Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer
Hui Shen(University of Southern California), Brooke L. Fridley(University of Kansas Medical Center), Honglin Song(University of Cambridge), Kate Lawrenson(University of Southern California), Julie M. Cunningham(Mayo Clinic), Susan J. Ramus(University of Southern California), Mine S. Cicek(Mayo Clinic in Florida), Jonathan P. Tyrer(University of Cambridge), Douglas Stram(University of Southern California), Melissa C. Larson(Mayo Clinic in Florida), Martin Köbel(University of Calgary), Argyrios Ziogas(University of California, Irvine), Wei Zheng(Vanderbilt University), Hannah Yang(National Cancer Institute), Anna H. Wu(University of Southern California), Eva Wozniak(University College London), Yin Ling Woo(University of Malaya), Boris Winterhoff(Mayo Clinic), Elisabeth Wik(Haukeland University Hospital), Alice S. Whittemore(Stanford University), Nicolas Wentzensen(National Cancer Institute), Rachel Palmieri Weber(Duke Medical Center), Allison F. Vitonis(Brigham and Women's Hospital), Daniel Vincent(Genome Canada), Robert A. Vierkant(Mayo Clinic in Florida), Ignace Vergote(KU Leuven), David Van Den Berg(University of Southern California), Anne M. van Altena(Radboud University Nijmegen), Shelley S. Tworoger(Brigham and Women's Hospital), Pamela J. Thompson(University of Hawaiʻi at Mānoa), Daniel C. Tessier(Genome Canada), Kathryn L. Terry(Brigham and Women's Hospital), Soo‐Hwang Teo(University Malaya Medical Centre), Claire Templeman(University of Southern California), Daniel O. Stram(University of Southern California), Melissa C. Southey(The University of Melbourne), Weiva Sieh(Stanford University), Nadeem Siddiqui(Glasgow Royal Infirmary), Yurii B. Shvetsov(University of Hawaiʻi at Mānoa), Xiao‐Ou Shu(University of California, Irvine), Viji Shridhar(Mayo Clinic), Shan Wang‐Gohrke(Universität Ulm), Gianluca Severi(The University of Melbourne), Ira Schwaab, Helga B. Salvesen(Haukeland University Hospital), Iwona K. Rzepecka(The Maria Sklodowska-Curie National Research Institute of Oncology), Ingo B. Runnebaum(Jena University Hospital), Mary Anne Rossing(University of Washington), Lorna Rodríguez-Rodríguez(Rutgers, The State University of New Jersey), Harvey A. Risch(Yale University), Stefan P. Renner(Universitätsklinikum Erlangen), Elizabeth M. Poole(Brigham and Women's Hospital), Malcolm C. Pike(University of Southern California), Catherine M. Phelan(Moffitt Cancer Center), Liisa M. Pelttari(University of Helsinki), Tanja Pejović(Oregon Health & Science University), James Paul(Beatson West of Scotland Cancer Centre), Irene Orlow(Memorial Sloan Kettering Cancer Center), Siti Zawiah Omar(University of Malaya), Sara H. Olson(Memorial Sloan Kettering Cancer Center), Kunle Odunsi(Roswell Park Comprehensive Cancer Center), Stefan Nickels(German Cancer Research Center), Heli Nevanlinna(University of Helsinki), Roberta B. Ness(The University of Texas Health Science Center at Houston), Steven A. Narod(University of Toronto), Toru Nakanishi(Aichi Cancer Center), Kirsten B. Moysich(Roswell Park Comprehensive Cancer Center), Álvaro N.A. Monteiro(Moffitt Cancer Center), Joanna Moes-Sosnowska(The Maria Sklodowska-Curie National Research Institute of Oncology), Francesmary Modugno(University of Pittsburgh), Usha Menon(University College London), John R. McLaughlin(Mount Sinai Hospital), Valerie McGuire(Stanford University), Keitaro Matsuo(Aichi Cancer Center), Noor Azmi Mat Adenan(University of Malaya), Leon F.A.G. Massuger(Radboud University Nijmegen), Galina Lurie(University of Hawaiʻi at Mānoa), Lene Lundvall(Copenhagen University Hospital), Jan Lubiński(International Hereditary Cancer Center), Jolanta Lissowska(The Maria Sklodowska-Curie National Research Institute of Oncology), Douglas A. Levine(Memorial Sloan Kettering Cancer Center), Arto Leminen(University of Helsinki), Alice W. Lee(University of Southern California), Nhu D. Le(BC Cancer Agency), Sandrina Lambrechts(KU Leuven), Diether Lambrechts(KU Leuven), Jolanta Kupryjańczyk(The Maria Sklodowska-Curie National Research Institute of Oncology), Camilla Krakstad(Haukeland University Hospital), Gottfried E. Konecny(University of California, Los Angeles), Susanne K. Kjær(Copenhagen University Hospital), Lambertus A. Kiemeney(Radboud University Nijmegen), Linda E. Kelemen(Alberta Health Services), Gary L. Keeney(Mayo Clinic), Beth Y. Karlan(Cedars-Sinai Medical Center), Rod Karevan(University of Southern California), Kimberly R. Kalli(Mayo Clinic), Hiroaki Kajiyama(Nagoya University), Bu‐Tian Ji(National Cancer Institute), Allan Jensen(Danish Cancer Society), Anna Jakubowska(International Hereditary Cancer Center), Edwin S. Iversen(Duke University), Satoyo Hosono(Aichi Cancer Center), Claus Høgdall(Copenhagen University Hospital), Estrid Høgdall(Herlev Hospital), Maureen E. Hoatlin(Oregon Health & Science University), Peter Hillemanns(Medizinische Hochschule Hannover), Florian Heitz(Helios Dr. Horst Schmidt Kliniken Wiesbaden), Rebecca Hein(German Cancer Research Center), Philipp Harter(Helios Dr. Horst Schmidt Kliniken Wiesbaden), Mari K. Halle(Haukeland University Hospital), Per Hall(Karolinska Institutet), Jacek Gronwald(International Hereditary Cancer Center), Martin Gore(Royal Marsden Hospital), Marc T. Goodman(Cedars-Sinai Medical Center), Graham G. Giles(The University of Melbourne), Aleksandra Gentry‐Maharaj(University College London), Montserrat García‐Closas(Institute of Cancer Research), James M. Flanagan(Imperial College London), Peter A. Fasching(University of California, Los Angeles), Arif B. Ekici(Friedrich-Alexander-Universität Erlangen-Nürnberg), Robert P. Edwards(Magee-Womens Hospital), Diana Eccles(University Hospital Southampton NHS Foundation Trust), Douglas F. Easton(University of Cambridge), Matthias Dürst(Jena University Hospital), Andreas du Bois(Helios Dr. Horst Schmidt Kliniken Wiesbaden), Thilo Dörk(Medizinische Hochschule Hannover), Jennifer A. Doherty(Dartmouth College), Evelyn Despierre(KU Leuven), Agnieszka Dansonka‐Mieszkowska(The Maria Sklodowska-Curie National Research Institute of Oncology), Cezary Cybulski(International Hereditary Cancer Center), Daniel W. Cramer(Brigham and Women's Hospital), Linda S. Cook(University of New Mexico), Xiaoqing Chen(QIMR Berghofer Medical Research Institute), Bridget Charbonneau(University of New Mexico), Jenny Chang‐Claude(German Cancer Research Center), Ian Campbell(The University of Melbourne), Ralf Bützow(University of Helsinki), Clareann H. Bunker(University of Pittsburgh), Doerthe Brueggmann(University of Southern California), Robert Brown(Imperial College London), Angela Brooks‐Wilson(BC Cancer Agency), Louise A. Brinton(National Cancer Institute), Natalia Bogdanova(Medizinische Hochschule Hannover), Matthew S. Block(Mayo Clinic), Elizabeth Benjamin(University College London), Jonathan Beesley(QIMR Berghofer Medical Research Institute), Matthias W. Beckmann(Universitätsklinikum Erlangen), Elisa V. Bandera(Rutgers, The State University of New Jersey), Laura Baglietto(The University of Melbourne), François Bacot(Genome Canada), Sebastian M. Armasu(Mayo Clinic in Florida), Natalia Antonenkova(Belarusian Research Center For Pediatric Oncology and Hematology), Hoda Anton‐Culver(University of California, Irvine), Katja K.H. Aben(Radboud University Nijmegen), Dong Liang(Texas Southern University), Xifeng Wu(The University of Texas MD Anderson Cancer Center), Karen Lu(The University of Texas MD Anderson Cancer Center), Michelle A.T. Hildebrandt(The University of Texas MD Anderson Cancer Center), Australian Ovarian Cancer Study Group(Duke Cancer Institute), Australian Cancer Study(Moffitt Cancer Center), Joellen M. Schildkraut(BC Cancer Agency), Thomas A. Sellers(Moffitt Cancer Center), David G. Huntsman(BC Cancer Agency), Andrew Berchuck(University of Southern California), Georgia Chenevix‐Trench(QIMR Berghofer Medical Research Institute), Simon A. Gayther(University of Southern California), Paul D.P. Pharoah(University of Cambridge), Peter W. Laird(University of Southern California), Ellen L. Goode(Mayo Clinic in Florida), Celeste Leigh Pearce(University of Southern California)
Cited by 169Open Access
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. HNF1B is overexpressed in the clear cell subtype and epigenetically silenced in the serous subtype of ovarian cancer. Pearce and colleagues now show that genetic variants in HNF1B are differentially associated with risks of developing these two cancer subtypes, possibly through an epigenetic mechanism.
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