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1. A Study of High-Grade Serous Ovarian Cancer Origins Implicates the SOX18 Transcription Factor in Tumor Development

Author

Annie Y. Liu, Forough Abbasi, Xianzhi Lin, Huy Q. Dinh, Amy C. Rowat, Kate Lawrenson, Felipe Segato Dezem, Kevin C. Vavra, Ronny Drapkin, Yvonne G. Lin, Houtan Noushmehr, Beth Y. Karlan, Rosario I. Corona, Janet M. Lee, Simon G. Coetzee, Navjot Kaur Gill, Ji-Heui Seo, Simon A. Gayther, Marcos A. S. Fonseca, Paulette Mhawech-Fauceglia, Matthew L. Freedman, Dennis J. Hazelett, and Tanja Pejovic

Subjects
0301 basic medicine, Adult, Epithelial-Mesenchymal Transition, RNA-Seq, Biology, General Biochemistry, Genetics and Molecular Biology, Cell Line, Machine Learning, 03 medical and health sciences, 0302 clinical medicine, Precursor cell, Cell Line, Tumor, Gene expression, medicine, Serous ovarian cancer, SOXF Transcription Factors, Humans, Transcription factor, lcsh:QH301-705.5, Fallopian Tubes, Aged, Ovarian Neoplasms, Ovary, EXPRESSÃO GÊNICA, Epithelial Cells, Middle Aged, female genital diseases and pregnancy complications, Chromatin, Gene Expression Regulation, Neoplastic, Serous fluid, 030104 developmental biology, medicine.anatomical_structure, lcsh:Biology (General), Cancer research, Female, Single-Cell Analysis, Transcriptome, 030217 neurology & neurosurgery, Fallopian tube
Abstract

Summary: Fallopian tube secretory epithelial cells (FTSECs) are likely the main precursor cell type of high-grade serous ovarian cancers (HGSOCs), but these tumors may also arise from ovarian surface epithelial cells (OSECs). We profiled global landscapes of gene expression and active chromatin to characterize molecular similarities between OSECs (n = 114), FTSECs (n = 74), and HGSOCs (n = 394). A one-class machine learning algorithm predicts that most HGSOCs derive from FTSECs, with particularly high FTSEC scores in mesenchymal-type HGSOCs (padj < 8 × 10−4). However, a subset of HGSOCs likely derive from OSECs, particularly HGSOCs of the proliferative type (padj < 2 × 10−4), suggesting a dualistic model for HGSOC origins. Super-enhancer (SE) landscapes were also more similar between FTSECs and HGSOCs than between OSECs and HGSOCs (p < 2.2 × 10−16). The SOX18 transcription factor (TF) coincided with a HGSOC-specific SE, and ectopic overexpression of SOX18 in FTSECs caused epithelial-to-mesenchymal transition, indicating that SOX18 plays a role in establishing the mesenchymal signature of fallopian-derived HGSOCs. : Lawrenson et al. profile gene expression and active chromatin in ∼200 ovarian and fallopian epithelial isolates and implement machine learning to demonstrate that most high-grade serous ovarian cancers (HGSOCs) derive from fallopian tube epithelial cells, but a subset may originate from ovarian epithelia. SOX18 induces mesenchymal features to drive early neoplasia in fallopian tube precursors. Keywords: high-grade serous ovarian cancer, ovarian surface epithelial cell, fallopian tube secretory epithelial cell, super enhancers, transcription factors, SOX18, single-cell RNA-seq, RNA-seq, machine learning, one-class logistic regression models, dual origins

Published
2018

2. A transcriptome-wide association study of high-grade serous epithelial ovarian cancer identifies new susceptibility genes and splice variants

Author

Houtan Noushmehr, Simon A. Gayther, Siddhartha Kar, Bogdan Pasaniuc, Matthew L. Freedman, Paulo C Lyra, Janet M. Lee, Alexander Gusev, Paul D.P. Pharoah, Felipe Segato, Tanya Pejovic, Beth Y. Karlan, Kevin C. Vavra, Gang Liu, Kate Lawrenson, Marcos A. S. Fonseca, Xianzhi Lin, and Alvaro N.A. Monteiro

Subjects
Candidate gene, ovarian surface epithelial cells (OSECs), Genome-wide association study, Cell Cycle Proteins, Biology, Carcinoma, Ovarian Epithelial, Polymorphism, Single Nucleotide, splice-Transcriptome-wide association study (spTWAS), Article, Transcriptome, 03 medical and health sciences, Exon, Gene Knockout Techniques, 0302 clinical medicine, RNA-sequencing (RNA-seq), fallopian tube secretory epithelial cells (FTSECs), Cell Line, Tumor, expression quantitative trait locus analysis (eQTL), Databases, Genetic, Genetics, medicine, Humans, Genetic Predisposition to Disease, Gene, Genome wide association studies (GWAS), 030304 developmental biology, Ovarian Neoplasms, 0303 health sciences, Endosomal Sorting Complexes Required for Transport, Models, Genetic, The Cancer Genome Atlas (TCGA), Alternative splicing, EXPRESSÃO GÊNICA, Nuclear Proteins, medicine.disease, 3. Good health, Gene Expression Regulation, Neoplastic, epithelial ovarian cancer (EOC), Serous fluid, Alternative Splicing, high-grade serous ovarian cancer (HGSOC), Cancer research, splice site quantitative trait locus analysis (spQTL), Female, Ovarian cancer, 030217 neurology & neurosurgery, Genome-Wide Association Study, Transcriptome-wide association study (TWAS)
Abstract

We sought to identify susceptibility genes for high-grade serous ovarian cancer (HGSOC) by performing a transcriptome-wide association study of gene expression and splice junction usage in HGSOC-relevant tissue types (N = 2,169) and the largest genome-wide association study available for HGSOC (N = 13,037 cases and 40,941 controls). We identified 25 transcriptome-wide association study significant genes, 7 at the junction level only, including LRRC46 at 19q21.32, (P = 1 × 10−9), CHMP4C at 8q21 (P = 2 × 10−11) and a PRC1 junction at 15q26 (P = 7 × 10−9). In vitro assays for CHMP4C showed that the associated variant induces allele-specific exon inclusion (P = 0.0024). Functional screens in HGSOC cell lines found evidence of essentiality for three of the new genes we identified: HAUS6, KANSL1 and PRC1, with the latter comparable to MYC. Our study implicates at least one target gene for 6 out of 13 distinct genome-wide association study regions, identifying 23 new candidate susceptibility genes for HGSOC. A multi-tissue transcriptome-wide association study based on genetic predictors of expression level and alternative splicing in relevant tissues identifies 25 candidate genes associated with high-grade serous ovarian cancer.

Published
2018

3. 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

4. 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

5. A three-dimensional microenvironment alters protein expression and chemosensitivity of epithelial ovarian cancer cells in vitro

Author

Paulette Mhawech-Fauceglia, Lucineh Cristina Parsanian, Janet M. Lee, Nathan Lee, Kate Lawrenson, Simon A. Gayther, and Yvonne G. Lin

Subjects
Oncology, medicine.medical_specialty, Cell Culture Techniques, Antineoplastic Agents, Cell Growth Processes, Biology, Pathology and Forensic Medicine, Mice, In vivo, Cell Line, Tumor, Spheroids, Cellular, Internal medicine, Biomarkers, Tumor, Cell Adhesion, Tumor Microenvironment, medicine, Animals, Humans, Neoplasm, Cell adhesion, Molecular Biology, Ovarian Neoplasms, Regulation of gene expression, Analysis of Variance, Tumor microenvironment, Histocytochemistry, Epithelial Cells, Cell Biology, medicine.disease, Xenograft Model Antitumor Assays, In vitro, Gene Expression Regulation, Neoplastic, Cytoskeletal Proteins, Drug development, Drug Resistance, Neoplasm, Cell culture, Cancer research, Female
Abstract

For many cancers, there is a real need for more effective therapies. Although many drugs show promising results in vitro, most fail to translate into an in vivo model system, and only ∼5% show anti-tumor activity in clinical trials. It remains a significant challenge to accurately replicate in vitro the complex in vivo microenvironment in which cancers thrive, but this will be key to increasing the success of translating novel therapies into clinical practice. Three-dimensional (3D) cell culture models may better mimic primary tumors in vivo than traditional two-dimensional (2D) cultures. Therefore, we established and characterized 3D in vitro models of 31 epithelial ovarian cancer (EOC) cell lines, compared their biological and molecular features with 2D cultures and primary tumors, and tested their efficacy as models for evaluating chemoresponse. When cultured in 3D using polyhydroxoethylamethacrylate-coated plastics, EOC lines formed multicellular aggregates that could be classified as 'large dense', 'large loose', and 'small', based on size, light permeability, and proportion of cells incorporated into the complex structures. Features of histological differentiation characteristic of primary tumors that were not present in 2D cultures were restored in 3D. For many cell lines, the transition from a 2D to 3D microenvironment induced changes in the expression of several biomarkers relevant to disease. Generally, EOC cell lines proliferated more slowly and were more chemoresistant in 3D compared with 2D culture. In summary, 3D models of EOCs better reflect the histological, biological, and molecular features of primary tumors than the same cells cultured using traditional 2D techniques; 3D in vitro models also exhibit different sensitivities to chemotherapeutic agents compared with 2D models, which may have a significant impact on the success of drug testing pipelines for EOC. These findings could also impact in vitro modeling approaches and drug development strategies for other solid tumor types.

Published
2013

6. 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

7. 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

8. Identification of novel candidate biomarkers of epithelial ovarian cancer by profiling the secretomes of three-dimensional genetic models of ovarian carcinogenesis

Author

Kate, Lawrenson, Paulette, Mhawech-Fauceglia, Jenny, Worthington, Tassja J, Spindler, Darragh, O'Brien, Janet M, Lee, Georgia, Spain, Maryam, Sharifian, Guisong, Wang, Kathleen M, Darcy, Tanja, Pejovic, Heidi, Sowter, John F, Timms, and Simon A, Gayther

Subjects
Ovarian Neoplasms, Proteomics, Models, Genetic, Nuclear Proteins, Carcinoma, Ovarian Epithelial, In Vitro Techniques, Prognosis, Gas Chromatography-Mass Spectrometry, Fatty Acid Synthase, Type I, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins c-myc, Proto-Oncogene Proteins p21(ras), Adipokines, Cell Line, Tumor, Lectins, Proto-Oncogene Proteins, Biomarkers, Tumor, ras Proteins, Humans, Female, Chitinase-3-Like Protein 1, Neoplasms, Glandular and Epithelial, Apoptosis Regulatory Proteins
Abstract

Epithelial ovarian cancer (EOC) is still considered the most lethal gynecological malignancy and improved early detection of ovarian cancer is crucial to improving patient prognoses. To address this need, we tested whether candidate EOC biomarkers can be identified using three-dimensional (3D) in vitro models. We quantified changes in the abundance of secreted proteins in a 3D genetic model of early-stage EOC, generated by expressing CMYC and KRAS(G) (12) (V) in TERT-immortalized normal ovarian epithelial cells. Cellular proteins were labeled in live cells using stable isotopic amino acid analogues, and secreted proteins identified and quantified using liquid chromatography-tandem mass spectrometry. Thirty-seven and 55 proteins were differentially expressed by CMYC and CMYC+KRAS(G) (12) (V) expressing cells respectively (p 0.05;2-fold). We evaluated expression of the top candidate biomarkers in ∼210 primary EOCs: CHI3L1 and FKBP4 are both expressed by96% of primary EOCs, and FASN and API5 are expressed by 86 and 75% of cases. High expression of CHI3L1 and FKBP4 was associated with worse patient survival (p = 0.042 and p = 0.002, respectively). Expression of LGALS3BP was positively associated with recurrence (p = 0.0001) and suboptimal debulking (p = 0.018) suggesting that these proteins may be novel prognostic biomarkers. Furthermore, within early stage tumours (I/II), high expression of API5, CHI3L1 and FASN was associated with high tumour grade (p = 3 × 10(-4) , p = 0.016, p = 0.010, respectively). We show in vitro cell biology models of early-stage cancer development can be used to identify novel candidate biomarkers for disease, and report the identification of proteins that represent novel potential candidate diagnostic and prognostic biomarkers for this highly lethal disease.

Published
2014

9. Src as a novel therapeutic target for endometriosis

Author

Hugo A.M. Torres, Nathan Lee, Janet M. Lee, P. Nagesh Rao, Kate Lawrenson, Simon A. Gayther, Houtan Noushmehr, and Doerthe Brueggmann

Subjects
Oncology, medicine.medical_specialty, Endometriosis, Mice, Epidermal growth factor, Internal medicine, Ovarian carcinoma, medicine, Animals, Humans, Neoplastic transformation, Ovarian Diseases, Cells, Cultured, Ovarian Neoplasms, business.industry, Obstetrics and Gynecology, Epithelial Cells, medicine.disease, Epithelium, DOENÇAS DOS GENITAIS FEMININOS, Genes, src, Cell Transformation, Neoplastic, medicine.anatomical_structure, Ovarian Endometriosis, Female, business, Ovarian cancer, Proto-oncogene tyrosine-protein kinase Src
Abstract

Background Endometriosis is a common condition that is associated with an increased risk of developing ovarian carcinoma. Improved in vitro models of this disease are needed to better understand how endometriosis, a benign disease, can undergo neoplastic transformation, and for the development of novel treatment strategies to prevent this progression. Methods We describe the generation and in vitro characterization of novel TERT immortalized ovarian endometriosis epithelial cell lines (EEC16-TERT). Results Expression of TERT alone was sufficient to immortalize endometriosis epithelial cells. TERT immortalization induces an epithelial-to-mesenchymal transition and perturbation in the expression of genes involved in the development of ovarian cancer. EEC16-TERT was non-tumorigenic when xenografted into immunocompromised mice but grew in anchorage-independent growth assays in an epidermal growth factor and hydrocortisone dependent manner. Colony formation in agar was abolished by inhibition of Src, and the Src pathway was found to be activated in human endometriosis lesions. Conclusions This new in vitro model system mimics endometriosis and the early stages of neoplastic transformation in the development of endometriosis associated ovarian cancer. We demonstrate the potential clinical relevance of this model by identifying Src activation as a novel pathway in endometriosis that could be targeted therapeutically, perhaps as a novel strategy to manage endometriosis clinically, or to prevent the development of endometriosis-associated ovarian cancer.

Published
2014

10. 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

11. 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

12. Molecular Analysis of Mixed Endometrioid and Serous Adenocarcinoma of the Endometrium

Author

Kara Duncan, Melissa K. Delgado, Lynda D. Roman, Simon A. Gayther, Song Liu, Janet M. Lee, Paulette Mhawech-Fauceglia, Elham Pakzamir, Biao Liu, and Kate Lawrenson

Subjects
Adult, Pathology, medicine.medical_specialty, Serous carcinoma, lcsh:Medicine, Biology, Uterine serous carcinoma, PAX8 Transcription Factor, 03 medical and health sciences, Serous Membrane, 0302 clinical medicine, Homer Scaffolding Proteins, CDKN2A, Uterine cancer, Biomarkers, Tumor, medicine, Carcinoma, Humans, Paired Box Transcription Factors, lcsh:Science, Cyclin-Dependent Kinase Inhibitor p16, Aged, 030304 developmental biology, 0303 health sciences, Multidisciplinary, lcsh:R, Serous membrane, Middle Aged, medicine.disease, Troponin, Endometrial Neoplasms, 3. Good health, Serous fluid, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Female, RNA, Long Noncoding, lcsh:Q, Carrier Proteins, PAX8, Carcinoma, Endometrioid, Research Article
Abstract

Background The molecular biology and cellular origins of mixed type endometrial carcinomas (MT-ECs) are poorly understood, and a Type II component of 10 percent or less may confer poorer prognoses. Methodology/Principal Findings We studied 10 cases of MT-EC (containing endometrioid and serous differentiation), 5 pure low-grade endometrioid adenocarcinoma (EAC) and 5 pure uterine serous carcinoma (USC). Endometrioid and serous components of the MT-ECs were macrodissected and the expression of 60 candidate genes compared between MT-EC, pure USC and pure EAC. We found that four genes were differentially expressed when MT-ECs were compared to pure low-grade EAC: CDKN2A (P = 0.006), H19 (P = 0.010), HOMER2 (P = 0.009) and TNNT1 (P = 0.006). Also while we found that even though MT-ECs closely resembled the molecular profiles of pure USCs, they also exhibit lower expression of PAX8 compared to all pure cases combined (P = 0.035). Conclusion Our data suggest that MT-EC exhibits the closest molecular and epidemiological similarities to pure USC and supports clinical observations that suggest patients with MT-EC should receive the same treatment as patients with pure serous carcinoma. Novel specific markers of MT-EC could be of diagnostic utility and could represent novel therapeutic targets in the future.

Published
2015

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