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

Hui Shen, Brooke L. Fridley, Honglin Song, Kate Lawrenson, Julie M. Cunningham, Susan J. Ramus, Mine S. Cicek, Jonathan Tyrer, Douglas Stram, Melissa C. Larson, Martin Köbel, Argyrios Ziogas, Wei Zheng, Hannah P. Yang, Anna H. Wu, Eva L. Wozniak, Yin Ling Woo, Boris Winterhoff, Elisabeth Wik, Alice S. Whittemore, Nicolas Wentzensen, Rachel Palmieri Weber, Allison F. Vitonis, Daniel Vincent, Robert A. Vierkant, Ignace Vergote, David Van Den Berg, Anne M. Van Altena, Shelley S. Tworoger, Pamela J. Thompson, Daniel C. Tessier, Kathryn L. Terry, Soo-Hwang Teo, Claire Templeman, Daniel O. Stram, Melissa C. Southey, Weiva Sieh, Nadeem Siddiqui, Yurii B. Shvetsov, Xiao-Ou Shu, Viji Shridhar, Shan Wang-Gohrke, Gianluca Severi, Ira Schwaab, Helga B. Salvesen, Iwona K. Rzepecka, Ingo B. Runnebaum, Mary Anne Rossing, Lorna Rodriguez-Rodriguez, Harvey A. Risch, Stefan P. Renner, Elizabeth M. Poole, Malcolm C. Pike, Catherine M. Phelan, Liisa M. Pelttari, Tanja Pejovic, James Paul, Irene Orlow, Siti Zawiah Omar, Sara H. Olson, Kunle Odunsi, Stefan Nickels, Heli Nevanlinna, Roberta B. Ness, Steven A. Narod, Toru Nakanishi, Kirsten B. Moysich, Alvaro N.A. Monteiro, Joanna Moes-Sosnowska, Francesmary Modugno, Usha Menon, John R. McLaughlin, Valerie McGuire, Keitaro Matsuo, Noor Azmi Mat Adenan, Leon F.A.G Massuger, Galina Lurie, Lene Lundvall, Jan Lubiński, Jolanta Lissowska, Douglas A. Levine, Arto Leminen, Alice W. Lee, Nhu D. Le, Sandrina Lambrechts, Diether Lambrechts, Jolanta Kupryjanczyk, Camilla Krakstad, Gottfried E. Konecny, Susanne Krüger Kjaer, Lambertus A. Kiemeney, Linda E. Kelemen, Gary L. Keeney, Beth Y. Karlan, Rod Karevan, Kimberly R. Kalli, Hiroaki Kajiyama, Bu-Tian Ji, Allan Jensen, Anna Jakubowska, Edwin Iversen, Satoyo Hosono, Claus K. Høgdall, Estrid Høgdall, Maureen Hoatlin, Peter Hillemanns, Florian Heitz, Rebecca Hein, Philipp Harter, Mari K. Halle, Per Hall, Jacek Gronwald, Martin Gore, Marc T. Goodman, Graham G. Giles, Aleksandra Gentry-Maharaj, Montserrat Garcia-Closas, James M. Flanagan, Peter A. Fasching, Arif B. Ekici, Robert Edwards, Diana Eccles, Douglas F. Easton, Matthias Dürst, Andreas du Bois, Thilo Dörk, Jennifer A. Doherty, Evelyn Despierre, Agnieszka Dansonka-Mieszkowska, Cezary Cybulski, Daniel W. Cramer, Linda S. Cook, Xiaoqing Chen, Bridget Charbonneau, Jenny Chang-Claude, Ian Campbell, Ralf Butzow, Clareann H. Bunker, Doerthe Brueggmann, Robert Brown, Angela Brooks-Wilson, Louise A. Brinton, Natalia Bogdanova, Matthew S. Block, Elizabeth Benjamin, Jonathan Beesley, Matthias W. Beckmann, Elisa V. Bandera, Laura Baglietto, François Bacot, Sebastian M. Armasu, Natalia Antonenkova, Hoda Anton-Culver, Katja K. Aben, Dong Liang, Xifeng Wu, Karen Lu, Michelle A.T. Hildebrandt, Joellen M. Schildkraut, Thomas A. Sellers, David Huntsman, Andrew Berchuck, Georgia Chenevix-Trench, Simon A. Gayther, Paul D.P. Pharoah, Peter W. Laird, Ellen L. Goode () and Celeste Leigh Pearce
Additional contact information
Hui Shen: USC Epigenome Center, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center
Brooke L. Fridley: University of Kansas Medical Center
Honglin Song: University of Cambridge
Kate Lawrenson: Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center
Julie M. Cunningham: Mayo Clinic
Susan J. Ramus: Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center
Mine S. Cicek: Mayo Clinic
Jonathan Tyrer: University of Cambridge
Douglas Stram: Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center
Melissa C. Larson: Mayo Clinic
Martin Köbel: Calgary Laboratory Services, University of Calgary
Argyrios Ziogas: Center for Cancer Genetics Research and Prevention, School of Medicine, University of California Irvine
Wei Zheng: Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Vanderbilt University
Hannah P. Yang: National Cancer Institute
Anna H. Wu: Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center
Eva L. Wozniak: Gynaecological Cancer Research Centre, UCL EGA Institute for Women's Health
Yin Ling Woo: Faculty of Medicine, Affiliated to UM Cancer Research Institute, University of Malaya
Boris Winterhoff: Mayo Clinic
Elisabeth Wik: Haukeland University Hospital
Alice S. Whittemore: Stanford University School of Medicine
Nicolas Wentzensen: National Cancer Institute
Rachel Palmieri Weber: Duke University Medical Center
Allison F. Vitonis: Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Harvard Medical School
Daniel Vincent: Génome Québec
Robert A. Vierkant: Mayo Clinic
Ignace Vergote: Vesalius Research Center, VIB
David Van Den Berg: Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center
Anne M. Van Altena: Radboud University Medical Centre
Shelley S. Tworoger: Harvard Medical School, Brigham and Women's Hospital
Pamela J. Thompson: Cancer Epidemiology Program, University of Hawaii Cancer Center
Daniel C. Tessier: Génome Québec
Kathryn L. Terry: Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Harvard Medical School
Soo-Hwang Teo: Cancer Research Initiatives Foundation, Sime Darby Medical Centre
Claire Templeman: Keck School of Medicine, University of Southern California
Daniel O. Stram: Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center
Melissa C. Southey: Genetic Epidemiology Laboratory, University of Melbourne
Weiva Sieh: Stanford University School of Medicine
Nadeem Siddiqui: Glasgow Royal Infirmary
Yurii B. Shvetsov: Cancer Epidemiology Program, University of Hawaii Cancer Center
Xiao-Ou Shu: Center for Cancer Genetics Research and Prevention, School of Medicine, University of California Irvine
Viji Shridhar: Mayo Clinic
Shan Wang-Gohrke: University of Ulm
Gianluca Severi: Cancer Epidemiology Centre, Cancer Council Victoria
Ira Schwaab: Institut für Humangenetik Wiesbaden
Helga B. Salvesen: Haukeland University Hospital
Iwona K. Rzepecka: Maria Sklodowska-Curie Memorial Cancer Center, Institute of Oncology
Ingo B. Runnebaum: Jena University Hospital
Mary Anne Rossing: Program in Epidemiology, Fred Hutchinson Cancer Research Center
Lorna Rodriguez-Rodriguez: Cancer Institute of New Jersey, Robert Wood Johnson Medical School
Harvey A. Risch: Yale School of Public Health
Stefan P. Renner: University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center
Elizabeth M. Poole: Harvard Medical School, Brigham and Women's Hospital
Malcolm C. Pike: Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center
Catherine M. Phelan: Moffitt Cancer Center
Liisa M. Pelttari: University of Helsinki and Helsinki University Central Hospital
Tanja Pejovic: Oregon Health and Science University
James Paul: Beatson West of Scotland Cancer Centre
Irene Orlow: Memorial Sloan-Kettering Cancer Center
Siti Zawiah Omar: Faculty of Medicine, Affiliated to UM Cancer Research Institute, University of Malaya
Sara H. Olson: Memorial Sloan-Kettering Cancer Center
Kunle Odunsi: Roswell Park Cancer Institute
Stefan Nickels: German Cancer Research Center
Heli Nevanlinna: University of Helsinki and Helsinki University Central Hospital
Roberta B. Ness: School of Public Health, University of Texas
Steven A. Narod: Women’s College Research Institute, University of Toronto
Toru Nakanishi: Aichi Cancer Center Central Hospital
Kirsten B. Moysich: Roswell Park Cancer Institute
Alvaro N.A. Monteiro: Moffitt Cancer Center
Joanna Moes-Sosnowska: Maria Sklodowska-Curie Memorial Cancer Center, Institute of Oncology
Francesmary Modugno: Gynecology and Reproductive Sciences, University of Pittsburgh
Usha Menon: Gynaecological Cancer Research Centre, UCL EGA Institute for Women's Health
John R. McLaughlin: Dalla Lana School of Public Health, Faculty of Medicine, University of Toronto
Valerie McGuire: Stanford University School of Medicine
Keitaro Matsuo: Aichi Cancer Center Research Institute
Noor Azmi Mat Adenan: Faculty of Medicine, Affiliated to UM Cancer Research Institute, University of Malaya
Leon F.A.G Massuger: Radboud University Medical Centre
Galina Lurie: Cancer Epidemiology Program, University of Hawaii Cancer Center
Lene Lundvall: Gynecologic Clinic, The Juliane Marie Center, Copenhagen University Hospital
Jan Lubiński: International Hereditary Cancer Center, Pomeranian Medical University
Jolanta Lissowska: Maria Sklodowska-Curie Memorial Cancer Center
Douglas A. Levine: Gynecology Service, Memorial Sloan-Kettering Cancer Center
Arto Leminen: University of Helsinki and Helsinki University Central Hospital
Alice W. Lee: Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center
Nhu D. Le: Cancer Control Research, BC Cancer Agency
Sandrina Lambrechts: Vesalius Research Center, VIB
Diether Lambrechts: Vesalius Research Center, VIB
Jolanta Kupryjanczyk: Maria Sklodowska-Curie Memorial Cancer Center, Institute of Oncology
Camilla Krakstad: Haukeland University Hospital
Gottfried E. Konecny: David Geffen School of Medicine, University of California at Los Angeles
Susanne Krüger Kjaer: Gynecologic Clinic, The Juliane Marie Center, Copenhagen University Hospital
Lambertus A. Kiemeney: Biostatistics and HTA, Radboud University Medical Centre
Linda E. Kelemen: Alberta Health Services-Cancer Care
Gary L. Keeney: Mayo Clinic
Beth Y. Karlan: Women’s Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center
Rod Karevan: Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center
Kimberly R. Kalli: Mayo Clinic
Hiroaki Kajiyama: Nagoya University Graduate School of Medicine
Bu-Tian Ji: National Cancer Institute
Allan Jensen: Virus, Lifestyle and Genes, Danish Cancer Society Research Center
Anna Jakubowska: International Hereditary Cancer Center, Pomeranian Medical University
Edwin Iversen: Duke University
Satoyo Hosono: Aichi Cancer Center Research Institute
Claus K. Høgdall: Gynecologic Clinic, The Juliane Marie Center, Copenhagen University Hospital
Estrid Høgdall: Virus, Lifestyle and Genes, Danish Cancer Society Research Center
Maureen Hoatlin: Oregon Health and Science University
Peter Hillemanns: Clinics of Obstetrics and Gynaecology, Hannover Medical School
Florian Heitz: Kliniken Essen-Mitte
Rebecca Hein: German Cancer Research Center
Philipp Harter: Kliniken Essen-Mitte
Mari K. Halle: Haukeland University Hospital
Per Hall: Karolinska Institutet
Jacek Gronwald: International Hereditary Cancer Center, Pomeranian Medical University
Martin Gore: Gynecological Oncology Unit, Royal Marsden Hospital
Marc T. Goodman: Cedars Sinai Medical Center, Samuel Oschin Comprehensive Cancer Center Institute
Graham G. Giles: Cancer Epidemiology Centre, Cancer Council Victoria
Aleksandra Gentry-Maharaj: Gynaecological Cancer Research Centre, UCL EGA Institute for Women's Health
Montserrat Garcia-Closas: Breakthrough Breast Cancer Research Centre, Institute of Cancer Research
James M. Flanagan: Imperial College London
Peter A. Fasching: University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center
Arif B. Ekici: Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg
Robert Edwards: Maggee Women’s Hospital
Diana Eccles: Faculty of Medicine, University of Southampton, University Hospital Southampton
Douglas F. Easton: University of Cambridge
Matthias Dürst: Jena University Hospital
Andreas du Bois: Kliniken Essen-Mitte
Thilo Dörk: Gynaecology Research Unit, Hannover Medical School
Jennifer A. Doherty: Section of Biostatistics and Epidemiology, Geisel School of Medicine at Dartmouth
Evelyn Despierre: Vesalius Research Center, VIB
Agnieszka Dansonka-Mieszkowska: Maria Sklodowska-Curie Memorial Cancer Center, Institute of Oncology
Cezary Cybulski: International Hereditary Cancer Center, Pomeranian Medical University
Daniel W. Cramer: Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Harvard Medical School
Linda S. Cook: University of New Mexico
Xiaoqing Chen: Queensland Institute of Medical Research
Bridget Charbonneau: University of New Mexico
Jenny Chang-Claude: German Cancer Research Center
Ian Campbell: Peter MacCallum Cancer Centre, Cancer Genetics Laboratory
Ralf Butzow: University of Helsinki and Helsinki University Central Hospital
Clareann H. Bunker: Graduate School of Public Health, University of Pittsburgh
Doerthe Brueggmann: Keck School of Medicine, University of Southern California
Robert Brown: Imperial College London
Angela Brooks-Wilson: Genome Sciences Centre, BC Cancer Agency
Louise A. Brinton: National Cancer Institute
Natalia Bogdanova: Gynaecology Research Unit, Hannover Medical School
Matthew S. Block: Mayo Clinic
Elizabeth Benjamin: Cancer Institute, University College London
Jonathan Beesley: Queensland Institute of Medical Research
Matthias W. Beckmann: University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center
Elisa V. Bandera: Cancer Institute of New Jersey, Robert Wood Johnson Medical School
Laura Baglietto: Cancer Epidemiology Centre, Cancer Council Victoria
François Bacot: Génome Québec
Sebastian M. Armasu: Mayo Clinic
Natalia Antonenkova: Belarusian Institute for Oncology and Medical Radiology Aleksandrov N.N.
Hoda Anton-Culver: Center for Cancer Genetics Research and Prevention, School of Medicine, University of California Irvine
Katja K. Aben: Biostatistics and HTA, Radboud University Medical Centre
Dong Liang: College of Pharmacy and Health Sciences, Texas Southern University
Xifeng Wu: University of Texas MD Anderson Cancer Center
Karen Lu: University of Texas MD Anderson Cancer Center
Michelle A.T. Hildebrandt: University of Texas MD Anderson Cancer Center
Joellen M. Schildkraut: Duke University Medical Center
Thomas A. Sellers: Moffitt Cancer Center
David Huntsman: Vancouver General Hospital, BC Cancer Agency
Andrew Berchuck: Gynecologic Cancer Program, Duke Cancer Institute
Georgia Chenevix-Trench: Queensland Institute of Medical Research
Simon A. Gayther: Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center
Paul D.P. Pharoah: University of Cambridge
Peter W. Laird: USC Epigenome Center, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center
Ellen L. Goode: Mayo Clinic
Celeste Leigh Pearce: Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center

Nature Communications, 2013, vol. 4, issue 1, 1-10

Abstract: Abstract 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 × 10−10) and clear cell (rs11651755 OR=0.77, P=1.6 × 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.

Date: 2013
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DOI: 10.1038/ncomms2629

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