title: Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci.
abstract: BACKGROUND
  Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis.
  
  
  METHODS
  All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals).
  
  
  RESULTS
  The PAX8-target gene set was ranked 1/615 in the discovery (PGSEA<0.001; FDR=0.21), 7/615 in the replication (PGSEA=0.004; FDR=0.37), and 1/615 in the combined (PGSEA<0.001; FDR=0.21) studies. Adding other genes reported to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P=0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P<10-5(including six with P<5 × 10-8). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (PGSEA=0.025) and IGROV1 (PGSEA=0.004) SOC cells and several PAX8 targets near SOC risk loci demonstrated in vitro transcriptomic perturbation.
  
  
  CONCLUSIONS
  Putative PAX8 target genes are enriched for common SOC risk variants. This finding from our agnostic evaluation is of particular interest given that PAX8 is well-established as a specific marker for the cell of origin of SOC.
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK.
authors.forename: Siddhartha P
authors.initials: SP
authors.lastname: Kar
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Adler
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK.|Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Tyrer
authors.affiliation: Bioinformatics and Computational Biology Research Center, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.|Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Hazelett
authors.affiliation: Department of Epidemiology, Director of Genetic Epidemiology Research Institute, UCI Center for Cancer Genetics Research & Prevention, School of Medicine, University of California Irvine, Irvine, CA 92697, USA.
authors.forename: Hoda
authors.initials: H
authors.lastname: Anton-Culver
authors.affiliation: Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
authors.forename: Elisa V
authors.initials: EV
authors.lastname: Bandera
authors.affiliation: University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen Nuremberg, Universitaetsstrasse 21-23, Erlangen 91054, Germany.
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Beckmann
authors.affiliation: Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Berchuck
authors.affiliation: Radiation Oncology Research Unit, Hannover Medical School, Hannover 30625, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Bogdanova
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Louise
authors.initials: L
authors.lastname: Brinton
authors.affiliation: Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki 00100, Finland.
authors.forename: Ralf
authors.initials: R
authors.lastname: Butzow
authors.affiliation: Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC 3002, Australia.|Department of Pathology, University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Ian
authors.initials: I
authors.lastname: Campbell
authors.affiliation: The Beatson West of Scotland Cancer Centre, Glasgow G12 0YN, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Carty
authors.affiliation: German Cancer Research Center, Division of Cancer Epidemiology, Heidelberg 69120, Germany.|University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
authors.affiliation: Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Cook
authors.affiliation: Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, MA 02215, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Cramer
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.affiliation: Department of Pathology, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw 02-781, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Dansonka-Mieszkowska
authors.affiliation: Department of Epidemiology, The Geisel School of Medicine-at Dartmouth, Hanover, NH 03756, USA.
authors.forename: Jennifer Anne
authors.initials: JA
authors.lastname: Doherty
authors.affiliation: Gynaecology Research Unit, Hannover Medical School, Hannover 30625, Germany.
authors.forename: Thilo
authors.initials: T
authors.lastname: Dörk
authors.affiliation: Department of Gynecology, Jena-University Hospital-Friedrich Schiller University, Jena 07737, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Dürst
authors.affiliation: Faculty of Medicine, University of Southampton, Southampton SO16 5YA, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Eccles
authors.affiliation: University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen Nuremberg, Universitaetsstrasse 21-23, Erlangen 91054, Germany.|Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Fasching
authors.affiliation: Department of Surgery & Cancer, Imperial College London, London SW7 2AZ, UK.
authors.forename: James
authors.initials: J
authors.lastname: Flanagan
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, London W1T 7DN, UK.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Gentry-Maharaj
authors.affiliation: The Beatson West of Scotland Cancer Centre, Glasgow G12 0YN, UK.
authors.forename: Rosalind
authors.initials: R
authors.lastname: Glasspool
authors.affiliation: Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MI 55905, USA.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Goode
authors.affiliation: Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.|Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Marc T
authors.initials: MT
authors.lastname: Goodman
authors.affiliation: International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin 70-001, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Gronwald
authors.affiliation: Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte/ Evang. Huyssens-Stiftung/ Knappschaft GmbH, Essen 45136, Germany.|Department of Gynecology and Gynecologic Oncology, Dr Horst Schmidt Kliniken Wiesbaden, Wiesbaden 65199, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Heitz
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Michelle A T
authors.initials: MA
authors.lastname: Hildebrandt
authors.affiliation: Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen 2100, Denmark.|Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen 1165, Denmark.
authors.forename: Estrid
authors.initials: E
authors.lastname: Høgdall
authors.affiliation: The Juliane Marie Centre, Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen 2100, Denmark.
authors.forename: Claus K
authors.initials: CK
authors.lastname: Høgdall
authors.affiliation: British Columbia's Ovarian Cancer Research (OVCARE) Program, Vancouver General Hospital, BC Cancer Agency and University of British Columbia, Vancouver, BC V5Z 1L3, Canada.|Departments of Pathology and Laboratory Medicine and Obstetrics and Gynaecology, University of British Columbia, Vancouver, BC V5Z 1L3, Canada.|Department of Molecular Oncology, BC Cancer Agency Research Centre, Vancouver, BC V5Z 1L3, Canada.
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
authors.affiliation: Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen 2100, Denmark.
authors.forename: Allan
authors.initials: A
authors.lastname: Jensen
authors.affiliation: Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Beth Y
authors.initials: BY
authors.lastname: Karlan
authors.affiliation: Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC 29435, USA.
authors.forename: Linda E
authors.initials: LE
authors.lastname: Kelemen
authors.affiliation: Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen 6500 HB, The Netherlands.
authors.forename: Lambertus A
authors.initials: LA
authors.lastname: Kiemeney
authors.affiliation: Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen 2100, Denmark.|Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen 2100, Denmark.
authors.forename: Susanne K
authors.initials: SK
authors.lastname: Kjaer
authors.affiliation: Department of Pathology, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw 02-781, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Kupryjanczyk
authors.affiliation: Vesalius Research Center, VIB, Leuven 3000, Belgium.|Laboratory for Translational Genetics, Department of Oncology, University of Leuven 3000, Belgium.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Levine
authors.affiliation: Department of Medical Oncology, The Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.|Medical College of Xiamen University, Xiamen 361102, China.
authors.forename: Qiyuan
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw 02-781, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Lissowska
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Karen H
authors.initials: KH
authors.lastname: Lu
authors.affiliation: International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin 70-001, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Lubiński
authors.affiliation: Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Department of Gynaecology, Nijmegen 6500 HB, The Netherlands.
authors.forename: Leon F A G
authors.initials: LF
authors.lastname: Massuger
authors.affiliation: Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Valerie
authors.initials: V
authors.lastname: McGuire
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Beatson Institute for Cancer Research, Glasgow G12 0YN, UK.
authors.forename: Iain
authors.initials: I
authors.lastname: McNeish
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, London W1T 7DN, UK.
authors.forename: Usha
authors.initials: U
authors.lastname: Menon
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.|Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15213, USA.|Ovarian Cancer Center of Excellence, Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
authors.forename: Francesmary
authors.initials: F
authors.lastname: Modugno
authors.affiliation: Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Alvaro N
authors.initials: AN
authors.lastname: Monteiro
authors.affiliation: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Kirsten B
authors.initials: KB
authors.lastname: Moysich
authors.affiliation: The University of Texas School of Public Health, Houston, TX 77030, USA.
authors.forename: Roberta B
authors.initials: RB
authors.lastname: Ness
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki 00100, Finland.
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
authors.affiliation: The Beatson West of Scotland Cancer Centre, Glasgow G12 0YN, UK.
authors.forename: James
authors.initials: J
authors.lastname: Paul
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA.|Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA.
authors.forename: Celeste L
authors.initials: CL
authors.lastname: Pearce
authors.affiliation: Department of Obstetrics & Gynecology, Oregon Health & Science University, Portland, OR 97239, USA.|Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Tanja
authors.initials: T
authors.lastname: Pejovic
authors.affiliation: Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Permuth
authors.affiliation: Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Phelan
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA.|Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Malcolm C
authors.initials: MC
authors.lastname: Pike
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Poole
authors.affiliation: Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Ramus
authors.affiliation: Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT 06510, USA.
authors.forename: Harvey A
authors.initials: HA
authors.lastname: Risch
authors.affiliation: Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.|Department of Epidemiology, University of Washington, Seattle, WA 98109, USA.
authors.forename: Mary Anne
authors.initials: MA
authors.lastname: Rossing
authors.affiliation: Department of Gynecology and Obstetrics, Haukeland University Horpital, Bergen 5058, Norway.|Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen 5058, Norway.
authors.forename: Helga B
authors.initials: HB
authors.lastname: Salvesen
authors.affiliation: Department of Community and Family Medicine, Duke University Medical Center, Durham, NC 27710, USA.|Cancer Control and Population Sciences, Duke Cancer Institute, Durham, NC 27710, USA.
authors.forename: Joellen M
authors.initials: JM
authors.lastname: Schildkraut
authors.affiliation: Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Sellers
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Sherman
authors.affiliation: Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow G4 0SF, UK.
authors.forename: Nadeem
authors.initials: N
authors.lastname: Siddiqui
authors.affiliation: Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Weiva
authors.initials: W
authors.lastname: Sieh
authors.affiliation: Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK.
authors.forename: Honglin
authors.initials: H
authors.lastname: Song
authors.affiliation: Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, VIC 3002, Australia.
authors.forename: Melissa
authors.initials: M
authors.lastname: Southey
authors.affiliation: Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, MA 02215, USA.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Terry
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA.
authors.forename: Shelley S
authors.initials: SS
authors.lastname: Tworoger
authors.affiliation: Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Walsh
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wentzensen
authors.affiliation: Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Alice S
authors.initials: AS
authors.lastname: Whittemore
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA.
authors.forename: Anna H
authors.initials: AH
authors.lastname: Wu
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Hannah
authors.initials: H
authors.lastname: Yang
authors.affiliation: Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center Medicine, Nashville, TN 37232, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Department of Epidemiology, University of California Irvine, Irvine, CA 92697, USA.
authors.forename: Argyrios
authors.initials: A
authors.lastname: Ziogas
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.|The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Freedman
authors.affiliation: Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.|Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Gayther
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK.|Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK.
authors.forename: Paul D P
authors.initials: PD
authors.lastname: Pharoah
authors.affiliation: Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.|Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Lawrenson
mesh_terms: D000077216:Carcinoma, Ovarian Epithelial; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000473:pathology; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015201:Meta-Analysis as Topic; D046228:Microarray Analysis; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide