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1. rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology

Author: Linda E. Kelemen, Madalene Earp, Brooke L. Fridley, Georgia Chenevix-Trench, on behalf of Australian Ovarian Cancer Study Group, Peter A. Fasching, Matthias W. Beckmann, Arif B. Ekici, Alexander Hein, Diether Lambrechts, Sandrina Lambrechts, Els Van Nieuwenhuysen, Ignace Vergote, Mary Anne Rossing, Jennifer A. Doherty, Jenny Chang-Claude, Sabine Behrens, Kirsten B. Moysich, Rikki Cannioto, Shashikant Lele, Kunle Odunsi, Marc T. Goodman, Yurii B. Shvetsov, Pamela J. Thompson, Lynne R. Wilkens, Thilo Dörk, Natalia Antonenkova, Natalia Bogdanova, Peter Hillemanns, Ingo B. Runnebaum, Andreas du Bois, Philipp Harter, Florian Heitz, Ira Schwaab, Ralf Butzow, Liisa M. Pelttari, Heli Nevanlinna, Francesmary Modugno, Robert P. Edwards, Joseph L. Kelley, Roberta B. Ness, Beth Y. Karlan, Jenny Lester, Sandra Orsulic, Christine Walsh, Susanne K. Kjaer, Allan Jensen, Julie M. Cunningham, Robert A. Vierkant, Graham G. Giles, Fiona Bruinsma, Melissa C. Southey, Michelle A.T. Hildebrandt, Dong Liang, Karen Lu, Xifeng Wu, Thomas A. Sellers, Douglas A. Levine, Joellen M. Schildkraut, Edwin S. Iversen, Kathryn L. Terry, Daniel W. Cramer, Shelley S. Tworoger, Elizabeth M. Poole, Elisa V. Bandera, Sara H. Olson, Irene Orlow, Liv Cecilie Vestrheim Thomsen, Line Bjorge, Camilla Krakstad, Ingvild L. Tangen, Lambertus A. Kiemeney, Katja K.H. Aben, Leon F.A.G. Massuger, Anne M. van Altena, Tanja Pejovic, Yukie Bean, Melissa Kellar, Linda S. Cook, Nhu D. Le, Angela Brooks-Wilson, Jacek Gronwald, Cezary Cybulski, Anna Jakubowska, Jan Lubiński, Nicolas Wentzensen, Louise A. Brinton, Jolanta Lissowska, Estrid Hogdall, Svend Aage Engelholm, Claus Hogdall, Lene Lundvall, Lotte Nedergaard, Paul D.P. Pharoah, Ed Dicks, Honglin Song, Jonathan P. Tyrer, Iain McNeish, Nadeem Siddiqui, Karen Carty, Rosalind Glasspool, James Paul, Ian G. Campbell, Diana Eccles, Alice S. Whittemore, Valerie McGuire, Joseph H. Rothstein, Weiva Sieh, Steven A. Narod, Catherine M. Phelan, John R. McLaughlin, Harvey A. Risch, Hoda Anton-Culver, Argyrios Ziogas, Usha Menon, Simon A. Gayther, Aleksandra Gentry-Maharaj, Susan J. Ramus, Anna H. Wu, Celeste Leigh Pearce, Alice W. Lee, Malcolm C. Pike, Jolanta Kupryjanczyk, Agnieszka Podgorska, Joanna Plisiecka-Halasa, Wlodzimierz Sawicki, Ellen L. Goode, Andrew Berchuck, and Ovarian Cancer Association Consortium
Subjects: consortia, enolase superfamily member 1, expression quantitative trait locus, genetics, gynecology, ovarian neoplasms, single-nucleotide polymorphism, thymidylate synthase, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3′ gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97–1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03–1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10−28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.
Published: 2018
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2. Assessment of small in-frame indels and C-terminal nonsense variants of BRCA1 using a validated functional assay

Author: Thales C. Nepomuceno, Ana P. P. dos Santos, Vanessa C. Fernandes, Anna B. R. Elias, Thiago T. Gomes, Guilherme Suarez-Kurtz, Edwin S. Iversen, Fergus J. Couch, Alvaro N. A. Monteiro, and Marcelo A. Carvalho
Subjects: Ovarian Neoplasms, Multidisciplinary, Amino Acid Substitution, BRCA1 Protein, Genes, BRCA1, Mutation, Missense, Humans, Bayes Theorem, Breast Neoplasms, Female, Genetic Predisposition to Disease, Alleles
Abstract: BRCA1 (Breast Cancer 1, early onset) is linked to breast and ovarian cancer predisposition. Still, the risks conferred by a significant portion of BRCA1 variants identified in the population remains unknown. Most of these variants of uncertain significance are missense alterations. However, the functional implications of small in-frame deletions and/or insertions (indels) are also difficult to predict. Our group has previously evaluated the functional impact of 347 missense variants using an extensively validated transcriptional activity assay. Here we show a systematic assessment of 30 naturally occurring in-frame indels located at the C-terminal region of BRCA1. We identified positions sensitive and tolerant to alterations, expanding the knowledge of structural determinants of BRCA1 function. We further designed and assessed the impact of four single codon deletions in the tBRCT linker region and six nonsense variants at the C-terminus end of BRCA1. Amino acid substitutions, deletions or insertions in the disordered region do not significantly impact activity and are not likely to constitute pathogenic alleles. On the other hand, a sizeable fraction of in-frame indels at the BRCT domain significantly impact function. We then use a Bayesian integrative statistical model to derive the probability of pathogenicity for each variant. Our data highlights the importance of assessing the impact of small in-frame indels in BRCA1 to improve risk assessment and clinical decisions for carriers.
Published: 2022

3. Integration of functional assay data results provides strong evidence for classification of hundreds of BRCA1 variants of uncertain significance

Author: Taciane B. Henriques, Iuly G. Ribeiro, Thales C. Nepomuceno, Marcy E. Richardson, Marcele L.M. de Souza, Géssica F. Machado, Mariana F. Veloso, Marcelo A. Carvalho, David E. Goldgar, Diandra Zipinotti dos Santos, Roberto S. Ribeiro, Alvaro N.A. Monteiro, Fergus J. Couch, Edwin S. Iversen, Paulo C Lyra, and Leticia Batista Azevedo Rangel
Subjects: 0301 basic medicine, Functional assay, medicine.medical_specialty, variants of uncertain significance, Genetic counseling, Genomics, Breast Neoplasms, Genetic Counseling, Computational biology, 030105 genetics & heredity, Biology, Article, 03 medical and health sciences, medicine, Missense mutation, Humans, Clinical significance, Genetic Predisposition to Disease, ACMG/AMP guidelines, Genetic Testing, Categorical variable, Genetics (clinical), Ovarian Neoplasms, functional assays, Molecular pathology, BRCA1 Protein, BRCA1, breast and ovarian cancer, 030104 developmental biology, Medical genetics, Female
Abstract: Purpose BRCA1 pathogenic variant heterozygotes are at a substantially increased risk for breast and ovarian cancer. The widespread uptake of testing has led to a significant increase in the detection of missense variants in BRCA1, the vast majority of which are variants of uncertain clinical significance (VUS), posing a challenge to genetic counseling. Here, we harness a wealth of functional data for thousands of variants to aid in variant classification. Methods We have collected, curated, and harmonized functional data for 2701 missense variants representing 24.5% of possible missense variants in BRCA1. Results were harmonized across studies by converting data into binary categorical variables (functional impact versus no functional impact). Using a panel of reference variants we identified a subset of assays with high sensitivity and specificity (≥80%) and apply the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) variant interpretation guidelines to assign evidence criteria for classification. Results Integration of data from validated assays provided ACMG/AMP evidence criteria in favor of pathogenicity for 297 variants or against pathogenicity for 2058 representing 96.2% of current VUS functionally assessed. We also explore discordant results and identify limitations in the approach. Conclusion High quality functional data are available for BRCA1 missense variants and provide evidence for classification of 2355 VUS according to their pathogenicity.
Published: 2020

4. Impact of amino acid substitutions at secondary structures in the BRCT domains of the tumor suppressor BRCA1: Implications for clinical annotation

Author: Fergus J. Couch, Guilherme Suarez-Kurtz, Alvaro N.A. Monteiro, Carly M. Harro, Ricceli F. Silva, Cara Shields, Volha A. Golubeva, Kwabena Amankwah, Marcelo A. Carvalho, Vanessa C. Fernandes, Thales C. Nepomuceno, Edwin S. Iversen, Giuliana de Gregoriis, Thiago T. Gomes, Renata B. V. Abreu, and Giuliano Di Pietro
Subjects: Models, Molecular, 0301 basic medicine, endocrine system diseases, Population, Mutation, Missense, Breast Neoplasms, Computational biology, Biology, Biochemistry, Structure-Activity Relationship, 03 medical and health sciences, Protein structure, Protein Domains, medicine, Humans, Missense mutation, skin and connective tissue diseases, education, Molecular Biology, Genetic testing, Ovarian Neoplasms, chemistry.chemical_classification, education.field_of_study, 030102 biochemistry & molecular biology, medicine.diagnostic_test, BRCA1 Protein, C-terminus, Cell Biology, Human genetics, Amino acid, HEK293 Cells, 030104 developmental biology, BRCT domain, Amino Acid Substitution, chemistry, Protein Structure and Folding, Female
Abstract: Genetic testing for BRCA1, a DNA repair protein, can identify carriers of pathogenic variants associated with a substantially increased risk for breast and ovarian cancers. However, an association with increased risk is unclear for a large fraction of BRCA1 variants present in the human population. Most of these variants of uncertain clinical significance lead to amino acid changes in the BRCA1 protein. Functional assays are valuable tools to assess the potential pathogenicity of these variants. Here, we systematically probed the effects of substitutions in the C terminus of BRCA1: the N- and C-terminal borders of its tandem BRCT domain, the BRCT-[N-C] linker region, and the α1 and α′1 helices in BRCT-[N] and -[C]. Using a validated transcriptional assay based on a fusion of the GAL4 DNA-binding domain to the BRCA1 C terminus (amino acids 1396–1863), we assessed the functional impact of 99 missense variants of BRCA1. We include the data obtained for these 99 missense variants in a joint analysis to generate the likelihood of pathogenicity for 347 missense variants in BRCA1 using VarCall, a Bayesian integrative statistical model. The results from this analysis increase our understanding of BRCA1 regions less tolerant to changes, identify functional borders of structural domains, and predict the likelihood of pathogenicity for 98% of all BRCA1 missense variants in this region recorded in the population. This knowledge will be critical for improving risk assessment and clinical treatment of carriers of BRCA1 variants.
Published: 2019

5. The risk of ovarian cancer increases with an increase in the lifetime number of ovulatory cycles : an analysis from the Ovarian Cancer Cohort Consortium (OC3)

Author: Kim Overvad, Patricia Hartge, Roger L. Milne, Kim Robien, Graham G. Giles, Louise A. Brinton, Katie M. O'Brien, Alpa V. Patel, Edwin S. Iversen, Rudolf Kaaks, Lynne R. Wilkens, Renée T. Fortner, Anne Zeleniuch-Jacquotte, Ruth C. Travis, Alicja Wolk, Catherine Schairer, Mia M. Gaudet, I-Min Lee, Britton Trabert, Inger T. Gram, Anthony J. Swerdlow, Veronica Wendy Setiawan, Emily White, Leo J. Schouten, Nicolas Wentzensen, Dale P. Sandler, Shelley S. Tworoger, Victoria A. Kirsh, Thomas E. Rohan, Mary K. Townsend, Julie E. Buring, Piet A. van den Brandt, Leslie Bernstein, Antonia Trichopoulou, Elio Riboli, K Visvanathan, N. Charlotte Onland-Moret, Marina Kvaskoff, James V. Lacey, Ulrike Peters, Judith A. Hoffman Bolton, Alan A. Arslan, Laure Dossus, Jenny N. Poynter, Holly R. Harris, Michael Jones, Gary E. Fraser, Annika Idahl, Pilar Amiano, Synnove F. Knutsen, Epidemiologie, and RS: GROW - R1 - Prevention
Subjects: 0301 basic medicine, Oncology, Cancer Research, endocrine system diseases, 0302 clinical medicine, Risk Factors, Prospective Studies, Prospective cohort study, Reproductive History, MUTANT P53, media_common, Ovarian Cancer Cohort Consortium (OC3), Ovarian Neoplasms, HYPOTHESIS, ORAL-CONTRACEPTIVES, CARCINOGENESIS, Absolute risk reduction, Middle Aged, female genital diseases and pregnancy complications, Serous fluid, medicine.anatomical_structure, 030220 oncology & carcinogenesis, INCESSANT OVULATION, Female, Life Sciences & Biomedicine, Ovulation, medicine.medical_specialty, CARCINOMA, media_common.quotation_subject, Ovary, Risk Assessment, Article, 03 medical and health sciences, ANDROGENS, Contraceptive Agents, INFLAMMATION, Internal medicine, medicine, Journal Article, Humans, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, REPRODUCTIVE FACTORS, Fallopian Tubes, Aged, Proportional Hazards Models, Science & Technology, Cancer prevention, business.industry, medicine.disease, 030104 developmental biology, OVEREXPRESSION, business, Ovarian cancer, Fallopian tube
Abstract: Repeated exposure to the acute proinflammatory environment that follows ovulation at the ovarian surface and distal fallopian tube over a woman's reproductive years may increase ovarian cancer risk. To address this, analyses included individual-level data from 558,709 naturally menopausal women across 20 prospective cohorts, among whom 3,246 developed invasive epithelial ovarian cancer (2,045 serous, 319 endometrioid, 184 mucinous, 121 clear cell, 577 other/unknown). Cox models were used to estimate multivariable-adjusted HRs between lifetime ovulatory cycles (LOC) and its components and ovarian cancer risk overall and by histotype. Women in the 90th percentile of LOC (>514 cycles) were almost twice as likely to be diagnosed with ovarian cancer than women in the 10th percentile ( Significance: Although ovarian cancer is rare, risk of most ovarian cancers doubles as the number of lifetime ovulatory cycles increases from approximately 300 to 500. Thus, identifying an important area for cancer prevention research.
Published: 2020

6. Functional Analysis and Fine Mapping of the 9p22.2 Ovarian Cancer Susceptibility Locus

Author: Natalia Bogdanova, Karen Carty, Brooke L. Fridley, Argyrios Ziogas, Matthias Dürst, Ignace Vergote, Anxhela Gjyshi, Barry P. Rosen, Heli Nevanlinna, Anna H. Wu, Estrid Høgdall, Sandra Orsulic, Alice W. Lee, Liisa M. Pelttari, Timothy P. Hughes, Francesmary Modugno, Kirsten B. Moysich, Malcolm C. Pike, Xifeng Wu, Anja Rudolph, Philipp Harter, Jolanta Lissowska, Edwin S. Iversen, Susan J. Ramus, Douglas F. Easton, Julie M. Cunningham, Katja K.H. Aben, Liv Cecilie Vestrheim Thomsen, Lynne R. Wilkens, Lene Lundvall, Melissa Buckley, Shelley S. Tworoger, Simon A. Gayther, Allan Jensen, Robert P. Edwards, Angela Brooks-Wilson, Jonathan Tyrer, Rosalind Glasspool, Soo Hwang Teo, Gerhard A. Coetzee, Renato S. Carvalho, Matthew L. Freedman, Jan Lubinski, Diether Lambrechts, Ellen L. Goode, Wei Zheng, Thomas A. Sellers, Y. Ann Chen, Harvey A. Risch, Leon F.A.G. Massuger, Kathryn L. Terry, Beata Spiewankiewicz, Andrew Berchuck, Jennifer A. Doherty, Usha Menon, Christine Walsh, Louise A. Brinton, Hoda Anton-Culver, Alice S. Whittemore, Kunle Odunsi, Linda S. Cook, John R. McLaughlin, Ralf Bützow, Joseph L. Kelley, Fiona Bruinsma, Iwona K. Rzepecka, Jennifer B. Permuth, Dong Liang, Jolanta Kupryjanczyk, Nicolas Wentzensen, Karen H. Lu, Marc T. Goodman, Katharina Bischof, Yin Ling Woo, Nicholas T. Woods, Yurii B. Shvetsov, Yu-Tang Gao, Ya Yu Tsai, Andreas du Bois, Aleksandra Gentry-Maharaj, Weiva Sieh, Nadeem Siddiqui, Mary Anne Rossing, Joellen M. Schildkraut, Thilo Dörk, Douglas A. Levine, RL Milne, Lotte Ansgaard Thomsen, Sara H. Olson, Jenny Chang-Claude, Jacek Gronwald, Hannah P. Yang, Peter Hillemanns, Hamed S. Najafabadi, Ed Dicks, Alvaro N.A. Monteiro, Tanja Pejovic, Diana Eccles, Peter A. Fasching, Honglin Song, Hanis Nazihah Hasmad, Beth Y. Karlan, Matthias W. Beckmann, Pamela J. Thompson, Dennis J. Hazelett, Elizabeth M. Poole, Sandrina Lambrechts, Alexander Hein, Gustavo Mendoza-Fandiño, Arif B. Ekici, Kate Lawrenson, Xiao-Ou Shu, Linda E. Kelemen, Elisa V. Bandera, Michelle A.T. Hildebrandt, Clareann H. Bunker, Madalene Earp, Anne M. van Altena, Simon G. Coetzee, Ally Yang, Roberta B. Ness, James Paul, Cezary Cybulski, Valerie McGuire, Line Bjørge, Lara E. Sucheston-Campbell, Ian G. Campbell, Ian McNeish, Shan Wang-Gohrke, Daniel W. Cramer, Paulo C Lyra, Yukie Bean, Agnieszka Dansonka-Mieszkowska, Melissa C. Southey, Celeste Leigh Pearce, Howard C. Shen, Susanne K. Kjaer, Keitaro Matsuo, Anna Jakubowska, Paul D.P. Pharoah, Lambertus A. Kiemeney, Graham G. Giles, Irene Orlow, Sean J. Yoder, Reidun K. Kopperud, Jenny Lester, Georgia Chenevix-Trench, Houtan Noushmehr, and Catherine M. Phelan
Subjects: 0301 basic medicine, Cancer Research, Linkage disequilibrium, Cell Cycle Proteins, Genome-wide association study, Single-nucleotide polymorphism, Locus (genetics), Carcinoma, Ovarian Epithelial, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, Cell Line, Tumor, medicine, Humans, Genetic Predisposition to Disease, Scaffold/matrix attachment region, Gene, Genotyping, Ovarian Neoplasms, Genetics, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Base Sequence, Chromosome Mapping, DNA, Neoplasm, medicine.disease, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Cystadenocarcinoma, Serous, 3. Good health, DNA-Binding Proteins, HEK293 Cells, 030104 developmental biology, Oncology, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Female, MAPEAMENTO GENÉTICO, Chromosomes, Human, Pair 9, Ovarian cancer, Genome-Wide Association Study
Abstract: Genome-wide association studies have identified 40 ovarian cancer risk loci. However, the mechanisms underlying these associations remain elusive. In this study, we conducted a two-pronged approach to identify candidate causal SNPs and assess underlying biological mechanisms at chromosome 9p22.2, the first and most statistically significant associated locus for ovarian cancer susceptibility. Three transcriptional regulatory elements with allele-specific effects and a scaffold/matrix attachment region were characterized and, through physical DNA interactions, BNC2 was established as the most likely target gene. We determined the consensus binding sequence for BNC2 in vitro, verified its enrichment in BNC2 ChIP-seq regions, and validated a set of its downstream target genes. Fine-mapping by dense regional genotyping in over 15,000 ovarian cancer cases and 30,000 controls identified SNPs in the scaffold/matrix attachment region as among the most likely causal variants. This study reveals a comprehensive regulatory landscape at 9p22.2 and proposes a likely mechanism of susceptibility to ovarian cancer. Significance: Mapping the 9p22.2 ovarian cancer risk locus identifies BNC2 as an ovarian cancer risk gene. See related commentary by Choi and Brown, p. 439
Published: 2019

7. rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology

Author: Peter Hillemanns, Ralf Bützow, Joseph H. Rothstein, Jennifer A. Doherty, Celeste Leigh Pearce, Louise A. Brinton, Sandra Orsulic, Lene Lundvall, Susanne K. Kjaer, Irene Orlow, Marc T. Goodman, Diether Lambrechts, Agnieszka Podgorska, Kathryn L. Terry, Yukie Bean, Joseph L. Kelley, Jonathan Tyrer, Svend Aage Engelholm, Linda S. Cook, John R. McLaughlin, Melissa Kellar, Graham G. Giles, Shashikant Lele, Anne M. van Altena, Tanja Pejovic, Lotte Nedergaard, Edwin S. Iversen, Robert P. Edwards, Ingvild L. Tangen, Andreas du Bois, Rosalind Glasspool, Florian Heitz, Beth Y. Karlan, Peter A. Fasching, Liisa M. Pelttari, Aleksandra Gentry-Maharaj, Argyrios Ziogas, Pamela J. Thompson, Jenny Chang-Claude, Camilla Krakstad, Andrew Berchuck, Simon A. Gayther, Alice S. Whittemore, Kunle Odunsi, Liv Cecilie Vestrheim Thomsen, Jolanta Kupryjanczyk, Leon F.A.G. Massuger, Nicolas Wentzensen, Karen H. Lu, Alexander Hein, Steven A. Narod, Harvey A. Risch, Francesmary Modugno, Fiona Bruinsma, Joanna Plisiecka-Halasa, Julie M. Cunningham, Sara H. Olson, Linda E. Kelemen, Xifeng Wu, Robert A. Vierkant, Daniel W. Cramer, Yurii B. Shvetsov, Elisa V. Bandera, Arif B. Ekici, Heli Nevanlinna, Lynne R. Wilkens, Jolanta Lissowska, Melissa C. Southey, Shelley S. Tworoger, Allan Jensen, Christine Walsh, Usha Menon, Line Bjørge, Iain A. McNeish, Katja K.H. Aben, Dong Liang, Joellen M. Schildkraut, Ellen L. Goode, Els Van Nieuwenhuysen, Ignace Vergote, Brooke L. Fridley, Weiva Sieh, Anna H. Wu, Thomas A. Sellers, Nhu D. Le, Jacek Gronwald, Anna Jakubowska, Paul D.P. Pharoah, Mary Anne Rossing, Thilo Dörk, Natalia Antonenkova, Lambertus A. Kiemeney, Douglas A. Levine, Cezary Cybulski, Diana Eccles, Hoda Anton-Culver, Matthias W. Beckmann, Valerie McGuire, Elizabeth M. Poole, Claus Høgdall, Ed Dicks, Honglin Song, Sandrina Lambrechts, Ian G. Campbell, Michelle A.T. Hildebrandt, Madalene Earp, Roberta B. Ness, James Paul, Jan Lubinski, Natalia Bogdanova, Estrid Høgdall, Alice W. Lee, Malcolm C. Pike, Ira Schwaab, Nadeem Siddiqui, Włodzimierz Sawicki, Kirsten B. Moysich, Philipp Harter, Angela Brooks-Wilson, Ingo B. Runnebaum, Karen Carty, Rikki Cannioto, Susan J. Ramus, Georgia Chenevix-Trench, Catherine M. Phelan, Sabine Behrens, Jenny Lester, Department of Pathology, Medicum, Clinicum, Department of Obstetrics and Gynecology, Kelemen, Linda E [0000-0003-4362-9784], Hein, Alexander [0000-0003-2601-3398], Behrens, Sabine [0000-0002-9714-104X], Hillemanns, Peter [0000-0001-9829-3531], Nevanlinna, Heli [0000-0002-0916-2976], Kjaer, Susanne K [0000-0002-8347-1398], Jensen, Allan [0000-0001-8124-4880], Cunningham, Julie M [0000-0002-8159-3025], Vierkant, Robert A [0000-0001-6242-5221], Bjorge, Line [0000-0002-0240-2770], Gronwald, Jacek [0000-0002-3643-2871], Brinton, Louise A [0000-0003-3853-8562], Pharoah, Paul DP [0000-0001-8494-732X], Tyrer, Jonathan P [0000-0003-3724-4757], McNeish, Iain [0000-0002-9387-7586], Eccles, Diana [0000-0002-9935-3169], Menon, Usha [0000-0003-3708-1732], Ramus, Susan J [0000-0003-0005-7798], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Oncology, Ovarian Cancer Association Consortium, consortia, Thymidylate synthase, Ovarian neoplasms, lcsh:Chemistry, 0302 clinical medicine, expression quantitative trait locus, Consortia, Ovarian carcinoma, Odds Ratio, genetics, Expression quantitative trait locus, lcsh:QH301-705.5, Spectroscopy, Single-nucleotide polymorphism, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], biology, GENETIC-VARIATION, General Medicine, Middle Aged, ovarian neoplasms, single-nucleotide polymorphism, Adenocarcinoma, Mucinous, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, Computer Science Applications, Gene Expression Regulation, Neoplastic, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Adenocarcinoma, Female, DIFFERENT HISTOTYPES, Signal Transduction, Australian Ovarian Cancer Study Group, Risk, EXPRESSION, medicine.medical_specialty, SUSCEPTIBILITY LOCI, 0699 Other Biological Sciences, Quantitative Trait Loci, 3122 Cancers, thymidylate synthase, Polymorphism, Single Nucleotide, Catalysis, Article, Inorganic Chemistry, 03 medical and health sciences, Internal medicine, 0399 Other Chemical Sciences, medicine, Genetics, CANCER ASSOCIATION CONSORTIUM, Humans, RNA, Antisense, ddc:610, Physical and Theoretical Chemistry, Allele, Molecular Biology, Genetic Association Studies, Hydro-Lyases, METAANALYSIS, 0604 Genetics, Chemical Physics, Organic Chemistry, gynecology, Case-control study, Proteins, Odds ratio, medicine.disease, SYNTHASE MESSENGER-RNA, 030104 developmental biology, Logistic Models, CARBON TRANSFER PATHWAY, lcsh:Biology (General), lcsh:QD1-999, Enolase superfamily member 1, Gynecology, enolase superfamily member 1, Case-Control Studies, Expression quantitative trait loci, biology.protein, 1182 Biochemistry, cell and molecular biology, CIGARETTE-SMOKING, Other Biological Sciences, Other Chemical Sciences
Abstract: Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3′ gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09, 95% CI = 0.97–1.22, p = 0.15, N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13, 95% CI = 1.03–1.24, p = 0.01, N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10−28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.
Published: 2018

8. Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk

Author: Ellen L. Goode, Andreas du Bois, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Joe Dennis, Celeste Leigh Pearce, Kristine G. Wicklund, Lynne R. Wilkens, Rosalind Glasspool, Diana Eccles, Susanne K. Kjaer, Roberta B. Ness, James Paul, Matthias Dürst, Camilla Krakstad, Irene Orlow, Rachel Palmieri Weber, Jonathan Tyrer, Valerie McGuire, Matthias W. Beckmann, Thomas A. Sellers, Elizabeth M. Poole, Ian G. Campbell, Arif B. Ekici, Steven A. Narod, Lotte Nedergaard, Shan Wang-Gohrke, Estrid Høgdall, Yurii B. Shvetsov, Douglas F. Easton, Sandrina Lambrechts, Linda E. Kelemen, Zhihua Chen, Karen Lu, Elisa V. Bandera, Qiyuan Li, Joellen M. Schildkraut, Agnieszka Dansonka-Mieszkowska, Liisa M. Pelttari, Kate Lawrenson, Sandra Orsulic, Ed Dicks, Kirsten B. Moysich, Melissa C. Southey, Christine Walsh, Louise A. Brinton, Argyrios Ziogas, Yukie Bean, Julie M. Cunningham, Patricia Harrington, Philipp Harter, Sara H. Olson, Keitaro Matsuo, Alvaro N.A. Monteiro, Claus Høgdall, Anne M. van Altena, Jenny Lester, Anna Jakubowska, Paul D.P. Pharoah, Lambertus A. Kiemeney, Yu-Tang Gao, Shelley S. Tworoger, Maria Bisogna, Michelle A.T. Hildebrandt, Yian Ann Chen, Iain A. McNeish, Allan Jensen, Diether Lambrechts, Usha Menon, Satoyo Hosono, Pamela J. Thompson, Yin Ling Woo, Jennifer Permuth-Wey, Francesmary Modugno, Matthew L. Freedman, Linda S. Cook, Harvey A. Risch, Ya-Yu Tsai, Marc T. Goodman, Dong Liang, Kathryn L. Terry, Soo Hwang Teo, Lara E. Sucheston-Campbell, Ira Schwaab, Robert A. Vierkant, Georgia Chenevix-Trench, Ralf Bützow, Siddhartha Kar, Wei Zheng, Nhu D. Le, Andrew Berchuck, Brooke L. Fridley, Edwin S. Iversen, Robert P. Edwards, Peter Hillemanns, Daniel W. Cramer, Mary Anne Rossing, Thilo Dörk, Malcolm C. Pike, Jolanta Kupryjanczyk, Anja Rudolph, Joseph H. Rothstein, Douglas A. Levine, Xiao-Ou Shu, Nicolas Wentzensen, Hannah P. Yang, Graham G. Giles, Hoda Anton-Culver, Line Bjørge, Peter A. Fasching, Catherine M. Phelan, Simon A. Gayther, Ignace Vergote, Alexander Hein, Cezary Cybulski, Ingvild L. Tangen, Els Van Nieuwenhuysen, Joseph L. Kelley, Honglin Song, Helen Baker, Alice S. Whittemore, Melissa Kellar, Kunle Odunsi, Bu Tian Ji, Heli Nevanlinna, Jolanta Lissowska, Shashi Lele, Barry P. Rosen, Katja K.H. Aben, Karen Carty, Leon F.A.G. Massuger, Iwona K. Rzepecka, Susan J. Ramus, Angela Brooks-Wilson, Xifeng Wu, Ingo B. Runnebaum, Lene Lundvall, Natalia Bogdanova, Helga B. Salvesen, Alice W. Lee, Jan Lubinski, Agnieszka Timorek, Nadeem Siddiqui, Anna H. Wu, Natalia Antonenkova, Weiva Sieh, Tanja Pejovic, John R. McLaughlin, Arto Leminen, Jennifer A. Doherty, Florian Heitz, Beth Y. Karlan, and Jacek Grownwald
Subjects: endocrine system diseases, Microarray, Epidemiology, Genome-wide association study, Global Health, Bioinformatics, Medical and Health Sciences, Risk Factors, 2.1 Biological and endogenous factors, Aetiology, Hox gene, Cancer, Ovarian Neoplasms, education.field_of_study, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Nuclear Proteins, DNA, Neoplasm, female genital diseases and pregnancy complications, Ovarian Cancer, Gene Expression Regulation, Neoplastic, Serous fluid, Oncology, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Biotechnology, Australian Ovarian Cancer Study Group, Genotype, Population, Cystadenocarcinoma, Single-nucleotide polymorphism, Computational biology, Biology, Article, Rare Diseases, Australian Cancer Study, Genetics, Humans, Genetic Predisposition to Disease, education, Gene, Genetic association, Neoplastic, Prevention, Human Genome, Serous, DNA, Cystadenocarcinoma, Serous, Gene Expression Regulation, Neoplasm, Morbidity, Transcription Factors, Genome-Wide Association Study
Abstract: Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. Cancer Epidemiol Biomarkers Prev; 24(10); 1574–84. ©2015 AACR.
Published: 2015

9. Genome-wide significant risk associations for mucinous ovarian carcinoma

Author: Jenny Lester, Arif B. Ekici, Xiao-Ou Shu, Georgia Chenevix-Trench, Julie M. Cunningham, Catherine M. Phelan, Tassja J. Spindler, Shelley S. Tworoger, Allan Jensen, Diana Eccles, Wei Zheng, Satoyo Hosono, Svend Aage Engelholm, Linda S. Cook, Thomas A. Sellers, John R. McLaughlin, Matthias W. Beckmann, Elizabeth M. Poole, Ignace Vergote, Francesmary Modugno, Jennifer A. Doherty, Sandrina Lambrechts, Lara Sucheston, Wang Gohrke Shan, Rosalind Glasspool, Barry P. Rosen, Pamela J. Thompson, Christine Walsh, Camilla Krakstad, Jennifer Permuth-Wey, Hoda Anton-Culver, Ralf Bützow, Ed Dicks, Yin Ling Woo, Honglin Song, Qiyuan Li, Leon F.A.G. Massuger, Yurii B. Shvetsov, Joellen M. Schildkraut, Xiaoqing Chen, Hannah P. Yang, Graham G. Giles, Sara H. Olson, Edwin S. Iversen, Claus Høgdall, Jacek Grownwald, Fiona Bruinsma, Peter Hillemanns, Iwona K. Rzepecka, Douglas T. Easton, Robert P. Edwards, Lynne R. Wilkens, Yukie Bean, Y. Ann Chen, Jonathan Tyrer, Tanja Pejovic, Patricia Harrington, Iain A. McNeish, Steven A. Narod, Joanna Moes-Sosnowska, Hanis Nazihah Hasmad, Ji-Heui Seo, Line Bjørge, Peter A. Fasching, Daniel W. Cramer, Florian Heitz, Beth Y. Karlan, Cezary Cybulski, Simon A. Gayther, Jolanta Kupryjanczyk, Nhu D. Le, Alexander Hein, Soo Hwang Teo, Nicolas Wentzensen, Valerie McGuire, Michelle A.T. Hildebrandt, Argyrios Ziogas, Heli Nevanlinna, Karen H. Lu, Diether Lambrechts, Kirsten B. Moysich, Jonathan Beesley, Kate Lawrenson, Ian G. Campbell, Andrew Berchuck, Philipp Harter, Lene Lundvall, Sandra Orsulic, Kathryn L. Terry, Jolanta Lissowska, Helen Baker, Matthew L. Freedman, Linda E. Kelemen, Maria Bisogna, Celeste Leigh Pearce, Ira Schwaab, Elisa V. Bandera, Kristine G. Wicklund, Arto Leminen, Nadeem Siddiqui, Joseph H. Rothstein, Melissa Kellar, Matthias Dürst, Harvey A. Risch, Włodzimierz Sawicki, Katja K.H. Aben, Alice S. Whittemore, Kunle Odunsi, Shashi Lele, Noor Azmi Mat Adenan, Susanne K. Kjaer, Robert A. Vierkant, Jan Lubinski, Natalia Bogdanova, Helga B. Salvesen, Anja Rudolph, Els Van Nieuwenhuysen, Irene Orlow, Joe Dennis, Ingvild L. Tangen, Estrid Høgdall, Alice W. Lee, Roberta B. Ness, James Paul, Malcolm C. Pike, Rachel Palmieri Weber, Anna H. Wu, Agnieszka Dansonka-Mieszkowska, Melissa C. Southey, Natalia Antonenkova, Anne M. van Altena, Xifeng Wu, Keitaro Matsuo, Anna Jakubowska, Paul D.P. Pharoah, Weiva Sieh, Lambertus A. Kiemeney, Lotte Nedergaard, Ursula Eilber, Janet M. Lee, Zhihua Chen, Andreas du Bois, Joseph L. Kelley, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Ellen L. Goode, Bu Tian Ji, Liisa M. Pelttari, Usha Menon, Dong Liang, Yu-Tang Gao, Brooke L. Fridley, Mary Anne Rossing, Thilo Dörk, Douglas A. Levine, Louise A. Brinton, Marc T. Goodman, Angela Brooks-Wilson, Ingo B. Runnebaum, Karen Carty, and Susan J. Ramus
Subjects: Green Fluorescent Proteins, Molecular Sequence Data, Quantitative Trait Loci, Single-nucleotide polymorphism, Genome-wide association study, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Cell Line, Tumor, Ovarian carcinoma, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic Association Studies, 030304 developmental biology, Genetic association, Cell Nucleus, Homeodomain Proteins, Ovarian Neoplasms, 0303 health sciences, Base Sequence, Reverse Transcriptase Polymerase Chain Reaction, medicine.disease, Adenocarcinoma, Mucinous, Neoplasm Proteins, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, Gene Expression Regulation, Neoplastic, Microscopy, Fluorescence, Chromosomes, Human, Pair 2, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Expression quantitative trait loci, Cancer research, Adenocarcinoma, Female, Ovarian cancer, Genome-Wide Association Study
Abstract: Genome-wide association studies have identified several risk associations for ovarian carcinomas (OC) but not for mucinous ovarian carcinomas (MOC). Genotypes from OC cases and controls were imputed into the 1000 Genomes Project reference panel. Analysis of 1,644 MOC cases and 21,693 controls identified three novel risk associations: rs752590 at 2q13 (P = 3.3 × 10−8), rs711830 at 2q31.1 (P = 7.5 × 10−12) and rs688187 at 19q13.2 (P = 6.8 × 10−13). Expression Quantitative Trait Locus (eQTL) analysis in ovarian and colorectal tumors (which are histologically similar to MOC) identified significant eQTL associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10−4, FDR = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors, and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.
Published: 2015

10. 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

11. Vitamin D receptor (VDR) polymorphisms and risk of ovarian cancer in Caucasian and African American women

Author: Cathrine Hoyo, Joellen M. Schildkraut, Edwin S. Iversen, Regina S. Whitaker, Delores J. Grant, Lucy Akushevich, Andrew Berchuck, and Jeffrey R. Marks
Subjects: Oncology, medicine.medical_specialty, Genotype, endocrine system diseases, Single-nucleotide polymorphism, Carcinoma, Ovarian Epithelial, Polymorphism, Single Nucleotide, Calcitriol receptor, White People, Article, Risk Factors, Internal medicine, Vitamin D and neurology, Humans, Medicine, Neoplasms, Glandular and Epithelial, Risk factor, Ovarian Neoplasms, Gynecology, business.industry, Case-control study, Obstetrics and Gynecology, Odds ratio, medicine.disease, Black or African American, Minor allele frequency, Logistic Models, Case-Control Studies, Receptors, Calcitriol, Female, business, Ovarian cancer
Abstract: Objective Polymorphisms in the vitamin D receptor (VDR) gene have been shown in some studies to be associated with the risk of epithelial ovarian cancer (EOC) in Caucasian women. There are no published reports among African Americans. Methods Case–control data from the North Carolina Ovarian Cancer Study were analyzed using logistic regression to determine the association between seven VDR polymorphisms and EOC in both Caucasians (513 cases, 532 controls) and African Americans (74 cases, 79 controls). In a larger sample of African–Americans (125 cases, 155 controls), we assessed associations between six SNPs in proximity of rs7975232. Results African American women who carried at least one minor allele of rs7975232 were at higher risk for invasive EOC controlling for age and admixture with an odds ratio (OR) for association under the log-additive model of 2.08 (95% confidence interval (CI)=1.19, 3.63, p=0.010). No association was observed between any of the VDR variants and EOC among Caucasians. A larger sample of African Americans revealed a nearly two-fold increased risk of invasive EOC associated with rs7305032, a SNP in proximity to rs7975232 (R 2 =0.369) with a log-additive OR of 1.87 (95% CI=1.20, 2.93, p=0.006). Conclusions This is the first report showing VDR variants associated with ovarian cancer risk in African American women. A larger study of African American women is needed to confirm these findings. These results imply that vitamin D exposure is a possible modifiable risk factor of ovarian cancer among African Americans.
Published: 2013

12. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

Author: Francesmary Modugno, Alice S. Whittemore, Kunle Odunsi, Heli Nevanlinna, Fiona Bruinsma, Iwona K. Rzepecka, Jolanta Lissowska, Malcolm C. Pike, Bu-Tian Ji, Michelle A.T. Hildebrandt, Warren Davis, Agnieszka Dansonka-Mieszkowska, Line Bjørge, Roberta B. Ness, James Paul, Katja K.H. Aben, Nonna Kolomeyevskaya, Melissa C. Southey, Bridget Kruszka, Daniel W. Cramer, Shashikant Lele, Edwin S. Iversen, Kristina Schmitt, Julie M. Cunningham, Xifeng Wu, Celeste Leigh Pearce, Keitaro Matsuo, Cezary Cybulski, Linda E. Kelemen, Kirsten B. Moysich, Kristine G. Wicklund, Ralf Bützow, Shelley S. Tworoger, Grace Friel, Robert P. Edwards, Agnieszka Timorek, Leah Preus, Anna Jakubowska, Paul D.P. Pharoah, Karen Lu, Lambertus A. Kiemeney, Allan Jensen, Elisa V. Bandera, Steven A. Narod, Soo-Hwang Teo, Susanne K. Kjaer, Jonathan Tyrer, Joseph H. Rothstein, Irene Orlow, Rachel Palmieri Weber, Janine M. Joseph, Anna M. van Altena, Mary Nesline, Rüdiger Klapdor, Hannah P. Yang, Graham G. Giles, Pamela J. Thompson, Christine Walsh, Jolanta Kupryjanczyk, Wei Zheng, Nicolas Wentzensen, Angela Brooks-Wilson, Arto Leminen, Philipp Harter, Nadeem Siddiqui, Joanna Moes-Sosnowska, Yin Ling Woo, Anja Rudolph, John R. McLaughlin, Louise A. Brinton, Ingo B. Runnebaum, Shalaka S. Hampras, Linda S. Cook, Lotte Nedergaard, Lara E. Sucheston-Campbell, Natalia Bogdanova, Alexander Hein, Joseph L. Kelley, Claus Høgdall, Matthias Dürst, Jennifer A. Doherty, Ignace Vergote, Argyrios Ziogas, Ian G. Campbell, Prashant Singh, Hoda Anton-Culver, Shan Wang-Gohrke, Helga B. Salvesen, Stefan Nickels, Ingvild L. Tangen, Joe Dennis, Georgia Chenevix-Trench, Eva S. Schernhammer, Paul K. Wallace, Leon F.A.G. Massuger, Lynne R. Wilkens, Ed Dicks, Yukie Bean, Alice W. Lee, Ian McNeish, Evelyn Despierre, Patricia Harrington, Kevin H. Eng, Maria Bisogna, Nhu D. Le, Sandrina Lambrechts, Andrew Berchuck, Honglin Song, Hanis Nazihah Hasmad, Nils Schoof, Diana Eccles, Harvey A. Risch, Xiao-Ou Shu, Rosalind Glasspool, Peter Hillemanns, Jenny Permuth-Wey, Chi-Chen Hong, Catherine M. Phelan, Marc T. Goodman, Peter A. Fasching, Matthias W. Beckmann, Helen Baker, Doug Easton, Robert A. Vierkant, Barbara Perkins, Lene Lundvall, Elizabeth M. Poole, Joanna Plisiecka-Halasa, Arif B. Ekici, Melissa Kellar, Jan Lubinski, Alyssa Clay, Diether Lambrechts, Jacek Gronwald, Keith L. Knutson, Karen Carty, Camilla Krakstad, Jenny Lester, Simon A. Gayther, Ya-Yu Tsai, Rikki Cannioto, Kathryn L. Terry, Ira Schwaab, Susan J. Ramus, Andreas du Bois, Thomas A. Sellers, Estrid Høgdall, Valeria McGuire, Yurii B. Shvetsov, Joellen M. Schildkraut, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Sara H. Olson, Ellen L. Goode, Song Liu, Usha Menon, Dong Liang, Tanja Pejovic, Yu-Tang Gao, Florian Heitz, Beth Y. Karlan, Brooke L. Fridley, Mary Anne Rossing, Thilo Dörk, Douglas A. Levine, Weiva Sieh, Liisa M. Pelttari, Anna H. Wu, Natalia Antonenkova, Satoyo Hosono, Dennis, Joe [0000-0003-4591-1214], Dicks, Ed [0000-0002-0617-0401], Easton, Douglas [0000-0003-2444-3247], Song, Honglin [0000-0001-5076-7371], Tyrer, Jonathan [0000-0003-3724-4757], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, endocrine system diseases, Carcinoma, Ovarian Epithelial, T-Lymphocytes, Regulatory, 0302 clinical medicine, STAGE, Gene Frequency, Risk Factors, Genotype, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, education.field_of_study, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], immunosuppression, Middle Aged, Protein-Serine-Threonine Kinases, female genital diseases and pregnancy complications, 3. Good health, TGFBR2, Gene Expression Regulation, Neoplastic, Serous fluid, ovarian cancer, Oncology, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Adenocarcinoma, Female, Life Sciences & Biomedicine, EXPRESSION, Adult, CARCINOMA, Population, chemical and pharmacologic phenomena, Single-nucleotide polymorphism, FCGR2B, Protein Serine-Threonine Kinases, PERIPHERAL-BLOOD, Biology, DENDRITIC CELLS, Polymorphism, Single Nucleotide, 03 medical and health sciences, LUNG-CANCER, medicine, BREAST-CANCER, Humans, Genetic Predisposition to Disease, REGULATORY T-CELLS, education, Aged, Science & Technology, RECEPTOR, Receptor, Transforming Growth Factor-beta Type II, biomarkers, Cell Biology, medicine.disease, 030104 developmental biology, FC-GAMMA-RIIB, Immunology, genetic variation, Cancer research, Ovarian cancer, Receptors, Transforming Growth Factor beta, Clear cell, Priority Research Paper, Adenocarcinoma, Clear Cell
Abstract: Contains fulltext : 167177.pdf (Publisher’s version ) (Open Access) BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with TGFBR2 (p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 (p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA (p = 0.035, endometrioid and mucinous), LGALS1 (p = 0.03, mucinous), STAT5B (p = 0.022, clear cell), TGFBR1 (p = 0.021 endometrioid) and TGFBR2 (p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.
Published: 2016

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

Author: Angela Brooks-Wilson, Estrid Høgdall, Usha Menon, Y. Ann Chen, Stacey J. Winham, Jan Lubinski, Aleksandra Gentry-Maharaj, Brooke L. Fridley, Dale P. Sandler, Jennifer A. Doherty, Mary Anne Rossing, Hoda Anton-Culver, Douglas A. Levine, Jennifer B. Permuth, Joellen M. Schildkraut, Jolanta Lissowska, Daniel W. Cramer, Pamela J. Thompson, Honglin Song, Ellen L. Goode, Tanja Pejovic, Brett M. Reid, Julie M. Cunningham, Toru Nakanishi, Beth Y. Karlan, Australian Cancer Study, Susan J. Ramus, Shelley S. Tworoger, Allan Jensen, Jacek Gronwald, Wei Zheng, Thomas A. Sellers, Alvaro N.A. Monteiro, Ailith Pirie, Peter Kraft, Michael E. Carney, Aimee A D'Aloisio, Simon A. Gayther, Andrew Berchuck, Jack A. Taylor, Keitaro Matsuo, Anna H. Wu, Penelope M. Webb, Anna Jakubowska, Paul D.P. Pharoah, Elizabeth M. Poole, Louise A. Brinton, Marc T. Goodman, Argyrios Ziogas, Kathryn L. Terry, Xiao-Ou Shu, Hannah P. Yang, S.K. Kjaer, Edwin S. Iversen, Robert P. Edwards, Nicolas Wentzensen, Celeste Leigh Pearce, Gustavo Mendoza-Fandiño, Soo-Hwang Teo, Hui-Yi Lin, Irene Orlow, Yin Ling Woo, Maria Bisogna, Cezary Cybulski, Roberta B. Ness, Linda E. Kelemen, Elisa V. Bandera, Georgia Chenevix-Trench, Linda S. Cook, Catherine M. Phelan, Rosemary Modugno, Madalene Earp, Joe Dennis, Zhihua Chen, Nhu D. Le, Kirsten B. Moysich, Sara H. Olson, and Lynne R. Wilkens
Subjects: 0301 basic medicine, Linkage disequilibrium, Genotype, Genome-wide association study, Biology, Carcinoma, Ovarian Epithelial, Polymorphism, Single Nucleotide, 03 medical and health sciences, Polymorphism (computer science), Genetics, medicine, Humans, Exome, Genetic Predisposition to Disease, Neoplasms, Glandular and Epithelial, Molecular Biology, Genotyping, Genetics (clinical), Ovarian Neoplasms, Biotinidase, Keratin-13, Association Studies Articles, Cancer, General Medicine, medicine.disease, Actins, Neoplasm Proteins, 030104 developmental biology, Human genome, Female, Receptor, Melanocortin, Type 2, Genome-Wide Association Study
Abstract: Rare and low frequency variants are not well covered in most germline genotyping arrays and are understudied in relation to epithelial ovarian cancer (EOC) risk. To address this gap, we used genotyping arrays targeting rarer protein-coding variation in 8,165 EOC cases and 11,619 controls from the international Ovarian Cancer Association Consortium (OCAC). Pooled association analyses were conducted at the variant and gene level for 98,543 variants directly genotyped through two exome genotyping projects. Only common variants that represent or are in strong linkage disequilibrium (LD) with previously-identified signals at established loci reached traditional thresholds for exome-wide significance (P ( )P≥5.0 ×10 (-) (7)) were detected for rare and low-frequency variants at 16 novel loci. Four rare missense variants were identified (ACTBL2 rs73757391 (5q11.2), BTD rs200337373 (3p25.1), KRT13 rs150321809 (17q21.2) and MC2R rs104894658 (18p11.21)), but only MC2R rs104894668 had a large effect size (OR = 9.66). Genes most strongly associated with EOC risk included ACTBL2 (PAML = 3.23 × 10 (-) (5); PSKAT-o = 9.23 × 10 (-) (4)) and KRT13 (PAML = 1.67 × 10 (-) (4); PSKAT-o = 1.07 × 10 (-) (5)), reaffirming variant-level analysis. In summary, this large study identified several rare and low-frequency variants and genes that may contribute to EOC susceptibility, albeit with possible small effects. Future studies that integrate epidemiology, sequencing, and functional assays are needed to further unravel the unexplained heritability and biology of this disease.
Published: 2016

14. 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

15. ABO blood group and risk of epithelial ovarian cancer within the Ovarian Cancer Association Consortium

Author: Ya-Yu Tsai, Kathryn L. Terry, Joellen M. Schildkraut, Julie M. Cunningham, Shelley S. Tworoger, Hannah P. Yang, Stephen J. Chanock, Jolanta Lissowska, Catherine M. Phelan, Ellen L. Goode, Daniel W. Cramer, Rebecca Sutphen, Rachel Palmieri Weber, Simon A. Gayther, Paul D.P. Pharoah, Brooke L. Fridley, Margaret A. Gates, Robert A. Vierkant, Brigit A. High, Elizabeth M. Poole, Jonathan Tyrer, Edwin S. Iversen, Nicolas Wentzensen, and Susan J. Ramus
Subjects: Oncology, congenital, hereditary, and neonatal diseases and abnormalities, Cancer Research, medicine.medical_specialty, Genotype, endocrine system diseases, Carcinoma, Ovarian Epithelial, Polymorphism, Single Nucleotide, White People, Article, ABO Blood-Group System, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, hemic and lymphatic diseases, Internal medicine, ABO blood group system, parasitic diseases, Epidemiology, medicine, Carcinoma, Humans, Genetic Predisposition to Disease, Neoplasms, Glandular and Epithelial, 030304 developmental biology, Ovarian Neoplasms, 0303 health sciences, Hematology, business.industry, Case-control study, medicine.disease, biological factors, 3. Good health, Genetic epidemiology, Case-Control Studies, 030220 oncology & carcinogenesis, Immunology, Female, Ovarian cancer, business, Cohort study
Abstract: Previous studies have examined the association between ABO blood group and ovarian cancer risk, with inconclusive results.In eight studies participating in the Ovarian Cancer Association Consortium, we determined ABO blood groups and diplotypes by genotyping 3 SNPs in the ABO locus. Odds ratios and 95 % confidence intervals were calculated in each study using logistic regression; individual study results were combined using random effects meta-analysis.Compared to blood group O, the A blood group was associated with a modestly increased ovarian cancer risk: (OR: 1.09; 95 % CI: 1.01-1.18; p = 0.03). In diplotype analysis, the AO, but not the AA diplotype, was associated with increased risk (AO: OR: 1.11; 95 % CI: 1.01-1.22; p = 0.03; AA: OR: 1.03; 95 % CI: 0.87-1.21; p = 0.76). Neither AB nor the B blood groups were associated with risk. Results were similar across ovarian cancer histologic subtypes.Consistent with most previous reports, the A blood type was associated modestly with increased ovarian cancer risk in this large analysis of multiple studies of ovarian cancer. Future studies investigating potential biologic mechanisms are warranted.
Published: 2012
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16. Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer

Author: Kate, Lawrenson, Edwin S, Iversen, Jonathan, Tyrer, Rachel Palmieri, Weber, Patrick, Concannon, Dennis J, Hazelett, Qiyuan, Li, Jeffrey R, Marks, Andrew, Berchuck, Janet M, Lee, Katja K H, Aben, Hoda, Anton-Culver, Natalia, Antonenkova, Elisa V, Bandera, Yukie, Bean, Matthias W, Beckmann, Maria, Bisogna, Line, Bjorge, Natalia, Bogdanova, Louise A, Brinton, Angela, Brooks-Wilson, Fiona, Bruinsma, Ralf, Butzow, Ian G, Campbell, Karen, Carty, Jenny, Chang-Claude, Georgia, Chenevix-Trench, Ann, Chen, Zhihua, Chen, Linda S, Cook, Daniel W, Cramer, Julie M, Cunningham, Cezary, Cybulski, Joanna, Plisiecka-Halasa, Joe, Dennis, Ed, Dicks, Jennifer A, Doherty, Thilo, Dörk, Andreas, du Bois, Diana, Eccles, Douglas T, Easton, Robert P, Edwards, Ursula, Eilber, Arif B, Ekici, Peter A, Fasching, Brooke L, Fridley, Yu-Tang, Gao, Aleksandra, Gentry-Maharaj, Graham G, Giles, Rosalind, Glasspool, Ellen L, Goode, Marc T, Goodman, Jacek, Gronwald, Philipp, Harter, Hanis Nazihah, Hasmad, Alexander, Hein, Florian, Heitz, Michelle A T, Hildebrandt, Peter, Hillemanns, Estrid, Hogdall, Claus, Hogdall, Satoyo, Hosono, Anna, Jakubowska, James, Paul, Allan, Jensen, Beth Y, Karlan, Susanne Kruger, Kjaer, Linda E, Kelemen, Melissa, Kellar, Joseph L, Kelley, Lambertus A, Kiemeney, Camilla, Krakstad, Diether, Lambrechts, Sandrina, Lambrechts, Nhu D, Le, Alice W, Lee, Rikki, Cannioto, Arto, Leminen, Jenny, Lester, Douglas A, Levine, Dong, Liang, Jolanta, Lissowska, Karen, Lu, Jan, Lubinski, Lene, Lundvall, Leon F A G, Massuger, Keitaro, Matsuo, Valerie, McGuire, John R, McLaughlin, Heli, Nevanlinna, Iain, McNeish, Usha, Menon, Francesmary, Modugno, Kirsten B, Moysich, Steven A, Narod, Lotte, Nedergaard, Roberta B, Ness, Mat Adenan, Noor Azmi, Kunle, Odunsi, Sara H, Olson, Irene, Orlow, Sandra, Orsulic, Celeste L, Pearce, Tanja, Pejovic, Liisa M, Pelttari, Jennifer, Permuth-Wey, Catherine M, Phelan, Malcolm C, Pike, Elizabeth M, Poole, Susan J, Ramus, Harvey A, Risch, Barry, Rosen, Mary Anne, Rossing, Joseph H, Rothstein, Anja, Rudolph, Ingo B, Runnebaum, Iwona K, Rzepecka, Helga B, Salvesen, Agnieszka, Budzilowska, Thomas A, Sellers, Xiao-Ou, Shu, Yurii B, Shvetsov, Nadeem, Siddiqui, Weiva, Sieh, Honglin, Song, Melissa C, Southey, Lara, Sucheston, Ingvild L, Tangen, Soo-Hwang, Teo, Kathryn L, Terry, Pamela J, Thompson, Agnieszka, Timorek, Shelley S, Tworoger, Els, Van Nieuwenhuysen, Ignace, Vergote, Robert A, Vierkant, Shan, Wang-Gohrke, Christine, Walsh, Nicolas, Wentzensen, Alice S, Whittemore, Kristine G, Wicklund, Lynne R, Wilkens, Yin-Ling, Woo, Xifeng, Wu, Anna H, Wu, Hannah, Yang, Wei, Zheng, Argyrios, Ziogas, Gerhard A, Coetzee, Matthew L, Freedman, Alvaro N A, Monteiro, Joanna, Moes-Sosnowska, Jolanta, Kupryjanczyk, Paul D, Pharoah, Simon A, Gayther, and Joellen M, Schildkraut
Subjects: Cancer Research, endocrine system diseases, Genome-wide association study, Carcinoma, Ovarian Epithelial, Risk Factors, Neoplasms, Ovarian Epithelial, 2.1 Biological and endogenous factors, Neoplasms, Glandular and Epithelial, Aetiology, skin and connective tissue diseases, Cancer, Genetics, Ovarian Neoplasms, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Glandular and Epithelial, General Medicine, Single Nucleotide, female genital diseases and pregnancy complications, Ovarian Cancer, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Biotechnology, Australian Ovarian Cancer Study Group, Quantitative Trait Loci, Oncology and Carcinogenesis, Locus (genetics), Single-nucleotide polymorphism, Original Manuscript, Biology, Polymorphism, Single Nucleotide, Rare Diseases, Clinical Research, Australian Cancer Study, SNP, Humans, Genetic Predisposition to Disease, Genetic Testing, Oncology & Carcinogenesis, 1000 Genomes Project, Polymorphism, CHEK2, Genetic association, Prevention, Carcinoma, Human Genome, Checkpoint Kinase 2, Genetic Loci, Case-Control Studies, Cancer research, Imputation (genetics), Genome-Wide Association Study
Abstract: Contains fulltext : 152042.pdf (Publisher’s version ) (Closed access) Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P
Published: 2015

17. Inherited Variants in Mitochondrial Biogenesis Genes May Influence Epithelial Ovarian Cancer Risk

Author: Ellen L. Goode, Xiaotao Qu, Jennifer Permuth-Wey, Harvey A. Risch, Steven A. Narod, Robert A. Vierkant, Johnathan M. Lancaster, Julie M. Cunningham, Thomas A. Sellers, Rebecca Sutphen, Joellen M. Schildkraut, Zhihua Chen, Brooke L. Fridley, Ya Yu Tsai, Catherine M. Phelan, John R. McLaughlin, Edwin S. Iversen, Heather G. Stockwell, Jill S. Barnholtz-Sloan, Y. Ann Chen, Getachew A. Dagne, and David Fenstermacher
Subjects: Mitochondrial DNA, Genotype, NF-E2-Related Factor 2, Epidemiology, Single-nucleotide polymorphism, Biology, Mitochondrion, Bioinformatics, DNA, Mitochondrial, Polymorphism, Single Nucleotide, Article, Mitochondrial Proteins, Risk Factors, Humans, NRF1, Heat-Shock Proteins, Ovarian Neoplasms, Genetics, Nuclear Respiratory Factor 1, Case-control study, Middle Aged, Adenocarcinoma, Mucinous, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Cystadenocarcinoma, Serous, Endometrial Neoplasms, Oxidative Stress, Basic-Leucine Zipper Transcription Factors, Genes, Mitochondrial, Receptors, Estrogen, Oncology, Mitochondrial biogenesis, Case-Control Studies, Female, PPARGC1A, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Steroid hormone metabolism, Adenocarcinoma, Clear Cell, Transcription Factors
Abstract: Background: Mitochondria contribute to oxidative stress, a phenomenon implicated in ovarian carcinogenesis. We hypothesized that inherited variants in mitochondrial-related genes influence epithelial ovarian cancer (EOC) susceptibility. Methods: Through a multicenter study of 1,815 Caucasian EOC cases and 1,900 controls, we investigated associations between EOC risk and 128 single nucleotide polymorphisms (SNPs) from 22 genes/regions within the mitochondrial genome (mtDNA) and 2,839 nuclear-encoded SNPs localized to 138 genes involved in mitochondrial biogenesis (BIO, n = 35), steroid hormone metabolism (HOR, n = 13), and oxidative phosphorylation (OXP, n = 90) pathways. Unconditional logistic regression was used to estimate OR and 95% CI between genotype and case status. Overall significance of each gene and pathway was evaluated by using Fisher's method to combine SNP-level evidence. At the SNP level, we investigated whether lifetime ovulation, hormone replacement therapy (HRT), and cigarette smoking were confounders or modifiers of associations. Results: Interindividual variation involving BIO was most strongly associated with EOC risk (empirical P = 0.050), especially for NRF1, MTERF, PPARGC1A, ESRRA, and CAMK2D. Several SNP-level associations strengthened after adjustment for nongenetic factors, particularly for MTERF. Statistical interactions with cigarette smoking and HRT use were observed with MTERF and CAMK2D SNPs, respectively. Overall variation within mtDNA, HOR, and OXP was not statistically significant (empirical P > 0.10). Conclusion: We provide novel evidence to suggest that variants in mitochondrial biogenesis genes may influence EOC susceptibility. Impact: A deeper understanding of the complex mechanisms implicated in mitochondrial biogenesis and oxidative stress may aid in developing strategies to reduce morbidity and mortality from EOC. Cancer Epidemiol Biomarkers Prev; 20(6); 1131–45. ©2011 AACR.
Published: 2011

18. Polymorphism in the GALNT1 Gene and Epithelial Ovarian Cancer in Non-Hispanic White Women: The Ovarian Cancer Association Consortium

Author: Jennifer A. Doherty, Galina Lurie, Ellen L. Goode, Daniel O. Stram, Roberta B. Ness, Valerie McGuire, Shan Wang-Gohrke, Claus Høgdall, David Van Den Berg, Jolanta Lissowska, Joellen M. Schildkraut, Edwin S. Iversen, Jan Blaakær, Brooke L. Fridley, Ya Yu Tsai, Robert P. Edwards, Stephen J. Chanock, Richard A. DiCioccio, Anna H. Wu, Mary Anne Rossing, Montserrat Garcia-Closas, Paul D.P. Pharoah, Lynne R. Wilkens, Julie M. Cunningham, David C. Whiteman, Michael E. Carney, Celeste Leigh Pearce, Lydia Quaye, Jenny Chang-Claude, Thomas A. Sellers, Jeffrey R. Marks, Rebecca Hein, Susanne K. Kjaer, Kirsten B. Moysich, Georgia Chenevix-Trench, Kathryn L. Terry, Hoda Anton-Culver, Alice S. Whittemore, Hannah P. Yang, Honglin Song, Susan J. Ramus, Catherine M. Phelan, Xiaoqing Chen, Penelope M. Webb, Simon A. Gayther, Ian Jacobs, Daniel W. Cramer, Estrid Høgdall, Malcolm C. Pike, Argyrios Ziogas, Marc T. Goodman, Jonathan Beesley, Adèle C. Green, Robert A. Vierkant, and Andrew Berchuck
Subjects: Oncology, medicine.medical_specialty, Epidemiology, European Continental Ancestry Group, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, White People, Internal medicine, Genotype, medicine, Humans, Genetic Predisposition to Disease, Neoplasms, Glandular and Epithelial, Genetic association, Ovarian Neoplasms, Case-control study, Cancer, Odds ratio, Middle Aged, medicine.disease, Endocrinology, Case-Control Studies, N-Acetylgalactosaminyltransferases, Population study, Female, Ovarian cancer
Abstract: Aberrant glycosylation is a well-described hallmark of cancer. In a previous ovarian cancer case control study that examined polymorphisms in 26 glycosylation-associated genes, we found strong statistical evidence (P = 0.00017) that women who inherited two copies of a single-nucleotide polymorphism in the UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferase, GALNT1, had decreased ovarian cancer risk. The current study attempted to replicate this observation. The GALNT1 single-nucleotide polymorphism rs17647532 was genotyped in 6,965 cases and 8,377 controls from 14 studies forming the Ovarian Cancer Association Consortium. The fixed effects estimate per rs17647532 allele was null (odds ratio, 0.99; 95% confidence interval, 0.92-1.07). When a recessive model was fit, the results were unchanged. Test for hetero geneity of the odds ratios revealed consistency across the 14 replication sites but significant differences compared with the original study population (P = 0.03). This study underscores the need for replication of putative findings in genetic association studies. Cancer Epidemiol Biomarkers Prev; 19(2); 600–4
Published: 2010

19. Variation at 8q24 and 9p24 and Risk of Epithelial Ovarian Cancer

Author: Sebastian M. Armasu, Andrew Berchuck, Kristin L. White, Mark Liebow, Joellen M. Schildkraut, Brooke L. Fridley, Ya Yu Tsai, Catherine M. Phelan, Melissa C. Larson, Julie M. Cunningham, Fergus J. Couch, Kimberly R. Kalli, Ellen L. Goode, David Duggan, Robert A. Vierkant, Thomas A. Sellers, Lynn C. Hartmann, Edwin S. Iversen, and Zachary S. Fredericksen
Subjects: Adult, Oncology, medicine.medical_specialty, Pathology, Genotype, Single-nucleotide polymorphism, Genome-wide association study, Biology, Article, Risk Factors, Prostate, Internal medicine, Genetic variation, medicine, Humans, Allele, Alleles, Genetics (clinical), Ovarian Neoplasms, Chi-Square Distribution, Case-control study, Genetic Variation, Obstetrics and Gynecology, Middle Aged, medicine.disease, Logistic Models, medicine.anatomical_structure, Case-Control Studies, Pediatrics, Perinatology and Child Health, Female, Chromosomes, Human, Pair 9, Ovarian cancer, Chromosomes, Human, Pair 8, Genome-Wide Association Study
Abstract: The chromosome 8q24 region (specifically, 8q24.21.a) is known to harbor variants associated with risk of breast, colorectal, prostate, and bladder cancers. In 2008, variants rs10505477 and rs6983267 in this region were associated with increased risk of invasive ovarian cancer (p < 0.01); however, three subsequent ovarian cancer reports of 8q24 variants were null. Here, we used a multi-site case-control study of 940 ovarian cancer cases and 1,041 controls to evaluate associations between these and other single-nucleotide polymorphisms (SNPs) in this 8q24 region, as well as in the 9p24 colorectal cancer associated-region (specifically, 9p24.1.b). A total of 35 SNPs from previous reports and additional tagging SNPs were assessed using an Illumina GoldenGate array and analyzed using logistic regression models, adjusting for population structure and other potential confounders. We observed no association between genotypes and risk of ovarian cancer considering all cases, invasive cases, or invasive serous cases. For example, at 8q24 SNPs rs10505477 and rs6983267, analyses yielded per-allele invasive cancer odds ratios of 0.95 (95% confidence interval (CI) 0.82–1.09, p trend 0.46) and 0.97 (95% CI 0.84–1.12, p trend 0.69), respectively. Analyses using an approach identical to that of the first positive 8q24 report also yielded no association with risk of ovarian cancer. In the 9p24 region, no SNPs were associated with risk of ovarian cancer overall or with invasive or invasive serous disease (all p values > 0.10). These results indicate that the SNPs studied here are not related to risk of this gynecologic malignancy and that the site-specific nature of 8q24.21.a associations may not include ovarian cancer.
Published: 2010

20. Association of Single Nucleotide Polymorphisms in Glycosylation Genes with Risk of Epithelial Ovarian Cancer

Author: Ellen L. Goode, Lynn C. Hartmann, Catherine M. Phelan, Mark Liebow, Rebecca Sutphen, V. Shane Pankratz, Julie M. Cunningham, Jeff Myer, Joellen M. Schildkraut, Thomas A. Sellers, Edwin S. Iversen, Yifan Huang, Zachary S. Fredericksen, Linda E. Kelemen, and Robert A. Vierkant
Subjects: Oncology, medicine.medical_specialty, Glycosylation, Genotype, Epidemiology, Minnesota, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, Risk Factors, Internal medicine, Genetic model, North Carolina, medicine, Humans, Risk factor, Ovarian Neoplasms, Genetics, Analysis of Variance, Chi-Square Distribution, Mucin-1, Haplotype, Cancer, Odds ratio, Middle Aged, medicine.disease, Minor allele frequency, Logistic Models, Haplotypes, Case-Control Studies, Female
Abstract: Studies suggest that underglycosylation of the cell membrane mucin MUC1 may be associated with epithelial ovarian cancer. We identified 26 genes involved in glycosylation and examined 93 single nucleotide polymorphisms (SNP) with a minor allele frequency of ≥0.05 in relation to incident ovarian cancer. Cases were ascertained at the Mayo Clinic, Rochester, MN (n = 396) or a 48-county region in North Carolina (Duke University; n = 534). Ovarian cancer–free controls (n = 1,037) were frequency matched to the cases on age, race, and residence. Subjects were interviewed to obtain data on risk factors and a sample of blood for DNA and genotyped using the Illumina GoldenGate assay. We excluded subjects and individual SNPs with genotype call rates of
Published: 2008

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

Author: S.K. Kjaer, Estrid Høgdall, Joellen M. Schildkraut, Susan J. Ramus, Claus Høgdall, Jonathan Tyrer, Adèle C. Green, Georgia Chenevix-Trench, Penelope M. Webb, Douglas F. Easton, Robert P. Edwards, Julie M. Cunningham, Anna H. Wu, Francesmary Modugno, Beata Peplonska, Ian Jacobs, Bruce A.J. Ponder, Richard A. DiCioccio, Danielle Shadforth, Valerie McGuire, Ellen L. Goode, Thomas A. Sellers, Lydia Quaye, Montserrat Garcia-Closas, Louise A. Brinton, Alice S. Whittemore, David C. Whiteman, C. Leigh Pearce, Malcolm C. Pike, Andrew Berchuck, Paul D.P. Pharoah, Marc T. Goodman, Galina Lurie, Edwin S. Iversen, Honglin Song, Jonathan Beesley, Fergus J. Couch, Simon A. Gayther, Jan Blaeker, Roberta B. Ness, Jeffrey R. Marks, Jolanta Lissowska, Kirsten B. Moysich, and Michael E. Carney
Subjects: Cancer Research, Cell Cycle Proteins, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, CDKN2A, Cyclins, medicine, Humans, SNP, Genetic Predisposition to Disease, Risk factor, Genetic association, Ovarian Neoplasms, Genetics, Cell Cycle, medicine.disease, Cyclin-Dependent Kinases, Genotype frequency, Genes, cdc, Minor allele frequency, Oncology, Case-Control Studies, Female, Ovarian cancer
Abstract: High-risk susceptibility genes explain
Published: 2007

22. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

Author: Rosalind Glasspool, Lynne R. Wilkens, Camilla Krakstad, Diana Eccles, Liisa M. Pelttari, Thomas A. Sellers, Anja Rudolph, Estrid Høgdall, Yurii B. Shvetsov, Matthias W. Beckmann, Ignace Vergote, Angela Brooks-Wilson, Ingo B. Runnebaum, Joellen M. Schildkraut, Joe Dennis, Ingvild L. Tangen, Elizabeth M. Poole, Arif B. Ekici, Xiao-Ou Shu, Alice S. Whittemore, Valerie McGuire, Kunle Odunsi, Agnieszka Dansonka-Mieszkowska, Melissa C. Southey, Keitaro Matsuo, Anna Jakubowska, Paul D.P. Pharoah, Lambertus A. Kiemeney, Douglas T. Easton, Simon A. Gayther, Anna deFazio, Ian G. Campbell, Hanis Nazihah Hasmad, Shashi Lele, Maria Bisogna, Zhihua Chen, Usha Menon, Jenny Lester, Ursula Eilber, Iwona K. Rzepecka, Shan Wang-Gohrke, Steven A. Narod, Qiyuan Li, Dong Liang, Jonathan Tyrer, Kate Lawrenson, Hoda Anton-Culver, Alvaro N.A. Monteiro, Ed Dicks, Lene Lundvall, Sandra Orsulic, Brooke L. Fridley, Ellen L. Goode, Linda E. Kelemen, Edwin S. Iversen, Ya Yu Tsai, Mary Anne Rossing, Karen Carty, Thilo Dörk, Penelope M. Webb, Yukie Bean, Matthias Dürst, Soo Hwang Teo, Claus Høgdall, Robert P. Edwards, Alison M. Karst, Yu-Tang Gao, Harvey A. Risch, Patricia Harrington, Daniel W. Cramer, Ji-Heui Seo, Douglas A. Levine, Christine Walsh, Karen Lu, Elisa V. Bandera, Louise A. Brinton, Satoyo Hosono, Hannah P. Yang, Graham G. Giles, Robert A. Vierkant, Argyrios Ziogas, Honglin Song, Ian McNeish, Anne M. van Altena, Tanja Pejovic, Florian Heitz, Beth Y. Karlan, Kirsten B. Moysich, Philipp Harter, Joseph L. Kelley, Andrew Berchuck, Paul A. James, Peter Hillemanns, Susan J. Ramus, Jacek Grownwald, Celeste Leigh Pearce, Ronny Drapkin, Kristine G. Wicklund, Mat Adenan Noor Azmi, Lara Sucheston, Alexander Hein, Jolanta Kupryjanczyk, Ralf Bützow, Georgia Chenevix-Trench, Michelle A.T. Hildebrandt, Francesmary Modugno, John R. McLaughlin, Arto Leminen, Nicolas Wentzensen, Siddhartha Kar, Sara H. Olson, Susanne K. Kjaer, Barry P. Rosen, Andreas du Bois, Linda S. Cook, Jennifer A. Doherty, Joseph H. Rothstein, Aleksandra Gentry-Maharaj, Julie M. Cunningham, Leon F.A.G. Massuger, Irene Orlow, Rachel Palmieri Weber, Pamela J. Thompson, Tassja J. Spindler, Jenny Chang-Claude, Jennifer Permuth-Wey, Catherine M. Phelan, Yi-Bu Chen, Bu Tian Ji, Heli Nevanlinna, Roberta B. Ness, Shelley S. Tworoger, Allan Jensen, Anna H. Wu, Malcolm C. Pike, Fiona Bruinsma, Line Bjørge, Jolanta Lissowska, Natalia Antonenkova, Cezary Cybulski, Wei Zheng, Lotte Nedergaard, Els Van Nieuwenhuysen, Anne Chen, Janet M. Lee, David D.L. Bowtell, Helen Baker, Katja K.H. Aben, Xifeng Wu, Melissa Kellar, Weiva Sieh, Nhu D. Le, Marc T. Goodman, Matthew L. Freedman, Yin Ling Woo, Sandrina Lambrechts, Peter A. Fasching, Diether Lambrechts, Kathryn L. Terry, Ira Schwaab, Jan Lubinski, Natalia Bogdanova, Helga B. Salvesen, Alice W. Lee, Agnieszka Timorek, Nadeem Siddiqui, Department of Pathology, Medicum, Department of Obstetrics and Gynecology, Clinicum, and HUS Gynecology and Obstetrics
Subjects: EXPRESSION, Quantitative Trait Loci, General Physics and Astronomy, Locus (genetics), Genome-wide association study, Quantitative trait locus, Biology, Carcinoma, Ovarian Epithelial, VARIANTS, ANALYSES REVEAL, BREAST, General Biochemistry, Genetics and Molecular Biology, Article, Nuchal Cord, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, 3123 Gynaecology and paediatrics, Cell Line, Tumor, Genetic predisposition, SNP, Humans, Genetic Predisposition to Disease, Neoplasms, Glandular and Epithelial, GENOME-WIDE ASSOCIATION, Genetic Association Studies, 030304 developmental biology, Genetic association, Genetics, Homeodomain Proteins, Ovarian Neoplasms, 0303 health sciences, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Multidisciplinary, LONG-RANGE INTERACTION, IDENTIFICATION, General Chemistry, RISK LOCI, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, FALLOPIAN-TUBE, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Expression quantitative trait loci, Female, 3111 Biomedicine, HOX GENES, Protein Binding
Abstract: Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10−5). For three cis-eQTL associations (P, Genome-wide association studies have identified regions which confer risk of high-grade serous epithelial ovarian cancer. Here the authors use expression quantitative train locus analysis to identify candidate genes and functionally characterise them, identifying a role for HOXD9 in ovarian cancer.
Published: 2015

23. A Cross-Cancer Genetic Association Analysis of the DNA Repair and DNA Damage Signaling Pathways for Lung, Ovary, Prostate, Breast, and Colorectal Cancer

Author: Rachel Palmieri Weber, Paul D.P. Pharoah, Zsofia Kote-Jarai, John S. Witte, Peter M. Scarbrough, Judy Garber, Stephen B. Gruber, Doug Easton, Jennifer A. Doherty, Thomas A. Sellers, Rayjean J. Hung, Yonathan Brhane, Peter Kraft, Christopher I. Amos, Joellen M. Schildkraut, Ros Eeles, Kevin McDonnell, Amit Joshi, Kenneth Muir, David J. Hunter, Brian E. Henderson, and Edwin S. Iversen
Subjects: 0301 basic medicine, Male, Aging, Lung Neoplasms, DNA Repair, Epidemiology, Cell Cycle Proteins, medicine.disease_cause, Medical and Health Sciences, Risk Factors, 2.1 Biological and endogenous factors, Aetiology, Cancer, Genetics, Ovarian Neoplasms, Tumor, Single Nucleotide, Base excision repair, BRCA2 Protein, Colo-Rectal Cancer, DNA-Binding Proteins, Oncology, DNA mismatch repair, Female, Colorectal Neoplasms, Signal Transduction, DNA damage, DNA repair, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Breast Cancer, medicine, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, Genetic Testing, Polymorphism, Prevention, Human Genome, Prostatic Neoplasms, medicine.disease, 030104 developmental biology, Digestive Diseases, Carcinogenesis, Biomarkers, Nucleotide excision repair, DNA Damage
Abstract: Background: DNA damage is an established mediator of carcinogenesis, although genome-wide association studies (GWAS) have identified few significant loci. This cross-cancer site, pooled analysis was performed to increase the power to detect common variants of DNA repair genes associated with cancer susceptibility. Methods: We conducted a cross-cancer analysis of 60,297 single nucleotide polymorphisms, at 229 DNA repair gene regions, using data from the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) Network. Our analysis included data from 32 GWAS and 48,734 controls and 51,537 cases across five cancer sites (breast, colon, lung, ovary, and prostate). Because of the unavailability of individual data, data were analyzed at the aggregate level. Meta-analysis was performed using the Association analysis for SubSETs (ASSET) software. To test for genetic associations that might escape individual variant testing due to small effect sizes, pathway analysis of eight DNA repair pathways was performed using hierarchical modeling. Results: We identified three susceptibility DNA repair genes, RAD51B (P < 5.09 × 10−6), MSH5 (P < 5.09 × 10−6), and BRCA2 (P = 5.70 × 10−6). Hierarchical modeling identified several pleiotropic associations with cancer risk in the base excision repair, nucleotide excision repair, mismatch repair, and homologous recombination pathways. Conclusions: Only three susceptibility loci were identified, which had all been previously reported. In contrast, hierarchical modeling identified several pleiotropic cancer risk associations in key DNA repair pathways. Impact: Results suggest that many common variants in DNA repair genes are likely associated with cancer susceptibility through small effect sizes that do not meet stringent significance testing criteria. Cancer Epidemiol Biomarkers Prev; 25(1); 193–200. ©2015 AACR.
Published: 2015

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

Author: Anna H. Wu, Joellen M. Schildkraut, Daniel O. Stram, Roberta B. Ness, Robert P. Edwards, Marc T. Goodman, Celeste Leigh Pearce, Alice S. Whittemore, Rachel Palmieri Weber, Pamela J. Thompson, Andrew Berchuck, Julie M. Cunningham, Mary Anne Rossing, Thomas A. Sellers, Weiva Sieh, Shelley S. Tworoger, Jennifer A. Doherty, Daniel W. Cramer, Elisa V. Bandera, Galina Lurie, Francesmary Modugno, Nicolas Wentzensen, Merlise A. Clyde, Harvey A. Risch, Kathryn L. Terry, Kristine G. Wicklund, Robert A. Vierkant, Hoda Anton-Culver, Michael E. Carney, Ellen L. Goode, Kara L. Cushing-Haugen, Edwin S. Iversen, Elizabeth M. Poole, Brooke L. Fridley, Valerie McGuire, Sara H. Olson, Malcolm C. Pike, Argyrios Ziogas, Joseph H. Rothstein, and Kirsten B. Moysich
Subjects: Oncology, Adult, medicine.medical_specialty, Epidemiology, Original Contributions, Single-nucleotide polymorphism, Carcinoma, Ovarian Epithelial, Logistic regression, Polymorphism, Single Nucleotide, Risk Assessment, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, 030212 general & internal medicine, Neoplasms, Glandular and Epithelial, Aged, Ovarian Neoplasms, Receiver operating characteristic, business.industry, Absolute risk reduction, Case-control study, Middle Aged, Missing data, United States, Logistic Models, Genetic Loci, 030220 oncology & carcinogenesis, Relative risk, Area Under Curve, Case-Control Studies, Female, Erratum, Risk assessment, business
Abstract: Previously developed models for predicting absolute risk of invasive epithelial ovarian cancer have included a limited number of risk factors and have had low discriminatory power (area under the receiver operating characteristic curve (AUC) < 0.60). Because of this, we developed and internally validated a relative risk prediction model that incorporates 17 established epidemiologic risk factors and 17 genome-wide significant single nucleotide polymorphisms (SNPs) using data from 11 case-control studies in the United States (5,793 cases; 9,512 controls) from the Ovarian Cancer Association Consortium (data accrued from 1992 to 2010). We developed a hierarchical logistic regression model for predicting case-control status that included imputation of missing data. We randomly divided the data into an 80% training sample and used the remaining 20% for model evaluation. The AUC for the full model was 0.664. A reduced model without SNPs performed similarly (AUC = 0.649). Both models performed better than a baseline model that included age and study site only (AUC = 0.563). The best predictive power was obtained in the full model among women younger than 50 years of age (AUC = 0.714); however, the addition of SNPs increased the AUC the most for women older than 50 years of age (AUC = 0.638 vs. 0.616). Adapting this improved model to estimate absolute risk and evaluating it in prospective data sets is warranted.
Published: 2015

25. Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk

Author: Ernest K, Amankwah, Hui-Yi, Lin, Jonathan P, Tyrer, Kate, Lawrenson, Joe, Dennis, Ganna, Chornokur, Katja K H, Aben, Hoda, Anton-Culver, Natalia, Antonenkova, Fiona, Bruinsma, Elisa V, Bandera, Yukie T, Bean, Matthias W, Beckmann, Maria, Bisogna, Line, Bjorge, Natalia, Bogdanova, Louise A, Brinton, Angela, Brooks-Wilson, Clareann H, Bunker, Ralf, Butzow, Ian G, Campbell, Karen, Carty, Zhihua, Chen, Y Ann, Chen, Jenny, Chang-Claude, Linda S, Cook, Daniel W, Cramer, Julie M, Cunningham, Cezary, Cybulski, Agnieszka, Dansonka-Mieszkowska, Andreas, du Bois, Evelyn, Despierre, Ed, Dicks, Jennifer A, Doherty, Thilo, Dörk, Matthias, Dürst, Douglas F, Easton, Diana M, Eccles, Robert P, Edwards, Arif B, Ekici, Peter A, Fasching, Brooke L, Fridley, Yu-Tang, Gao, Aleksandra, Gentry-Maharaj, Graham G, Giles, Rosalind, Glasspool, Marc T, Goodman, Jacek, Gronwald, Patricia, Harrington, Philipp, Harter, Hanis N, Hasmad, Alexander, Hein, Florian, Heitz, Michelle A T, Hildebrandt, Peter, Hillemanns, Claus K, Hogdall, Estrid, Hogdall, Satoyo, Hosono, Edwin S, Iversen, Anna, Jakubowska, Allan, Jensen, Bu-Tian, Ji, Beth Y, Karlan, Heather, Jim, Melissa, Kellar, Lambertus A, Kiemeney, Camilla, Krakstad, Susanne K, Kjaer, Jolanta, Kupryjanczyk, Diether, Lambrechts, Sandrina, Lambrechts, Nhu D, Le, Alice W, Lee, Shashi, Lele, Arto, Leminen, Jenny, Lester, Douglas A, Levine, Dong, Liang, Boon Kiong, Lim, Jolanta, Lissowska, Karen, Lu, Jan, Lubinski, Lene, Lundvall, Leon F A G, Massuger, Keitaro, Matsuo, Valerie, McGuire, John R, McLaughlin, Ian, McNeish, Usha, Menon, Roger L, Milne, Francesmary, Modugno, Kirsten B, Moysich, Roberta B, Ness, Heli, Nevanlinna, Ursula, Eilber, Kunle, Odunsi, Sara H, Olson, Irene, Orlow, Sandra, Orsulic, Rachel Palmieri, Weber, James, Paul, Celeste L, Pearce, Tanja, Pejovic, Liisa M, Pelttari, Jennifer, Permuth-Wey, Malcolm C, Pike, Elizabeth M, Poole, Harvey A, Risch, Barry, Rosen, Mary Anne, Rossing, Joseph H, Rothstein, Anja, Rudolph, Ingo B, Runnebaum, Iwona K, Rzepecka, Helga B, Salvesen, Eva, Schernhammer, Ira, Schwaab, Xiao-Ou, Shu, Yurii B, Shvetsov, Nadeem, Siddiqui, Weiva, Sieh, Honglin, Song, Melissa C, Southey, Beata, Spiewankiewicz, Lara, Sucheston-Campbell, Soo-Hwang, Teo, Kathryn L, Terry, Pamela J, Thompson, Lotte, Thomsen, Ingvild L, Tangen, Shelley S, Tworoger, Anne M, van Altena, Robert A, Vierkant, Ignace, Vergote, Christine S, Walsh, Shan, Wang-Gohrke, Nicolas, Wentzensen, Alice S, Whittemore, Kristine G, Wicklund, Lynne R, Wilkens, Anna H, Wu, Xifeng, Wu, Yin-Ling, Woo, Hannah, Yang, Wei, Zheng, Argyrios, Ziogas, Linda E, Kelemen, Andrew, Berchuck, Joellen M, Schildkraut, Susan J, Ramus, Ellen L, Goode, Alvaro N A, Monteiro, Simon A, Gayther, Steven A, Narod, Paul D P, Pharoah, Thomas A, Sellers, and Catherine M, Phelan
Subjects: Adult, Ovarian Neoplasms, Risk, Epithelial-Mesenchymal Transition, Genotype, Carcinoma, Ovarian Epithelial, Middle Aged, Polymorphism, Single Nucleotide, White People, Article, Odds Ratio, Humans, Female, Genetic Predisposition to Disease, Neoplasms, Glandular and Epithelial, Aged, Genome-Wide Association Study
Abstract: Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value0.05 and a false discovery rate (FDR)0.2 were considered statistically significant. In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (odds ratio (OR) = 1.16, 95% CI = 1.07-1.25, P = 0.0003, FDR = 0.19), whereas F8 rs7053448 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), F8 rs7058826 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), and CAPN13 rs1983383 (OR = 0.79, 95% CI = 0.69-0.90, P = 0.0005, FDR = 0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC.
Published: 2015

26. Evaluating the ovarian cancer gonadotropin hypothesis: a candidate gene study

Author: Linda E. Kelemen, Argyrios Ziogas, Celeste Leigh Pearce, Karen Lu, Agnieszka Dansonka-Mieszkowska, Melissa C. Southey, Elisa V. Bandera, Hoda Anton-Culver, Nadeem Siddiqui, Kristine G. Wicklund, Hannah P. Yang, Graham G. Giles, Georgia Chenevix-Trench, Anna Jakubowska, Paul D.P. Pharoah, Susanne K. Kjaer, Jonathan Tyrer, Catherine M. Phelan, Honglin Song, Lambertus A. Kiemeney, John R. McLaughlin, Arto Leminen, Jennifer A. Doherty, Irene Orlow, Natalia Bogdanova, Helga B. Salvesen, Lara E. Sucheston-Campbell, Liisa M. Pelttari, Alexander Hein, Jenny Lester, Lynne R. Wilkens, Alice W. Lee, Valerie McGuire, Yukie Bean, Julie M. Cunningham, Diana Eccles, Rosalind Glasspool, Patricia Harrington, Shelley S. Tworoger, Joseph H. Rothstein, Allan Jensen, Rachel Palmieri Weber, Ian G. Campbell, Nhu D. Le, Matthias W. Beckmann, Marc T. Goodman, Sandra Orsulic, Shan Wang-Gohrke, Elizabeth M. Poole, Usha Menon, Harvey A. Risch, Anja Rudolph, Tanja Pejovic, Lotte Nedergaard, Dong Liang, Jan Lubinski, Els Van Nieuwenhuysen, Arif B. Ekici, Camilla Krakstad, Ignace Vergote, Robert A. Vierkant, Ingvild L. Tangen, Ursula Eilber, Florian Heitz, Beth Y. Karlan, Diether Lambrechts, Brooke L. Fridley, Malcolm C. Pike, Anne M. van Altena, Alice S. Whittemore, Estrid Høgdall, Kunle Odunsi, Mary Anne Rossing, Thilo Dörk, Douglas A. Levine, Yurii B. Shvetsov, Joellen M. Schildkraut, Daniel O. Stram, Francesmary Modugno, Melissa Kellar, Christine Walsh, Roberta B. Ness, James Paul, Line Bjørge, Edwin S. Iversen, Robert P. Edwards, Louise A. Brinton, Joanna Plisiecka-Halasa, Anna H. Wu, Linda S. Cook, Joseph L. Kelley, Jolanta Kupryjanczyk, Nicolas Wentzensen, Matthias Dürst, Andreas du Bois, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Cezary Cybulski, Douglas A. Stram, Michelle A.T. Hildebrandt, Weiva Sieh, Kathryn L. Terry, Ira Schwaab, Sara H. Olson, Iain A. McNeish, Ellen L. Goode, Heli Nevanlinna, Maria Bisogna, Jolanta Lissowska, Katja K.H. Aben, Leon F.A.G. Massuger, Beata Spiewankiewicz, Peter A. Fasching, Fiona Bruinsma, Claus Høgdall, Kirsten B. Moysich, Philipp Harter, Jacek Gronwald, Xifeng Wu, Lene Lundvall, Andrew Berchuck, Peter Hillemanns, Pamela J. Thompson, Karen Carty, Susan J. Ramus, Emily Myers, Angela Brooks-Wilson, Ingo B. Runnebaum, and Daniel W. Cramer
Subjects: Candidate gene, Aging, Genome-wide association study, Bioinformatics, Gene, FSHB, Risk Factors, Genotype, 2.1 Biological and endogenous factors, Aetiology, Cancer, Genetics, Ovarian Neoplasms, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Tumor, Obstetrics and Gynecology, Single Nucleotide, 3. Good health, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Oncology, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Signal Transduction, Biotechnology, Australian Ovarian Cancer Study Group, Genetic Markers, endocrine system, Oncology and Carcinogenesis, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, Paediatrics and Reproductive Medicine, Rare Diseases, Ovarian cancer, Australian Cancer Study, medicine, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, Genetic variation, Oncology & Carcinogenesis, Polymorphism, Prevention, Human Genome, Case-control study, medicine.disease, INHBB, Logistic Models, Case-Control Studies, Polymorphisms, Gonadotropins, Biomarkers, Genome-Wide Association Study
Abstract: Contains fulltext : 155211.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted. METHODS: Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations. RESULTS: We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p=0.045, mucinous), LHCGR (p=0.046, high-grade serous), GNRH (p=0.041, high-grade serous), and FSHB (p=0.036, overall invasive). There was also suggestive evidence for INHA (p=0.060, overall invasive). CONCLUSIONS: Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available.
Published: 2015

27. Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk

Author: Ganna Chornokur, Hui-Yi Lin, Jonathan P Tyrer, Kate Lawrenson, Joe Dennis, Ernest K Amankwah, Xiaotao Qu, Ya-Yu Tsai, Heather S L Jim, Zhihua Chen, Ann Y Chen, Jennifer Permuth-Wey, Katja K H Aben, Hoda Anton-Culver, Natalia Antonenkova, Fiona Bruinsma, Elisa V Bandera, Yukie T Bean, Matthias W Beckmann, Maria Bisogna, Line Bjorge, Natalia Bogdanova, Louise A Brinton, Angela Brooks-Wilson, Clareann H Bunker, Ralf Butzow, Ian G Campbell, Karen Carty, Jenny Chang-Claude, Linda S Cook, Daniel W Cramer, Julie M Cunningham, Cezary Cybulski, Agnieszka Dansonka-Mieszkowska, Andreas du Bois, Evelyn Despierre, Ed Dicks, Jennifer A Doherty, Thilo Dörk, Matthias Dürst, Douglas F Easton, Diana M Eccles, Robert P Edwards, Arif B Ekici, Peter A Fasching, Brooke L Fridley, Yu-Tang Gao, Aleksandra Gentry-Maharaj, Graham G Giles, Rosalind Glasspool, Marc T Goodman, Jacek Gronwald, Patricia Harrington, Philipp Harter, Alexander Hein, Florian Heitz, Michelle A T Hildebrandt, Peter Hillemanns, Claus K Hogdall, Estrid Hogdall, Satoyo Hosono, Anna Jakubowska, Allan Jensen, Bu-Tian Ji, Beth Y Karlan, Linda E Kelemen, Mellissa Kellar, Lambertus A Kiemeney, Camilla Krakstad, Susanne K Kjaer, Jolanta Kupryjanczyk, Diether Lambrechts, Sandrina Lambrechts, Nhu D Le, Alice W Lee, Shashi Lele, Arto Leminen, Jenny Lester, Douglas A Levine, Dong Liang, Boon Kiong Lim, Jolanta Lissowska, Karen Lu, Jan Lubinski, Lene Lundvall, Leon F A G Massuger, Keitaro Matsuo, Valerie McGuire, John R McLaughlin, Iain McNeish, Usha Menon, Roger L Milne, Francesmary Modugno, Kirsten B Moysich, Roberta B Ness, Heli Nevanlinna, Ursula Eilber, Kunle Odunsi, Sara H Olson, Irene Orlow, Sandra Orsulic, Rachel Palmieri Weber, James Paul, Celeste L Pearce, Tanja Pejovic, Liisa M Pelttari, Malcolm C Pike, Elizabeth M Poole, Harvey A Risch, Barry Rosen, Mary Anne Rossing, Joseph H Rothstein, Anja Rudolph, Ingo B Runnebaum, Iwona K Rzepecka, Helga B Salvesen, Eva Schernhammer, Ira Schwaab, Xiao-Ou Shu, Yurii B Shvetsov, Nadeem Siddiqui, Weiva Sieh, Honglin Song, Melissa C Southey, Beata Spiewankiewicz, Lara Sucheston, Soo-Hwang Teo, Kathryn L Terry, Pamela J Thompson, Lotte Thomsen, Ingvild L Tangen, Shelley S Tworoger, Anne M van Altena, Robert A Vierkant, Ignace Vergote, Christine S Walsh, Shan Wang-Gohrke, Nicolas Wentzensen, Alice S Whittemore, Kristine G Wicklund, Lynne R Wilkens, Anna H Wu, Xifeng Wu, Yin-Ling Woo, Hannah Yang, Wei Zheng, Argyrios Ziogas, Hanis N Hasmad, Andrew Berchuck, Georgia Chenevix-Trench, AOCS management group, Edwin S Iversen, Joellen M Schildkraut, Susan J Ramus, Ellen L Goode, Alvaro N A Monteiro, Simon A Gayther, Steven A Narod, Paul D P Pharoah, Thomas A Sellers, Catherine M Phelan, Agoulnik, Irina U, Department of Pathology, Medicum, Department of Obstetrics and Gynecology, Clinicum, and HUS Gynecology and Obstetrics
Subjects: endocrine system diseases, lcsh:Medicine, Genome-wide association study, Carcinoma, Ovarian Epithelial, Bioinformatics, 0302 clinical medicine, 3123 Gynaecology and paediatrics, Neoplasms, Ovarian Epithelial, Odds Ratio, 2.1 Biological and endogenous factors, Neoplasms, Glandular and Epithelial, Aetiology, lcsh:Science, FAMILY SLC25, Cancer, Ovarian Neoplasms, African Americans, 0303 health sciences, Multidisciplinary, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], COLON-CANCER, Glandular and Epithelial, Single Nucleotide, 3. Good health, Ovarian Cancer, Serous fluid, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, HEPHAESTIN, Research Article, EXPRESSION, Risk, medicine.medical_specialty, CARCINOMA, General Science & Technology, 3122 Cancers, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Georgia Chenevix-Trench, 03 medical and health sciences, Rare Diseases, Molecular genetics, medicine, Carcinoma, Genetics, SNP, BREAST-CANCER, Humans, Genetic Predisposition to Disease, Hormone transport, UDP-GLUCURONOSYLTRANSFERASES, GENOME-WIDE ASSOCIATION, Polymorphism, Alleles, Genetic Association Studies, 030304 developmental biology, Asian, lcsh:R, IRON TRANSPORT, Genetic Variation, Biological Transport, medicine.disease, POLYMORPHISM, Black or African American, Asian Americans, Case-Control Studies, Cancer research, lcsh:Q, 3111 Biomedicine, Ovarian cancer, AOCS management group, Carrier Proteins, 030217 neurology & neurosurgery
Abstract: Contains fulltext : 154822.PDF (Publisher’s version ) (Open Access) BACKGROUND: Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. METHODS: In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q
Published: 2015

28. Characterization ofBRCA1andBRCA2Mutations in a Large United States Sample

Author: Joellen M. Schildkraut, Gail E. Tomlinson, Leif E. Peterson, Louise C. Strong, Christopher I. Amos, Leoni Leondaridis, David M. Euhus, Beth N. Peshkin, Dianne M. Finkelstein, Tara M. Friebel, Giovanni Parmigiani, Andrea Eisen, Donald A. Berry, Sining Chen, Claudine Isaacs, Edwin S. Iversen, Camille Corio, Rich Kerber, Debra Dutson, and Barbara L. Weber
Subjects: Adult, Heterozygote, Cancer Research, Genotype, Genetic counseling, Genes, BRCA2, Population, Genes, BRCA1, Breast Neoplasms, Genetic Counseling, Penetrance, Risk Assessment, Article, Breast cancer, Gene Frequency, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Family history, education, Aged, Retrospective Studies, Genetic testing, Ovarian Neoplasms, Genetics, education.field_of_study, medicine.diagnostic_test, business.industry, Incidence, Age Factors, Retrospective cohort study, Middle Aged, medicine.disease, United States, Ashkenazi jews, Oncology, Jews, Mutation, Female, business, Demography
Abstract: PurposeAn accurate evaluation of the penetrance of BRCA1 and BRCA2 mutations is essential to the identification and clinical management of families at high risk of breast and ovarian cancer. Existing studies have focused on Ashkenazi Jews (AJ) or on families from outside the United States. In this article, we consider the US population using the largest US-based cohort to date of both AJ and non-AJ families.MethodsWe collected 676 AJ families and 1,272 families of other ethnicities through the Cancer Genetics Network. Two hundred eighty-two AJ families were population based, whereas the remainder was collected through counseling clinics. We used a retrospective likelihood approach to correct for bias induced by oversampling of participants with a positive family history. Our approach takes full advantage of detailed family history information and the Mendelian transmission of mutated alleles in the family.ResultsIn the US population, the estimated cumulative breast cancer risk at age 70 years was 0.46 (95% CI, 0.39 to 0.54) in BRCA1 carriers and 0.43 (95% CI, 0.36 to 0.51) in BRCA2 carriers, whereas ovarian cancer risk was 0.39 (95% CI, 0.30 to 0.50) in BRCA1 carriers and 0.22 (95% CI, 0.14 to 0.32) in BRCA2 carriers. We also reported the prospective risks of developing cancer for cancer-free carriers in 10-year age intervals. We noted a rapid decrease in the relative risk of breast cancer with age and derived its implication for genetic counseling.ConclusionThe penetrance of BRCA mutations in the United States is largely consistent with previous studies on Western populations given the large CIs on existing estimates. However, the absolute cumulative risks are on the lower end of the spectrum.
Published: 2006

29. Patterns of Gene Expression That Characterize Long-term Survival in Advanced Stage Serous Ovarian Cancers

Author: Johnathan M. Lancaster, Mike West, Jingqin Luo, Andrew Berchuck, Holly K. Dressman, Phillip G. Febbo, Paula S. Lee, Joseph R. Nevins, Jennifer Pittman, Jeffrey R. Marks, Susan K. Murphy, and Edwin S. Iversen
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Pathology, Disease, Biology, Internal medicine, medicine, Humans, Neoplasm Invasiveness, Stage (cooking), Survival analysis, Neoplasm Staging, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms, Gene Expression Profiling, Case-control study, Middle Aged, medicine.disease, Survival Analysis, Gene expression profiling, Serous fluid, Case-Control Studies, RNA, Female, DNA microarray, Ovarian cancer
Abstract: Purpose: A better understanding of the underlying biology of invasive serous ovarian cancer is critical for the development of early detection strategies and new therapeutics. The objective of this study was to define gene expression patterns associated with favorable survival. Experimental Design: RNA from 65 serous ovarian cancers was analyzed using Affymetrix U133A microarrays. This included 54 stage III/IV cases (30 short-term survivors who lived 7 years) and 11 stage I/II cases. Genes were screened on the basis of their level of and variability in expression, leaving 7,821 for use in developing a predictive model for survival. A composite predictive model was developed that combines Bayesian classification tree and multivariate discriminant models. Leave-one-out cross-validation was used to select and evaluate models. Results: Patterns of genes were identified that distinguish short-term and long-term ovarian cancer survivors. The expression model developed for advanced stage disease classified all 11 early-stage ovarian cancers as long-term survivors. The MAL gene, which has been shown to confer resistance to cancer therapy, was most highly overexpressed in short-term survivors (3-fold compared with long-term survivors, and 29-fold compared with early-stage cases). These results suggest that gene expression patterns underlie differences in outcome, and an examination of the genes that provide this discrimination reveals that many are implicated in processes that define the malignant phenotype. Conclusions: Differences in survival of advanced ovarian cancers are reflected by distinct patterns of gene expression. This biological distinction is further emphasized by the finding that early-stage cancers share expression patterns with the advanced stage long-term survivors, suggesting a shared favorable biology.
Published: 2005

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

Author: Weiva Sieh, Angela Brooks-Wilson, Rachel Palmieri Weber, Jennifer A. Doherty, Maria Bisogna, Steven A. Narod, Linda E. Kelemen, Elisa V. Bandera, Daniel W. Cramer, Usha Menon, Peter Hillemanns, Claus Høgdall, Graham G. Giles, Michelle A.T. Hildebrandt, Andreas du Bois, Melissa Kellar, Aleksandra Gentry-Maharaj, Rosalind Glasspool, Francesmary Modugno, Jenny Chang-Claude, Galina Lurie, Argyrios Ziogas, Edwin S. Iversen, Brooke L. Fridley, Tanja Pejovic, Camilla Krakstad, Robert P. Edwards, Cezary Cybulski, Antonenkova Nn, Alexander Hein, Florian Heitz, Beth Y. Karlan, Acs Investigators, Dong Liang, Xifeng Wu, Mary Anne Rossing, Thilo Dörk, Valerie McGuire, Celeste Leigh Pearce, Douglas A. Levine, Joellen M. Schildkraut, Ian G. Campbell, Linda S. Cook, Jacek Gronwald, Susanne K. Kjaer, Jolanta Kupryjanczyk, Anna H. Wu, Nicolas Wentzensen, Thomas A. Sellers, Irene Orlow, Matthias Dürst, Peter A. Fasching, Diana Eccles, Jonathan Tyrer, Joanna Plisiecka-Halasa, Ellen L. Goode, Simon A. Gayther, Sara H. Olson, Karen Carty, Penelope M. Webb, Yukie Bean, Lynne R. Wilkens, I. Runnebaum, Elizabeth M. Poole, Agnieszka Dansonka-Mieszkowska, Melissa C. Southey, Daniel O. Stram, Harvey A. Risch, Diether Lambrechts, Roberta B. Ness, James Paul, Matthias W. Beckmann, Philipp Harter, Louise A. Brinton, Susan J. Ramus, Agnieszka Timorek, Marc T. Goodman, Liisa M. Pelttari, Els Van Nieuwenhuysen, Anna Jakubowska, Paul D.P. Pharoah, Nhu D. Le, Robert A. Vierkant, Lambertus A. Kiemeney, Andrew Berchuck, Sandrina Lambrechts, Heli Nevanlinna, Kathryn L. Terry, Kunle Odunsi, Christine Walsh, Jolanta Lissowska, Qinggang Wang, Joseph H. Rothstein, Katja K.H. Aben, Kirsten B. Moysich, Jonathan Beesley, Joseph L. Kelley, Ingvild L. Tangen, Karen Lu, Pamela J. Thompson, Ira Schwaab, Arto Leminen, Montserrat Garcia-Closas, Arif B. Ekici, Nadeem Siddiqui, Jan Lubinski, Natalia Bogdanova, Helga B. Salvesen, Estrid Høgdall, Malcolm C. Pike, Anja Rudolph, Line Bjørge, Ignace Vergote, Svend Aage Engelholm, John R. McLaughlin, Anne M. van Altena, Alice S. Whittemore, Jenny Lester, Sandra Orsulic, Ralf Bützow, Leon F.A.G. Massuger, Fiona Bruinsma, Catherine M. Phelan, Hoda Anton-Culver, Ed Dicks, Lene Lundvall, Honglin Song, Julie M. Cunningham, Shelley S. Tworoger, and Allan Jensen
Subjects: Purine, Folate, Genome-wide association study, Global Health, chemistry.chemical_compound, 0302 clinical medicine, Polymorphism (computer science), Risk Factors, AOCS Study Group/ACS Investigators, 2.1 Biological and endogenous factors, Aetiology, Purine metabolism, Cancer, Genetics, Ovarian Neoplasms, 0303 health sciences, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Nutrition and Dietetics, Single Nucleotide, Case-control, Neoplasm Proteins, Ovarian Cancer, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Pyrimidine metabolism, Public Health and Health Services, Female, Dihydropyrimidine dehydrogenase, Biotechnology, medicine.medical_specialty, European Continental Ancestry Group, Biology, Folic Acid Deficiency, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, Folic Acid, Rare Diseases, Food Sciences, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Polymorphism, Dihydrouracil Dehydrogenase (NADP), 030304 developmental biology, Nutrition, Nutrition & Dietetics, Carcinoma, Case-control study, Diet, Endocrinology, chemistry, Case-Control Studies, Multivariate Analysis, Dietary Supplements, DPYD, Serine hydroxymethyltransferase 1, Energy Intake, Genome-Wide Association Study, Food Science
Abstract: Contains fulltext : 137688.pdf (Publisher’s version ) (Closed access) SCOPE: We reevaluated previously reported associations between variants in pathways of one-carbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake. METHODS AND RESULTS: Odds ratios (OR) for 446 genetic variants were estimated among 13,410 OC cases and 22,635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 x 10(-5)) and rs828054 (OR = 1.06; p = 1 x 10(-4)). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 x 10(-6)) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1-C transfer, previously reported with OC, suggested lower risk at higher folate (p(interaction) = 0.03-0.006). CONCLUSION: Variation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-by-folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.
Published: 2014

31. Functional Annotation Signatures of Disease Susceptibility Loci Improve SNP Association Analysis

Author: Alvaro N.A. Monteiro, Merlise A. Clyde, Gary Bruce Lipton, and Edwin S. Iversen
Subjects: dbSNP, Bayesian analysis, Genome-wide association study, Single-nucleotide polymorphism, Computational biology, Biology, Functional annotations, ENCODE, Polymorphism, Single Nucleotide, 01 natural sciences, 010104 statistics & probability, 03 medical and health sciences, Annotation, Genetics, Humans, GWAS, ENCODE project, SNP, 0101 mathematics, Genetic Association Studies, 030304 developmental biology, Genetic association, Ovarian Neoplasms, 0303 health sciences, Methodology Article, Molecular Sequence Annotation, Statistical model, 3. Good health, Association study, Genetic Loci, Female, Disease Susceptibility, Genome-Wide Association Study, SNPs, Biotechnology
Abstract: Background Genetic association studies are conducted to discover genetic loci that contribute to an inherited trait, identify the variants behind these associations and ascertain their functional role in determining the phenotype. To date, functional annotations of the genetic variants have rarely played more than an indirect role in assessing evidence for association. Here, we demonstrate how these data can be systematically integrated into an association study’s analysis plan. Results We developed a Bayesian statistical model for the prior probability of phenotype–genotype association that incorporates data from past association studies and publicly available functional annotation data regarding the susceptibility variants under study. The model takes the form of a binary regression of association status on a set of annotation variables whose coefficients were estimated through an analysis of associated SNPs in the GWAS Catalog (GC). The functional predictors examined included measures that have been demonstrated to correlate with the association status of SNPs in the GC and some whose utility in this regard is speculative: summaries of the UCSC Human Genome Browser ENCODE super–track data, dbSNP function class, sequence conservation summaries, proximity to genomic variants in the Database of Genomic Variants and known regulatory elements in the Open Regulatory Annotation database, PolyPhen–2 probabilities and RegulomeDB categories. Because we expected that only a fraction of the annotations would contribute to predicting association, we employed a penalized likelihood method to reduce the impact of non–informative predictors and evaluated the model’s ability to predict GC SNPs not used to construct the model. We show that the functional data alone are predictive of a SNP’s presence in the GC. Further, using data from a genome–wide study of ovarian cancer, we demonstrate that their use as prior data when testing for association is practical at the genome–wide scale and improves power to detect associations. Conclusions We show how diverse functional annotations can be efficiently combined to create ‘functional signatures’ that predict the a priori odds of a variant’s association to a trait and how these signatures can be integrated into a standard genome–wide–scale association analysis, resulting in improved power to detect truly associated variants. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-398) contains supplementary material, which is available to authorized users.
Published: 2013

32. Molecular signatures of epithelial ovarian cancer: analysis of associations with tumor characteristics and epidemiologic risk factors

Author: Jeffrey R. Marks, Andrew Berchuck, Joellen M. Schildkraut, Rex C. Bentley, Lucy Akushevich, Edwin S. Iversen, and Regina S. Whitaker
Subjects: Oncology, Adult, medicine.medical_specialty, Pathology, Epidemiology, Gene Expression, Disease, Biology, Carcinoma, Ovarian Epithelial, Article, Young Adult, Risk Factors, Internal medicine, medicine, Carcinoma, North Carolina, Humans, Neoplasms, Glandular and Epithelial, Young adult, Family history, Risk factor, Aged, Ovarian Neoplasms, Middle Aged, medicine.disease, Serous fluid, Female, Ovarian cancer, Breast feeding
Abstract: Background: Six gene expression subtypes of invasive epithelial ovarian cancer were recently defined using microarrays by Tothill and colleagues. The Cancer Genome Atlas (TCGA) project subsequently replicated these subtypes and identified a signature predictive of survival in high-grade serous (HGS) cancers. We previously validated these signatures for use in formalin-fixed paraffin-embedded tissues. The aim of the present study was to determine whether these signatures are associated with specific ovarian cancer risk factors, which would add to the evidence that they reflect the heterogeneous etiology of this disease. Methods: We modeled signature-specific tumor characteristics and epidemiologic risk factor relationships using multiple regression and multivariate response multiple regression models in 193 patients from a case–control study of epithelial ovarian cancer. Results: We observed associations between the Tothill gene expression subtype signatures and both age at diagnosis (P = 0.0008) and race (P = 0.008). Although most established epidemiologic risk factors were not associated with molecular signatures, there was an association between breast feeding (P = 0.024) and first-degree family history of breast or ovarian cancer (P = 0.034) among the 106 HGS cases. Some of the above associations were validated using gene expression microarray data from the TCGA project. Weak associations were seen with age at menarche and duration of oral contraceptive use and the TCGA survival signature. Conclusions: These data support the potential for genomic characterization to elucidate the etiologic heterogeneity of epithelial ovarian cancer. Impact: This study suggests that molecular signatures may augment the ability to define etiologic subtypes of epithelial ovarian cancer. Cancer Epidemiol Biomarkers Prev; 22(10); 1709–21. ©2013 AACR.
Published: 2013

33. Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31

Author: Francois Bacot, Julie M. Cunningham, Shelley S. Tworoger, Robert S. Brown, Allan Jensen, Anja Rudolph, Jonathan Tyrer, Edwin S. Iversen, Tanja Pejovic, Lynne R. Wilkens, Sebastian M. Armasu, Alice S. Whittemore, Florian Heitz, Beth Y. Karlan, Yin Ling Woo, Karen Lu, Heather S. L. Jim, Bohdan Górski, Wei Zheng, Harvey A. Risch, Hui-Yi Lin, Arif B. Ekici, Rosalind Glasspool, Kimberly R. Kalli, Diether Lambrechts, Nathan Lee, Toru Nakanishi, Diana Eccles, Gottfried E. Konecny, Ian G. Campbell, Heli Nevanlinna, Thomas A. Sellers, Jin Q. Cheng, Agnieszka Dansonka-Mieszkowska, Argyrios Ziogas, Matthias W. Beckmann, Michael J. Birrer, Melissa C. Southey, Liisa M. Pelttari, Jolanta Kupryjanczyk, Camilla Krakstad, Elizabeth M. Poole, Robert A. Vierkant, Xiao-Ou Shu, Nicolas Wentzensen, Fumitaka Kikkawa, Y. Ann Chen, Celeste Leigh Pearce, Howard C. Shen, Allison F. Vitonis, Ya-Yu Tsai, Gerhard A. Coetzee, Jolanta Lissowska, Sandrina Lambrechts, Dong Liang, Kathryn L. Terry, Hannah P. Yang, Graham G. Giles, Daniel C. Tessier, Ira Schwaab, Anna H. Wu, Hoda Anton-Culver, Gianluca Severi, Stephen J. Chanock, Douglas F. Easton, Weiva Sieh, Natalia Antonenkova, Anne M. van Altena, Keitaro Matsuo, Anna Jakubowska, Paul D.P. Pharoah, Peter Hillemanns, Qiuyin Cai, Susanne K. Kjaer, Katja K.H. Aben, Kirsten B. Moysich, Estrid Høgdall, Ellen L. Goode, Lambertus A. Kiemeney, David Fenstermacher, Xiaotao Qu, Jesus Gonzalez-Bosquet, Daniel O. Stram, Irene Orlow, Joellen M. Schildkraut, Antonis C. Antoniou, Rachel Palmieri Weber, Satoyo Hosono, Jie Lin, Roberta B. Ness, Shan Wang-Gohrke, Simon A. Gayther, James Paul, Jill S. Barnholtz-Sloan, Usha Menon, Johnathan M. Lancaster, Jennifer A. Doherty, Stefan Nickels, Paola Raska, Jan Lubinski, Boon Kiong Lim, Elisabeth Wik, Aleksandra Gentry-Maharaj, Kate Lawrenson, Georgia Chenevix-Trench, Maureen E. Hoatlin, Stanley B. Kaye, Lotte Nedergaard, Natalia Bogdanova, Zhihua Chen, Janet M. Lee, Laura Baglietto, Francesmary Modugno, Linda E. Kelemen, Elisa V. Bandera, Montserrat Garcia-Closas, Helga B. Salvesen, Brooke L. Fridley, Rod Karevan, Houtan Noushmehr, Thilo Dörk, Ralf Bützow, Nhu D. Le, Douglas A. Levine, Sara H. Olson, Mine S. Cicek, Louise A. Brinton, Soo-Hwang Teo, Ignace Vergote, Pamela J. Thompson, Catherine M. Phelan, Marc T. Goodman, Linda S. Cook, Matthias Dürst, Malcolm C. Pike, Boris Winterhoff, Mari K. Halle, Andreas du Bois, Daniel Vincent, Valerie McGuire, Rebecca Sutphen, Peter A. Fasching, Jenny Chang-Claude, Stefan P. Renner, Jennifer Permuth-Wey, Aneliya Velkova, John McLaughlin, Kunle Odunsi, Greg Bloom, Leon F.A.G. Massuger, Arto Leminen, Melissa C. Larson, Iwona K. Rzepecka, Philipp Harter, Beata Spiewankiewicz, Mary Anne Rossing, Jacek Gronwald, Yurii B. Shvetsov, Claus Høgdall, Martin Gore, Angela Brooks-Wilson, Evelyn Despierre, Fergus J. Couch, Vijayalakshmi Shridhar, Ingo B. Runnebaum, James M. Flanagan, Galina Lurie, Alvaro N.A. Monteiro, Per Hall, Andrew Berchuck, Robert Edwards, Yong-Bing Xiang, Honglin Song, Susan J. Ramus, Famida Zulkifli, Lorna Rodriguez-Rodriguez, Steven A. Narod, Daniel W. Cramer, and Cancer Research UK
Subjects: Genetics and Molecular Biology (all), endocrine system diseases, General Physics and Astronomy, Genome-wide association study, Australian Ovarian Cancer Study, Aetiology, screening and detection [ONCOL 5], Female, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Chromosomes, Human, Pair 17, Genetic Predisposition to Disease, Chemistry (all), Biochemistry, Genetics and Molecular Biology (all), Physics and Astronomy (all), Carcinoma, Ovarian Epithelial, SITE POLYMORPHISMS, Biochemistry, 0302 clinical medicine, Polymorphism (computer science), Neoplasms, Ovarian Epithelial, Consortium of Investigators of Modifiers of BRCA1/2, GENETIC-VARIANTS, 2.1 Biological and endogenous factors, Aetiology, Cancer, Genetics, Midical sciences: 700::Clinical medical sciences: 750::Gynaecology and obstetrics: 756 [VDP], RISK, 0303 health sciences, COMMON INVERSION, Multidisciplinary, Glandular and Epithelial, Single Nucleotide, Aetiology, screening and detection Immune Regulation [ONCOL 5], female genital diseases and pregnancy complications, 3. Good health, Ovarian Cancer, Multidisciplinary Sciences, GENÉTICA, 030220 oncology & carcinogenesis, Science & Technology - Other Topics, FUNCTIONAL ANNOTATION, Human, Biotechnology, Biology, Medisinske fag: 700::Klinisk medisinske fag: 750::Gynekologi og obstetrikk: 756 [VDP], BINDING-SITES, General Biochemistry, Genetics and Molecular Biology, Article, Chromosomes, 03 medical and health sciences, Rare Diseases, Translational research [ONCOL 3], Australian Cancer Study, MD Multidisciplinary, medicine, Polymorphism, GENOME-WIDE ASSOCIATION, Genotyping, PARKINSON-DISEASE, MAPT REGION, 030304 developmental biology, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], Science & Technology, Molecular epidemiology, Hereditary cancer and cancer-related syndromes [ONCOL 1], MULTIDISCIPLINARY SCIENCES, MICRORNA EXPRESSION, Pair 17, Carcinoma, Human Genome, General Chemistry, Odds ratio, medicine.disease, Human genome, Ovarian cancer
Abstract: Contains fulltext : 118576.pdf (Publisher’s version ) (Open Access) Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3' untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio=1.12, P=10(-8)) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10(-10)). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes.
Published: 2013

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

Author: Camilla Krakstad, Andreas du Bois, Aleksandra Gentry-Maharaj, Agnieszka Dansonka-Mieszkowska, Melissa C. Southey, David Van Den Berg, Estrid Høgdall, Yurii B. Shvetsov, Melissa C. Larson, Joellen M. Schildkraut, Gianluca Severi, Jenny Chang-Claude, Peter A. Fasching, Keitaro Matsuo, Anna Jakubowska, Toru Nakanishi, Stefan P. Renner, Paul D.P. Pharoah, Lambertus A. Kiemeney, Liisa M. Pelttari, Pamela J. Thompson, Bridget Charbonneau, Francois Bacot, Julie M. Cunningham, Martin Gore, Shelley S. Tworoger, Robert S. Brown, Allan Jensen, Evelyn Despierre, Jonathan Tyrer, Matthew S. Block, Usha Menon, Peter W. Laird, Dong Liang, Claus Høgdall, Cezary Cybulski, Wei Zheng, Thomas A. Sellers, Heli Nevanlinna, Gary L. Keeney, Elizabeth Benjamin, Brooke L. Fridley, Mary Anne Rossing, Thilo Dörk, Douglas A. Levine, Jolanta Lissowska, Valerie McGuire, Sebastian M. Armasu, Ignace Vergote, Satoyo Hosono, Hoda Anton-Culver, Katja K.H. Aben, Jacek Gronwald, Francesmary Modugno, Lene Lundvall, Lorna Rodriguez-Rodriguez, Ian G. Campbell, Steven A. Narod, Louise A. Brinton, Daniel W. Cramer, Honglin Song, David G. Huntsman, Shan Wang-Gohrke, Alice S. Whittemore, Eva Wozniak, Marc T. Goodman, Kunle Odunsi, Daniel C. Tessier, Alvaro N.A. Monteiro, Georgia Chenevix-Trench, Ralf Bützow, Jennifer A. Doherty, Hui Shen, Doerthe Brueggmann, Bu Tian Ji, Xifeng Wu, Noor Azmi Mat Adenan, Philipp Harter, Elisabeth Wik, Hiroaki Kajiyama, Daniel O. Stram, Gottfried E. Konecny, Roberta B. Ness, James Paul, James M. Flanagan, Hannah P. Yang, Graham G. Giles, Martin Köbel, Mine S. Cicek, Maureen E. Hoatlin, Galina Lurie, Argyrios Ziogas, Arto Leminen, Leon F.A.G. Massuger, Catherine M. Phelan, Nadeem Siddiqui, Natalia Bogdanova, Xiao-Ou Shu, Helga B. Salvesen, Linda E. Kelemen, Ellen L. Goode, Joanna Moes-Sosnowska, Rod Karevan, Elisa V. Bandera, Alice W. Lee, Malcolm C. Pike, Laura Baglietto, Edwin S. Iversen, Linda S. Cook, Jonathan Beesley, Susan J. Ramus, John R. McLaughlin, Stefan Nickels, Simon A. Gayther, Jolanta Kupryjanczyk, Nicolas Wentzensen, Daniel Vincent, Karen H. Lu, Diana Eccles, Matthias Dürst, Arif B. Ekici, Clareann H. Bunker, Diether Lambrechts, Peter Hillemanns, Siti Zawiah Omar, Matthias W. Beckmann, Douglas A. Stram, Elizabeth M. Poole, Sandrina Lambrechts, Michelle A.T. Hildebrandt, Douglas F. Easton, Iwona K. Rzepecka, Kathryn L. Terry, Ira Schwaab, Kate Lawrenson, Jan Lubinski, Anne M. van Altena, Harvey A. Risch, Montserrat Garcia-Closas, Robert A. Vierkant, Per Hall, Robert Edwards, Angela Brooks-Wilson, Ingo B. Runnebaum, Soo Hwang Teo, Andrew Berchuck, Weiva Sieh, Kimberly R. Kalli, Claire Templeman, Boris Winterhoff, Mari K. Halle, Viji Shridhar, Yin Ling Woo, Xiaoqing Chen, Sara H. Olson, Rachel Palmieri Weber, Allison F. Vitonis, Anna H. Wu, Nhu D. Le, Natalia Antonenkova, Kirsten B. Moysich, Tanja Pejovic, Florian Heitz, Beth Y. Karlan, Celeste Leigh Pearce, Rebecca Hein, Susanne K. Kjaer, and Irene Orlow
Subjects: Genetics and Molecular Biology (all), endocrine system diseases, General Physics and Astronomy, Aetiology, screening and detection [ONCOL 5], Biochemistry, Epigenesis, Genetic, Prostate cancer, 0302 clinical medicine, Promoter Regions, Genetic, Ovarian Neoplasms, Genetics, Midical sciences: 700::Clinical medical sciences: 750::Gynaecology and obstetrics: 756 [VDP], 0303 health sciences, Multidisciplinary, Chemistry (all), Single Nucleotide, Methylation, Aetiology, screening and detection Immune Regulation [ONCOL 5], female genital diseases and pregnancy complications, 3. Good health, Serous fluid, 030220 oncology & carcinogenesis, Clear cell carcinoma, DNA methylation, Female, Biology, Medisinske fag: 700::Klinisk medisinske fag: 750::Gynekologi og obstetrikk: 756 [VDP], ta3111, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Promoter Regions, Physics and Astronomy (all), 03 medical and health sciences, Genetic, Translational research [ONCOL 3], medicine, Humans, Genetic Predisposition to Disease, Polymorphism, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], Hepatocyte Nuclear Factor 1-beta, 030304 developmental biology, Hereditary cancer and cancer-related syndromes [ONCOL 1], Gene Expression Profiling, General Chemistry, DNA Methylation, medicine.disease, ta3122, ta3123, Biochemistry, Genetics and Molecular Biology (all), Gene expression profiling, Cancer research, Ovarian cancer, Clear cell, Epigenesis
Abstract: Contains fulltext : 118378.pdf (Publisher’s version ) (Open Access) HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 x 10(-10)) and clear cell (rs11651755 OR=0.77, P=1.6 x 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.
Published: 2013

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

Author: Michael Lush, Hans Wildiers, Christopher A. Haiman, Nils Schoof, Per Hall, Beatrice Melin, Hiltrud Brauch, Liisa M. Pelttari, Angela Brooks-Wilson, Laima Tihomirova, Ingo B. Runnebaum, Hui Cai, Kenneth Offit, Michael P. Lux, Robert Edwards, Julia A. Knight, Ignace Vergote, Arto Leminen, Alan Ashworth, Kyriaki Michailidou, Martha J. Shrubsole, Sophie Giraud, Nadeem Siddiqui, Katri Pylkäs, Sune F. Nielsen, Vernon S. Pankratz, Lenka Foretova, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Anna Marie Mulligan, Andreas du Bois, Christi J. van Asperen, Nuria Álvarez, M. Pilar Zamora, Theo A. Mvan Os, Susan J. Ramus, Olivia Fletcher, Usha Menon, Olivier Caron, Dieter Flesch-Janys, Sara H. Olson, Ellen L. Goode, Yael Laitman, Jingmei Li, Lynne R. Wilkens, Carmel Apicella, Brooke L. Fridley, Robert Luben, Mark S. Goldberg, Mary Anne Rossing, Dominique Stoppa-Lyonnet, Jonathan Beesley, Jan Lubinski, Paolo Peterlongo, Phuong L. Mai, Henrik Flyger, Thilo Dörk, Douglas A. Levine, Rob B. van der Luijt, Stig E. Bojesen, Javier Benitez, Natalia Bogdanova, Stephen J. Chanock, Andrew K. Godwin, Sharon E. Johnatty, Helga B. Salvesen, Juliet D. French, Daphne Gschwantler Kaulich, Rod Karevan, Arif B. Ekici, Marc Frenay, Taru A. Muranen, Jirong Long, Catherine S. Healey, Craig Luccarini, Chen-Yang Shen, Lorna Gibson, Pascal Guénel, Hidemi Ito, Nicholas T. Woods, Drakoulis Yannoukakos, Thomas Hansen, Francesca Damiola, Valérie Bonadona, Satoyo Hosono, Marion Piedmonte, Steve Ellis, Suleeporn Sangrajrang, Aleksandra Gentry-Maharaj, James McKay, Olga M. Sinilnikova, Jennifer A. Doherty, Xiao-Ou Shu, Curtis Olswold, Nhu D. Le, Michael J. Kerin, Malcolm C. Pike, Jenny Chang-Claude, Gianluca Severi, Michael Jones, Linda E. Kelemen, Loic Le Marchand, Maureen E. Hoatlin, Fredrick R. Schumacher, Dieter Niederacher, Michael E. Carney, Angela Cox, Attila Teoman, Hannah P. Yang, Graham G. Giles, Jianjun Liu, Xiaoqing Chen, Elisa V. Bandera, Tanja Pejovic, Galina Lurie, Karoline Kuchenbaecker, Mariusz Bidziński, Chanel E. Smart, Maartje J. Hooning, Jose Ignacio Arias Perez, Anne-Marie Gerdes, L. Rogmann, Christoph Engel, Harvey A. Risch, Ignacio Blanco, Isabel dos Santos Silva, Hoda Anton-Culver, Camilla Krakstad, Volker Arndt, Foluso O. Ademuyiwa, Frans B. L. Hogervorst, Stacey L. Edwards, Florian Heitz, Veli-Matti Kosma, Beth Y. Karlan, Robert A. Vierkant, Irene L. Andrulis, Agnieszka Dansonka-Mieszkowska, Hanne Meijers-Heijboer, Alison M. Dunning, Sabapathy P. Balasubramanian, Penny Soucy, Edwin S. Iversen, Heli Nevanlinna, Celeste Leigh Pearce, Melissa C. Southey, Howard C. Shen, Kenneth Muir, Jolanta Lissowska, Clareann H. Bunker, Judy Garber, David Van Den Berg, Yin Ling Woo, Brigitte Bressac-de Paillerets, Rebecca Hein, Norbert Arnold, Saila Kauppila, Lisa Walker, Cezary Cybulski, Estrid Høgdall, Anthony J. Swerdlow, Robert Winqvist, Susanne K. Kjaer, Christa Stegmaier, Kazuo Tajima, Caroline Baynes, Valerie Gaborieau, Keitaro Matsuo, Ed Dicks, Irene Orlow, Torben A Kruse, Rachel Palmieri Weber, David E. Goldgar, Anna Jakubowska, Honglin Song, Antonis C. Antoniou, Paul D.P. Pharoah, Katja K.H. Aben, Lambertus A. Kiemeney, Laurence Faivre, Stefan Nickels, Joellen M. Schildkraut, Yu Tang Gao, Valerie McGuire, Charles L. Shapiro, Sebastian M. Armasu, Katherine L. Nathanson, Marjanka K. Schmidt, Susan L. Neuhausen, Jolanta Kupryjanczyk, Janet E. Olson, Nicolas Wentzensen, Dong Young Noh, Maya Ghoussaini, Ian G. Campbell, Annegien Broeks, Gustavo C. Rodriguez, Rebecca L. Johnston, Shan Wang-Gohrke, Monica Barile, Vesa Kataja, Melanie Maranian, Shahana Ahmed, Christof Sohn, Julie M. Cunningham, Weiva Sieh, Shani Shimon Paluch, Riccardo Dolcetti, John W.M. Martens, Manjeet K. Bolla, Shelley S. Tworoger, Robert S. Brown, Allan Jensen, Hui Miao, Boris Winterhoff, Mari K. Halle, Arndt Hartmann, Loris Bernard, Brian E. Henderson, Els Wauters, Carl Blomqvist, Daniel O. Stram, Karen A. Pooley, Roberta B. Ness, James Paul, Hilda A. Pickett, Wei Zheng, Sandra Deming-Halverson, Soo Hwang Teo, Andrew Lee, Thomas A. Sellers, Philip Iau, D. Gareth Evans, Françis Bacot, Sunil R. Lakhani, Qin Wang, Nick Orr, Celine M. Vachon, Edith Olah, Gong Yang, Svend Aage Engelholm, Martine Dumont, Linda S. Cook, Daniel C. Tessier, Evgeny N. Imyanitov, Paolo Radice, Mikael Hartman, Annika Lindblom, John R. McLaughlin, Radka Platte, Jenny Permuth-Wey, Keun-Young Yoo, Andrew Berchuck, Roger R. Reddel, M. John Kennedy, Toru Nakanishi, Allison F. Vitonis, Melissa C. Larson, Anna H. Wu, Helmut Deissler, Giuseppe Giannini, Barbara Wappenschmidt, Tomasz Byrski, M. Kamran Ikram, Natalia Antonenkova, Banu Arun, Peter Hillemanns, William Blot, Siti Zawiah Omar, Sue Healey, Trevor Cole, Cheng Har Yip, Matthias Dürst, Mark E. Robson, Roger L. Milne, Timothy R. Rebbeck, Jaana M. Hartikainen, Mieke Kriege, C. Ellen van der Schoot, Hansjoerg Plendl, Yasushi Yatabe, Jan C. Oosterwijk, Claus Høgdall, Rob A. E. M. Tollenaar, Jacek Gronwald, Yi Lu, Kate Lawrenson, Michael D. Stutz, Chia-Ni Hsiung, Alvaro N.A. Monteiro, Maren Weischer, Philipp Harter, Nicola Miller, Lisa B. Signorello, Katarzyna Durda, Peter Lichtner, Ritu Salani, Alfons Meindl, Montserrat Garcia-Closas, George Fountzilas, Uffe Birk Jensen, Thomas Brüning, Laura Baglietto, Anne M. van Altena, Kristine M. Hillman, Bernard Peissel, Trinidad Caldés, Rosemarie Davidson, Julian Barwell, Peter Devilee, Jenny Lester, Qiuyin Cai, Heiko Müller, Jyh Cherng Yu, Kerstin Rhiem, Muy Kheng Tea, Sharon A. Savage, Åke Borg, Daniel Vincent, Antoinette Hollestelle, Katarzyna Jaworska, Mat Adenan Noor Azmi, Yon Ko, Kimberly R. Kalli, Debra Frost, Martin Gore, Chiu-Chen Tseng, Georgia Chenevix-Trench, Pornthep Siriwanarangsan, Evelyn Despierre, Fergus J. Couch, Vijayalakshmi Shridhar, Artitaya Lophatananon, Amanda B. Spurdle, Joe Dennis, Ute Hamann, Vessela N. Kristensen, Frederik Marmé, Jonathan Tyrer, Arja Jukkola-Vuorinen, Wei Lu, Peter A. Fasching, Bruno Buecher, Kristiina Aittomäki, Kirsten B. Moysich, Lesley McGuffog, Mine S. Cicek, Guillermo Pita, Arjen R. Mensenkamp, Agnes Jager, Catherine M. Phelan, Jacques Simard, Ming-Feng Hou, Hiroji Iwata, James M. Flanagan, Elena Fineberg, Susan M. Domchek, Csilla Szabo, Diether Lambrechts, Anja Rudolph, Daehee Kang, Gottfried E. Konecny, Eitan Friedman, Argyrios Ziogas, Arto Mannermaa, Susan Peock, Matti A. Rookus, Christian F. Singer, Claire Mulot, Siranoush Manoukian, Johanna Rantala, Helen Tsimiklis, Gord Glendon, Pierre Laurent-Puig, Barbara Brouwers, Filomena Ficarazzi, Jonine D. Figueroa, Anne-Bine Skytte, Caroline Seynaeve, Christian Sutter, Rita K. Schmutzler, Julian Peto, Jeffrey N. Weitzel, Kathryn L. Terry, Børge G. Nordestgaard, Simon A. Gayther, Barbara Burwinkel, Ira Schwaab, Steven A. Narod, Elisabeth Wik, Ralf Bützow, Marco Montagna, Mark H. Greene, Linde M. Braaf, Janusz Menkiszak, Kamila Czene, Sarah Stewart-Brown, Kees E. P. van Roozendaal, Andreas Schneeweiss, Daniel Barrowdale, Elinor J. Sawyer, Alice S. Whittemore, Marc T. Goodman, Judith E. Brown, Kunle Odunsi, John L. Hopper, Nina Ditsch, Leon F.A.G. Massuger, Hermann Brenner, Joaquin J. Garcia, Xianshu Wang, Susan L. Slager, Aleksandra Tołoczko-Grabarek, Sylvie Mazoyer, Diana Eccles, Yik Ying Teo, Iwona K. Rzepecka, Bernardo Bonanni, Sara Margolin, Daniela Zaffaroni, Yew Ching Teh, Ans M Wvan Den Ouweland, Bent Ejlertsen, Maria Soller, Mitul Shah, Matthias W. Beckmann, Elizabeth M. Poole, J. Margriet Collée, Lorna Rodriguez-Rodriguez, Sandrina Lambrechts, Daniel W. Cramer, Douglas F. Easton, Virginie Caux-Moncoutier, Mads Thomassen, Keith Humphreys, ~, Landsteiner Laboratory, Clinical Haematology, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Human Genetics, MUMC+: DA KG Lab Centraal Lab (9), Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction, Human genetics, CCA - Oncogenesis, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Clinical Genetics, Cardiothoracic Surgery, and Medical Oncology
Subjects: Telomerase, Messenger, Càncer d'ovari, Estrogen receptor, Aetiology, screening and detection [ONCOL 5], 0302 clinical medicine, Breast cancer, Risk Factors, Alternative Splicing, Biomarkers, Tumor, Breast Neoplasms, Case-Control Studies, Chromatin, DNA Methylation, Female, Gene Expression Profiling, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Luciferases, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms, Polymorphism, Single Nucleotide, RNA, Messenger, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Telomere, Genetics, BUCCAL CELLS, 0303 health sciences, Tumor, Telòmer, GENETIC-VARIATION, COMMON VARIANTS, Single Nucleotide, tert-clptm1l locus, genome-wide association, genetic-variation, susceptibility loci, buccal cells, fibroblasts, common variants, carcinoma, reverse-transcriptase htert, metaanalysis, Aetiology, screening and detection Immune Regulation [ONCOL 5], 3. Good health, Tumor Markers, Biological, 030220 oncology & carcinogenesis, FIBROBLASTS, SUSCEPTIBILITY LOCI, CARCINOMA, Single-nucleotide polymorphism, Biology, Article, Càncer de mama, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Translational research [ONCOL 3], Ovarian cancer, medicine, Polymorphism, Allele, GENOME-WIDE ASSOCIATION, METAANALYSIS, 030304 developmental biology, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], Breast cancer susceptibility, Hereditary cancer and cancer-related syndromes [ONCOL 1], Translational research Genomic disorders and inherited multi-system disorders [ONCOL 3], medicine.disease, Molecular biology, TERT-CLPTM1L LOCUS, Minor allele frequency, RNA, Biomarkers, REVERSE-TRANSCRIPTASE HTERT
Abstract: Journal article TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ~480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10!-7), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10!-8) and BRCA1 mutation carrier (P = 1.1 × 10!-5) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10!-14), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10!-15) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10!-12) and BRCA1 mutation carrier (P = 1.6 × 10!-14) breast and invasive ovarian (P = 1.3 × 10!-11) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant. European Commission Seventh Framework Programme (agreement 223175-HEALTH-F2-2009-223175); Cancer Research UK (C1287/A10118 and C1287/A12014) peer-reviewed
Published: 2013

36. Combined and Interactive Effects of Environmental and GWAS-Identified Risk Factors in Ovarian Cancer

Author: Valerie McGuire, Jolanta Lissowska, Rachel Palmieri Weber, Katja K.H. Aben, Anne M. van Altena, Kathryn L. Terry, Andrew Berchuck, Montserrat Garcia-Closas, Jennifer A. Doherty, Pamela J. Thompson, Michael E. Carney, Paul D.P. Pharoah, Galina Lurie, Celeste Leigh Pearce, Lambertus A. Kiemeney, Daniel O. Stram, Aleksandra Gentry-Maharaj, Douglas A. Stram, Jenny Chang-Claude, Rebecca Hein, Stefan Nickels, Roberta B. Ness, Susanne K. Kjaer, Susan J. Jordan, Estrid Høgdall, Alice W. Lee, Malcolm C. Pike, Ellen L. Goode, Penelope M. Webb, Weiva Sieh, Simon A. Gayther, Georgia Chenevix-Trench, Louise A. Brinton, Marc T. Goodman, Patricia G. Moorman, Argyrios Ziogas, Harvey A. Risch, Anna H. Wu, Kirsten B. Moysich, Robert A. Vierkant, Joellen M. Schildkraut, Alice S. Whittemore, Hoda Anton-Culver, Julie M. Cunningham, Allan Jensen, Usha Menon, Brooke L. Fridley, Mary Anne Rossing, Susan J. Ramus, Edwin S. Iversen, Nicolas Wentzensen, and Leon F.A.G. Massuger
Subjects: Oncology, medicine.medical_specialty, Genotype, Epidemiology, Genome-wide association study, Aetiology, screening and detection [ONCOL 5], Bioinformatics, Article, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Translational research [ONCOL 3], Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Gene–environment interaction, Risk factor, Aged, 030304 developmental biology, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], Ovarian Neoplasms, 0303 health sciences, Framingham Risk Score, Hereditary cancer and cancer-related syndromes [ONCOL 1], business.industry, Case-control study, Absolute risk reduction, Cancer, Environmental Exposure, Environmental exposure, Middle Aged, medicine.disease, Aetiology, screening and detection Immune Regulation [ONCOL 5], 3. Good health, Case-Control Studies, 030220 oncology & carcinogenesis, Female, Gene-Environment Interaction, business, Genome-Wide Association Study
Abstract: Background: There are several well-established environmental risk factors for ovarian cancer, and recent genome-wide association studies have also identified six variants that influence disease risk. However, the interplay between such risk factors and susceptibility loci has not been studied. Methods: Data from 14 ovarian cancer case–control studies were pooled, and stratified analyses by each environmental risk factor with tests for heterogeneity were conducted to determine the presence of interactions for all histologic subtypes. A genetic “risk score” was created to consider the effects of all six variants simultaneously. A multivariate model was fit to examine the association between all environmental risk factors and genetic risk score on ovarian cancer risk. Results: Among 7,374 controls and 5,566 cases, there was no statistical evidence of interaction between the six SNPs or genetic risk score and the environmental risk factors on ovarian cancer risk. In a main effects model, women in the highest genetic risk score quartile had a 65% increased risk of ovarian cancer compared with women in the lowest [95% confidence interval (CI), 1.48–1.84]. Analyses by histologic subtype yielded risk differences across subtype for endometriosis (Phet < 0.001), parity (Phet < 0.01), and tubal ligation (Phet = 0.041). Conclusions: The lack of interactions suggests that a multiplicative model is the best fit for these data. Under such a model, we provide a robust estimate of the effect of each risk factor that sets the stage for absolute risk prediction modeling that considers both environmental and genetic risk factors. Further research into the observed differences in risk across histologic subtype is warranted. Cancer Epidemiol Biomarkers Prev; 22(5); 880–90. ©2013 AACR.
Published: 2013

37. GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer

Author: Louise A. Brinton, Marc T. Goodman, Gottfried E. Konecny, Argyrios Ziogas, Martin Gore, Evelyn Despierre, Vijayalakshmi Shridhar, Ignace Vergote, Anne M. van Altena, Gianluca Severi, Jennifer A. Doherty, Hoda Anton-Culver, Edwin S. Iversen, Jonathan Tyrer, Anxhela Gjyshi, Ed Dicks, Wong Ho Chow, Georgia Chenevix-Trench, Agnieszka Timorek, Liisa M. Pelttari, Angela Brooks-Wilson, Ingo B. Runnebaum, Maureen E. Hoatlin, Houtan Noushmehr, Lene Lundvall, Galina Lurie, Qi Guo, Mine S. Cicek, Melissa Buckley, Arto Leminen, Catherine M. Phelan, Harvey A. Risch, Hannah P. Yang, Graham G. Giles, Francois Bacot, Julie M. Cunningham, Nathan Lee, Agnieszka Dansonka-Mieszkowska, Usha Menon, Shelley S. Tworoger, Robert S. Brown, Allan Jensen, Linda S. Cook, Ralf Bützow, Linda E. Kelemen, John R. McLaughlin, Robert A. Vierkant, Yu-Tang Gao, Allison F. Vitonis, Wei Zheng, Thomas A. Sellers, Anna H. Wu, Brooke L. Fridley, Ya Yu Tsai, Daniel C. Tessier, Mary Anne Rossing, Thilo Dörk, Melissa C. Southey, Famida Zulkifli, Peter Hillemanns, Jan Lubinski, Jolanta Kupryjanczyk, Elisa V. Bandera, Camilla Krakstad, Nicolas Wentzensen, Natalia Bogdanova, Helga B. Salvesen, Hui Shen, Per Hall, Natalia Antonenkova, Rod Karevan, Leon F.A.G. Massuger, Lorna Rodriguez-Rodriguez, Alexander Hein, Kate Lawrenson, Jenny Chang-Claude, Kazuo Tajima, Malcolm C. Pike, Keitaro Matsuo, Steven A. Narod, Robert Edwards, David Van Den Berg, Stefan Nickels, Daniel W. Cramer, James M. Flanagan, Anna Jakubowska, Paul D.P. Pharoah, Estrid Høgdall, Honglin Song, Cezary Cybulski, Zhihua Chen, Iwona K. Rzepecka, Tanja Pejovic, Lambertus A. Kiemeney, Joellen M. Schildkraut, Florian Heitz, Boon Kiong Lim, Beth Y. Karlan, Valerie McGuire, Sebastian M. Armasu, Kimberly R. Kalli, Gerhard A. Coetzee, Ian G. Campbell, Andreas du Bois, Ellen L. Goode, Xiaotao Qu, Y. Anne Chen, Simon A. Gayther, Shan Wang-Gohrke, Yin Ling Woo, Susan J. Ramus, Weiva Sieh, Arif B. Ekici, Alice S. Whittemore, Xiao-Ou Shu, Peter A. Fasching, Kunle Odunsi, James D. Brenton, Jenny Permuth-Wey, Toru Nakanishi, Roberta B. Ness, James Paul, Renato S. Carvalho, Montserrat Garcia-Closas, Philipp Harter, Joe Dennis, Daniel Vincent, Elisabeth Wik, Diether Lambrechts, Matthias Dürst, Anja Rudolph, Kathryn L. Terry, Ira Schwaab, Laura Baglietto, Michael E. Carney, Heli Nevanlinna, Satoyo Hosono, Francesmary Modugno, Jolanta Lissowska, Melissa C. Larson, Pamela J. Thompson, Katja K.H. Aben, Claus Høgdall, Diana Eccles, Matthias W. Beckmann, Michael J. Birrer, Elizabeth M. Poole, Sandrina Lambrechts, Douglas F. Easton, David Fenstermacher, Jacek Gronwald, Alvaro N.A. Monteiro, Boris Winterhoff, Mari K. Halle, Greg Bloom, Soo Hwang Teo, Rachel Palmieri Weber, Andrew Berchuck, Aleksandra Gentry-Maharaj, Janet M. Lee, Sara H. Olson, Celeste Leigh Pearce, Howard C. Shen, Susanne K. Kjaer, Paul T. Spellman, Irene Orlow, Nhu D. Le, Kirsten B. Moysich, and Cancer Research UK
Subjects: endocrine system diseases, ESTUDOS DE CASOS E CONTROLES, Genome-wide association study, Aetiology, screening and detection [ONCOL 5], MYC, Case-Control Studies, Cooperative Behavior, Cystadenocarcinoma, Serous, Female, Gene-Environment Interaction, Genetic Loci, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Neoplasm Invasiveness, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Risk Factors, Genetic Predisposition to Disease, Genetics, 0302 clinical medicine, 19P13, GENETICS & HEREDITY, RISK, 0303 health sciences, Single Nucleotide, 11 Medical And Health Sciences, Aetiology, screening and detection Immune Regulation [ONCOL 5], 3. Good health, 030220 oncology & carcinogenesis, Life Sciences & Biomedicine, EXPRESSION, Australian Ovarian Cancer Study Group, CARCINOMA, Cystadenocarcinoma, Single-nucleotide polymorphism, Locus (genetics), Biology, NEBULETTE, Article, 03 medical and health sciences, Translational research [ONCOL 3], Australian Cancer Study, Polymorphism, GENOME-WIDE ASSOCIATION, Genotyping, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], 030304 developmental biology, Genetic association, Science & Technology, Hereditary cancer and cancer-related syndromes [ONCOL 1], Molecular epidemiology, Case-control study, Serous, 06 Biological Sciences, GENE, CELLS, LEUKEMIA, Developmental Biology
Abstract: Contains fulltext : 118459.pdf (Publisher’s version ) (Closed access) Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 x 10(-9)) and 10p12 (rs1243180, P = 1.8 x 10(-8)) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 x 10(-10)). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.
Published: 2013

38. Evidence of a genetic link between endometriosis and ovarian cancer

Author: Alice W. Lee, Claire Templeman, Douglas A. Stram, Jonathan Beesley, Jonathan Tyrer, Andrew Berchuck, Paul P. Pharoah, Georgia Chenevix-Trench, Celeste Leigh Pearce, Roberta B. Ness, Agnieszka Dansonka-Mieszkowska, Aleksandra Gentry-Maharaj, Alexander Hein, Alice S. Whittemore, Allan Jensen, Andreas du Bois, Angela Brooks-Wilson, Anja Rudolph, Anna Jakubowska, Anna H. Wu, Argyrios Ziogas, Arif B. Ekici, Arto Leminen, Barry Rosen, Beata Spiewankiewicz, Beth Y. Karlan, Britton Trabert, Brooke L. Fridley, C. Blake Gilks, Camilla Krakstad, Catherine M. Phelan, Cezary Cybulski, Christine Walsh, Claus Hogdall, Daniel W. Cramer, David G. Huntsman, Diana Eccles, Diether Lambrechts, Dong Liang, Douglas A. Levine, Edwin S. Iversen, Elisa V. Bandera, Elizabeth M. Poole, Ellen L. Goode, Els Van Nieuwenhuysen, Estrid Hogdall, Fiona Bruinsma, Florian Heitz, Francesmary Modugno, Graham G. Giles, Harvey A. Risch, Helen Baker, Helga B. Salvesen, Heli Nevanlinna, Hoda Anton-Culver, Honglin Song, Iain McNeish, Ian G. Campbell, Ignace Vergote, Ingo B. Runnebaum, Ingvild L. Tangen, Ira Schwaab, Jacek Gronwald, James Paul, Jan Lubinski, Jennifer A. Doherty, Jenny Chang-Claude, Jenny Lester, Joellen M. Schildkraut, John R. McLaughlin, Jolanta Lissowska, Jolanta Kupryjanczyk, Joseph L. Kelley, Joseph H. Rothstein, Julie M. Cunningham, Karen Lu, Karen Carty, Kathryn L. Terry, Katja K.H. Aben, Kirsten B. Moysich, Kristine G. Wicklund, Kunle Odunsi, Lambertus A. Kiemeney, Lara Sucheston-Campbell, Lene Lundvall, Leon F.A.G. Massuger, Liisa M. Pelttari, Linda E. Kelemen, Linda S. Cook, Line Bjorge, Lotte Nedergaard, Louise A. Brinton, Lynne R. Wilkens, Malcolm C. Pike, Marc T. Goodman, Maria Bisogna, Mary Anne Rossing, Matthias W. Beckmann, Matthias Dürst, Melissa C. Southey, Melissa Kellar, Michelle A.T. Hildebrandt, Nadeem Siddiqui, Natalia Antonenkova, Natalia Bogdanova, Nhu D. Le, Nicolas Wentzensen, Pamela J. Thompson, Patricia Harrington, Penelope M. Webb, Peter A. Fasching, Peter Hillemanns, Philipp Harter, Piotr Sobiczewski, Rachel Palmieri Weber, Ralf Butzow, Robert P. Edwards, Robert A. Vierkant, Rosalind Glasspool, Sandra Orsulic, Sandrina Lambrechts, Sara H. Olson, Shan Wang-Gohrke, Shashi Lele, Shelley S. Tworoger, Simon A. Gayther, Stacey A. Missmer, Steven A. Narod, Susan J. Ramus, Susanne K. Kjaer, Tanja Pejovic, Thilo Dörk, Ursula Eilber, Usha Menon, Valerie McGuire, Weiva Sieh, Xifeng Wu, Yukie Bean, and Yurii B. Shvetsov
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, endocrine system diseases, Endometriosis, Genome-wide association study, Single-nucleotide polymorphism, Disease, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Article, 03 medical and health sciences, Risk Factors, Internal medicine, Databases, Genetic, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, Genetic testing, Ovarian Neoplasms, Gynecology, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], medicine.diagnostic_test, Case-control study, Computational Biology, Obstetrics and Gynecology, medicine.disease, female genital diseases and pregnancy complications, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Phenotype, 030104 developmental biology, Reproductive Medicine, Case-Control Studies, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Neoplasm Grading, Ovarian cancer, Genome-Wide Association Study
Abstract: Contains fulltext : 172500.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To evaluate whether endometriosis-associated genetic variation affects risk of ovarian cancer. DESIGN: Pooled genetic analysis. SETTING: University hospital. PATIENT(S): Genetic data from 46,176 participants (15,361 ovarian cancer cases and 30,815 controls) from 41 ovarian cancer studies. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Endometriosis-associated genetic variation and ovarian cancer. RESULT(S): There was significant evidence of an association between endometriosis-related genetic variation and ovarian cancer risk, especially for the high-grade serous and clear cell histotypes. Overall we observed 15 significant burden statistics, which was three times more than expected. CONCLUSION(S): By focusing on candidate regions from a phenotype associated with ovarian cancer, we have shown a clear genetic link between endometriosis and ovarian cancer that warrants further follow-up. The functional significance of the identified regions and SNPs is presently uncertain, though future fine mapping and histotype-specific functional analyses may shed light on the etiologies of both gynecologic conditions.
Published: 2016

39. Validation of ovarian cancer gene expression signatures for survival and subtype in formalin fixed paraffin embedded tissues

Author: Liudmila Akushevich, Edwin S. Iversen, Regina S. Whitaker, Joellen M. Schildkraut, Jeffrey R. Marks, Gregory Sfakianos, Andrew Berchuck, and Susan K. Murphy
Subjects: Regulation of gene expression, Ovarian Neoplasms, Pathology, medicine.medical_specialty, Paraffin Embedding, Microarray, Gene Expression Profiling, Hazard ratio, Obstetrics and Gynecology, Biology, medicine.disease, Article, Gene expression profiling, Gene Expression Regulation, Neoplastic, Serous fluid, Oncology, Formaldehyde, Cancer research, medicine, Humans, Female, DNA microarray, Ovarian cancer, Clear cell
Abstract: Introduction Gene expression signatures have been identified for epithelial ovarian cancer survival (TCGA) and intrinsic subtypes (Tothill et al.). One obstacle to clinical translation is that these signatures were developed using frozen tissue, whereas usually only formalin-fixed, paraffin embedded (FFPE) tissue is available. The aim of this study was to determine if gene expression signatures can be translated to fixed archival tissues. Methods RNA extracted from FFPE sections from 240 primary ovarian cancers was analyzed by DASL on Illumina BeadChip arrays. Concordance of expression at the individual gene level was assessed by comparing array data from the same cancers (30 frozen samples analyzed on Affymetrix arrays versus FFPE DASL). Results The correlation between FFPE and frozen survival signature estimates was 0.774. The TCGA signature using DASL was predictive of survival in 106 advanced stage high grade serous ovarian cancers (median survival 33 versus 60months, estimated hazard ratio for death 2.30, P=0.0007). Similar to Tothill, we found using DASL that most high grade serous ovarian cancers (102/110, 93%) were assigned to subtypes 1, 2, 4 and 5, whereas most endometrioid, clear cell, mucinous and low grade serous cases (39/57, 68%) were assigned to subtypes 3 and 6 (P Conclusions Although individual probe estimates of microarrays may be weakly correlated between FFPE and frozen samples, combinations of probes have robust ability to predict survival and subtype. This suggests that it may be possible to use these signatures for prognostic and predictive purposes as we seek to individualize the treatment of ovarian cancer.
Published: 2012

40. Ovarian cancer risk associated with inherited inflammation-related variants

Author: Honglin Song, Julie M. Cunningham, Thomas A. Sellers, Joellen M. Schildkraut, Kristin L. White, Brooke L. Fridley, Ellen L. Goode, Rachel T. Palmieri, David N. Rider, Rebecca Sutphen, Michael J. Birrer, Paul P.D. Pharoah, Bridget Charbonneau, Edwin S. Iversen, Andrew Berchuck, Nicolas Wentzensen, Montserrat Garcia-Closas, Mine S. Cicek, Hannah P. Yang, Catherine M. Phelan, Susan J. Ramus, Jonathan Tyrer, Simon A. Gayther, and Robert A. Vierkant
Subjects: Oncology, Risk, Cancer Research, medicine.medical_specialty, 5-Lipoxygenase-Activating Proteins, Single-nucleotide polymorphism, Biology, Carcinoma, Ovarian Epithelial, medicine.disease_cause, Polymorphism, Single Nucleotide, Article, Internal medicine, Interleukin-1alpha, Genotype, medicine, Humans, Genetic Predisposition to Disease, Neoplasms, Glandular and Epithelial, Genetic association, Inflammation, Ovarian Neoplasms, Case-control study, medicine.disease, Serous fluid, IL1A, Case-Control Studies, Immunology, Female, Carcinogenesis, Ovarian cancer
Abstract: The importance of inflammation pathways to the development of many human cancers prompted us to examine the associations between single-nucleotide polymorphisms (SNP) in inflammation-related genes and risk of ovarian cancer. In a multisite case–control study, we genotyped SNPs in a large panel of inflammatory genes in 930 epithelial ovarian cancer cases and 1,037 controls using a custom array and analyzed by logistic regression. SNPs with P < 0.10 were evaluated among 3,143 cases and 2,102 controls from the Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI) post-GWAS collaboration. Combined analysis revealed association with SNPs rs17561 and rs4848300 in the interleukin gene IL1A which varied by histologic subtype (Pheterogeneity = 0.03). For example, IL1A rs17561, which correlates with numerous inflammatory phenotypes, was associated with decreased risk of clear cell, mucinous, and endometrioid subtype, but not with the most common serous subtype. Genotype at rs1864414 in the arachidonate 5-lipoxygenase ALOX5 was also associated with decreased risk. Thus, inherited variation in IL1A and ALOX5 seems to affect ovarian cancer risk which, for IL1A, is limited to rarer subtypes. Given the importance of inflammation in tumorigenesis and growing evidence of subtype-specific features in ovarian cancer, functional investigations will be important to help clarify the importance of inherited variation related to inflammation in ovarian carcinogenesis. Cancer Res; 72(5); 1064–9. ©2012 AACR.
Published: 2012

41. European American stratification in ovarian cancer case control data: the utility of genome-wide data for inferring ancestry

Author: Jennifer Permuth-Wey, Brooke L. Fridley, Ya Yu Tsai, Paola Raska, Joellen M. Schildkraut, Ellen L. Goode, Harvey A. Risch, Robert A. Vierkant, Ann Chen, Edwin S. Iversen, Thomas A. Sellers, Jill S. Barnholtz-Sloan, and Zhihua Chen
Subjects: Epidemiology, lcsh:Medicine, Genome-wide association study, Genome, Biochemistry, Major Histocompatibility Complex, 0302 clinical medicine, Neoplasms, Glandular and Epithelial, lcsh:Science, Genome Evolution, Epidemiological Methods, Genetics, Ovarian Neoplasms, 0303 health sciences, Multidisciplinary, Genomics, Ovarian Cancer, Oncology, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 2, Genetic Epidemiology, Principal component analysis, Medicine, Chromosomes, Human, Pair 6, Female, Research Article, Immunology, Single-nucleotide polymorphism, Ancestry-informative marker, Human leukocyte antigen, Biology, Population stratification, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Chromosome (genetic algorithm), Genome-Wide Association Studies, Cancer Genetics, Humans, 030304 developmental biology, Evolutionary Biology, Population Biology, lcsh:R, Genetic Drift, Proteins, Computational Biology, Cancers and Neoplasms, Human Genetics, Major Histocompatibility Antigens, Evolutionary biology, Genetic Loci, Case-Control Studies, North America, Genetic Polymorphism, lcsh:Q, Clinical Immunology, Gynecological Tumors, Population Genetics, Genome-Wide Association Study
Abstract: We investigated the ability of several principal components analysis (PCA)-based strategies to detect and control for population stratification using data from a multi-center study of epithelial ovarian cancer among women of European-American ethnicity. These include a correction based on an ancestry informative markers (AIMs) panel designed to capture European ancestral variation and corrections utilizing un-thinned genome-wide SNP data; case-control samples were drawn from four geographically distinct North-American sites. The AIMs-only and genome-wide first principal components (PC1) both corresponded to the previously described North or Northwest-Southeast axis of European variation. We found that the genome-wide PCA captured this primary dimension of variation more precisely and identified additional axes of genome-wide variation of relevance to epithelial ovarian cancer. Associations evident between the genome-wide PCs and study site corroborate North American immigration history and suggest that undiscovered dimensions of variation lie within Northern Europe. The structure captured by the genome-wide PCA was also found within control individuals and did not reflect the case-control variation present in the data. The genome-wide PCA highlighted three regions of local LD, corresponding to the lactase (LCT) gene on chromosome 2, the human leukocyte antigen system (HLA) on chromosome 6 and to a common inversion polymorphism on chromosome 8. These features did not compromise the efficacy of PCs from this analysis for ancestry control. This study concludes that although AIMs panels are a cost-effective way of capturing population structure, genome-wide data should preferably be used when available.
Published: 2011

42. MicroRNA processing and binding site polymorphisms are not replicated in the Ovarian Cancer Association Consortium

Author: Steven A. Narod, Daniel W. Cramer, Jonathan Tyrer, Jin Q. Cheng, Paul D.P. Pharoah, Jill S. Barnholtz-Sloan, Usha Menon, Michael J. Birrer, Jennifer Permuth-Wey, Montserrat Garcia-Closas, Rebecca Sutphen, Aleksandra Gentry-Maharaj, John R. McLaughlin, Zhihua Chen, David Fenstermacher, Stephen J. Chanock, Brooke L. Fridley, Ya Yu Tsai, Ellen L. Goode, Johnathan M. Lancaster, Honglin Song, Julie M. Cunningham, Joellen M. Schildkraut, Harvey A. Risch, Kathryn L. Terry, Catherine M. Phelan, Heather S.L. Jim, Robert A. Vierkant, Andrew Berchuck, Thomas A. Sellers, Edwin S. Iversen, Susan J. Ramus, Jesus Gonzalez-Bosquet, Nicolas Wentzensen, Hui-Yi Lin, Y. Ann Chen, and Simon A. Gayther
Subjects: endocrine system diseases, Genotype, Epidemiology, Population, Single-nucleotide polymorphism, MiRNA binding, Biology, Carcinoma, Ovarian Epithelial, Population stratification, medicine.disease_cause, Polymorphism, Single Nucleotide, Article, Risk Factors, medicine, SNP, Humans, Genetic Predisposition to Disease, Neoplasms, Glandular and Epithelial, education, Genetics, Ovarian Neoplasms, education.field_of_study, Binding Sites, MicroRNAs, Oncology, Female, KRAS, Imputation (genetics)
Abstract: Background: Single nucleotide polymorphisms (SNP) in microRNA-related genes have been associated with epithelial ovarian cancer (EOC) risk in two reports, yet associated alleles may be inconsistent across studies. Methods: We conducted a pooled analysis of previously identified SNPs by combining genotype data from 3,973 invasive EOC cases and 3,276 controls from the Ovarian Cancer Association Consortium. We also conducted imputation to obtain dense coverage of genes and comparable genotype data for all studies. In total, 226 SNPs within 15 kb of 4 miRNA biogenesis genes (DDX20, DROSHA, GEMIN4, and XPO5) and 23 SNPs located within putative miRNA binding sites of 6 genes (CAV1, COL18A1, E2F2, IL1R1, KRAS, and UGT2A3) were genotyped or imputed and analyzed in the entire dataset. Results: After adjustment for European ancestry, no overall association was observed between any of the analyzed SNPs and EOC risk. Conclusions: Common variants in these evaluated genes do not seem to be strongly associated with EOC risk. Impact: This analysis suggests earlier associations between EOC risk and SNPs in these genes may have been chance findings, possibly confounded by population admixture. To more adequately evaluate the relationship between genetic variants and cancer risk, large sample sizes are needed, adjustment for population stratification should be carried out, and use of imputed SNP data should be considered. Cancer Epidemiol Biomarkers Prev; 20(8); 1793–7. ©2011 AACR.
Published: 2011

43. Genetic variation in insulin-like growth factor 2 may play a role in ovarian cancer risk

Author: Estrid Høgdall, Georgia Chenevix-Trench, Malcolm C. Pike, Christopher K. Edlund, Simon A. Gayther, Daniel O. Stram, Anna Jakubowska, Usha Menon, Paul D.P. Pharoah, Roberta B. Ness, David Van Den Berg, Valerie McGuire, Alice S. Whittemore, Jonathan Beesley, Joellen M. Schildkraut, Jan Lubinski, Krzysztof Mędrek, Mary Anne Rossing, Susan J. Ramus, Anna H. Wu, Chris Hsu, Jacek Gronwald, Kara L. Cushing-Haugen, Penelope M. Webb, Weiva Sieh, Aleksandra Gentry-Maharaj, Andrew Berchuck, Claus Høgdall, David V. Conti, Edwin S. Iversen, Jennifer A. Doherty, Patricia G. Moorman, Kirsten B. Moysich, Celeste Leigh Pearce, Susanne K. Kjaer, and Honglin Song
Subjects: Oncology, Adult, medicine.medical_specialty, endocrine system diseases, Genotype, IGFBP3, Single-nucleotide polymorphism, Biology, Carcinoma, Ovarian Epithelial, Polymorphism, Single Nucleotide, White People, Genetic Heterogeneity, Insulin-Like Growth Factor II, Risk Factors, Internal medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, Neoplasms, Glandular and Epithelial, Risk factor, Insulin-Like Growth Factor I, Molecular Biology, Genetics (clinical), Aged, Ovarian Neoplasms, Genetic heterogeneity, Association Studies Articles, Case-control study, Cancer, General Medicine, Middle Aged, medicine.disease, female genital diseases and pregnancy complications, Minor allele frequency, Insulin-Like Growth Factor Binding Protein 1, Insulin-Like Growth Factor Binding Proteins, Endocrinology, Insulin-Like Growth Factor Binding Protein 3, Case-Control Studies, Female, Ovarian cancer
Abstract: The insulin-like growth factor (IGF) signaling axis plays an important role in cancer biology. We hypothesized that genetic variation in this pathway may influence risk of ovarian cancer. A three-center study of non-Hispanic whites including 1880 control women, 1135 women with invasive epithelial ovarian cancer and 321 women with borderline epithelial ovarian tumors was carried out to test the association between tag single-nucleotide polymorphisms (tSNPs) (n=58) in this pathway and risk of ovarian cancer. We found no association between variation in IGF1, IGFBP1 or IGFBP3 and risk of invasive disease, whereas five tSNPs in IGF2 were associated with risk of invasive epithelial ovarian cancer at P
Published: 2011

44. The role of KRAS rs61764370 in invasive epithelial ovarian cancer: implications for clinical testing

Author: Edwin S. Iversen, Julie M. Cunningham, Trinidad Caldés, Robert S. Brown, Malcolm C. Pike, Y. Ann Chen, Ellen L. Goode, Thomas A. Sellers, Tuomas Heikkinen, Christian F. Singer, Jenny Gross, Irene L. Andrulis, Celeste Leigh Pearce, Simon A. Gayther, Linda E. Kelemen, Georgia Chenevix-Trench, Sharon E. Johnatty, James P. LaPolla, Stefan Nickels, Rebecca Hein, Allison F. Vitonis, Anna H. Wu, Heli Nevanlinna, Linda S. Cook, Annika Lindblom, John R. McLaughlin, Susanne K. Kjaer, Jennifer A. Doherty, Hoda Anton-Culver, Natalia Antonenkova, Douglas F. Easton, Arif B. Ekici, Olga M. Sinilnikova, Usha Menon, Barbara Wappenschmidt, Angela Brooks-Wilson, David Fenstermacher, Catherine M. Phelan, James M. Flanagan, Arto Leminen, Mary S. Beattie, Yi Lu, Brooke L. Fridley, Ya Yu Tsai, Mary Anne Rossing, Antonis C. Antoniou, Aleksandra Gentry-Maharaj, Thilo Dörk, Lotte Nedergaard, Noah D. Kauff, Douglas A. Levine, Christine Walsh, Maria A. Caligo, Matti A. Rookus, Harvey A. Risch, Ignace Vergote, Beth Y. Karlan, Tamara Marees, Steven A. Narod, Jenny Chang-Claude, Daniel W. Cramer, Thomas Hansen, Conxi Lázaro, Paolo Radice, Robert A. Vierkant, Paul R. Harnett, Diana Eccles, Andrew Berchuck, Estrid Høgdall, Wendy R. Brewster, Daniel O. Stram, Matthias W. Beckmann, Joellen M. Schildkraut, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Roberta B. Ness, James Paul, Karin Leunen, Michael J. Birrer, Lambertus A. Kiemeney, Susan J. Ramus, Marco Montagna, Andrew K. Godwin, Rebecca Sutphen, Anne M. van Altena, Katherine L. Nathanson, Ian G. Campbell, Marc T. Goodman, Shan Wang-Gohrke, Stuart MacGregor, Eitan Friedman, Honglin Song, Argyrios Ziogas, Matthias Dürst, Kelly L. Bolton, Bo Gao, Nhu D. Le, Kirsten B. Moysich, Ana Osorio, Rachel T. Palmieri, Evelyn Despierre, Fergus J. Couch, Lene Lundvall, Diether Lambrechts, Ralf Bützow, Kathryn L. Terry, Anna de Fazio, Leon F.A.G. Massuger, Peter A. Fasching, Claus Høgdall, Stanley B. Kaye, and Natalia Bogdanova
Subjects: Oncology, Cancer Research, Genetics and epigenetic pathways of disease [NCMLS 6], endocrine system diseases, Genes, BRCA1, Carcinoma, Ovarian Epithelial, medicine.disease_cause, chemistry.chemical_compound, 0302 clinical medicine, Neoplasms, Glandular and Epithelial, 3' Untranslated Regions, Early Detection of Cancer, Ovarian Neoplasms, 0303 health sciences, Aetiology, screening and detection Immune Regulation [ONCOL 5], female genital diseases and pregnancy complications, 3. Good health, Serous fluid, 030220 oncology & carcinogenesis, Female, KRAS, Risk, medicine.medical_specialty, Genotype, MiRNA binding, Biology, Polymorphism, Single Nucleotide, Disease-Free Survival, Molecular epidemiology [NCEBP 1], Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, Breast cancer, Translational research [ONCOL 3], Internal medicine, Proto-Oncogene Proteins, medicine, Carcinoma, Humans, Genetic Predisposition to Disease, Neoplasm Invasiveness, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], 030304 developmental biology, Gynecology, Hereditary cancer and cancer-related syndromes [ONCOL 1], Cancer, medicine.disease, Carboplatin, MicroRNAs, chemistry, ras Proteins, Ovarian cancer
Abstract: Purpose: An assay for the single-nucleotide polymorphism (SNP), rs61764370, has recently been commercially marketed as a clinical test to aid ovarian cancer risk evaluation in women with family histories of the disease. rs67164370 is in a 3′-UTR miRNA binding site of the KRAS oncogene and is a candidate for epithelial ovarian cancer (EOC) susceptibility. However, only one published article, analyzing fewer than 1,000 subjects in total, has examined this association. Experimental Design: Risk association was evaluated in 8,669 cases of invasive EOC and 10,012 controls from 19 studies participating in the Ovarian Cancer Association Consortium, and in 683 cases and 2,044 controls carrying BRCA1 mutations from studies in the Consortium of Investigators of Modifiers of BRCA1/2. Prognosis association was also examined in a subset of five studies with progression-free survival (PFS) data and 18 studies with all-cause mortality data. Results: No evidence of association was observed between genotype and risk of unselected EOC (OR = 1.02, 95% CI: 0.95–1.10), serous EOC (OR = 1.08, 95% CI: 0.98–1.18), familial EOC (OR = 1.09, 95% CI: 0.78–1.54), or among women carrying deleterious mutations in BRCA1 (OR = 1.09, 95% CI: 0.88–1.36). There was little evidence for association with survival time among unselected cases (HR = 1.10, 95% CI: 0.99–1.22), among serous cases (HR = 1.12, 95% CI = 0.99–1.28), or with PFS in 540 cases treated with carboplatin and paclitaxel (HR = 1.18, 95% CI: 0.93–1.52). Conclusions: These data exclude the possibility of an association between rs61764370 and a clinically significant risk of ovarian cancer or of familial ovarian cancer. Use of this SNP for ovarian cancer clinical risk prediction, therefore, seems unwarranted. Clin Cancer Res; 17(11); 3742–50. ©2011 AACR.
Published: 2011

45. Epigenetic suppression of the TGF-beta pathway revealed by transcriptome profiling in ovarian cancer

Author: Noriomi Matsumura, Shingo Fujii, Seiichi Mori, Andrew Berchuck, Ikuo Konishi, Zhiqing Huang, Tsukasa Baba, Susan K. Murphy, and Edwin S. Iversen
Subjects: Epigenomics, Biology, Carcinoma, Ovarian Epithelial, medicine.disease_cause, DNA methyltransferase, Epigenesis, Genetic, Transforming Growth Factor beta, Cell Line, Tumor, Genetics, medicine, Tumor Cells, Cultured, Humans, Epigenetics, Neoplasms, Glandular and Epithelial, Genetics (clinical), Oligonucleotide Array Sequence Analysis, Regulation of gene expression, Ovarian Neoplasms, Microarray analysis techniques, Research, Gene Expression Profiling, DNA Methylation, Gene expression profiling, Gene Expression Regulation, Neoplastic, DNA methylation, Cancer research, Female, Carcinogenesis, Signal Transduction
Abstract: Epithelial ovarian cancer is the leading cause of death among gynecologic malignancies. Diagnosis usually occurs after metastatic spread, largely reflecting vague symptoms of early disease combined with lack of an effective screening strategy. Epigenetic mechanisms of gene regulation, including DNA methylation, are fundamental to normal cellular function and also play a major role in carcinogenesis. To elucidate the biological and clinical relevance of DNA methylation in ovarian cancer, we conducted expression microarray analysis of 39 cell lines and 17 primary culture specimens grown in the presence or absence of DNA methyltransferase (DNMT) inhibitors. Two parameters, induction of expression and standard deviation among untreated samples, identified 378 candidate methylated genes, many relevant to TGF-beta signaling. We analyzed 43 of these genes and they all exhibited methylation. Treatment with DNMT inhibitors increased TGF-beta pathway activity. Hierarchical clustering of ovarian cancers using the 378 genes reproducibly generated a distinct gene cluster strongly correlated with TGF-beta pathway activity that discriminates patients based on age. These data suggest that accumulation of age-related epigenetic modifications leads to suppression of TGF-beta signaling and contributes to ovarian carcinogenesis.
Published: 2011

46. Expression signatures of TP53 mutations in serous ovarian cancers

Author: Tsukasa Baba, Gregory Sfakianos, Angeles Alvarez Secord, Marcus Q. Bernardini, Jeffrey R. Marks, Andrew Berchuck, Jason C. Barnett, Paula S. Lee, Susan K. Murphy, and Edwin S. Iversen
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Time Factors, endocrine system diseases, DNA Mutational Analysis, Context (language use), Biology, medicine.disease_cause, lcsh:RC254-282, Breast cancer, Internal medicine, Genetics, medicine, Cluster Analysis, Humans, Missense mutation, Survivors, Neoplasm Staging, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms, Regulation of gene expression, Mutation, Gene Expression Profiling, Prognosis, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Survival Analysis, Gene Expression Regulation, Neoplastic, Gene expression profiling, Serous fluid, Female, Tumor Suppressor Protein p53, Ovarian cancer, Algorithms, Research Article
Abstract: Background Mutations in the TP53 gene are extremely common and occur very early in the progression of serous ovarian cancers. Gene expression patterns that relate to mutational status may provide insight into the etiology and biology of the disease. Methods The TP53 coding region was sequenced in 89 frozen serous ovarian cancers, 40 early stage (I/II) and 49 advanced stage (III/IV). Affymetrix U133A expression data was used to define gene expression patterns by mutation, type of mutation, and cancer stage. Results Missense or chain terminating (null) mutations in TP53 were found in 59/89 (66%) ovarian cancers. Early stage cancers had a significantly higher rate of null mutations than late stage disease (38% vs. 8%, p < 0.03). In advanced stage cases, mutations were more prevalent in short term survivors than long term survivors (81% vs. 30%, p = 0.0004). Gene expression patterns had a robust ability to predict TP53 status within training data. By using early versus late stage disease for out of sample predictions, the signature derived from early stage cancers could accurately (86%) predict mutation status of late stage cancers. Conclusions This represents the first attempt to define a genomic signature of TP53 mutation in ovarian cancer. Patterns of gene expression characteristic of TP53 mutation could be discerned and included several genes that are known p53 targets or have been described in the context of expression signatures of TP53 mutation in breast cancer.
Published: 2010

47. Association between DNA Damage Response and Repair Genes and Risk of Invasive Serous Ovarian Cancer

Author: Rex C. Bentley, Merlise A. Clyde, Edwin S. Iversen, Joellen M. Schildkraut, Regina S. Whitaker, Jeffrey R. Marks, Rachel T. Palmieri, Andrew Berchuck, Melanie A. Wilson, and Patricia G. Moorman
Subjects: Risk, medicine.medical_specialty, endocrine system diseases, DNA Repair, DNA repair, DNA damage, lcsh:Medicine, Single-nucleotide polymorphism, Biology, Genetics and Genomics/Complex Traits, Bioinformatics, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Molecular genetics, Genotype, medicine, Humans, Neoplasm Invasiveness, lcsh:Science, Cystadenocarcinoma, Genetics and Genomics/Cancer Genetics, 030304 developmental biology, Probability, Ovarian Neoplasms, 0303 health sciences, Multidisciplinary, Models, Statistical, Data Collection, lcsh:R, Case-control study, Bayes Theorem, medicine.disease, female genital diseases and pregnancy complications, 3. Good health, Cystadenocarcinoma, Serous, 030220 oncology & carcinogenesis, Case-Control Studies, Cancer research, lcsh:Q, Female, Mathematics/Statistics, Public Health and Epidemiology/Epidemiology, Tumor Suppressor Protein p53, Ovarian cancer, Research Article, DNA Damage
Abstract: Background We analyzed the association between 53 genes related to DNA repair and p53-mediated damage response and serous ovarian cancer risk using case-control data from the North Carolina Ovarian Cancer Study (NCOCS), a population-based, case-control study. Methods/Principal Findings The analysis was restricted to 364 invasive serous ovarian cancer cases and 761 controls of white, non-Hispanic race. Statistical analysis was two staged: a screen using marginal Bayes factors (BFs) for 484 SNPs and a modeling stage in which we calculated multivariate adjusted posterior probabilities of association for 77 SNPs that passed the screen. These probabilities were conditional on subject age at diagnosis/interview, batch, a DNA quality metric and genotypes of other SNPs and allowed for uncertainty in the genetic parameterizations of the SNPs and number of associated SNPs. Six SNPs had Bayes factors greater than 10 in favor of an association with invasive serous ovarian cancer. These included rs5762746 (median OR(odds ratio)per allele = 0.66; 95% credible interval (CI) = 0.44–1.00) and rs6005835 (median ORper allele = 0.69; 95% CI = 0.53–0.91) in CHEK2, rs2078486 (median ORper allele = 1.65; 95% CI = 1.21–2.25) and rs12951053 (median ORper allele = 1.65; 95% CI = 1.20–2.26) in TP53, rs411697 (median OR rare homozygote = 0.53; 95% CI = 0.35 – 0.79) in BACH1 and rs10131 (median OR rare homozygote = not estimable) in LIG4. The six most highly associated SNPs are either predicted to be functionally significant or are in LD with such a variant. The variants in TP53 were confirmed to be associated in a large follow-up study. Conclusions/Significance Based on our findings, further follow-up of the DNA repair and response pathways in a larger dataset is warranted to confirm these results.
Published: 2010

48. Common alleles in candidate susceptibility genes associated with risk and development of epithelial ovarian cancer

Author: Chris Jones, Anna Jakubowska, Paul D.P. Pharoah, Andrew Berchuck, Xiaoqing Chen, Jan Blaakær, Tanya Sher, Jacek Gronwald, Georgia Chenevix-Trench, Honglin Song, Patricia G. Moorman, Estrid Høgdall, Lydia Quaye, Malcolm C. Pike, Jenny Chang-Claude, Claus Høgdall, Kirsten B. Moysich, Alice S. Whittemore, Jonathan Beesley, Matthias W. Beckmann, Maria Notaridou, Edwin S. Iversen, Anna H. Wu, Susanne K. Kjaer, Lise Christensen, Usha Menon, David Van Den Berg, Krzysztof Mȩdrek, Lynne R. Wilkens, Roberta B. Ness, Joellen M. Schildkraut, Jan Lubinski, Susan J. Ramus, Valerie McGuire, Peter A. Fasching, Mary Anne Rossing, Shan Wang-Gohrke, C. Leigh Pearce, Aleksandra Gentry-Maharaj, Dimitra Dafou, Ian Jacobs, Arif B. Ekici, Eva Wozniak, Falk Thiel, Simon A. Gayther, Jennifer A. Doherty, Jonathan Tyrer, Michael E. Carney, and Marc T. Goodman
Subjects: Cancer Research, Candidate gene, Population, Loss of Heterozygosity, Single-nucleotide polymorphism, Genome-wide association study, Cell Cycle Proteins, Biology, Polymorphism, Single Nucleotide, Article, Loss of heterozygosity, Risk Factors, Genotype, medicine, Humans, Genetic Predisposition to Disease, Neoplasms, Glandular and Epithelial, education, Alleles, Oligonucleotide Array Sequence Analysis, Genetics, Ovarian Neoplasms, education.field_of_study, Cancer, Nuclear Proteins, medicine.disease, Oncology, Cancer research, Female, Ovarian cancer
Abstract: Common germline genetic variation in the population is associated with susceptibility to epithelial ovarian cancer. Microcell-mediated chromosome transfer and expression microarray analysis identified nine genes associated with functional suppression of tumorogenicity in ovarian cancer cell lines; AIFM2, AKTIP, AXIN2, CASP5, FILIP1L, RBBP8, RGC32, RUVBL1 and STAG3. Sixty-three tagging single nucleotide polymorphisms (tSNPs) in these genes were genotyped in 1,799 invasive ovarian cancer cases and 3,045 controls to look for associations with disease risk. Two SNPs in RUVBL1, rs13063604 and rs7650365, were associated with increased risk of serous ovarian cancer [HetOR = 1.42 (1.15-1.74) and the HomOR = 1.63 (1.10-1.42), p-trend = 0.0002] and [HetOR = 0.97 (0.80-1.17), HomOR = 0.74 (0.58-0.93), p-trend = 0.009], respectively. We genotyped rs13063604 and rs7650365 in an additional 4,590 cases and 6,031 controls from ten sites from the United States, Europe and Australia; however, neither SNP was significant in Stage 2. We also evaluated the potential role of tSNPs in these nine genes in ovarian cancer development by testing for allele-specific loss of heterozygosity (LOH) in 286 primary ovarian tumours. We found frequent LOH for tSNPs in AXIN2, AKTIP and RGC32 (64, 46 and 34%, respectively) and one SNP, rs1637001, in STAG3 showed significant allele-specific LOH with loss of the common allele in 94% of informative tumours (p = 0.015). Array comparative genomic hybridisation indicated that this nonrandom allelic imbalance was due to amplification of the rare allele. In conclusion, we show evidence for the involvement of a common allele of STAG3 in the development of epithelial ovarian cancer.
Published: 2010

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

Author: Francesmary Modugno, Argyrios Ziogas, Ian Tomlinson, David Van Den Berg, Stanley B. Kaye, Natalia Bogdanova, Chu Chen, Julie M. Cunningham, Estrid Høgdall, T A Sellers, Susan J. Ramus, Joellen M. Schildkraut, Søren Besenbacher, Jonathan Tyrer, Tanya Sher, Wendy R. Brewster, Matthias Dürst, Penelope M. Webb, Patrick Sulem, Falk Thiel, Pamela J. Thompson, Robert S. Brown, Daniel W. Cramer, Celeste Leigh Pearce, Simon A. Gayther, Brooke L. Fridley, Mary Anne Rossing, Beth Y. Karlan, Michael J. Birrer, Alice S. Whittemore, Kunle Odunsi, Thilo Doerk, Honglin Song, Patricia G. Moorman, Daniel Paik, Douglas A. Levine, Kara L. Cushing-Haugen, Marc T. Goodman, Nhu D. Le, Thorunn Rafnar, Ingo B. Runnebaum, Julie A. Baker, Jacek Gronwald, Jan Lubinski, Anne M. van Altena, Rebecca Hein, Hoda Anton-Culver, Kirsten B. Moyisch, James M. Flanagan, Jonathan Beesley, Douglas F. Easton, Peter A. Fasching, Claus Høgdall, Jenny Gross, Arto Leminen, Susan Kruger-Kjaer, Peter Hillemanns, Weiva Sieh, Andrew Berchuck, Georgia Chenevix-Trench, Edwin S. Iversen, Robert P. Edwards, Chris Jones, Xiaoqing Chen, Jan Blaeker, Catherine M. Phelan, Krzysztof Mędrek, Michael E. Carney, Linda S. Cook, Robert A. Vierkant, Montserrat Garcia-Closas, Matthias W. Beckmann, Aleksandra Gentry-Maharaj, Frédéric Amant, Kari Stefansson, Heli Nevanlinna, Dena G. Hernandez, Diether Lambrechts, Jolanta Lissowska, Ya-Yu Tsai, Kathryn L. Terry, Kelly L. Bolton, Katja K.H. Aben, Anna H. Wu, Natalia Antonenkova, Eva Wozniak, Anna Jakubowska, Paul D.P. Pharoah, Ellen L. Goode, Lambertus A. Kiemeney, Steven A. Narod, Angela Brook-Wilson, Ignace Vergote, Tuomas Heikkinenen, Sharon E. Johnatty, Arif B. Ekici, Jenny Chang-Claude, Hanna P. Yang, Richard S. Houlston, Martin Gore, Evelyn Despierre, Rachel T. Palmieri, Ralf Bützow, Stephen J. Chanock, Jennifer A. Doherty, Leon F.A.G. Massuger, Maria Notaridou, Galina Lurie, Joanne B. Weidhaas, Daniel O. Stram, Roberta B. Ness, James Paul, Valerie McGuire, Ian G. Campbell, Shan Wang-Gohrke, Linda E. Kelemen, and Other departments
Subjects: Oncology, Candidate gene, endocrine system diseases, Ovarian Cancer Association Consortium, Genome-wide association study, Aetiology, screening and detection [ONCOL 5], 0302 clinical medicine, Tumor Cells, Cultured, GENETICS & HEREDITY, Oligonucleotide Array Sequence Analysis, Genetics, Ovarian Neoplasms, 0303 health sciences, 11 Medical And Health Sciences, Middle Aged, Adenocarcinoma, Mucinous, female genital diseases and pregnancy complications, 3. Good health, Serous fluid, 030220 oncology & carcinogenesis, Adenocarcinoma, Female, Life Sciences & Biomedicine, Australian Ovarian Cancer Study Group, medicine.medical_specialty, Genotype, Single-nucleotide polymorphism, Biology, BREAST, Polymorphism, Single Nucleotide, Article, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, Translational research [ONCOL 3], Internal medicine, Australian Cancer Study (Ovarian Cancer), medicine, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, 030304 developmental biology, Adaptor Proteins, Signal Transducing, Science & Technology, COMPLEX, Genome, Human, Gene Expression Profiling, Ovary, Case-control study, Cancer, 06 Biological Sciences, medicine.disease, BRCA1, GENOTYPES, Cystadenocarcinoma, Serous, Endometrial Neoplasms, Evaluation of complex medical interventions [NCEBP 2], Case-Control Studies, CELLS, Ovarian cancer, Chromosomes, Human, Pair 19, Adenocarcinoma, Clear Cell, Genome-Wide Association Study, Developmental Biology
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(1). 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 x 10(-4) and P = 6 x 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 x 10(-9) and P = 4 x 10(-11), respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1-interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development.
Published: 2010

50. Risk of ovarian cancer and inherited variants in relapse-associated genes

Author: Melissa C. Larson, Andrew Berchuck, Matthew L. Kosel, Ellen L. Goode, Brooke L. Fridley, Ya Yu Tsai, Kristin L. White, Lynn C. Hartmann, Julie M. Cunningham, Robert A. Vierkant, Kimberly R. Kalli, Abraham Peedicayil, Joellen M. Schildkraut, Catherine M. Phelan, Thomas A. Sellers, David N. Rider, Mark Liebow, Zachary S. Fredericksen, Elaine A. Elliott, Edwin S. Iversen, Fergus J. Couch, Vijayalakshmi Shridhar, and Prema Peethamabaran
Subjects: Oncology, Candidate gene, medicine.medical_specialty, lcsh:Medicine, Single-nucleotide polymorphism, Biology, Bioinformatics, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Recurrence, Internal medicine, Genotype, medicine, Humans, Genetic Predisposition to Disease, Molecular Biology/Chromatin Structure, lcsh:Science, Genetics and Genomics/Cancer Genetics, Aged, 030304 developmental biology, Ovarian Neoplasms, 0303 health sciences, Multidisciplinary, Haplotype, lcsh:R, Case-control study, Cancer, Genetics and Genomics/Gene Expression, Middle Aged, medicine.disease, 3. Good health, Serous fluid, Haplotypes, Women's Health/Gynecological Cancers, Case-Control Studies, 030220 oncology & carcinogenesis, Oncology/Gynecological Cancers, Female, lcsh:Q, Ovarian cancer, Research Article
Abstract: Background We previously identified a panel of genes associated with outcome of ovarian cancer. The purpose of the current study was to assess whether variants in these genes correlated with ovarian cancer risk. Methods and Findings Women with and without invasive ovarian cancer (749 cases, 1,041 controls) were genotyped at 136 single nucleotide polymorphisms (SNPs) within 13 candidate genes. Risk was estimated for each SNP and for overall variation within each gene. At the gene-level, variation within MSL1 (male-specific lethal-1 homolog) was associated with risk of serous cancer (p = 0.03); haplotypes within PRPF31 (PRP31 pre-mRNA processing factor 31 homolog) were associated with risk of invasive disease (p = 0.03). MSL1 rs7211770 was associated with decreased risk of serous disease (OR 0.81, 95% CI 0.66–0.98; p = 0.03). SNPs in MFSD7, BTN3A3, ZNF200, PTPRS, and CCND1A were inversely associated with risk (p
Published: 2010

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