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

Author

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

Subjects
Medicine, Genetics, QH426-470
Abstract

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

Published
2024
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2. CA-125 Levels Are Predictive of Survival in Low-Grade Serous Ovarian Cancer—A Multicenter Analysis

Author

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

Subjects
ovarian cancer, low-grade serous cancer, CA-125, survival, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Objective: Studies on low-grade serous ovarian cancer (LGSC) are limited by a low number of cases. The aim of this study was to define the prognostic significance of age, stage, and CA-125 levels on survival in a multi-institutional cohort of women with pathologically confirmed LGSC. Methods: Women with LGSC were identified from the collaborative Ovarian Cancer Association Consortium (OCAC). Cases of newly diagnosed primary LGSC were included if peri-operative CA-125 levels were available. Age at diagnosis, FIGO stage, pre- and post-treatment CA-125 levels, residual disease, adjuvant chemotherapy, disease recurrence, and vital status were collected by the participating institutions. Progression-free (PFS) and overall survival (OS) were calculated. Multivariable (MVA) Cox proportional hazard models were used and hazard ratios (HR) calculated. Results: A total of 176 women with LGSC were included in this study; 82% had stage III/IV disease. The median PFS was 2.3 years and the median OS was 6.4 years. Age at diagnosis was not significantly associated with worse PFS (p = 0.23) or OS (p = 0.3) (HR per year: 0.99; 95%CI, 0.96–1.01 and 0.98; 95%CI 0.95–1.01). FIGO stage III/IV was independently associated with PFS (HR 4.26, 95%CI 1.43–12.73) and OS (HR 1.69, 95%CI 0.56–5.05). Elevated CA-125 (≥35 U/mL) at diagnosis was not significantly associated with worse PFS (p = 0.87) or OS (p = 0.78) in MVA. Elevated CA-125 (≥35 U/mL) after completion of primary treatment was independently associated with worse PFS (HR 2.81, 95%CI 1.36–5.81) and OS (HR 6.62, 95%CI 2.45–17.92). In the MVA, residual disease was independently associated with PFS (0.022), but not OS (0.85). Conclusion: Advanced LGSC was associated with poor long-term prognosis. FIGO stage and abnormal post-treatment CA-125 level are key prognostic factors inversely associated with PFS and OS. Highlights: 1. Through a multi-center collaborative effort, data from 176 women with low-grade serous ovarian cancer were analyzed. 2. Although low-grade serous ovarian cancer is often considered indolent, the progression-free and overall survival are poor. 3. Elevated post-treatment CA-125 levels are independently associated with poor survival.

Published
2022
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3. Genome-wide association study of paclitaxel and carboplatin disposition in women with epithelial ovarian cancer

Author

Bo Gao, Yi Lu, Annemieke J. M. Nieuweboer, Hongmei Xu, Jonathan Beesley, Ingrid Boere, Anne-Joy M. de Graan, Peter de Bruijn, Howard Gurney, Catherine J. Kennedy, Yoke-Eng Chiew, Sharon E. Johnatty, Philip Beale, Michelle Harrison, Craig Luccarini, Don Conroy, Ron H. J. Mathijssen, Paul R. Harnett, Rosemary L. Balleine, Georgia Chenevix-Trench, Stuart Macgregor, and Anna de Fazio

Subjects
Medicine, Science
Abstract

Abstract Identifying single nucleotide polymorphisms (SNPs) that influence chemotherapy disposition may help to personalize cancer treatment and limit toxicity. Genome-wide approaches are unbiased, compared with candidate gene studies, but usually require large cohorts. As most chemotherapy is given cyclically multiple blood sampling is required to adequately define drug disposition, limiting patient recruitment. We found that carboplatin and paclitaxel disposition are stable phenotypes in ovarian cancer patients and tested a genome-wide association study (GWAS) design to identify SNPs associated with chemotherapy disposition. We found highly significant SNPs in ABCC2, a known carboplatin transporter, associated with carboplatin clearance (asymptotic P = 5.2 × 106, empirical P = 1.4 × 10−5), indicating biological plausibility. We also identified novel SNPs associated with paclitaxel disposition, including rs17130142 with genome-wide significance (asymptotic P = 2.0 × 10−9, empirical P = 1.3 × 10−7). Although requiring further validation, our work demonstrated that GWAS of chemotherapeutic drug disposition can be effective, even in relatively small cohorts, and can be adopted in drug development and treatment programs.

Published
2018
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4. Supplementary Tables 1 - 4 from Large-Scale Evaluation of Common Variation in Regulatory T Cell–Related Genes and Ovarian Cancer Outcome

Author

Ellen L. Goode, Keith L. Knutson, Lara E. Sucheston, Kunle Odunsi, Roberta B. Ness, Simon A. Gayther, Paul D.P. Pharoah, Georgia Chenevix-Trench, Mary Anne Rossing, Daniel W. Cramer, Celeste Leigh Pearce, Joellen M. Schildkraut, Usha Menon, Susanne K. Kjaer, Douglas A. Levine, Jacek Gronwald, Hoda Anton Culver, Alice S. Whittemore, Beth Y. Karlan, Diether Lambrechts, Nicolas Wentzensen, Jolanta Kupryjanczyk, Jenny Chang-Claude, Elisa V. Bandera, Estrid Hogdall, Florian Heitz, Stanley B. Kaye, Gottfried Konecny, Peter A. Fasching, Ian Campbell, Marc T. Goodman, Tanja Pejovic, Yukie T. Bean, Laura E. Hays, Galina Lurie, Diana Eccles, Alexander Hein, Matthias W. Beckmann, Arif B. Ekici, James Paul, Robert Brown, James M. Flanagan, Philipp Harter, Andreas du Bois, Ira Schwaab, Claus K. Hogdall, Sara H. Olson, Lene Lundvall, Irene Orlow, Lisa E. Paddock, Anja Rudolph, Petra Seibold, Agnieszka Dansonka-Mieszkowska, Iwona K. Rzepecka, Beata Spiewankiewicz, Louise A. Brinton, Hannah Yang, Montserrat Garcia-Closas, Evelyn Despierre, Sandrina Lambrechts, Ignace Vergote, Christine Walsh, Jenny Lester, Weiva Sieh, Valerie McGuire, Joseph H. Rothstein, Argyrios Ziogas, Jan Lubiński, Cezary Cybulski, Janusz Menkiszak, Allan Jensen, Howard Shen, Brenda Diergaarde, Susan J. Ramus, Aleksandra Gentry-Maharaj, Andrew Berchuck, Anna H. Wu, Malcolm C. Pike, David Van Den Berg, Kathryn L. Terry, Allison F. Vitonis, Starr M. Ramirez, Thomas A. Sellers, Catherine M. Phelan, Jennifer A. Doherty, Sharon E. Johnatty, Anna deFazio, Honglin Song, Jonathan Tyrer, Chen Wang, Kate Lawrenson, Lynn C. Hartmann, Claudia Preston, David N. Rider, Julie M. Cunningham, Brooke L. Fridley, Krista M. Goergen, Matthew J. Maurer, Matthew S. Block, Zachary C. Fogarty, Robert A. Vierkant, Ann L. Oberg, Kimberly R. Kalli, Kirsten B. Moysich, and Bridget Charbonneau

Abstract

PDF file - 157K, Supplemental Table 1. Regulatory T cell genes included in this study (N=25). Supplemental Table 2. Regulatory T cell SNPs included in this study. Supplemental Table 3. Participating invasive epithelial ovarian cancer studies. Supplemental Table 4. Association between clinical variables and overall survival.

Published
2023

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

Author

Ellen L. Goode, Keith L. Knutson, Lara E. Sucheston, Kunle Odunsi, Roberta B. Ness, Simon A. Gayther, Paul D.P. Pharoah, Georgia Chenevix-Trench, Mary Anne Rossing, Daniel W. Cramer, Celeste Leigh Pearce, Joellen M. Schildkraut, Usha Menon, Susanne K. Kjaer, Douglas A. Levine, Jacek Gronwald, Hoda Anton Culver, Alice S. Whittemore, Beth Y. Karlan, Diether Lambrechts, Nicolas Wentzensen, Jolanta Kupryjanczyk, Jenny Chang-Claude, Elisa V. Bandera, Estrid Hogdall, Florian Heitz, Stanley B. Kaye, Gottfried Konecny, Peter A. Fasching, Ian Campbell, Marc T. Goodman, Tanja Pejovic, Yukie T. Bean, Laura E. Hays, Galina Lurie, Diana Eccles, Alexander Hein, Matthias W. Beckmann, Arif B. Ekici, James Paul, Robert Brown, James M. Flanagan, Philipp Harter, Andreas du Bois, Ira Schwaab, Claus K. Hogdall, Sara H. Olson, Lene Lundvall, Irene Orlow, Lisa E. Paddock, Anja Rudolph, Petra Seibold, Agnieszka Dansonka-Mieszkowska, Iwona K. Rzepecka, Beata Spiewankiewicz, Louise A. Brinton, Hannah Yang, Montserrat Garcia-Closas, Evelyn Despierre, Sandrina Lambrechts, Ignace Vergote, Christine Walsh, Jenny Lester, Weiva Sieh, Valerie McGuire, Joseph H. Rothstein, Argyrios Ziogas, Jan Lubiński, Cezary Cybulski, Janusz Menkiszak, Allan Jensen, Howard Shen, Brenda Diergaarde, Susan J. Ramus, Aleksandra Gentry-Maharaj, Andrew Berchuck, Anna H. Wu, Malcolm C. Pike, David Van Den Berg, Kathryn L. Terry, Allison F. Vitonis, Starr M. Ramirez, Thomas A. Sellers, Catherine M. Phelan, Jennifer A. Doherty, Sharon E. Johnatty, Anna deFazio, Honglin Song, Jonathan Tyrer, Chen Wang, Kate Lawrenson, Lynn C. Hartmann, Claudia Preston, David N. Rider, Julie M. Cunningham, Brooke L. Fridley, Krista M. Goergen, Matthew J. Maurer, Matthew S. Block, Zachary C. Fogarty, Robert A. Vierkant, Ann L. Oberg, Kimberly R. Kalli, Kirsten B. Moysich, and Bridget Charbonneau

Abstract

The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22–1.64; P = 5.7 × 10−6], rs791587 (HR, 1.36; 95% CI, 1.17–1.57; P = 6.2 × 10−5), rs2476491 (HR, = 1.40; 95% CI, 1.19–1.64; P = 5.6 × 10−5), and rs10795763 (HR, 1.35; 95% CI, 1.17–1.57; P = 7.9 × 10−5), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54–0.82; P = 9.3 × 10−5) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer. Cancer Immunol Res; 2(4); 332–40. ©2014 AACR.

Published
2023

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 1-3 from Platinum Sensitivity–Related Germline Polymorphism Discovered via a Cell-Based Approach and Analysis of Its Association with Outcome in Ovarian Cancer Patients

Author

M. Eileen Dolan, Georgia Chenevix-Trench, Anna deFazio, Beth Y. Karlan, Jenny Gross, Ignace Vergote, Evelyn Despierre, Diether Lambrechts, Jim Paul, Robert Brown, Kunle Odunsi, Matthew Grasela, Kirsten B. Moysich, Allan Jensen, Susanne K. Kjaer, Estrid Hogdall, Brooke L. Fridley, Robert A. Vierkant, Ellen L. Goode, Stuart MacGregor, Yi Lu, Nancy J. Cox, Soma Das, Yarden S. Fraiman, Peter H. O'Donnell, Shuangli Mi, Jonathan Beesley, Peixian Chen, Emily O. Kistner, Wei Zhang, Shiwei Duan, Dana Ziliak, Hae Kyung Im, Eric R. Gamazon, Sharon E. Johnatty, and R. Stephanie Huang

Abstract

PDF file - 263K

Published
2023

8. 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

9. 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

10. Data from Platinum Sensitivity–Related Germline Polymorphism Discovered via a Cell-Based Approach and Analysis of Its Association with Outcome in Ovarian Cancer Patients

Author

M. Eileen Dolan, Georgia Chenevix-Trench, Anna deFazio, Beth Y. Karlan, Jenny Gross, Ignace Vergote, Evelyn Despierre, Diether Lambrechts, Jim Paul, Robert Brown, Kunle Odunsi, Matthew Grasela, Kirsten B. Moysich, Allan Jensen, Susanne K. Kjaer, Estrid Hogdall, Brooke L. Fridley, Robert A. Vierkant, Ellen L. Goode, Stuart MacGregor, Yi Lu, Nancy J. Cox, Soma Das, Yarden S. Fraiman, Peter H. O'Donnell, Shuangli Mi, Jonathan Beesley, Peixian Chen, Emily O. Kistner, Wei Zhang, Shiwei Duan, Dana Ziliak, Hae Kyung Im, Eric R. Gamazon, Sharon E. Johnatty, and R. Stephanie Huang

Abstract

Purpose: Cell-based approaches were used to identify genetic markers predictive of patients' risk for poor response prior to chemotherapy.Experimental Design: We conducted genome-wide association studies (GWAS) to identify single-nucleotide polymorphisms (SNP) associated with cellular sensitivity to carboplatin through their effects on mRNA expression using International HapMap lymphoblastoid cell lines (LCL) and replicated them in additional LCLs. SNPs passing both stages of the cell-based study were tested for association with progression-free survival (PFS) in patients. Phase 1 validation was based on 377 ovarian cancer patients receiving at least four cycles of carboplatin and paclitaxel from the Australian Ovarian Cancer Study (AOCS). Positive associations were then assessed in phase 2 validation analysis of 1,326 patients from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas.Results: In the initial GWAS, 342 SNPs were associated with carboplatin-induced cytotoxicity, of which 18 unique SNPs were retained after assessing their association with gene expression. One SNP (rs1649942) was replicated in an independent LCL set (Bonferroni adjusted P < 0.05). It was found to be significantly associated with decreased PFS in phase 1 AOCS patients (Pper-allele = 2 × 10−2), with a stronger effect in the subset of women with optimally debulked tumors (Pper-allele = 4 × 10−3). rs1649942 was also associated with poorer overall survival in women with optimally debulked tumors (Pper-allele = 9 × 10−3). However, this SNP was not significant in phase 2 validation analysis with patients from numerous cohorts.Conclusion: This study shows the potential of cell-based, genome-wide approaches to identify germline predictors of treatment outcome and highlights the need for extensive validation in patients to assess their clinical effect. Clin Cancer Res; 17(16); 5490–500. ©2011 AACR.

Published
2023

11. Supplemental Figure 1 from Assessment of Multifactor Gene–Environment Interactions and Ovarian Cancer Risk: Candidate Genes, Obesity, and Hormone-Related Risk Factors

Author

Brooke L. Fridley, Ellen L. Goode, Paul Pharoah, Joellen M. Schildkraut, Celeste Leigh Pearce, Hannah Yang, Anna H. Wu, Lynne R. Wilkens, Alice S. Whittemore, Nicolas Wentzensen, Shan Wang-Gohrke, Robert A. Vierkant, David J. van den Berg, Pamela J. Thompson, Honglin Song, Joseph Rothstein, Mary Anne Rossing, Susan J. Ramus, Malcolm C. Pike, Roberta B. Ness, Kirsten B. Moysich, Francesmary Modugno, Usha Menon, Leon Massuger, Galina Lurie, Melissa C. Larson, Susanne K. Kjaer, Lambertus A. Kiemeney, Sharon E. Johnatty, Allan Jensen, Estrid Høgdall, Marc T. Goodman, Aleksandra Gentry-Maharaj, Simon A. Gayther, Robert P. Edwards, Jennifer A. Doherty, Anna DeFazio, Julie M. Cunningham, Louise Brinton, Andrew Berchuck, Hoda Anton-Culver, Anja Rudolph, Jenny Chang-Claude, Penelope Webb, Weiva Sieh, Valerie McGuire, Jonathan P. Tyrer, Rama Raghavan, and Joseph L. Usset

Abstract

Potential hormonal mechanism to motivate investigation of multi-factor obesity-hormone related risk factors - SNP interactions.

Published
2023

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

Author

Brooke L. Fridley, Ellen L. Goode, Paul Pharoah, Joellen M. Schildkraut, Celeste Leigh Pearce, Hannah Yang, Anna H. Wu, Lynne R. Wilkens, Alice S. Whittemore, Nicolas Wentzensen, Shan Wang-Gohrke, Robert A. Vierkant, David J. van den Berg, Pamela J. Thompson, Honglin Song, Joseph Rothstein, Mary Anne Rossing, Susan J. Ramus, Malcolm C. Pike, Roberta B. Ness, Kirsten B. Moysich, Francesmary Modugno, Usha Menon, Leon Massuger, Galina Lurie, Melissa C. Larson, Susanne K. Kjaer, Lambertus A. Kiemeney, Sharon E. Johnatty, Allan Jensen, Estrid Høgdall, Marc T. Goodman, Aleksandra Gentry-Maharaj, Simon A. Gayther, Robert P. Edwards, Jennifer A. Doherty, Anna DeFazio, Julie M. Cunningham, Louise Brinton, Andrew Berchuck, Hoda Anton-Culver, Anja Rudolph, Jenny Chang-Claude, Penelope Webb, Weiva Sieh, Valerie McGuire, Jonathan P. Tyrer, Rama Raghavan, and Joseph L. Usset

Abstract

Background: Many epithelial ovarian cancer (EOC) risk factors relate to hormone exposure and elevated estrogen levels are associated with obesity in postmenopausal women. Therefore, we hypothesized that gene–environment interactions related to hormone-related risk factors could differ between obese and non-obese women.Methods: We considered interactions between 11,441 SNPs within 80 candidate genes related to hormone biosynthesis and metabolism and insulin-like growth factors with six hormone-related factors (oral contraceptive use, parity, endometriosis, tubal ligation, hormone replacement therapy, and estrogen use) and assessed whether these interactions differed between obese and non-obese women. Interactions were assessed using logistic regression models and data from 14 case–control studies (6,247 cases; 10,379 controls). Histotype-specific analyses were also completed.Results: SNPs in the following candidate genes showed notable interaction: IGF1R (rs41497346, estrogen plus progesterone hormone therapy, histology = all, P = 4.9 × 10−6) and ESR1 (rs12661437, endometriosis, histology = all, P = 1.5 × 10−5). The most notable obesity–gene–hormone risk factor interaction was within INSR (rs113759408, parity, histology = endometrioid, P = 8.8 × 10−6).Conclusions: We have demonstrated the feasibility of assessing multifactor interactions in large genetic epidemiology studies. Follow-up studies are necessary to assess the robustness of our findings for ESR1, CYP11A1, IGF1R, CYP11B1, INSR, and IGFBP2. Future work is needed to develop powerful statistical methods able to detect these complex interactions.Impact: Assessment of multifactor interaction is feasible, and, here, suggests that the relationship between genetic variants within candidate genes and hormone-related risk factors may vary EOC susceptibility. Cancer Epidemiol Biomarkers Prev; 25(5); 780–90. ©2016 AACR.

Published
2023

13. 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

14. Supplementary Tables 1, 2 and 4 from Platinum Sensitivity–Related Germline Polymorphism Discovered via a Cell-Based Approach and Analysis of Its Association with Outcome in Ovarian Cancer Patients

Author

M. Eileen Dolan, Georgia Chenevix-Trench, Anna deFazio, Beth Y. Karlan, Jenny Gross, Ignace Vergote, Evelyn Despierre, Diether Lambrechts, Jim Paul, Robert Brown, Kunle Odunsi, Matthew Grasela, Kirsten B. Moysich, Allan Jensen, Susanne K. Kjaer, Estrid Hogdall, Brooke L. Fridley, Robert A. Vierkant, Ellen L. Goode, Stuart MacGregor, Yi Lu, Nancy J. Cox, Soma Das, Yarden S. Fraiman, Peter H. O'Donnell, Shuangli Mi, Jonathan Beesley, Peixian Chen, Emily O. Kistner, Wei Zhang, Shiwei Duan, Dana Ziliak, Hae Kyung Im, Eric R. Gamazon, Sharon E. Johnatty, and R. Stephanie Huang

Abstract

PDF file - 115K

Published
2023

15. Data from Variation in NF-κB Signaling Pathways and Survival in Invasive Epithelial Ovarian Cancer

Author

Ellen L. Goode, Julie M. Cunningham, Brooke L. Fridley, Kimberly R. Kalli, Jonathan Tyrer, Honglin Song, Anna deFazio, Sharon E. Johnatty, Jennifer A. Doherty, Catherine M. Phelan, Thomas A. Sellers, Keith L. Knutson, David N. Rider, Starr M. Ramirez, Allison F. Vitonis, Kathryn L. Terry, David Van Den Berg, Malcolm C. Pike, Anna H. Wu, Andrew Berchuck, Aleksandra Gentry-Maharaj, Susan J. Ramus, Simon A. Gayther, Allan Jensen, Janusz Menkiszak, Cezary Cybulski, Jan Lubiński, Argyrios Ziogas, Joseph H. Rothstein, Valerie McGuire, Weiva Sieh, Jenny Lester, Christine S. Walsh, Ignace Vergote, Sandrina Lambrechts, Evelyn Despierre, Montserrat Garcia-Closas, Hannah Yang, Louise A. Brinton, Izabela Ziolkowska-Seta, Iwona K. Rzepecka, Agnieszka Dansonka-Mieszkowska, Ursula Eilber, Anja Rudolph, Lisa E. Paddock, Irene Orlow, Sara H. Olson, Lene Lundvall, Claus K. Hogdall, Ira Schwaab, Andreas du Bois, Philipp Harter, James M. Flanagan, Robert Brown, James Paul, Arif B. Ekici, Matthias W. Beckmann, Alexander Hein, Diana Eccles, Galina Lurie, Laura E. Hays, Yukie T. Bean, Tanja Pejovic, Marc T. Goodman, Ian Campbell, Peter A. Fasching, Stanley B. Kaye, Florian Heitz, Estrid Hogdall, Elisa V. Bandera, Jenny Chang-Claude, Jolanta Kupryjanczyk, Nicolas Wentzensen, Diether Lambrechts, Beth Y. Karlan, Alice S. Whittemore, Hoda Anton Culver, Jacek Gronwald, Douglas A. Levine, Susanne K. Kjaer, Usha Menon, Joellen Schildkraut, Celeste Leigh Pearce, Daniel Cramer, Mary Anne Rossing, Paul D.P. Pharoah, William R. Bamlet, Zachary Fogarty, Robert A. Vierkant, Bridget Charbonneau, and Matthew S. Block

Abstract

Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-κB (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance, P < 2.5 × 10−5). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41–2.35; P = 4.13 × 10−6] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56–0.82; P = 2.33 × 10−5). Other associations of note included TNF receptor–associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77–0.92; P = 6.49 × 10−5) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26–0.73; P = 4.56 × 10−4). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies. Cancer Epidemiol Biomarkers Prev; 23(7); 1421–7. ©2014 AACR.

Published
2023

16. 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

17. 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

18. Supplementary Tables 1 through 3 from Variation in NF-κB Signaling Pathways and Survival in Invasive Epithelial Ovarian Cancer

Author

Ellen L. Goode, Julie M. Cunningham, Brooke L. Fridley, Kimberly R. Kalli, Jonathan Tyrer, Honglin Song, Anna deFazio, Sharon E. Johnatty, Jennifer A. Doherty, Catherine M. Phelan, Thomas A. Sellers, Keith L. Knutson, David N. Rider, Starr M. Ramirez, Allison F. Vitonis, Kathryn L. Terry, David Van Den Berg, Malcolm C. Pike, Anna H. Wu, Andrew Berchuck, Aleksandra Gentry-Maharaj, Susan J. Ramus, Simon A. Gayther, Allan Jensen, Janusz Menkiszak, Cezary Cybulski, Jan Lubiński, Argyrios Ziogas, Joseph H. Rothstein, Valerie McGuire, Weiva Sieh, Jenny Lester, Christine S. Walsh, Ignace Vergote, Sandrina Lambrechts, Evelyn Despierre, Montserrat Garcia-Closas, Hannah Yang, Louise A. Brinton, Izabela Ziolkowska-Seta, Iwona K. Rzepecka, Agnieszka Dansonka-Mieszkowska, Ursula Eilber, Anja Rudolph, Lisa E. Paddock, Irene Orlow, Sara H. Olson, Lene Lundvall, Claus K. Hogdall, Ira Schwaab, Andreas du Bois, Philipp Harter, James M. Flanagan, Robert Brown, James Paul, Arif B. Ekici, Matthias W. Beckmann, Alexander Hein, Diana Eccles, Galina Lurie, Laura E. Hays, Yukie T. Bean, Tanja Pejovic, Marc T. Goodman, Ian Campbell, Peter A. Fasching, Stanley B. Kaye, Florian Heitz, Estrid Hogdall, Elisa V. Bandera, Jenny Chang-Claude, Jolanta Kupryjanczyk, Nicolas Wentzensen, Diether Lambrechts, Beth Y. Karlan, Alice S. Whittemore, Hoda Anton Culver, Jacek Gronwald, Douglas A. Levine, Susanne K. Kjaer, Usha Menon, Joellen Schildkraut, Celeste Leigh Pearce, Daniel Cramer, Mary Anne Rossing, Paul D.P. Pharoah, William R. Bamlet, Zachary Fogarty, Robert A. Vierkant, Bridget Charbonneau, and Matthew S. Block

Abstract

PDF - 149K, Supplemental Table 1. Participating invasive epithelial ovarian cancer studies. Supplementary Table 2. NF-κB genes studied. Supplemental Table 3. Association between clinical variables and overall survival.

Published
2023

19. Supplementary Table 3 from Platinum Sensitivity–Related Germline Polymorphism Discovered via a Cell-Based Approach and Analysis of Its Association with Outcome in Ovarian Cancer Patients

Author

M. Eileen Dolan, Georgia Chenevix-Trench, Anna deFazio, Beth Y. Karlan, Jenny Gross, Ignace Vergote, Evelyn Despierre, Diether Lambrechts, Jim Paul, Robert Brown, Kunle Odunsi, Matthew Grasela, Kirsten B. Moysich, Allan Jensen, Susanne K. Kjaer, Estrid Hogdall, Brooke L. Fridley, Robert A. Vierkant, Ellen L. Goode, Stuart MacGregor, Yi Lu, Nancy J. Cox, Soma Das, Yarden S. Fraiman, Peter H. O'Donnell, Shuangli Mi, Jonathan Beesley, Peixian Chen, Emily O. Kistner, Wei Zhang, Shiwei Duan, Dana Ziliak, Hae Kyung Im, Eric R. Gamazon, Sharon E. Johnatty, and R. Stephanie Huang

Abstract

PDF - 76K

Published
2023

20. Data from Assessment of Hepatocyte Growth Factor in Ovarian Cancer Mortality

Author

Thomas A. Sellers, Fergus J. Couch, Rebecca Sutphen, Vijayalakshmi Shridhar, Joellen M. Schildkraut, Prema P. Peethambaram, Linda E. Kelemen, Catherine M. Phelan, Ya-Yu Tsai, David J. Duggan, Jeremy Chien, Robert Brown, Jenny Gross, Beth Y. Karlan, Lene Lundvall, Claus Høgdall, Evelyn Despierre, Diether Lambrechts, Arif B. Ekici, Peter A. Fasching, Susanne Krüger Kjær, Estrid Høgdall, Elaine A. Elliott, Michele M. Schmidt, Hugues Sicotte, David N. Rider, Sebastian M. Armasu, Katelyn E. Goodman, Xiaoqing Chen, Sharon E. Johnatty, Jonathan Beesley, Julie M. Cunningham, Trynda N. Oberg, Gary L. Keeney, Kristin L. White, Melissa C. Larson, Robert A. Vierkant, Kimberly R. Kalli, Brooke L. Fridley, Lynn C. Hartmann, Georgia Chenevix-Trench, and Ellen L. Goode

Abstract

Background: Invasive ovarian cancer is a significant cause of gynecologic cancer mortality.Methods: We examined whether this mortality was associated with inherited variation in approximately 170 candidate genes/regions [993 single-nucleotide polymorphisms (SNPs)] in a multistage analysis based initially on 312 Mayo Clinic cases (172 deaths). Additional analyses used The Cancer Genome Atlas (TCGA; 127 cases, 62 deaths). For the most compelling gene, we immunostained Mayo Clinic tissue microarrays (TMA, 326 cases) and conducted consortium-based SNP replication analysis (2,560 cases, 1,046 deaths).Results: The strongest initial mortality association was in HGF (hepatocyte growth factor) at rs1800793 (HR = 1.7, 95% CI = 1.3–2.2, P = 2.0 × 10−5) and with overall variation in HGF (gene-level test, P = 3.7 × 10−4). Analysis of TCGA data revealed consistent associations [e.g., rs5745709 (r2 = 0.96 with rs1800793): TCGA HR = 2.4, CI = 1.4–4.1, P = 2.2 × 10−3; Mayo Clinic + TCGA HR = 1.6, CI = 1.3–1.9, P = 7.0 × 10−5] and suggested genotype correlation with reduced HGF mRNA levels (P = 0.01). In Mayo Clinic TMAs, protein levels of HGF, its receptor MET (C-MET), and phospho-MET were not associated with genotype and did not serve as an intermediate phenotype; however, phospho-MET was associated with reduced mortality (P = 0.01) likely due to higher expression in early-stage disease. In eight additional ovarian cancer case series, HGF rs5745709 was not associated with mortality (HR = 1.0, CI = 0.9–1.1, P = 0.87).Conclusions: We conclude that although HGF signaling is critical to migration, invasion, and apoptosis, it is unlikely that HGF genetic variation plays a major role in ovarian cancer mortality. Furthermore, any minor role is not related to genetically-determined expression.Impact: Our study shows the utility of multiple data types and multiple data sets in observational studies. Cancer Epidemiol Biomarkers Prev; 20(8); 1638–48. ©2011 AACR.

Published
2023

21. Supplementary Tables 1-7 from Assessment of Hepatocyte Growth Factor in Ovarian Cancer Mortality

Author

Thomas A. Sellers, Fergus J. Couch, Rebecca Sutphen, Vijayalakshmi Shridhar, Joellen M. Schildkraut, Prema P. Peethambaram, Linda E. Kelemen, Catherine M. Phelan, Ya-Yu Tsai, David J. Duggan, Jeremy Chien, Robert Brown, Jenny Gross, Beth Y. Karlan, Lene Lundvall, Claus Høgdall, Evelyn Despierre, Diether Lambrechts, Arif B. Ekici, Peter A. Fasching, Susanne Krüger Kjær, Estrid Høgdall, Elaine A. Elliott, Michele M. Schmidt, Hugues Sicotte, David N. Rider, Sebastian M. Armasu, Katelyn E. Goodman, Xiaoqing Chen, Sharon E. Johnatty, Jonathan Beesley, Julie M. Cunningham, Trynda N. Oberg, Gary L. Keeney, Kristin L. White, Melissa C. Larson, Robert A. Vierkant, Kimberly R. Kalli, Brooke L. Fridley, Lynn C. Hartmann, Georgia Chenevix-Trench, and Ellen L. Goode

Abstract

Supplementary Tables 1-7 from Assessment of Hepatocyte Growth Factor in Ovarian Cancer Mortality

Published
2023

22. Supplementary Figures 1-4 from Assessment of Hepatocyte Growth Factor in Ovarian Cancer Mortality

Author

Thomas A. Sellers, Fergus J. Couch, Rebecca Sutphen, Vijayalakshmi Shridhar, Joellen M. Schildkraut, Prema P. Peethambaram, Linda E. Kelemen, Catherine M. Phelan, Ya-Yu Tsai, David J. Duggan, Jeremy Chien, Robert Brown, Jenny Gross, Beth Y. Karlan, Lene Lundvall, Claus Høgdall, Evelyn Despierre, Diether Lambrechts, Arif B. Ekici, Peter A. Fasching, Susanne Krüger Kjær, Estrid Høgdall, Elaine A. Elliott, Michele M. Schmidt, Hugues Sicotte, David N. Rider, Sebastian M. Armasu, Katelyn E. Goodman, Xiaoqing Chen, Sharon E. Johnatty, Jonathan Beesley, Julie M. Cunningham, Trynda N. Oberg, Gary L. Keeney, Kristin L. White, Melissa C. Larson, Robert A. Vierkant, Kimberly R. Kalli, Brooke L. Fridley, Lynn C. Hartmann, Georgia Chenevix-Trench, and Ellen L. Goode

Abstract

Supplementary Figures 1-4 from Assessment of Hepatocyte Growth Factor in Ovarian Cancer Mortality

Published
2023

23. Case–case analysis addressing ascertainment bias for multigene panel testing implicates BRCA1 and PALB2 in endometrial cancer

Author

Tracy A. O'Mara, Tina Pesaran, Sharon E. Johnatty, Amanda B. Spurdle, Holly LaDuca, Paul A. James, Amal Yussuf, and Jill S. Dolinsky

Subjects
Oncology, medicine.medical_specialty, PALB2, Biology, MLH1, DNA Mismatch Repair, Cohort Studies, Breast cancer, Internal medicine, Genetics, medicine, Humans, Genetic Testing, Family history, Genetics (clinical), BRCA1 Protein, Endometrial cancer, Cancer, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Lynch syndrome, Endometrial Neoplasms, MSH2, Female, Fanconi Anemia Complementation Group N Protein, MutL Protein Homolog 1
Abstract

Hereditary endometrial cancer (EC) is most commonly attributed to pathogenic variants in mismatch repair (MMR) genes. Evidence supports existence of additional genetic risk factors in the context of multiple cancer diagnoses and/or family history of EC. EC patients (n=5292) referred for diagnostic multi-gene cancer panel testing were annotated for: presence of a pathogenic gene variant; personal history of prior, concurrent or subsequent cancer of another type; reported family history of Lynch syndrome or endometrial cancer. The Pearson χ2 test was used to assess differences in gene variant prevalence between case sub-groups defined by personal and/or family history of cancer/s, using cases with no family history of Lynch/EC as reference. Another cancer diagnosis was reported for 55% of EC cases. EC cases with prior and reported family history of Lynch cancer were enriched for variants in MLH1 (p=3.5x10-7 ), MSH2 (p=3.1x10-7 ), and PMS2 (p=0.02). Consistent with expectations for a breast cancer (BC) gene also predisposing to EC, variant frequency was increased in EC patients with prior BC and family history of EC for BRCA1 (p=1.7x10-5 ) and PALB2 (p=0.0002). Strategic case-case analyses to address cohort ascertainment bias has provided rationale to direct future studies of candidate hereditary EC genes. This article is protected by copyright. All rights reserved.

Published
2021

24. 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

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

Author

Ellen L. Goode, Diether Lambrechts, Usha Menon, Sharon E. Johnatty, Kathryn L. Terry, Kelly M. Bakulski, Mary Anne Rossing, Simon A. Gayther, Gillian E. Hanley, Dale W. Garsed, Katharine Brieger, Harvey A. Risch, Celeste Leigh Pearce, Daniel W. Cramer, Susan J. Ramus, Kathleen R. Cho, Allan Jensen, Karen McLean, Anna deFazio, Holly R. Harris, Francesmary Modugno, Anna H. Wu, Paul D.P. Pharoah, Andrew Berchuck, Aleksandra Gentry-Maharaj, Susanne K. Kjaer, Britton Trabert, David D.L. Bowtell, Renée T. Fortner, Bhramar Mukherjee, Estrid Høgdall, Alice W. Lee, Aliya Alimujiang, Elisa V. Bandera, David G. Huntsman, Malcolm C. Pike, Michael S. Anglesio, Georgia Chenevix-Trench, Hoda Anton-Culver, Kirsten B. Moysich, Roberta B. Ness, Jolanta Kupryjanczyk, Nicolas Wentzensen, Susan J. Jordan, Jean L. Richardson, Hui Shen, Jennifer A. Doherty, Argyrios Ziogas, Penelope M. Webb, Marc T. Goodman, and Siri Peterson

Subjects
0301 basic medicine, Oncology, PROGNOSIS, Neoplasm, Residual, IMPACT, medicine.medical_treatment, DISEASE, 0302 clinical medicine, Ovarian carcinoma, RISK, Ovarian Neoplasms, Estrogen Replacement Therapy, Hazard ratio, Obstetrics & Gynecology, WOMEN, Obstetrics and Gynecology, Hormone replacement therapy (menopause), Middle Aged, Debulking, Progression-Free Survival, Postmenopause, Survival Rate, 030220 oncology & carcinogenesis, Female, Life Sciences & Biomedicine, medicine.medical_specialty, CARCINOMA, Hormone Replacement Therapy, ESTROGENS, Article, REPLACEMENT THERAPY, 03 medical and health sciences, AGE, Internal medicine, medicine, Humans, Survival rate, Aged, Neoplasm Staging, Proportional Hazards Models, Science & Technology, Proportional hazards model, business.industry, medicine.disease, 030104 developmental biology, Hormone therapy, Progestins, Ovarian cancer, business
Abstract

PURPOSE: Prior studies of menopausal hormone therapy (MHT) and ovarian cancer survival have been limited by lack of hormone regimen detail and insufficient sample sizes. To address these limitations, a comprehensive analysis of 6419 post-menopausal women with pathologically confirmed ovarian carcinoma was conducted to examine the association between MHT use prior to diagnosis and survival. METHODS: Data from 15 studies in the Ovarian Cancer Association Consortium were included. MHT use was examined by type (estrogen-only (ET) or estrogen+progestin (EPT)), duration, and recency of use relative to diagnosis. Cox proportional hazards models were used to estimate the association between hormone therapy use and survival. Logistic regression and mediation analysis was used to explore the relationship between MHT use and residual disease following debulking surgery. RESULTS: Use of ET or EPT for at least five years prior to diagnosis was associated with better ovarian cancer survival (hazard ratio, 0.80; 95% CI, 0.74 to 0.87). Among women with advanced stage, high-grade serous carcinoma, those who used MHT were less likely to have any macroscopic residual disease at the time of primary debulking surgery (p for trend

Published
2020

26. 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

27. Generating high-quality data abstractions from scanned clinical records: text-mining-assisted extraction of endometrial carcinoma pathology features as proof of principle

Author

Anthony Nguyen, Amanda B. Spurdle, Sharon E. Johnatty, John O'Dwyer, Thanh Vu, and Penelope M. Webb

Subjects
Adult, Pathology, medicine.medical_specialty, Adolescent, lcsh:Medicine, Health Informatics, computer.software_genre, Health informatics, Proof of Concept Study, Text mining, information technology, Medicine, Data Mining, Electronic Health Records, Humans, Aged, Clinical pathology, business.industry, lcsh:R, General Medicine, Optical character recognition, Middle Aged, Automation, Endometrial Neoplasms, Feature (computer vision), Data quality, Test set, oncology, pathology, Female, business, computer
Abstract

ObjectiveMedical research studies often rely on the manual collection of data from scanned typewritten clinical records, which can be laborious, time consuming and error prone because of the need to review individual clinical records. We aimed to use text mining to assist with the extraction of clinical features from complex text-based scanned pathology records for medical research studies.DesignText mining performance was measured by extracting and annotating three distinct pathological features from scanned photocopies of endometrial carcinoma clinical pathology reports, and comparing results to manually abstracted terms. Inclusion and exclusion keyword trigger terms to capture leiomyomas, endometriosis and adenomyosis were provided based on expert knowledge. Terms were expanded with character variations based on common optical character recognition (OCR) error patterns as well as negation phrases found in sample reports. The approach was evaluated on an unseen test set of 1293 scanned pathology reports originating from laboratories across Australia.SettingScanned typewritten pathology reports for women aged 18–79 years with newly diagnosed endometrial cancer (2005–2007) in Australia.ResultsHigh concordance with final abstracted codes was observed for identifying the presence of three pathology features (94%–98% F-measure). The approach was more consistent and reliable than manual abstractions, identifying 3%–14% additional feature instances.ConclusionKeyword trigger-based automation with OCR error correction and negation handling proved not only to be rapid and convenient, but also providing consistent and reliable data abstractions from scanned clinical records. In conjunction with manual review, it can assist in the generation of high-quality data abstractions for medical research studies.

Published
2020

28. Co-existence of leiomyomas, adenomyosis and endometriosis in women with endometrial cancer

Author

Colin J.R. Stewart, Amanda B. Spurdle, Penelope M. Webb, Deborah Smith, Anthony Nguyen, John O’ Dwyer, Tracy A. O'Mara, and Sharon E. Johnatty

Subjects
Adult, medicine.medical_specialty, Endometriosis, lcsh:Medicine, Article, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Ovarian carcinoma, medicine, Carcinoma, Prevalence, Humans, Adenomyosis, Stage (cooking), Young adult, lcsh:Science, Cancer, Aged, Gynecology, Aged, 80 and over, 030219 obstetrics & reproductive medicine, Multidisciplinary, Leiomyoma, business.industry, Endometrial cancer, lcsh:R, Australia, Middle Aged, medicine.disease, 3. Good health, Endometrial Neoplasms, 030220 oncology & carcinogenesis, Menarche, lcsh:Q, Female, business
Abstract

Leiomyomas, adenomyosis, and endometriosis are reported to be risk factors for endometrial carcinoma (EC), and adenomyosis and endometriosis also for ovarian carcinoma (OC). We aimed to describe the prevalence of these conditions in EC patients with or without an OC diagnosis, and to investigate their relationship with EC risk and prognostic factors in these patients. We evaluated the co-existence of these three conditions in 1399 EC patients, and compared the prevalence of epidemiological risk factors and tumor prognostic features in patients with each condition versus not. Prevalence of conditions was also assessed in the subset of patients with prior/concurrent OC. The observed coexistence of leiomyomas, adenomyosis and endometriosis significantly deviated from that expected (P = 1.2 × 10−8). Patients were more likely to: report a younger age at menarche (PTrend = 0.004) if they had leiomyomas; have used oral contraceptives (P = 6.6 × 10−5) or had ≥2 full-term pregnancies (PTrend = 2.0 × 10−9) if they had adenomyosis; be diagnosed with EC at younger age (P = 5.0 × 10−11) if they had endometriosis. Patients with prior/concurrent OC were more likely to be diagnosed at younger age (P = 5.0 × 10−5), have endometriosis (P = 9.9 × 10−7), and present with higher stage EC (PTrend = 6.6 × 10−5). These findings justify further consideration of these gynecologic conditions as independent risk and prognostic factors for EC.

Published
2020

29. MyD88 and TLR4 Expression in Epithelial Ovarian Cancer

Author

Matthew S. Block, Robert A. Vierkant, Peter F. Rambau, Stacey J. Winham, Philipp Wagner, Nadia Traficante, Aleksandra Tołoczko, Daniel G. Tiezzi, Florin Andrei Taran, Peter Sinn, Weiva Sieh, Raghwa Sharma, Joseph H. Rothstein, Teresa Ramón y Cajal, Luis Paz-Ares, Oleg Oszurek, Sandra Orsulic, Roberta B. Ness, Gregg Nelson, Francesmary Modugno, Janusz Menkiszak, Valerie McGuire, Bryan M. McCauley, Marie Mack, Jan Lubiński, Teri A. Longacre, Zheng Li, Jenny Lester, Catherine J. Kennedy, Kimberly R. Kalli, Audrey Y. Jung, Sharon E. Johnatty, Mercedes Jimenez-Linan, Allan Jensen, Maria P. Intermaggio, Jillian Hung, Esther Herpel, Brenda Y. Hernandez, Andreas D. Hartkopf, Paul R. Harnett, Prafull Ghatage, José M. García-Bueno, Bo Gao, Sian Fereday, Ursula Eilber, Robert P. Edwards, Christiani B. de Sousa, Jurandyr M. de Andrade, Anita Chudecka-Głaz, Georgia Chenevix-Trench, Alicia Cazorla, Sara Y. Brucker, Jennifer Alsop, Alice S. Whittemore, Helen Steed, Annette Staebler, Kirsten B. Moysich, Usha Menon, Jennifer M. Koziak, Stefan Kommoss, Susanne K. Kjaer, Linda E. Kelemen, Beth Y. Karlan, David G. Huntsman, Estrid Høgdall, Jacek Gronwald, Marc T. Goodman, Blake Gilks, María José García, Peter A. Fasching, Anna de Fazio, Suha Deen, Jenny Chang-Claude, Francisco J. Candido dos Reis, Ian G. Campbell, James D. Brenton, David D. Bowtell, Javier Benítez, Paul D.P. Pharoah, Martin Köbel, Susan J. Ramus, Ellen L. Goode, D. Bowtell, G. Chenevix-Trench, A. Green, P. Webb, A. DeFazio, D. Gertig, N. Traficante, S. Fereday, S. Moore, J. Hung, K. Harrap, T. Sadkowsky, N. Pandeya, M. Malt, A. Mellon, R. Robertson, T. Vanden Bergh, M. Jones, P. Mackenzie, J. Maidens, K. Nattress, Y.E. Chiew, A. Stenlake, H. Sullivan, B. Alexander, P. Ashover, S. Brown, T. Corrish, L. Green, L. Jackman, K. Ferguson, K. Martin, A. Martyn, B. Ranieri, J. White, V. Jayde, P. Mamers, L. Bowes, L. Galletta, D. Giles, J. Hendley, K. Alsop, T. Schmidt, H. Shirley, C. Ball, C. Young, S. Viduka, Hoa Tran, Sanela Bilic, Lydia Glavinas, Julia Brooks, R. Stuart-Harris, F. Kirsten, J. Rutovitz, P. Clingan, A. Glasgow, A. Proietto, S. Braye, G. Otton, J. Shannon, T. Bonaventura, J. Stewart, S. Begbie, M. Friedlander, D. Bell, S. Baron-Hay, A. Ferrier, G. Gard, D. Nevell, N. Pavlakis, S. Valmadre, B. Young, C. Camaris, R. Crouch, L. Edwards, N. Hacker, D. Marsden, G. Robertson, P. Beale, J. Beith, J. Carter, C. Dalrymple, R. Houghton, P. Russell, M. Links, J. Grygiel, J. Hill, A. Brand, K. Byth, R. Jaworski, P. Harnett, R. Sharma, G. Wain, B. Ward, D. Papadimos, A. Crandon, M. Cummings, K. Horwood, A. Obermair, L. Perrin, D. Wyld, J. Nicklin, M. Davy, M.K. Oehler, C. Hall, T. Dodd, T. Healy, K. Pittman, D. Henderson, J. Miller, J. Pierdes, P. Blomfield, D. Challis, R. McIntosh, A. Parker, B. Brown, R. Rome, D. Allen, P. Grant, S. Hyde, R. Laurie, M. Robbie, D. Healy, T. Jobling, T. Manolitsas, J. McNealage, P. Rogers, B. Susil, E. Sumithran, I. Simpson, K. Phillips, D. Rischin, S. Fox, D. Johnson, S. Lade, M. Loughrey, N. O'Callaghan, W. Murray, P. Waring, V. Billson, J. Pyman, D. Neesham, M. Quinn, C. Underhill, R. Bell, L.F. Ng, R. Blum, V. Ganju, I. Hammond, Y. Leung, A. McCartney, M. Buck, I. Haviv, D. Purdie, D. Whiteman, and N. Zeps

Subjects
Carcinoma, Ovarian Epithelial/metabolism, Adult, 0301 basic medicine, Oncology, medicine.medical_specialty, Myeloid Differentiation Factor 88/metabolism, Carcinoma, Ovarian Epithelial, Article, 03 medical and health sciences, Ovarian tumor, 0302 clinical medicine, Internal medicine, Immunohistochemistry/methods, Biomarkers, Tumor, medicine, Carcinoma, Humans, Clear-cell ovarian carcinoma, Tissue Array Analysis/methods, Survival analysis, Aged, Ovarian Neoplasms, Tissue microarray, business.industry, Hazard ratio, General Medicine, Middle Aged, Ovarian Neoplasms/metabolism, medicine.disease, ANÁLISE DE SOBREVIVÊNCIA, Immunohistochemistry, Survival Analysis, 3. Good health, Toll-Like Receptor 4, Serous fluid, Toll-Like Receptor 4/metabolism, 030104 developmental biology, Tissue Array Analysis, Biomarkers, Tumor/metabolism, 030220 oncology & carcinogenesis, Myeloid Differentiation Factor 88, Female, business, Ovarian cancer
Abstract

Objective: To evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival. Patients and Methods: We conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time. Tissue microarrays were stained for MyD88 and TLR4, and staining intensity was classified using a 2-tiered system for each marker (weak vs strong). Results: Expression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P

Published
2018

30. Risk and prognostic factors for endometrial carcinoma after diagnosis of breast or Lynch-associated cancers-A population-based analysis

Author

Deborah Smith, Yee Leung, Martin K. Oehler, Amanda B. Spurdle, Alison Brand, Colin J.R. Stewart, Penelope M. Webb, Sharon E. Johnatty, and Daniel D. Buchanan

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Antineoplastic Agents, Hormonal, Population, Breast Neoplasms, DNA Mismatch Repair, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Risk Factors, Internal medicine, medicine, Carcinoma, Humans, Radiology, Nuclear Medicine and imaging, education, Original Research, risk, education.field_of_study, business.industry, Endometrial cancer, Cancer, prior cancer, Middle Aged, medicine.disease, Prognosis, Colorectal Neoplasms, Hereditary Nonpolyposis, Lynch syndrome, 3. Good health, Endometrial Neoplasms, Tamoxifen, 030104 developmental biology, MMR status, 030220 oncology & carcinogenesis, endometrial cancer, Female, business, Breast carcinoma, Cancer Prevention, medicine.drug
Abstract

We hypothesized that endometrial carcinoma (EC) patients with a prior cancer diagnosis, after accounting for EC arising after tamoxifen‐treated prior breast carcinoma, are more likely to have an underlying genetic basis. We used information from a population‐based study to compare measured risk factors, tumor characteristics, survival, and known mismatch repair (MMR) pathogenic variant status for EC subgroups according to prior diagnosis of cancer (none, breast cancer tamoxifen‐treated or not, Lynch Syndrome (LS)‐associated cancer). Family history of any cancer was increased for EC cases with prior breast cancer, both tamoxifen treated (P = 0.005) and untreated (P = 0.01). EC cases with prior LS‐associated cancer more often reported family history of LS‐associated cancer (P = 0.04) and breast cancer (P = 0.05). EC patients with a germline pathogenic MMR gene variant were more likely to report a prior cancer than cases with a MMR proficient tumor (P = 0.0001), but more than half (54.5%) of MMR carriers reported no prior cancer. Women developing EC after tamoxifen treatment for breast cancer were significantly more likely to develop EC of malignant mixed mullerian tumor subtype (13.2% vs 2.6%, P = 1.3 × 10^{-6}), present with stage IV disease (8.8% vs 1.2%, P = 1.6 × 10^{-6}), and have poorer survival (HR_{adj} 1.96; P = 0.001). While report of prior cancer is an indicator of MMR pathogenic variant status, molecular analysis of all ECs at diagnosis is warranted to detect all patients with LS. Results also indicate the importance of longer‐term monitoring of women treated with tamoxifen for symptoms of EC, and the need for studies assessing the biological mechanism underlying the poorer prognosis of this subset of EC patients.

Published
2018

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

Author

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

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, CD8 Antigens, chemical and pharmacologic phenomena, Carcinoma, Ovarian Epithelial, Article, Cohort Studies, 03 medical and health sciences, Ovarian tumor, 0302 clinical medicine, Breast cancer, Lymphocytes, Tumor-Infiltrating, Internal medicine, Medicine, Humans, Prospective Studies, Prospective cohort study, Survival analysis, BRCA2 Protein, Ovarian Neoplasms, business.industry, Tumor-infiltrating lymphocytes, hemic and immune systems, Middle Aged, Debulking, medicine.disease, Survival Analysis, Cystadenocarcinoma, Serous, Serous fluid, 030104 developmental biology, Treatment Outcome, CITOTOXICIDADE IMUNOLÓGICA, 030220 oncology & carcinogenesis, Mutation, Female, Neoplasm Grading, business, Ovarian cancer
Abstract

Importance Cytotoxic CD8+tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+TILs by histotype and in relation to other clinical factors. Objective To define the prognostic role of CD8+TILs in epithelial ovarian cancer. Design, Setting, and Participants This was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years. Exposures Following immunohistochemical analysis, CD8+TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (≥20). CD8+TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines. Main Outcomes and Measures Overall survival time. Results The final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+TILs, respectively (Pvalue for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germlineBRCA1pathogenic mutation, but were not prognostic forBRCA2mutation carriers. Evaluation of uncategorized CD8+TIL counts showed a near-log-linear functional form. Conclusions and Relevance This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer.

Published
2017

32. Genome-wide association study of paclitaxel and carboplatin disposition in women with epithelial ovarian cancer

Author

Ingrid A. Boere, Georgia Chenevix-Trench, Rosemary L. Balleine, Anne Joy M. de Graan, Hongmei Xu, Yoke Eng Chiew, Howard Gurney, Michelle Harrison, Paul R. Harnett, Stuart MacGregor, Jonathan Beesley, Craig Luccarini, Peter de Bruijn, Yi Lu, Anna de Fazio, Don M. Conroy, Ron H.J. Mathijssen, Sharon E. Johnatty, Annemieke J.M. Nieuweboer, Bo Gao, Catherine J. Kennedy, Philip Beale, and Medical Oncology

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Candidate gene, Paclitaxel, Science, medicine.medical_treatment, Single-nucleotide polymorphism, Genome-wide association study, Antineoplastic Agents, Carcinoma, Ovarian Epithelial, Polymorphism, Single Nucleotide, Article, Carboplatin, 03 medical and health sciences, chemistry.chemical_compound, SDG 3 - Good Health and Well-being, Internal medicine, Medicine, Humans, Chemotherapy, Multidisciplinary, business.industry, Genome, Human, Disposition, medicine.disease, Multidrug Resistance-Associated Protein 2, 3. Good health, 030104 developmental biology, chemistry, Female, Multidrug Resistance-Associated Proteins, business, Ovarian cancer, Blood sampling, Genome-Wide Association Study
Abstract

Identifying single nucleotide polymorphisms (SNPs) that influence chemotherapy disposition may help to personalize cancer treatment and limit toxicity. Genome-wide approaches are unbiased, compared with candidate gene studies, but usually require large cohorts. As most chemotherapy is given cyclically multiple blood sampling is required to adequately define drug disposition, limiting patient recruitment. We found that carboplatin and paclitaxel disposition are stable phenotypes in ovarian cancer patients and tested a genome-wide association study (GWAS) design to identify SNPs associated with chemotherapy disposition. We found highly significant SNPs in ABCC2, a known carboplatin transporter, associated with carboplatin clearance (asymptotic P = 5.2 × 106, empirical P = 1.4 × 10−5), indicating biological plausibility. We also identified novel SNPs associated with paclitaxel disposition, including rs17130142 with genome-wide significance (asymptotic P = 2.0 × 10−9, empirical P = 1.3 × 10−7). Although requiring further validation, our work demonstrated that GWAS of chemotherapeutic drug disposition can be effective, even in relatively small cohorts, and can be adopted in drug development and treatment programs.

Published
2017

33. 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

34. Family history of cancer predicts endometrial cancer risk independently of Lynch Syndrome: Implications for genetic counselling

Author

Michael A Bowman, Amanda B. Spurdle, Tracy A. O'Mara, Alison Brand, Michael A. Quinn, Andreas Obermair, Martin K. Oehler, Yen Y. Tan, Judy Kirk, Sharon E. Johnatty, Penelope Blomfield, Rhiannon J. Walters, Yee Leung, Daniel D. Buchanan, and Penelope M. Webb

Subjects
0301 basic medicine, Oncology, Proband, medicine.medical_specialty, Family Cancer History, Genetic counseling, Genetic Counseling, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Family history, Medical History Taking, Second-degree relative, Gynecology, business.industry, Endometrial cancer, Case-control study, Australia, Obstetrics and Gynecology, Middle Aged, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Lynch syndrome, Endometrial Neoplasms, 030104 developmental biology, Logistic Models, 030220 oncology & carcinogenesis, Case-Control Studies, Female, business
Abstract

Objective To determine endometrial cancer (EC) risk according to family cancer history, including assessment by degree of relatedness, type of and age at cancer diagnosis of relatives. Methods Self-reported family cancer history was available for 1353 EC patients and 628 controls. Logistic regression was used to quantify the association between EC and cancer diagnosis in ≥1 first or second degree relative, and to assess whether level of risk differed by degree of relationship and/or relative's age at diagnosis. Risk was also evaluated for family history of up to three cancers from known familial syndromes (Lynch, Cowden, hereditary breast and ovarian cancer) overall, by histological subtype and, for a subset of 678 patients, by EC tumor mismatch repair (MMR) gene expression. Results Report of EC in ≥1 first- or second-degree relative was associated with significantly increased risk of EC ( P =3.8×10 −7 ), independent of lifestyle risk factors. There was a trend in increasing EC risk with closer relatedness and younger age at EC diagnosis in relatives ( P Trend =4.43×10 −6 ), and with increasing numbers of Lynch cancers in relatives ( P Trend ≤0.0001). EC risk associated with family history did not differ by proband tumor MMR status, or histological subtype. Reported EC in first- or second-degree relatives remained associated with EC risk after conservative correction for potential misreported family history (OR 2.0; 95% CI, 1.24–3.37, P =0.004). Conclusion The strongest predictor of EC risk was closer relatedness and younger EC diagnosis age in ≥1 relative. Associations remained significant irrespective of proband MMR status, and after excluding MMR pathogenic variant carriers, indicating that Lynch syndrome genes do not fully explain familial EC risk.

Published
2017

35. Breastfeeding and Endometrial Cancer Risk: An Analysis from the Epidemiology of Endometrial Cancer Consortium

Author

Herbert Yu, Immaculata De Vivo, Lauren A. Wise, Carlo La Vecchia, Harvey A. Risch, Susan J. Jordan, Christine M. Friedenreich, Hannah P. Yang, Stacey Petruzella, Jo L. Freudenheim, Louise A. Brinton, Todd R. Sponholtz, Renhua Na, Elisabete Weiderpass, C. Sacerdote, Nicolas Wentzensen, Xiao-Ou Shu, Linda S. Cook, Sharon E. Johnatty, Penelope M. Webb, Timothy R. Rebbeck, Hans-Olov Adami, Sara H. Olson, Lingeng Lu, Chu Chen, Veronica Wendy Setiawan, Kirsten B. Moysich, Susan E. McCann, Luigino Dal Maso, Fulvio Ricceri, Malcolm C. Pike, Julie R. Palmer, and Amanda B. Spurdle

Subjects
Oncology, medicine.medical_specialty, Breastfeeding, Endometrial Neoplasms, Female, Global Health, Humans, Risk Factors, Risk Reduction Behavior, Women's Health, Breast Feeding, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Epidemiology, Global health, medicine, Pooled data, 030212 general & internal medicine, Gynecology, business.industry, Endometrial cancer, Obstetrics and Gynecology, medicine.disease, 030220 oncology & carcinogenesis, Meta-analysis, Cohort, business, Breast feeding
Abstract

To investigate the association between breastfeeding and endometrial cancer risk using pooled data from 17 studies participating in the Epidemiology of Endometrial Cancer Consortium.We conducted a meta-analysis with individual-level data from three cohort and 14 case-control studies. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for the association between breastfeeding and risk of endometrial cancer using multivariable logistic regression and pooled using random-effects meta-analysis. We investigated between-study heterogeneity with I and Q statistics and metaregression.After excluding nulliparous women, the analyses included 8,981 women with endometrial cancer and 17,241 women in a control group. Ever breastfeeding was associated with an 11% reduction in risk of endometrial cancer (pooled OR 0.89, 95% CI 0.81-0.98). Longer average duration of breastfeeding per child was associated with lower risk of endometrial cancer, although there appeared to be some leveling of this effect beyond 6-9 months. The association with ever breastfeeding was not explained by greater parity and did not vary notably by body mass index or histologic subtype (grouped as endometrioid and mucinous compared with serous and clear cell).Our findings suggest that reducing endometrial cancer risk can be added to the list of maternal benefits associated with breastfeeding. Ongoing promotion, support, and facilitation of this safe and beneficial behavior might therefore contribute to the prevention of this increasingly common cancer.

Published
2017

36. Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci

Author

Penny Webb, Digna R. Velez Edwards, Bryan M. McCauley, Melissa Moffitt, Ignace Vergote, Marcus Q. Bernardini, Bo Gao, Peter A. Fasching, Ellen L. Goode, Susanne K. Kjaer, Matthias W. Beckmann, Diether Lambrechts, Matthias Dürst, Kirsten B. Moysich, David G. Huntsman, Michelle M.M. Woo, Julie M. Cunningham, Kathryn L. Terry, Rosalind Glasspool, Allan Jensen, Stuart MacGregor, Sharon E. Johnatty, Catherine J. Kennedy, James Paul, Paul D.P. Pharoah, Thilo Dörk, Tanja Pejovic, Florian Heitz, Line Bjørge, Jacobus Pfisterer, Joellen M. Schildkraut, Javier Benitez, Beth Y. Karlan, Michael C.J. Quinn, Melissa C. Larson, Peter Grant, Jenny Lester, Andreas du Bois, Jonathan Tyrer, Dylan M. Glubb, Peter Hillemanns, Stacey J. Winham, Andrew Berchuck, Georgia Chenevix-Trench, Tracy A. O'Mara, Claus Høgdall, Anna deFazio, Marc T. Goodman, Pamela J. Thompson, Helga B. Salvesen, Alicia A. Tone, Alicia Beeghly-Fadiel, Estrid Høgdall, María Josefa Mosteiro García, Francesmary Modungo, Daniel W. Cramer, National Science Foundation (Estados Unidos), European Commission, Cancer Research UK (Reino Unido), Canadian Institutes of Health Research, Cancer Council Western Australia (Australia), Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), and North Carolina Ovarian Cancer Study

Subjects
0301 basic medicine, genetic association, Oncology and Carcinogenesis, Medizin, Gene Expression, Biology, Germline, 03 medical and health sciences, Rare Diseases, medicine, Genetics, 2.1 Biological and endogenous factors, Aetiology, Promoter Regions, Genetic, MEF2D, Gene, POLYMORPHISMS, Genetic association, Cancer, Regulation of gene expression, Prevention, Haplotype, transition, Promoter, medicine.disease, 3. Good health, Ovarian Cancer, meta-analysis, ENHANCERS, 030104 developmental biology, Orphan Drug, Oncology, Meta-analysis, Disease Progression, ovarian cancer outcome, OVEREXPRESSION, Ovarian cancer, gene regulation, TCF Transcription Factors, Consortium, Priority Research Paper
Abstract

We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that MEF2D and ZNF100 are targets of candidate outcome variants at 1q22 and 19p12, respectively. At 19p12, the chromatin interaction of a putative regulatory element with the ZNF100 promoter region correlated with candidate outcome variants. At 1q22, putative regulatory elements enhanced MEF2D promoter activity and haplotypes containing candidate outcome variants modulated these effects. In a public dataset, MEF2D and ZNF100 expression were both associated with ovarian cancer progression-free or overall survival time. In an extended set of 6,162 epithelial ovarian cancer patients, we found that functional candidates at the 1q22 and 19p12 loci, as well as other regional variants, were nominally associated with patient outcome; however, no associations reached our threshold for statistical significance (p

Published
2017

37. Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study

Author

Bruce R. Rosen, A. Hartmann, Bo Gao, Georgia Chenevix-Trench, Gregg Nelson, Marcus Q. Bernardini, Carl Morrison, Mercedes Jimenez-Linan, Usha Menon, C Ewanowich, E Benjamin, Joshy George, S Liu, Blaise Clarke, Sian Fereday, Brooke L. Fridley, Allan Jensen, A Gentry-Maharaj, Peter A. Fasching, Suha Deen, Zachary C. Fogarty, Kunle Odunsi, David L. Wachter, Falk Thiel, Simon A. Gayther, Anna deFazio, Shashikant Lele, David D.L. Bowtell, Lara Sucheston, Kristy Driver, James D. Brenton, Michael S. Anglesio, Gary L. Keeney, Helen Steed, Ellen L. Goode, Martin Köbel, Robert A. Vierkant, Alexander Hein, Helen J. Mackay, Linda E. Kelemen, Paul D.P. Pharoah, David G. Huntsman, Sharon E. Johnatty, Amit M. Oza, S.K. Kjaer, S Cho, Martin Widschwendter, Maria P. Intermaggio, Claus Høgdall, Marie Mack, J Madore, Kimberly R. Kalli, Jennifer M Koziak, M. W. Beckmann, Prafull Ghatage, P Shaw, Jennifer Alsop, Estrid Høgdall, Susan J. Ramus, K. Moysich, Wiam Bshara, and Laura Galletta

Subjects
Oncology, endocrine system, Cancer Research, medicine.medical_specialty, Pathology, endocrine system diseases, medicine.medical_treatment, Biology, Carcinoma, Ovarian Epithelial, Disease-Free Survival, folate receptor alpha, chemistry.chemical_compound, Ovarian carcinoma, Internal medicine, Carcinoma, medicine, Biomarkers, Tumor, Humans, Folate Receptor 1, Neoplasms, Glandular and Epithelial, Survival analysis, Ovarian Neoplasms, Chemotherapy, Farletuzumab, FRA, TCGA, Middle Aged, medicine.disease, Immunohistochemistry, Survival Analysis, female genital diseases and pregnancy complications, 3. Good health, ovarian cancer, chemistry, Tissue Array Analysis, Female, Folate receptor 1, prognosis, Ovarian cancer, Translational Therapeutics
Abstract

Background: Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa. Methods: Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival. Results: FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20–0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10–3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25–0.94). Conclusions: FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis.

Published
2014

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

Author

Weiva Sieh, Anna H. Wu, Tanja Pejovic, Florian Heitz, Beth Y. Karlan, David Van Den Berg, Joellen M. Schildkraut, Kimberly R. Kalli, Gottfried E. Konecny, Argyrios Ziogas, Usha Menon, Montserrat Garcia-Closas, Anja Rudolph, Jonathan Tyrer, Ann L. Oberg, Alice S. Whittemore, Brooke L. Fridley, Kunle Odunsi, Mary Anne Rossing, Beata Spiewankiewicz, Douglas A. Levine, Jennifer A. Doherty, Peter A. Fasching, Janusz Menkiszak, Matthew J. Maurer, Claus Høgdall, Zachary C. Fogarty, Louise A. Brinton, Galina Lurie, Diether Lambrechts, Allison F. Vitonis, Keith L. Knutson, Diana Eccles, Agnieszka Dansonka-Mieszkowska, Marc T. Goodman, Jenny Lester, Jolanta Kupryjanczyk, Nicolas Wentzensen, Celeste Leigh Pearce, Howard C. Shen, Simon A. Gayther, Kathryn L. Terry, Ira Schwaab, Bridget Charbonneau, Claudia C. Preston, Jan Lubinski, Krista M. Goergen, Georgia Chenevix-Trench, Susanne K. Kjaer, Irene Orlow, Sara H. Olson, Stanley B. Kaye, Matthias W. Beckmann, Daniel W. Cramer, Kate Lawrenson, Matthew S. Block, Paul D.P. Pharoah, Robert A. Vierkant, Chen Wang, Yukie Bean, Laura E. Hays, Sandrina Lambrechts, Catherine M. Phelan, Hoda Anton Culver, Kirsten B. Moysich, Estrid Høgdall, Malcolm C. Pike, Iwona K. Rzepecka, Ignace Vergote, Lara Sucheston, Joseph H. Rothstein, David N. Rider, Christine Walsh, Starr M. Ramirez, Evelyn Despierre, Lene Lundvall, Arif B. Ekici, Cezary Cybulski, Valerie McGuire, Anna deFazio, Ian G. Campbell, Hannah P. Yang, Alexander Hein, Roberta B. Ness, James Paul, Elisa V. Bandera, Jacek Gronwald, Andrew Berchuck, Andreas du Bois, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Ellen L. Goode, Lisa E. Paddock, Lynn C. Hartmann, Sharon E. Johnatty, Philipp Harter, James M. Flanagan, Brenda Diergaarde, Julie M. Cunningham, Robert S. Brown, Allan Jensen, Thomas A. Sellers, Honglin Song, Susan J. Ramus, and Petra Seibold

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Immunology, Gene Expression, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, T-Lymphocytes, Regulatory, Article, Internal medicine, Genotype, medicine, Carcinoma, Humans, Mucinous carcinoma, Genetic Predisposition to Disease, Neoplasm Invasiveness, Germ-Line Mutation, Ovarian Neoplasms, Gene Expression Profiling, Interleukin-2 Receptor alpha Subunit, Genetic Variation, FOXP3, Prognosis, medicine.disease, Patient Outcome Assessment, Clear cell carcinoma, Female, Neoplasm Grading, Ovarian cancer, Clear cell
Abstract

The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22–1.64; P = 5.7 × 10−6], rs791587 (HR, 1.36; 95% CI, 1.17–1.57; P = 6.2 × 10−5), rs2476491 (HR, = 1.40; 95% CI, 1.19–1.64; P = 5.6 × 10−5), and rs10795763 (HR, 1.35; 95% CI, 1.17–1.57; P = 7.9 × 10−5), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54–0.82; P = 9.3 × 10−5) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer. Cancer Immunol Res; 2(4); 332–40. ©2014 AACR.

Published
2014

39. 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

40. Analysis of Over 10,000 Cases Finds No Association between Previously Reported Candidate Polymorphisms and Ovarian Cancer Outcome

Author

Jolanta Kupryjanczyk, Nicolas Wentzensen, Simon A. Gayther, Celeste Leigh Pearce, Susanne K. Kjaer, Irene Orlow, Zachary C. Fogarty, Evelyn Despierre, Yukie Bean, Georgia Chenevix-Trench, Robert A. Vierkant, Agnieszka Dansonka-Mieszkowska, Lene Lundvall, Jonathan Tyrer, Joellen M. Schildkraut, Izabela Ziolkowska-Seta, Diana Eccles, Iwona K. Rzepecka, Catherine M. Phelan, Hoda Anton Culver, Jennifer A. Doherty, Ignace Vergote, Daniel W. Cramer, Matthias W. Beckmann, Susan J. Ramus, Paul D.P. Pharoah, Honglin Song, Ursula Eilber, Galina Lurie, Jan Lubinski, Philipp Harter, Sandrina Lambrechts, David Van DenBerg, James Paul, Ellen L. Goode, Claus Høgdall, Janusz Menkiszak, James M. Flanagan, Christine Walsh, Julie M. Cunningham, Jenny Lester, Kristin L. White, Elisa V. Bandera, Robert S. Brown, Allan Jensen, Stanley B. Kaye, Matthew S. Block, Sharon E. Johnatty, Louise A. Brinton, Estrid Høgdall, Malcolm C. Pike, Thomas A. Sellers, Arif B. Ekici, Andreas du Bois, Hannah P. Yang, Aleksandra Gentry-Maharaj, Cezary Cybulski, Jenny Chang-Claude, Valerie McGuire, Marc T. Goodman, Anna deFazio, Ian G. Campbell, Argyrios Ziogas, Alexander Hein, Lisa E. Paddock, Usha Menon, Brooke L. Fridley, Mary Anne Rossing, Douglas A. Levine, Bridget Charbonneau, Andrew Berchuck, Jacek Gronwald, Alice S. Whittemore, Joseph H. Rothstein, Anja Rudolph, Weiva Sieh, Kimberly R. Kalli, Sara H. Olson, Allison F. Vitonis, Anna H. Wu, Tanja Pejovic, Peter A. Fasching, Florian Heitz, Beth Y. Karlan, Diether Lambrechts, Kathryn L. Terry, Ira Schwaab, and Montserrat Garcia-Closas

Subjects
Oncology, medicine.medical_specialty, Genotype, Epidemiology, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, SNP, Humans, Genetic Predisposition to Disease, Survival analysis, Genetic Association Studies, 030304 developmental biology, Genetic association, Proportional Hazards Models, Ovarian Neoplasms, 0303 health sciences, Polymorphism, Genetic, Proportional hazards model, business.industry, Cancer, medicine.disease, Prognosis, Survival Analysis, 3. Good health, 030220 oncology & carcinogenesis, Immunology, Female, business, Ovarian cancer
Abstract

Background: Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNP) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes. Methods: Twenty-seven SNPs in VHL, HGF, IL18, PRKACB, ABCB1, CYP2C8, ERCC2, and ERCC1 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000-observed person-years and 4,478 deaths. Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates. Results: We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined. Conclusions: These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies. Impact: These variants should not be used in prognostic models. Alternate approaches to uncovering inherited prognostic factors, if they exist, are needed. Cancer Epidemiol Biomarkers Prev; 22(5); 987–. ©2013 AACR.

Published
2013
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41. No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer

Author

Agnieszka Dansonka-Mieszkowska, Angela Brooks-Wilson, Ingo B. Runnebaum, Kenneth Offit, Melissa C. Southey, Ramunas Janavicius, Finn Cilius Nielsen, Christine Maugard, Marco Montagna, Annette Fontaine, Janusz Menkiszak, Robert Winqvist, Pascal Guénel, Rosalind Glasspool, Usha Menon, Daniel Barrowdale, Elinor J. Sawyer, Anna Jakubowska, Paul D.P. Pharoah, Martha J. Shrubsole, Lambertus A. Kiemeney, Camilla Krakstad, Dong Liang, Minouk J. Schoemaker, Judith S. Brand, Joseph Vijai, Marc T. Goodman, Thomas A. Sellers, David Van Den Berg, Celeste Leigh Pearce, Alice S. Whittemore, Irene L. Andrulis, Radka Platte, Kunle Odunsi, Orland Diez, Estrid Høgdall, Brooke L. Fridley, C. J. van Asperen, Mary Anne Rossing, Vessela N. Kristensen, Jonathan Tyrer, Tara M. Friebel, Douglas F. Easton, Per Hall, Mads Thomassen, Christine Walsh, Thilo Dörk, Louise A. Brinton, Keith Humphreys, Douglas A. Levine, Allison F. Vitonis, Anna H. Wu, Hermann Brenner, Maria Bisogna, Joellen M. Schildkraut, Maria A. Caligo, Jonine D. Figueroa, Lynne R. Wilkens, Grace Friel, Michael G. Schrauder, Evgeny N. Imyanitov, Sune F. Nielsen, Sylvie Mazoyer, Diana Eccles, Andrew Berchuck, Sara Margolin, Mitul Shah, Matthias W. Beckmann, Elizabeth M. Poole, Gad Rennert, Arif B. Ekici, Elisa Alducci, Bjarni A. Agnarsson, Linda S. Cook, Javier Benitez, Paolo Peterlongo, Natalia Antonenkova, Annika Lindblom, Patrick Neven, Julia A. Knight, Alan Ashworth, Matti A. Rookus, Frans B. L. Hogervorst, Daniela Zaffaroni, Banu Arun, Sue Healey, Robert P. Edwards, Susanne K. Kjaer, Laura J. van't Veer, John W.M. Martens, Christa Stegmaier, Claudine Isaacs, Daniel W. Cramer, Lars Beckmann, Liisa M. Pelttari, Dieter Flesch-Janys, Irene Orlow, Atocha Romero, Diana Torres, Marjanka K. Schmidt, Simon S. Cross, Alison M. Dunning, Rosemary L. Balleine, Sandra L. Halverson, Benoit Beuselinck, Melissa C. Larson, Senno Verhoef, Jirong Long, Angela Cox, Maartje J. Hooning, Bruce Poppe, Katarzyna Jaworska, Jolanta Kupryjanczyk, Nicolas Wentzensen, Gustavo C. Rodriguez, Tanja Pejovic, Roberta B. Ness, James Paul, Dominique Stoppa-Lyonnet, Nadine Tung, Gianluca Severi, Malcolm C. Pike, Hoda Anton-Culver, Ans M.W. van den Ouweland, Mark E. Robson, Roger L. Milne, Jan C. Oosterwijk, Laima Tihomirova, Helen Tsimiklis, Pierre Laurent-Puig, Florian Heitz, Beth Y. Karlan, Ian Tomlinson, Thérèse Truong, Bernardo Bonanni, Frederik Marmé, Qin Wang, Conxi Lázaro, Volker Arndt, Antoinette Hollestelle, Jacek Gronwald, M. Pilar Zamora, Barbara Wappenschmidt, Maren Weischer, Veli-Matti Kosma, Giulietta Scuvera, Jenny Lester, Andreas Berger, Stephen J. Chanock, Line Bjørge, Anthony J. Swerdlow, Andrew K. Godwin, Mervi Grip, Amanda E. Toland, Anna Marie Mulligan, Noralane M. Lindor, Paolo Radice, Bent Ejlertsen, Frederieke H. van der Baan, Lothar Haeberle, Valerie McGuire, Kamila Czene, Rob A. E. M. Tollenaar, Maria Soller, Katherine L. Nathanson, Sandrina Lambrechts, Susan J. Ramus, Anja Rudolph, Penny Soucy, Caroline Weltens, Hiltrud Brauch, Olivia Fletcher, Sara H. Olson, Yael Laitman, Marion Piedmonte, Arto Mannermaa, Agnieszka Budzilowska, Olga M. Sinilnikova, Christian F. Singer, Cezary Cybulski, Weiva Sieh, Ed Dicks, Elizabeth J. van Rensburg, Isabel dos Santos Silva, Hans Ehrencrona, Timothy R. Rebbeck, Jaana M. Hartikainen, Sandra Orsulic, Jingmei Li, Carmel Apicella, Anna deFazio, Ian G. Campbell, Ignace Vergote, Rita K. Schmutzler, Fredrick R. Schumacher, Julian Peto, Nadeem Siddiqui, Brian E. Henderson, Starr R. Guzman, Maria Kabisch, John L. Hopper, Arto Leminen, Jeffrey N. Weitzel, Honglin Song, J. Margriet Collée, Ingvild L. Tangen, Børge G. Nordestgaard, Antonis C. Antoniou, Lara Sucheston, Helena C. van Doorn, Lídia Feliubadaló, Leon F.A.G. Massuger, Iain A. McNeish, Nichola Johnson, Simon A. Gayther, Jennifer A. Doherty, Anders Bojesen, Gord Glendon, Yukie Bean, Celine M. Vachon, Barbara Burwinkel, Edith Olah, Shan Wang-Gohrke, Brita Arver, Marc Tischkowitz, Arja Jukkola-Vuorinen, Martin Gore, Vesa Kataja, Nicola Miller, Pamela J. Thompson, Malcolm W.R. Reed, Michelle A.T. Hildebrandt, Ritu Salani, Janet E. Olson, Catriona McLean, Cecilia M. Dorfling, Georgia Chenevix-Trench, Frederique Mariette, Laura Ottini, Fergus J. Couch, Linda E. Kelemen, Nhu D. Le, Michael J. Kerin, Claus Høgdall, Miguel de la Hoya, Jonathan Carter, Mercedes Durán, Inge Søkilde Pedersen, Julie M. Cunningham, Manjeet K. Bolla, Galina Lurie, Loic Le Marchand, Ute Hamann, Muy-Kheng Tea, Karoline Kuchenbaecker, Irene Konstantopoulou, Thomas Hansen, Francesca Damiola, Stefano Fortuzzi, Shelley S. Tworoger, Mikael Eriksson, Carl Blomqvist, Joan Brunet, Allan Jensen, Karen Lu, Elisa V. Bandera, Anne M. van Altena, Anne-Marie Gerdes, Lene Lundvall, Susan L. Neuhausen, Wei Zheng, Ana Osorio, Fiona Bruinsma, Hannah P. Yang, Graham G. Giles, Christoph Engel, Nick Orr, Harvey A. Risch, Jan Lubinski, Jacoba P. Knol-Bout, Phuong L. Mai, Martine Dumont, Xifeng Wu, Christof Sohn, Noah D. Kauff, Kristiina Aittomäki, Natalia Bogdanova, Alexander Hein, Francesmary Modugno, Heli Nevanlinna, Helga B. Salvesen, Adriana Lasa, Daphne Gschwantler Kaulich, Dominiek Smeets, Jenny Permuth-Wey, Josef Herzog, Catherine M. Phelan, Clareann H. Bunker, Steve Ellis, Christopher A. Haiman, Jolanta Lissowska, Judy Garber, Joanna Plisiecka-Halasa, Robert A. Vierkant, Steven A. Narod, Mark H. Greene, Florence Menegaux, Norbert Arnold, Primitiva Menéndez, Robert L. Nussbaum, Katja K.H. Aben, Andreas Schneeweiss, Katri Pylkäs, Els Van Nieuwenhuysen, Tomasz Huzarski, Joe Dennis, Susan M. Domchek, Andreas du Bois, Aleksandra Gentry-Maharaj, Florentia Fostira, Mary Beth Terry, Jenny Chang-Claude, Eitan Friedman, Argyrios Ziogas, Hatef Darabi, Kathleen Claes, Ellen L. Goode, Olufunmilayo I. Olopade, Stig E. Bojesen, Jo Perkins, Raanan Berger, Sharon E. Johnatty, Taru A. Muranen, Montserrat Garcia-Closas, Uffe Birk Jensen, Thomas Brüning, Heiko Müller, Debra Frost, Peter A. Fasching, Lesley McGuffog, Diether Lambrechts, Kelly-Anne Phillips, Caroline M. Seynaeve, Kathryn L. Terry, Ira Schwaab, Ralf Bützow, Manuel R. Teixeira, Joseph H. Rothstein, Bernard Peissel, Anna von Wachenfeldt, Saundra S. Buys, Peter Devilee, Alfons Meindl, Laura Baglietto, Kirsten B. Moysich, Arjen R. Mensenkamp, Philipp Harter, Jacques Simard, Generalitat de Catalunya, Ministerio de Ciencia e Innovación (España), Fundación Mutua Madrileña, Asociación Española Contra el Cáncer, Instituto de Salud Carlos III, National Institutes of Health (US), Wellcome Trust, European Commission, National Cancer Institute (US), Medical Oncology, Clinical Genetics, Erasmus MC other, Pediatric Surgery, Pathology, and Neurology

Subjects
0301 basic medicine, Oncology, endocrine system diseases, Endometriosis, Breast cancer, Clinical outcome, Genetic association, KRAS variant, Ovarian cancer, Genome-wide association study, Carcinoma, Ovarian Epithelial, medicine.disease_cause, Prostate, Brjóstakrabbamein, Clinical outcomes, Genotype, Obstetrics and Gynaecology, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], PROSTATE, Neoplasms, Glandular and Epithelial, skin and connective tissue diseases, RISK, Ovarian Neoplasms, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Obstetrics and Gynecology, WOMEN, female genital diseases and pregnancy complications, 3. Good health, medicine.anatomical_structure, Treatment Outcome, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, KRAS, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Breast Neoplasms, Article, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Carcinoma, Humans, GENOME-WIDE ASSOCIATION, Genetic Association Studies, POLYMORPHISMS, Krabbamein, MICRORNA-BINDING-SITE, IDENTIFICATION, business.industry, ENDOMETRIOSIS, Arfgengi, medicine.disease, 030104 developmental biology, PTT12, Eggjastokkar, business
Abstract

Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, and Consortium of Modifiers of BRCA1 and BRCA2: et al., [Objective]: Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. [Methods]: Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). [Results]: We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. [Conclusions]: rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers., The COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 — HEALTH-F2-2009-223175). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME-ON Post-GWAS Initiative (U19-CA148112). Funding for the project was provided by the Wellcome Trust under award 076113. This work was partially supported by Spanish Association against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrileña Foundation (FMMA) and SAF2010-20493. Was supported by a grant RD12/00369/0006 and 12/00539 from ISCIII (Spain), partially supported by European Regional Development FEDER funds. Contract grant sponsor: Asociación Española Contra el Cáncer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia. Contract grant numbers: ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285 and 2009SGR290.

Published
2016

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

Author

Melissa C. Larson, Jonathan Tyrer, Estrid Høgdall, Malcolm C. Pike, Julie M. Cunningham, Penelope M. Webb, Aleksandra Gentry-Maharaj, Allan Jensen, Jenny Chang-Claude, Louise A. Brinton, David Van Den Berg, Anja Rudolph, Joellen M. Schildkraut, Marc T. Goodman, Paul D.P. Pharoah, Joseph Usset, Lambertus A. Kiemeney, Ellen L. Goode, Sharon E. Johnatty, Hannah P. Yang, Francesmary Modugno, Joseph H. Rothstein, Susan J. Ramus, Alice S. Whittemore, Simon A. Gayther, Robert A. Vierkant, Valerie McGuire, Usha Menon, Pamela J. Thompson, Brooke L. Fridley, Mary Anne Rossing, Hoda Anton-Culver, Anna deFazio, Leon F.A.G. Massuger, Honglin Song, Shan Wang-Gohrke, Andrew Berchuck, Roberta B. Ness, Robert P. Edwards, Nicolas Wentzensen, Jennifer A. Doherty, Galina Lurie, Weiva Sieh, Rama Raghavan, Celeste Leigh Pearce, Anna H. Wu, Kirsten B. Moysich, Susanne K. Kjaer, and Lynne R. Wilkens

Subjects
0301 basic medicine, Candidate gene, Epidemiology, medicine.drug_class, medicine.medical_treatment, Bioinformatics, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Medicine, Humans, Obesity, Risk factor, Gene–environment interaction, Ovarian Neoplasms, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], business.industry, Cancer, Hormone replacement therapy (menopause), Middle Aged, medicine.disease, 030104 developmental biology, Oncology, Genetic epidemiology, Estrogen, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Female, Gene-Environment Interaction, Hormone therapy, business
Abstract

Background: Many epithelial ovarian cancer (EOC) risk factors relate to hormone exposure and elevated estrogen levels are associated with obesity in postmenopausal women. Therefore, we hypothesized that gene–environment interactions related to hormone-related risk factors could differ between obese and non-obese women. Methods: We considered interactions between 11,441 SNPs within 80 candidate genes related to hormone biosynthesis and metabolism and insulin-like growth factors with six hormone-related factors (oral contraceptive use, parity, endometriosis, tubal ligation, hormone replacement therapy, and estrogen use) and assessed whether these interactions differed between obese and non-obese women. Interactions were assessed using logistic regression models and data from 14 case–control studies (6,247 cases; 10,379 controls). Histotype-specific analyses were also completed. Results: SNPs in the following candidate genes showed notable interaction: IGF1R (rs41497346, estrogen plus progesterone hormone therapy, histology = all, P = 4.9 × 10−6) and ESR1 (rs12661437, endometriosis, histology = all, P = 1.5 × 10−5). The most notable obesity–gene–hormone risk factor interaction was within INSR (rs113759408, parity, histology = endometrioid, P = 8.8 × 10−6). Conclusions: We have demonstrated the feasibility of assessing multifactor interactions in large genetic epidemiology studies. Follow-up studies are necessary to assess the robustness of our findings for ESR1, CYP11A1, IGF1R, CYP11B1, INSR, and IGFBP2. Future work is needed to develop powerful statistical methods able to detect these complex interactions. Impact: Assessment of multifactor interaction is feasible, and, here, suggests that the relationship between genetic variants within candidate genes and hormone-related risk factors may vary EOC susceptibility. Cancer Epidemiol Biomarkers Prev; 25(5); 780–90. ©2016 AACR.

Published
2016

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

Author

Falk Thiel, Simon A. Gayther, Susan Kruger-Kjaer, Matthias Dürst, Robert M Brown, Thilo Doerk, Martin Gore, James M. Flanagan, Ian Tomlinson, Stephen J. Chanock, Thorunn Rafnar, Susan J. Ramus, Brooke L. Fridley, Jonathan Beesley, Jennifer A. Doherty, Tanya Sher, Jan Lubinski, Ya Yu Tsai, Wendy Brewster, Edwin S. Iversen, Evelyn Despierre, Mary Anne Rossing, Jenny Gross, Stanley B. Kaye, Galina Lurie, Natalia Bogdanova, Douglas A. Levine, Peter A. Fasching, Honglin Song, Patrick Sulem, Anna H. Wu, Angela Brooks-Wilson, Ingo B. Runnebaum, Estrid Høgdall, Natalia Antonenkova, Robert P. Edwards, Kara L. Cushing-Haugen, Francesmary Modugno, Ignace Vergote, Søren Besenbacher, Matthias W. Beckmann, Michael J. Birrer, Anna Jakubowska, Paul D.P. Pharoah, Kirsten B. Moyisch, David Van Den Berg, Steven A. Narod, Anne M. van Altena, Lambertus A. Kiemeney, Andrew Berchuck, Daniel W. Cramer, Arto Leminen, Peter Hillemanns, Alice S. Whittemore, Kunle Odunsi, Beth Y. Karlan, Douglas F. Easton, Diether Lambrechts, T A Sellers, Joellen M. Schildkraut, Heli Nevanlinna, Jolanta Lissowska, Kathryn L. Terry, Robert A. Vierkant, Ralf Bützow, Tuomas Heikkinenen, Jan Blaeker, Katja K.H. Aben, Krzysztof Mędrek, Georgia Chenevix-Trench, Weiva Sieh, Leon F.A.G. Massuger, Maria Notaridou, Linda S. Cook, Montserrat Garcia-Closas, Julie A. Baker, Kari Stefansson, Frédéric Amant, Michael E. Carney, Rachel T. Palmieri, Jacek Gronwald, Catherine M. Phelan, Chu Chen, Claus Høgdall, Pamela J. Thompson, Arif B. Ekici, Xiaoqing Chen, Eva Wozniak, Argyrios Ziogas, Aleksandra Gentry-Maharaj, Daniel Paik, Valerie McGuire, Marc T. Goodman, Ian G. Campbell, Hoda Anton-Culver, Shan Wang-Gohrke, Linda E. Kelemen, Jonathan Tyrer, Julie M. Cunningham, Celeste Leigh Pearce, Penelope M. Webb, Rebecca Hein, Dena G. Hernandez, Kelly L. Bolton, Chris Jones, Patricia G. Moorman, Joanne B. Weidhaas, Nhu D. Le, Daniel O. Stram, Roberta B. Ness, James Paul, Hanna P. Yang, Richard S. Houlston, Ellen L. Goode, Sharon E. Johnatty, and Jenny Chang-Claude

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Genotype, MEDLINE, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Internal medicine, Genetics, medicine, Biomarkers, Tumor, Tumor Cells, Cultured, Humans, Genetic Predisposition to Disease, Adaptor Proteins, Signal Transducing, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms, Genome, Human, Published Erratum, Gene Expression Profiling, Ovary, Middle Aged, medicine.disease, Adenocarcinoma, Mucinous, Cystadenocarcinoma, Serous, Endometrial Neoplasms, 030104 developmental biology, Case-Control Studies, Female, Ovarian cancer, Chromosomes, Human, Pair 19, Adenocarcinoma, Clear Cell, Genome-Wide Association Study
Abstract

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women. We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available survival time data and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P = 5 × 10⁻⁴ and P = 6 × 10⁻⁴, respectively), but they did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P = 3 × 10⁻⁹ and P = 4 × 10⁻¹¹, respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1-interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development.

Published
2016

44. Platinum Sensitivity–Related Germline Polymorphism Discovered via a Cell-Based Approach and Analysis of Its Association with Outcome in Ovarian Cancer Patients

Author

Brooke L. Fridley, Soma Das, Kunle Odunsi, Evelyn Despierre, Robert A. Vierkant, Peixian Chen, Ignace Vergote, Peter H. O'Donnell, Kirsten B. Moysich, Yi Lu, Estrid Høgdall, Diether Lambrechts, Stuart MacGregor, Jonathan Beesley, Jenny Gross, Beth Y. Karlan, Hae Kyung Im, Eric R. Gamazon, Georgia Chenevix-Trench, Shuangli Mi, Anna deFazio, Yarden S. Fraiman, Ellen L. Goode, Shiwei Duan, Wei Zhang, Emily O. Kistner, James Paul, Sharon E. Johnatty, Nancy J. Cox, M. Eileen Dolan, R. Stephanie Huang, Robert S. Brown, Allan Jensen, Dana Ziliak, Susanne K. Kjaer, and Matthew Grasela

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Antineoplastic Agents, Genome-wide association study, Single-nucleotide polymorphism, Kaplan-Meier Estimate, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Article, Carboplatin, Cell Line, chemistry.chemical_compound, Cell Line, Tumor, Internal medicine, medicine, Humans, SNP, International HapMap Project, Genetic association, Ovarian Neoplasms, Genome, Human, Gene Expression Profiling, Prognosis, medicine.disease, Gene Expression Regulation, Neoplastic, Gene expression profiling, Treatment Outcome, chemistry, Female, Ovarian cancer, Genome-Wide Association Study
Abstract

Purpose: Cell-based approaches were used to identify genetic markers predictive of patients' risk for poor response prior to chemotherapy. Experimental Design: We conducted genome-wide association studies (GWAS) to identify single-nucleotide polymorphisms (SNP) associated with cellular sensitivity to carboplatin through their effects on mRNA expression using International HapMap lymphoblastoid cell lines (LCL) and replicated them in additional LCLs. SNPs passing both stages of the cell-based study were tested for association with progression-free survival (PFS) in patients. Phase 1 validation was based on 377 ovarian cancer patients receiving at least four cycles of carboplatin and paclitaxel from the Australian Ovarian Cancer Study (AOCS). Positive associations were then assessed in phase 2 validation analysis of 1,326 patients from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas. Results: In the initial GWAS, 342 SNPs were associated with carboplatin-induced cytotoxicity, of which 18 unique SNPs were retained after assessing their association with gene expression. One SNP (rs1649942) was replicated in an independent LCL set (Bonferroni adjusted P < 0.05). It was found to be significantly associated with decreased PFS in phase 1 AOCS patients (Pper-allele = 2 × 10−2), with a stronger effect in the subset of women with optimally debulked tumors (Pper-allele = 4 × 10−3). rs1649942 was also associated with poorer overall survival in women with optimally debulked tumors (Pper-allele = 9 × 10−3). However, this SNP was not significant in phase 2 validation analysis with patients from numerous cohorts. Conclusion: This study shows the potential of cell-based, genome-wide approaches to identify germline predictors of treatment outcome and highlights the need for extensive validation in patients to assess their clinical effect. Clin Cancer Res; 17(16); 5490–500. ©2011 AACR.

Published
2011

45. The BARD1 Cys557Ser polymorphism and breast cancer risk: an Australian case–control and family analysis

Author

Amanda B. Spurdle, Graham G. Giles, Jonathan Beesley, Melissa C. Southey, David E. Goldgar, Sharon E. Johnatty, Georgia Chenevix-Trench, John L. Hopper, and Xiaoqing Chen

Subjects
Adult, Risk, Oncology, Cancer Research, medicine.medical_specialty, Ubiquitin-Protein Ligases, Population, Breast Neoplasms, Disease, Biology, Breast cancer, Internal medicine, Genotype, Serine, medicine, Humans, Cysteine, education, Aged, Aged, 80 and over, Family Health, Genetics, education.field_of_study, Polymorphism, Genetic, Tumor Suppressor Proteins, Australia, Case-control study, Cancer, Middle Aged, medicine.disease, Gene Expression Regulation, Neoplastic, Case-Control Studies, Breast disease, Ovarian cancer
Abstract

BARD1 was first identified as a BRCA1-interacting protein with tumour-suppressor functions. Some association studies suggested that the BARD1 Cys557Ser variant might be associated with increased risk of breast cancer, but the evidence remains uncertain. We found that the BARD1 Cys557Ser variant was carried by 50 of 1,136 cases (4.4%) and 30 of 623 controls (5.0%) from the population-based Australian Breast Cancer Family Study, 14 of 324 (4.3%) cases from the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab), and 30 of 760 controls (4.0%) from the Australian Ovarian Cancer Study. Case-control comparisons showed no evidence that the variant frequency differed by case-control status (P >or= 0.3). Segregation analysis of 14 kConFab variant-carrying families containing 157 genotyped individuals provided no evidence of segregation with disease. We conclude that the BARD1 Cys557Ser variant is not associated with breast cancer risk.

Published
2008

46. Consortium analysis of 7 candidate SNPs for ovarian cancer

Author

Jonathan Beesley, Penelope M. Webb, Julie M. Cunningham, Estrid Høgdall, Jolanta Lissowska, Shelley S. Tworoger, Susan J. Ramus, Patricia G. Moorman, Robert P. Edwards, Malcolm C. Pike, Douglas F. Easton, Galina Lurie, Usha Menon, Kirsten B. Moysich, Louise A. Brinton, Claus Høgdall, Xiaoqing Chen, Ellen L. Goode, Alice S. Whittemore, Marc T. Goodman, David Van Den Berg, Celeste Leigh Pearce, Daniel W. Cramer, Roberta B. Ness, Michael E. Carney, Stephen J. Chanock, Robert A. Vierkant, Susanne K. Kjaer, Andrew Berchuck, Joellen M. Schildkraut, Valerie McGuire, Honglin Song, Sharon E. Johnatty, Jan Blaakær, Silke Kropp, Shan Wang-Gohrke, Paul D.P. Pharoah, Anna H. Wu, Mark Liebow, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Georgia Chenevix-Trench, Richard A. DiCioccio, Montserrat Garcia-Closas, Susan E. Hankinson, Kathryn L. Terry, and Simon A. Gayther

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Colorectal cancer, Case-control study, Cancer, Single-nucleotide polymorphism, Genome-wide association study, Odds ratio, Biology, medicine.disease, Endocrinology, Breast cancer, Internal medicine, medicine, Ovarian cancer
Abstract

The Ovarian Cancer Association Consortium selected 7 candidate single nucleotide polymorphisms (SNPs), for which there is evidence from previous studies of an association with variation in ovarian cancer or breast cancer risks. The SNPs selected for analysis were F31I (rs2273535) in AURKA, N372H (rs144848) in BRCA2, rs2854344 in intron 17 of RB1, rs2811712 5' flanking CDKN2A, rs523349 in the 3' UTR of SRD5A2, D302H (rs1045485) in CASP8 and L10P (rs1982073) in TGFB1. Fourteen studies genotyped 4,624 invasive epithelial ovarian cancer cases and 8,113 controls of white non-Hispanic origin. A marginally significant association was found for RB1 when all studies were included [ordinal odds ratio (OR) 0.88 (95% confidence interval (CI) 0.79-1.00) p = 0.041 and dominant OR 0.87 (95% CI 0.76-0.98) p = 0.025]; when the studies that originally suggested an association were excluded, the result was suggestive although no longer statistically significant (ordinal OR 0.92, 95% CI 0.79-1.06). This SNP has also been shown to have an association with decreased risk in breast cancer. There was a suggestion of an association for AURKA, when one study that caused significant study heterogeneity was excluded [ordinal OR 1.10 (95% CI 1.01-1.20) p = 0.027; dominant OR 1.12 (95% CI 1.01-1.24) p = 0.03]. The other 5 SNPs in BRCA2, CDKN2A, SRD5A2, CASP8 and TGFB1 showed no association with ovarian cancer risk; given the large sample size, these results can also be considered to be informative. These null results for SNPs identified from relatively large initial studies shows the importance of replicating associations by a consortium approach.

Published
2008

47. The MnSOD Val9Ala polymorphism, dietary antioxidant intake, risk and survival in ovarian cancer (Australia)

Author

Georgia Chenevix-Trench, Amanda B. Spurdle, Xiaoqing Chen, Christina M. Nagle, Penelope M. Webb, and Sharon E. Johnatty

Subjects
Adult, Oncology, medicine.medical_specialty, Antioxidants, Internal medicine, Genotype, medicine, Humans, Genetic Predisposition to Disease, Survival analysis, Ovarian Neoplasms, Gynecology, Alanine, Polymorphism, Genetic, Risk modification, Superoxide Dismutase, business.industry, Australia, Case-control study, Obstetrics and Gynecology, Valine, Middle Aged, medicine.disease, Diet, Case-Control Studies, Dietary antioxidant, Etiology, Female, Ovarian cancer, business
Abstract

Objective. We assessed the MnSOD Val9Ala polymorphism and its interaction with dietary antioxidant intake in ovarian cancer risk and survival. Methods. The MnSOD polymorphism was assessed in 543 ovarian cancer cases and 1130 controls. We used regression analysis to model the association between genotype and risk, case-only analyses to estimate risk modification by dietary variables, and proportional hazard models for survival analysis. Results. We found no association between this polymorphism and ovarian cancer risk or survival, nor was there evidence of any interaction with dietary antioxidant intake. Conclusion. The Val9Ala MnSOD polymorphism does not influence ovarian cancer risk or survival.

Published
2007

48. Letter to the editor re: 'Women with double primary cancers of the colorectum and endometrium: do they have Lynch syndrome?' from T. Song and colleagues

Author

Amanda B. Spurdle and Sharon E. Johnatty

Subjects
0301 basic medicine, Gynecology, medicine.medical_specialty, Letter to the editor, business.industry, Obstetrics and Gynecology, Endometrium, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Lynch syndrome, Endometrial Neoplasms, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Reproductive Medicine, 030220 oncology & carcinogenesis, medicine, Humans, Female, business
Published
2015

49. Obesity and survival among women with ovarian cancer: results from the Ovarian Cancer Association Consortium

Author

Weiva Sieh, Alice S. Whittemore, Satoyo Hosono, Francesmary Modugno, Ellen L. Goode, Joseph H. Rothstein, Elisa V. Bandera, Penelope M. Webb, Hoda Anton-Culver, Brooke L. Fridley, A. du Bois, Mary Anne Rossing, Ignace Vergote, Melissa C. Larson, Argyrios Ziogas, Sharon E. Johnatty, Sandrina Lambrechts, Jolanta Lissowska, Claus Høgdall, Jennifer A. Doherty, Keitaro Matsuo, Joellen M. Schildkraut, Allan Jensen, Anna H. Wu, Suzanne C. Dixon, N. Wentzensen, Roberta B. Ness, Rebecca Sutphen, M. W. Beckmann, Jillian Hung, Diether Lambrechts, Lorna Rodriguez-Rodriguez, Christina M. Nagle, Harvey A. Risch, Ira Schwaab, Daniel W. Cramer, Kathryn L. Terry, Robert A. Vierkant, Lisa E. Paddock, L A Brinton, K. Moysich, M. T. Goodman, Peter A. Fasching, E Van Nieuwenhuysen, Florian Heitz, Estrid Høgdall, Lene Lundvall, P. Harter, Celeste Leigh Pearce, Kristine G. Wicklund, Susanne K. Kjaer, Rachel Palmieri Weber, Hannah P. Yang, Sian Fereday, Jenny Chang-Claude, Valerie McGuire, and Anna deFazio

Subjects
Oncology, obesity, Cancer Research, medicine.medical_specialty, ovarian cancer-specific survival, Epidemiology, overall survival, Kaplan-Meier Estimate, Carcinoma, Ovarian Epithelial, Disease-Free Survival, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Ovarian carcinoma, medicine, Humans, Neoplasms, Glandular and Epithelial, Progression-free survival, 030304 developmental biology, Ovarian Neoplasms, 2. Zero hunger, Gynecology, 0303 health sciences, business.industry, Hazard ratio, Cancer, medicine.disease, 3. Good health, Serous fluid, ovarian cancer, 030220 oncology & carcinogenesis, Meta-analysis, Female, business, Ovarian cancer, Body mass index, progression-free survival
Abstract

© 2015 Cancer Research UK. All rights reserved. Background: Observational studies have reported a modest association between obesity and risk of ovarian cancer; however, whether it is also associated with survival and whether this association varies for the different histologic subtypes are not clear. We undertook an international collaborative analysis to assess the association between body mass index (BMI), assessed shortly before diagnosis, progression-free survival (PFS), ovarian cancer-specific survival and overall survival (OS) among women with invasive ovarian cancer. Methods: We used original data from 21 studies, which included 12 390 women with ovarian carcinoma. We combined study-specific adjusted hazard ratios (HRs) using random-effects models to estimate pooled HRs (pHR). We further explored associations by histologic subtype. Results: Overall, 6715 (54%) deaths occurred during follow-up. A significant OS disadvantage was observed for women who were obese (BMI: 30-34.9, pHR: 1.10 (95% confidence intervals (CIs): 0.99-1.23); BMI: ≥35, pHR: 1.12 (95% CI: 1.01-1.25)). Results were similar for PFS and ovarian cancer-specific survival. In analyses stratified by histologic subtype, associations were strongest for women with low-grade serous (pHR: 1.12 per 5 kg m -2) and endometrioid subtypes (pHR: 1.08 per 5 kg m -2), and more modest for the high-grade serous (pHR: 1.04 per 5 kg m -2) subtype, but only the association with high-grade serous cancers was significant. Conclusions: Higher BMI is associated with adverse survival among the majority of women with ovarian cancer.

Published
2015

50. β2adrenergic receptor 5′ haplotypes influence promoter activity

Author

Eric Boerwinkle, Sharon E Johnatty, Maha Abdellatif, Lawrence C. Shimmin, and Richard B. Clark

Subjects
Pharmacology, Genetics, Mutation, Adrenergic receptor, Haplotype, Biology, medicine.disease_cause, Molecular biology, Chromosomal region, medicine, Luciferase, Signal transduction, Receptor, Gene
Abstract

Transcriptional control of the human β2 adrenergic receptor gene (ADRB2) predominantly resides within a 549 base pair region immediately 5′ to the start of translation. Within this region, four naturally occurring polymorphisms, −468 C→G, −367 T→C, −47 T→C, and −20 T→C, have been identified. To determine the individual site and haplotype effects of these polymorphisms, we generated 16 luciferase-based mutant constructs which were transiently transfected into HEK293 cells, and measured ADRB2 promoter-driven luciferase activity. Two of the 16 mutant constructs, GCCT (−468G, −367C, −47C, −20T) and CTCT, showed a highly significant 3 fold decrease in luciferase induction relative to the reference CTTT. These haplotype effects could not be accounted for by the separate and additive effects of each site. These findings indicate that promoter polymorphisms interact to significantly alter β2 adrenergic receptor expression, and should be examined further for their association with disease-related phenotypes. Keywords: ADRB2, polymorphisms, promoter, human β2 adrenergic receptor, beta2-adrenergic receptor, transfection, luciferase, HEK293 cells, haplotype Introduction Adrenergic receptors are members of the superfamily of seven transmembrane-spanning domain receptors that carry out signal transduction. They are an integral part of the sympathetic nervous system and have been shown to play important roles in cardiovascular, respiratory and metabolic functions (Kobilka, 1991). Adrenergic receptors were first identified in pharmacological studies and have been subdivided into two major types, α and β, on the basis of agonist-mediated responses, with subsequent classification into subtypes based on differential tissue localization. To date, nine different subtypes have been cloned and pharmacologically characterized, including three β subtypes (Guimaraes & Moura, 2001). The human β2 adrenergic receptor gene (ADRB2) is encoded by a single intronless gene consisting of 1239 nucleotides, located on the distal portion of the long arm of chromosome 5 (5q32–q34). This chromosomal region has been shown in linkage studies to be significantly related to blood pressure control (Krushkal et al., 1999). Positional candidate gene studies have identified the ADRB2 gene as a susceptibility locus for human hypertension (Bray et al., 2000). In addition, genetic association studies have also implicated ADRB2 polymorphisms in other disease phenotypes (Turki et al., 1995; Yamada et al., 1999). Studies of deletion fragments of a 1470 bp sequence 5′ to the start of translation indicate that the majority of promoter activity resides within a 549 bp fragment immediately upstream of the ATG start codon (Scott et al., 1999). This fragment not only contains important known and predicted regulatory elements (Kobilka et al., 1987), but also multiple genetic polymorphisms: −468 C→G, −367 T→C, −47 T→C, and −20 T→C. This study was undertaken to delineate the functional significance of these promoter polymorphisms individually and as haplotypes, using luciferase-based expression studies. We report here highly significant alterations in luciferase expression among the 16 haplotypes, indicating the potential for variations in ADRB2 expression depending on the promoter haplotypes.

Published
2002

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