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

Author

Listed:
  • 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
    University of Bergen)

  • 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
    University Hospitals Leuven)

  • 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
    Harvard School of Public Health)

  • 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
    Harvard School of Public Health)

  • Soo-Hwang Teo

    (Cancer Research Initiatives Foundation, Sime Darby Medical Centre
    University Malaya Cancer Research Institute, University Malaya Medical Centre, University of Malaya)

  • 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
    Centre for Molecular, Environmental, Genetic and Analytical Epidemiology, University of Melbourne)

  • Ira Schwaab

    (Institut für Humangenetik Wiesbaden)

  • Helga B. Salvesen

    (Haukeland University Hospital
    University of Bergen)

  • 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
    University of Washington)

  • 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
    Harvard School of Public Health)

  • Malcolm C. Pike

    (Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center
    Memorial Sloan-Kettering 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
    Knight Cancer Institute, 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
    Graduate School of Public Health, University of Pittsburgh
    Women’s Cancer Research Program, Magee-Womens Research Institute, University of Pittsburgh Cancer Institute)

  • 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
    Samuel Lunenfeld Research Institute, Mount Sinai Hospital)

  • 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
    University Hospitals Leuven
    Laboratory for Translational Genetics, University of Leuven)

  • Diether Lambrechts

    (Vesalius Research Center, VIB
    Laboratory for Translational Genetics, University of Leuven)

  • Jolanta Kupryjanczyk

    (Maria Sklodowska-Curie Memorial Cancer Center, Institute of Oncology)

  • Camilla Krakstad

    (Haukeland University Hospital
    University of Bergen)

  • 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
    Virus, Lifestyle and Genes, Danish Cancer Society Research Center)

  • Lambertus A. Kiemeney

    (Biostatistics and HTA, Radboud University Medical Centre
    Radboud University Medical Centre
    Comprehensive Cancer Center)

  • Linda E. Kelemen

    (Alberta Health Services-Cancer Care
    University of Calgary)

  • 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
    Molecular Unit, Herlev Hospital, University of Copenhagen)

  • Maureen Hoatlin

    (Oregon Health and Science University)

  • Peter Hillemanns

    (Clinics of Obstetrics and Gynaecology, Hannover Medical School)

  • Florian Heitz

    (Kliniken Essen-Mitte
    Dr. Horst Schmidt Klinik)

  • Rebecca Hein

    (German Cancer Research Center
    PMV Research Group, University of Cologne)

  • Philipp Harter

    (Kliniken Essen-Mitte
    Dr. Horst Schmidt Klinik)

  • Mari K. Halle

    (Haukeland University Hospital
    University of Bergen)

  • 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
    Centre for Molecular, Environmental, Genetic and Analytical Epidemiology, University of Melbourne
    Monash University)

  • 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
    David Geffen School of Medicine, University of California at Los Angeles)

  • 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
    Dr. Horst Schmidt Klinik)

  • 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
    University Hospitals Leuven
    Laboratory for Translational Genetics, University of Leuven)

  • 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
    Harvard School of Public Health)

  • 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
    University of Melbourne
    University of Melbourne)

  • Ralf Butzow

    (University of Helsinki and Helsinki University Central Hospital
    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
    Centre for Molecular, Environmental, Genetic and Analytical Epidemiology, University of Melbourne)

  • 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
    Comprehensive Cancer Center)

  • 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
    Cancer Prevention, Detection and Control Research Program, Duke Cancer Institute)

  • 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
    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)

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.

Suggested Citation

  • 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 Zioga, 2013. "Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer," Nature Communications, Nature, vol. 4(1), pages 1-10, June.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2629
    DOI: 10.1038/ncomms2629
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    1. Nikolaos Giannareas & Qin Zhang & Xiayun Yang & Rong Na & Yijun Tian & Yuehong Yang & Xiaohao Ruan & Da Huang & Xiaoqun Yang & Chaofu Wang & Peng Zhang & Aki Manninen & Liang Wang & Gong-Hong Wei, 2022. "Extensive germline-somatic interplay contributes to prostate cancer progression through HNF1B co-option of TMPRSS2-ERG," Nature Communications, Nature, vol. 13(1), pages 1-22, December.

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