala, Chris Sander, Michael S. Noble, Benjamin Gross, Janae V. Simons, Phillip H. Lai, Laura Monovich, Andrew J. Mungall, Peter J. Park, Fedor Moiseenko, Liming Yang, Gad Getz, John Deardurff, Matthew Meyerson, Jeremy Parfitt, A. Gordon Robertson, Bradley M. Broom, Blaise A. Clarke, Greg Eley, Jennifer O. Fisher, Andrey Sivachenko, Narciso Olvera, Carrie Hirst, Adam M. Farkas, Karuna Garg, Wendy Winckler, Eric Chuah, Stacey Gabriel, Michael E. Carney, Stephen B. Baylin, Doug Voet, Miruna Balasundaram, Christine Czerwinski, Daphne W. Bell, Richard Varhol, Alexandra Meuter, Alan P. Hoyle, Darlene Lee, Elizabeth Buda, Li Ding, Xingzhi Song, Steven E. Schumacher, Anna L. Chu, Attila Teoman, Mary Iacocca, Semin Lee, Rileen Sinha, Itai Pashtan, Haiyan I. Li, Mikhail Abramov, Mark S. Guyer, Robert Penny, Margi Sheth, Scott L. Carter, Corbin D. Jones, Michael J. Birrer, Julie M. Gastier-Foster, D. Neil Hayes, Nathan Vanhoose, Brenda Rabeno, Raju Kucherlapati, Martin L. Ferguson, Joshua M. Stuart, Steve E. Kalloger, Mark G. Cadungog, Petar Stojanov, Tara M. Lichtenberg, Bradley A. Ozenberger, Angela Hadjipanayis, Barry S. Taylor, Boris Reva, Massachusetts Institute of Technology. Department of Biology, Lander, Eric S., and Park, Peter J.

Subjects
DNA Copy Number Variations, endocrine system diseases, ARID1A, DNA Mutational Analysis, Breast Neoplasms, Biology, medicine.disease_cause, Article, Uterine serous carcinoma, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, PTEN, Exome, Poly-ADP-Ribose Binding Proteins, neoplasms, 030304 developmental biology, Chromosome Aberrations, Ovarian Neoplasms, 0303 health sciences, Endometrial intraepithelial neoplasia, Multidisciplinary, Genome, Human, Microsatellite instability, DNA Polymerase II, Genomics, medicine.disease, Molecular biology, female genital diseases and pregnancy complications, Endometrial Neoplasms, 3. Good health, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Serous fluid, 030220 oncology & carcinogenesis, DNA methylation, Cancer research, biology.protein, Female, KRAS, Signal Transduction, Transcription Factors
Abstract

We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and ~25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours., National Institutes of Health (U.S.) (Grant 5U24CA143799-04), National Institutes of Health (U.S.) (Grant 5U24CA143835-04), National Institutes of Health (U.S.) (Grant 5U24CA143840-04), National Institutes of Health (U.S.) (Grant 5U24CA143843-04), National Institutes of Health (U.S.) (Grant 5U24CA143845-04), National Institutes of Health (U.S.) (Grant 5U24CA143848-04), National Institutes of Health (U.S.) (Grant 5U24CA143858-04), National Institutes of Health (U.S.) (Grant 5U24CA143866-04), National Institutes of Health (U.S.) (Grant 5U24CA143867-04), National Institutes of Health (U.S.) (Grant 5U24CA143882-04), National Institutes of Health (U.S.) (Grant 5U24CA143883-04), National Institutes of Health (U.S.) (Grant 5U24CA144025-04), National Institutes of Health (U.S.) (Grant U54HG003067-11), National Institutes of Health (U.S.) (Grant U54HG003079-10), National Institutes of Health (U.S.) (Grant U54HG003273-10)

Published
2013

49. Cigarette smoking and risk of ovarian cancer: a pooled analysis of 21 case–control studies

Author

Lambertus A. Kiemeney, Klaus Kaae Andersen, Melissa C. Larson, Pamela J. Thompson, Mitul Shah, Kathryn L. Terry, Alice S. Whittemore, Michael E. Carney, Kunle Odunsi, Harvey A. Risch, Mette Tuxen Faber, Aleksandra Gentry-Maharaj, Allan Jensen, Robert A. Vierkant, Jenny Chang-Claude, Celeste Leigh Pearce, Penelope M. Webb, Urmila Chandran, Jennifer A. Doherty, Hannah P. Yang, Ellen L. Goode, Joellen M. Schildkraut, Susanne K. Kjaer, Karin A. Kasza, Anne M. van Altena, Galina Lurie, Simon A. Gayther, Oluwatosin Odunsi-Akanji, Robert P. Edwards, Elisa V. Bandera, Usha Menon, Allison F. Vitonis, Anna H. Wu, Honglin Song, Nicolas Wentzensen, Louise A. Brinton, Clareann H. Bunker, Sara H. Olson, Francesmary Modugno, Marc T. Goodman, Susan J. Ramus, Brooke L. Fridley, Mary Anne Rossing, Sita H. Vermeulen, Rebecca Sutphen, Paul D. Pharaoh, Roberta B. Ness, Susan J. Jordan, Valerie McGuire, Kirsten B. Moysich, Melony King, Christian Dehlendorff, Weiva Sieh, Jolanta Lissowska, Estrid Høgdall, Leon F.A.G. Massuger, Malcolm C. Pike, and Daniel W. Cramer

Subjects
Adult, Oncology, Cancer Research, medicine.medical_specialty, endocrine system diseases, Adolescent, Aetiology, screening and detection [ONCOL 5], Carcinoma, Ovarian Epithelial, Article, Molecular epidemiology [NCEBP 1], Young Adult, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Translational research [ONCOL 3], Internal medicine, Epidemiology, medicine, Carcinoma, Humans, Neoplasms, Glandular and Epithelial, Young adult, Aged, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], 030304 developmental biology, Aged, 80 and over, Ovarian Neoplasms, Gynecology, 0303 health sciences, Hereditary cancer and cancer-related syndromes [ONCOL 1], business.industry, Smoking, Case-control study, Cancer, Middle Aged, medicine.disease, Aetiology, screening and detection Immune Regulation [ONCOL 5], 3. Good health, Logistic Models, Case-Control Studies, 030220 oncology & carcinogenesis, Meta-analysis, Female, business, Ovarian cancer, Risk assessment
Abstract

Contains fulltext : 118139.pdf (Publisher’s version ) (Closed access) PURPOSE: The majority of previous studies have observed an increased risk of mucinous ovarian tumors associated with cigarette smoking, but the association with other histological types is unclear. In a large pooled analysis, we examined the risk of epithelial ovarian cancer associated with multiple measures of cigarette smoking with a focus on characterizing risks according to tumor behavior and histology. METHODS: We used data from 21 case-control studies of ovarian cancer (19,066 controls, 11,972 invasive and 2,752 borderline cases). Study-specific odds ratios (OR) and 95 % confidence intervals (CI) were obtained from logistic regression models and combined into a pooled odds ratio using a random effects model. RESULTS: Current cigarette smoking increased the risk of invasive mucinous (OR = 1.31; 95 % CI: 1.03-1.65) and borderline mucinous ovarian tumors (OR = 1.83; 95 % CI: 1.39-2.41), while former smoking increased the risk of borderline serous ovarian tumors (OR = 1.30; 95 % CI: 1.12-1.50). For these histological types, consistent dose-response associations were observed. No convincing associations between smoking and risk of invasive serous and endometrioid ovarian cancer were observed, while our results provided some evidence of a decreased risk of invasive clear cell ovarian cancer. CONCLUSIONS: Our results revealed marked differences in the risk profiles of histological types of ovarian cancer with regard to cigarette smoking, although the magnitude of the observed associations was modest. Our findings, which may reflect different etiologies of the histological types, add to the fact that ovarian cancer is a heterogeneous disease.

Published
2013

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

Author

Angela Brooks-Wilson, Estrid Høgdall, Usha Menon, Y. Ann Chen, Stacey J. Winham, Jan Lubinski, Aleksandra Gentry-Maharaj, Brooke L. Fridley, Dale P. Sandler, Jennifer A. Doherty, Mary Anne Rossing, Hoda Anton-Culver, Douglas A. Levine, Jennifer B. Permuth, Joellen M. Schildkraut, Jolanta Lissowska, Daniel W. Cramer, Pamela J. Thompson, Honglin Song, Ellen L. Goode, Tanja Pejovic, Brett M. Reid, Julie M. Cunningham, Toru Nakanishi, Beth Y. Karlan, Australian Cancer Study, Susan J. Ramus, Shelley S. Tworoger, Allan Jensen, Jacek Gronwald, Wei Zheng, Thomas A. Sellers, Alvaro N.A. Monteiro, Ailith Pirie, Peter Kraft, Michael E. Carney, Aimee A D'Aloisio, Simon A. Gayther, Andrew Berchuck, Jack A. Taylor, Keitaro Matsuo, Anna H. Wu, Penelope M. Webb, Anna Jakubowska, Paul D.P. Pharoah, Elizabeth M. Poole, Louise A. Brinton, Marc T. Goodman, Argyrios Ziogas, Kathryn L. Terry, Xiao-Ou Shu, Hannah P. Yang, S.K. Kjaer, Edwin S. Iversen, Robert P. Edwards, Nicolas Wentzensen, Celeste Leigh Pearce, Gustavo Mendoza-Fandiño, Soo-Hwang Teo, Hui-Yi Lin, Irene Orlow, Yin Ling Woo, Maria Bisogna, Cezary Cybulski, Roberta B. Ness, Linda E. Kelemen, Elisa V. Bandera, Georgia Chenevix-Trench, Linda S. Cook, Catherine M. Phelan, Rosemary Modugno, Madalene Earp, Joe Dennis, Zhihua Chen, Nhu D. Le, Kirsten B. Moysich, Sara H. Olson, and Lynne R. Wilkens

Subjects
0301 basic medicine, Linkage disequilibrium, Genotype, Genome-wide association study, Biology, Carcinoma, Ovarian Epithelial, Polymorphism, Single Nucleotide, 03 medical and health sciences, Polymorphism (computer science), Genetics, medicine, Humans, Exome, Genetic Predisposition to Disease, Neoplasms, Glandular and Epithelial, Molecular Biology, Genotyping, Genetics (clinical), Ovarian Neoplasms, Biotinidase, Keratin-13, Association Studies Articles, Cancer, General Medicine, medicine.disease, Actins, Neoplasm Proteins, 030104 developmental biology, Human genome, Female, Receptor, Melanocortin, Type 2, Genome-Wide Association Study
Abstract

Rare and low frequency variants are not well covered in most germline genotyping arrays and are understudied in relation to epithelial ovarian cancer (EOC) risk. To address this gap, we used genotyping arrays targeting rarer protein-coding variation in 8,165 EOC cases and 11,619 controls from the international Ovarian Cancer Association Consortium (OCAC). Pooled association analyses were conducted at the variant and gene level for 98,543 variants directly genotyped through two exome genotyping projects. Only common variants that represent or are in strong linkage disequilibrium (LD) with previously-identified signals at established loci reached traditional thresholds for exome-wide significance (P ( )P≥5.0 ×10 (-) (7)) were detected for rare and low-frequency variants at 16 novel loci. Four rare missense variants were identified (ACTBL2 rs73757391 (5q11.2), BTD rs200337373 (3p25.1), KRT13 rs150321809 (17q21.2) and MC2R rs104894658 (18p11.21)), but only MC2R rs104894668 had a large effect size (OR = 9.66). Genes most strongly associated with EOC risk included ACTBL2 (PAML = 3.23 × 10 (-) (5); PSKAT-o = 9.23 × 10 (-) (4)) and KRT13 (PAML = 1.67 × 10 (-) (4); PSKAT-o = 1.07 × 10 (-) (5)), reaffirming variant-level analysis. In summary, this large study identified several rare and low-frequency variants and genes that may contribute to EOC susceptibility, albeit with possible small effects. Future studies that integrate epidemiology, sequencing, and functional assays are needed to further unravel the unexplained heritability and biology of this disease.

Published
2016

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