Human Genetics

, Volume 133, Issue 5, pp 481–497 | Cite as

Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA

  • Madalene A. Earp
  • Linda E. Kelemen
  • Anthony M. Magliocco
  • Kenneth D. Swenerton
  • Georgia Chenevix-Trench
  • Australian Cancer Study
  • Australian Ovarian Cancer Study Group
  • Yi Lu
  • Alexander Hein
  • Arif B. Ekici
  • Matthias W. Beckmann
  • Peter A. Fasching
  • Diether Lambrechts
  • Evelyn Despierre
  • Ignace Vergote
  • Sandrina Lambrechts
  • Jennifer A. Doherty
  • Mary Anne Rossing
  • Jenny Chang-Claude
  • Anja Rudolph
  • Grace Friel
  • Kirsten B. Moysich
  • Kunle Odunsi
  • Lara Sucheston-Campbell
  • Galina Lurie
  • Marc T. Goodman
  • Michael E. Carney
  • Pamela J. Thompson
  • Ingo B. Runnebaum
  • Matthias Dürst
  • Peter Hillemanns
  • Thilo Dörk
  • Natalia Antonenkova
  • Natalia Bogdanova
  • Arto Leminen
  • Heli Nevanlinna
  • Liisa M. Pelttari
  • Ralf Butzow
  • Clareann H. Bunker
  • Francesmary Modugno
  • Robert P. Edwards
  • Roberta B. Ness
  • Andreas du Bois
  • Florian Heitz
  • Ira Schwaab
  • Philipp Harter
  • Beth Y. Karlan
  • Christine Walsh
  • Jenny Lester
  • Allan Jensen
  • Susanne K. Kjær
  • Claus K. Høgdall
  • Estrid Høgdall
  • Lene Lundvall
  • Thomas A. Sellers
  • Brooke L. Fridley
  • Ellen L. Goode
  • Julie M. Cunningham
  • Robert A. Vierkant
  • Graham G. Giles
  • Laura Baglietto
  • Gianluca Severi
  • Melissa C. Southey
  • Dong Liang
  • Xifeng Wu
  • Karen Lu
  • Michelle A. T. Hildebrandt
  • Douglas A. Levine
  • Maria Bisogna
  • Joellen M. Schildkraut
  • Edwin S. Iversen
  • Rachel Palmieri Weber
  • Andrew Berchuck
  • Daniel W. Cramer
  • Kathryn L. Terry
  • Elizabeth M. Poole
  • Shelley S. Tworoger
  • Elisa V. Bandera
  • Urmila Chandran
  • Irene Orlow
  • Sara H. Olson
  • Elisabeth Wik
  • Helga B. Salvesen
  • Line Bjorge
  • Mari K. Halle
  • Anne M. van Altena
  • Katja K. H. Aben
  • Lambertus A. Kiemeney
  • Leon F. A. G. Massuger
  • Tanja Pejovic
  • Yukie T. Bean
  • Cezary Cybulski
  • Jacek Gronwald
  • Jan Lubinski
  • Nicolas Wentzensen
  • Louise A. Brinton
  • Jolanta Lissowska
  • Montserrat Garcia-Closas
  • Ed Dicks
  • Joe Dennis
  • Douglas F. Easton
  • Honglin Song
  • Jonathan P. Tyrer
  • Paul D. P. Pharoah
  • Diana Eccles
  • Ian G. Campbell
  • Alice S. Whittemore
  • Valerie McGuire
  • Weiva Sieh
  • Joseph H. Rothstein
  • James M. Flanagan
  • James Paul
  • Robert Brown
  • Catherine M. Phelan
  • Harvey A. Risch
  • John R. McLaughlin
  • Steven A. Narod
  • Argyrios Ziogas
  • Hoda Anton-Culver
  • Aleksandra Gentry-Maharaj
  • Usha Menon
  • Simon A. Gayther
  • Susan J. Ramus
  • Anna H. Wu
  • Celeste L. Pearce
  • Malcolm C. Pike
  • Agnieszka Dansonka-Mieszkowska
  • Iwona K. Rzepecka
  • Lukasz M. Szafron
  • Jolanta Kupryjanczyk
  • Linda S. Cook
  • Nhu D. Le
  • Angela Brooks-Wilson
  • On behalf of the Ovarian Cancer Association Consortium
Original Investigation

Abstract

Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.

Supplementary material

439_2013_1383_MOESM1_ESM.doc (428 kb)
Supplementary material 1 (DOC 427 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Madalene A. Earp
    • 1
  • Linda E. Kelemen
    • 2
    • 3
  • Anthony M. Magliocco
    • 4
  • Kenneth D. Swenerton
    • 5
  • Georgia Chenevix-Trench
    • 6
  • Australian Cancer Study
    • 6
  • Australian Ovarian Cancer Study Group
    • 6
    • 7
  • Yi Lu
    • 6
  • Alexander Hein
    • 8
  • Arif B. Ekici
    • 9
  • Matthias W. Beckmann
    • 8
  • Peter A. Fasching
    • 8
    • 10
  • Diether Lambrechts
    • 11
    • 12
  • Evelyn Despierre
    • 13
  • Ignace Vergote
    • 13
  • Sandrina Lambrechts
    • 13
  • Jennifer A. Doherty
    • 14
    • 15
  • Mary Anne Rossing
    • 15
    • 16
  • Jenny Chang-Claude
    • 17
  • Anja Rudolph
    • 17
  • Grace Friel
    • 18
  • Kirsten B. Moysich
    • 18
  • Kunle Odunsi
    • 18
  • Lara Sucheston-Campbell
    • 18
  • Galina Lurie
    • 19
  • Marc T. Goodman
    • 20
  • Michael E. Carney
    • 19
  • Pamela J. Thompson
    • 20
  • Ingo B. Runnebaum
    • 21
  • Matthias Dürst
    • 21
  • Peter Hillemanns
    • 22
  • Thilo Dörk
    • 23
  • Natalia Antonenkova
    • 24
  • Natalia Bogdanova
    • 23
  • Arto Leminen
    • 25
  • Heli Nevanlinna
    • 25
  • Liisa M. Pelttari
    • 25
  • Ralf Butzow
    • 25
    • 26
  • Clareann H. Bunker
    • 27
  • Francesmary Modugno
    • 27
    • 28
    • 29
  • Robert P. Edwards
    • 28
    • 29
  • Roberta B. Ness
    • 30
  • Andreas du Bois
    • 31
    • 32
  • Florian Heitz
    • 31
    • 32
  • Ira Schwaab
    • 33
  • Philipp Harter
    • 31
    • 32
  • Beth Y. Karlan
    • 34
  • Christine Walsh
    • 34
  • Jenny Lester
    • 34
  • Allan Jensen
    • 35
  • Susanne K. Kjær
    • 35
    • 36
  • Claus K. Høgdall
    • 36
  • Estrid Høgdall
    • 35
    • 37
  • Lene Lundvall
    • 36
  • Thomas A. Sellers
    • 38
  • Brooke L. Fridley
    • 39
  • Ellen L. Goode
    • 40
  • Julie M. Cunningham
    • 41
  • Robert A. Vierkant
    • 42
  • Graham G. Giles
    • 43
    • 44
  • Laura Baglietto
    • 43
    • 44
  • Gianluca Severi
    • 43
    • 44
  • Melissa C. Southey
    • 45
  • Dong Liang
    • 46
  • Xifeng Wu
    • 47
  • Karen Lu
    • 48
  • Michelle A. T. Hildebrandt
    • 47
  • Douglas A. Levine
    • 49
  • Maria Bisogna
    • 49
  • Joellen M. Schildkraut
    • 50
    • 51
  • Edwin S. Iversen
    • 51
    • 52
  • Rachel Palmieri Weber
    • 50
  • Andrew Berchuck
    • 53
  • Daniel W. Cramer
    • 54
    • 55
  • Kathryn L. Terry
    • 54
    • 55
  • Elizabeth M. Poole
    • 55
    • 56
  • Shelley S. Tworoger
    • 55
    • 56
  • Elisa V. Bandera
    • 57
  • Urmila Chandran
    • 57
  • Irene Orlow
    • 58
  • Sara H. Olson
    • 58
  • Elisabeth Wik
    • 59
    • 60
  • Helga B. Salvesen
    • 60
    • 61
  • Line Bjorge
    • 60
    • 61
  • Mari K. Halle
    • 60
    • 61
  • Anne M. van Altena
    • 62
  • Katja K. H. Aben
    • 63
    • 64
  • Lambertus A. Kiemeney
    • 63
    • 65
  • Leon F. A. G. Massuger
    • 62
  • Tanja Pejovic
    • 66
    • 67
  • Yukie T. Bean
    • 66
    • 67
  • Cezary Cybulski
    • 68
  • Jacek Gronwald
    • 68
  • Jan Lubinski
    • 68
  • Nicolas Wentzensen
    • 69
  • Louise A. Brinton
    • 69
  • Jolanta Lissowska
    • 70
  • Montserrat Garcia-Closas
    • 71
    • 72
  • Ed Dicks
    • 73
  • Joe Dennis
    • 74
  • Douglas F. Easton
    • 74
  • Honglin Song
    • 73
  • Jonathan P. Tyrer
    • 73
  • Paul D. P. Pharoah
    • 73
    • 74
  • Diana Eccles
    • 75
  • Ian G. Campbell
    • 7
    • 45
    • 76
  • Alice S. Whittemore
    • 77
  • Valerie McGuire
    • 77
  • Weiva Sieh
    • 77
  • Joseph H. Rothstein
    • 77
  • James M. Flanagan
    • 78
  • James Paul
    • 79
  • Robert Brown
    • 78
  • Catherine M. Phelan
    • 38
  • Harvey A. Risch
    • 80
  • John R. McLaughlin
    • 81
  • Steven A. Narod
    • 82
  • Argyrios Ziogas
    • 83
  • Hoda Anton-Culver
    • 83
  • Aleksandra Gentry-Maharaj
    • 84
  • Usha Menon
    • 84
  • Simon A. Gayther
    • 85
  • Susan J. Ramus
    • 85
  • Anna H. Wu
    • 85
  • Celeste L. Pearce
    • 85
  • Malcolm C. Pike
    • 58
    • 85
  • Agnieszka Dansonka-Mieszkowska
    • 86
  • Iwona K. Rzepecka
    • 86
  • Lukasz M. Szafron
    • 86
  • Jolanta Kupryjanczyk
    • 86
  • Linda S. Cook
    • 2
    • 87
    • 88
  • Nhu D. Le
    • 89
  • Angela Brooks-Wilson
    • 1
    • 90
  • On behalf of the Ovarian Cancer Association Consortium
  1. 1.Canada’s Michael Smith Genome Sciences CentreBC Cancer AgencyVancouverCanada
  2. 2.Department of Population Health ResearchAlberta Health Services-Cancer CareCalgaryCanada
  3. 3.Departments of Medical Genetics and OncologyUniversity of CalgaryCalgaryCanada
  4. 4.Department of Anatomic PathologyH. Lee Moffitt Cancer CenterTampaUSA
  5. 5.Department of MedicineUniversity of British ColumbiaVancouverCanada
  6. 6.Genetics and Population HealthQIMR Berghofer Medical Research InstituteHerstonAustralia
  7. 7.Research DivisionPeter MacCallum Cancer CentreMelbourneAustralia
  8. 8.Department of Gynecology and Obstetrics, Comprehensive Cancer Center, University Hospital ErlangenFriedrich-Alexander-University Erlangen-NurembergErlangenGermany
  9. 9.Institute of Human GeneticsFriedrich-Alexander-Universität Erlangen-NürnbergErlangenGermany
  10. 10.Division of Hematology and Oncology, Department of Medicine, David Geffen School of MedicineUniversity of CaliforniaLos AngelesUSA
  11. 11.Vesalius Research CenterVIBLouvainBelgium
  12. 12.Laboratory for Translational Genetics, Department of OncologyUniversity of LeuvenLouvainBelgium
  13. 13.Division of Gynecologic Oncology, Department of Obstetrics and GynaecologyLeuven Cancer InstituteLouvainBelgium
  14. 14.Section of Biostatistics and EpidemiologyThe Geisel School of Medicine at DartmouthLebanonUSA
  15. 15.Program in Epidemiology, Division of Public Health SciencesFred Hutchinson Cancer Research CenterSeattleUSA
  16. 16.Department of EpidemiologyUniversity of WashingtonSeattleUSA
  17. 17.Division of Cancer EpidemiologyGerman Cancer Research CenterHeidelbergGermany
  18. 18.Department of Cancer Prevention and ControlRoswell Park Cancer InstituteBuffaloUSA
  19. 19.Cancer Epidemiology ProgramUniversity of Hawaii Cancer CenterHonoluluUSA
  20. 20.Cedars-Sinai Medical CenterSamuel Oschin Comprehensive Cancer InstituteLos AngelesUSA
  21. 21.Department of Obstetrics and Gynaecology, Jena University HospitalFriedrich Schiller University JenaJenaGermany
  22. 22.Clinics of Obstetrics and GynaecologyHannover Medical SchoolHannoverGermany
  23. 23.Gynaecology Research UnitHannover Medical SchoolHannoverGermany
  24. 24.Aleksandrov Byelorussian Institute for Oncology and Medical RadiologyMinskBelarus
  25. 25.Department of Obstetrics and Gynecology, Helsinki University Central HospitalUniversity of HelsinkiHelsinkiFinland
  26. 26.Department of Pathology, Helsinki University Central HospitalUniversity of HelsinkiHelsinkiFinland
  27. 27.Department of Epidemiology, Graduate School of Public HealthUniversity of PittsburghPittsburghUSA
  28. 28.Department of Obstetrics, Gynecology and Reproductive SciencesUniversity of PittsburghPittsburghUSA
  29. 29.Women’s Cancer Research Center, Magee-Womens Research InstituteUniversity of Pittsburgh Cancer InstitutePittsburghUSA
  30. 30.The University of Texas School of Public HealthHoustonUSA
  31. 31.Department of Gynecology and Gynecologic OncologyKliniken Essen-Mitte/Evang. Huyssens Stiftung/Knappschaft GmbHEssenGermany
  32. 32.Department of Gynecology and Gynecologic OncologyDr. Horst Schmidt Kliniken WiesbadenWiesbadenGermany
  33. 33.Institut für HumangenetikWiesbadenGermany
  34. 34.Cedars-Sinai Medical CenterWomen’s Cancer Program at the Samuel Oschin Comprehensive Cancer InstituteLos AngelesUSA
  35. 35.Department of Virus, Lifestyle and GenesDanish Cancer Society Research CenterCopenhagenDenmark
  36. 36.Department of GynecologyCopenhagen University Hospital RigshospitaletCopenhagenDenmark
  37. 37.Molecular Unit, Department of Pathology, Herlev HospitalUniversity of CopenhagenCopenhagenDenmark
  38. 38.Division of Population Sciences, Department of Cancer EpidemiologyMoffitt Cancer CenterTampaUSA
  39. 39.Department of BiostatisticsUniversity of Kansas Medical CenterKansasUSA
  40. 40.Division of Epidemiology, Department of Health Sciences ResearchMayo ClinicRochesterUSA
  41. 41.Department of Laboratory Medicine and PathologyMayo ClinicRochesterUSA
  42. 42.Division of Biomedical Statistics and Informatics, Department of Health Science ResearchMayo ClinicRochesterUSA
  43. 43.Cancer Epidemiology CentreCancer Council VictoriaMelbourneAustralia
  44. 44.Centre for Molecular, Environmental, Genetic and Analytic EpidemiologyThe University of MelbourneMelbourneAustralia
  45. 45.Department of PathologyThe University of MelbourneMelbourneAustralia
  46. 46.College of Pharmacy and Health SciencesTexas Southern UniversityHoustonUSA
  47. 47.Department of EpidemiologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  48. 48.Department of Gynecologic OncologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  49. 49.Gynecology Service, Department of SurgeryMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  50. 50.Department of Community and Family MedicineDuke University Medical CenterDurhamUSA
  51. 51.Cancer Control and Population SciencesDuke Cancer InstituteDurhamUSA
  52. 52.Department of Statistical ScienceDuke UniversityDurhamUSA
  53. 53.Department of Obstetrics and GynecologyDuke University Medical CenterDurhamUSA
  54. 54.Obstetrics and Gynecology Epidemiology CenterBrigham and Women’s HospitalBostonUSA
  55. 55.Department of EpidemiologyHarvard School of Public HealthBostonUSA
  56. 56.Channing Division of Network Medicine, Harvard Medical SchoolBrigham and Women’s HospitalBostonUSA
  57. 57.Rutgers Cancer Institute of New JerseyNew BrunswickUSA
  58. 58.Department of Epidemiology and BiostatisticsMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  59. 59.Department of PathologyHaukeland University HospitalBergenNorway
  60. 60.Department of Clinical Science, Centre for Cancer BiomarkersUniversity of BergenBergenNorway
  61. 61.Department of Gynecology and ObstetricsHaukeland University HospitalBergenNorway
  62. 62.Department of GynecologyRadboud University Medical CentreNijmegenNetherlands
  63. 63.Department for Health EvidenceRadboud University Medical CentreNijmegenThe Netherlands
  64. 64.Comprehensive Cancer Center The NetherlandsUtrechtThe Netherlands
  65. 65.Department of UrologyRadboud University Medical CentreNijmegenThe Netherlands
  66. 66.Department of Obstetrics and GynecologyOregon Health and Science UniversityPortlandUSA
  67. 67.Knight Cancer InstituteOregon Health and Science UniversityPortlandUSA
  68. 68.Department of Genetics and Pathology, International Hereditary Cancer CenterPomeranian Medical UniversitySzczecinPoland
  69. 69.Division of Cancer Epidemiology and GeneticsNational Cancer InstituteBethesdaUSA
  70. 70.Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer CenterInstitute of OncologyWarsawPoland
  71. 71.Division of Genetics and EpidemiologyInstitute of Cancer ResearchSuttonUK
  72. 72.Breakthrough Breast Cancer Research CentreLondonUK
  73. 73.Department of OncologyUniversity of CambridgeCambridgeUK
  74. 74.Department of Public Health and Primary CareUniversity of CambridgeCambridgeUK
  75. 75.Faculty of Medicine, University Hospital SouthamptonUniversity of SouthamptonSouthamptonUK
  76. 76.Sir Peter MacCallum Department of OncologyUniversity of MelbourneParkvilleAustralia
  77. 77.Department of Health Research and Policy, EpidemiologyStanford University School of MedicinePalo AltoUSA
  78. 78.Department of Surgery and CancerImperial College LondonLondonUK
  79. 79.The Beatson West of Scotland Cancer CentreGlasgowUK
  80. 80.Department of Chronic Disease EpidemiologyYale School of Public HealthNew HavenUSA
  81. 81.Prosserman Centre for Health Research, Samuel Lunenfeld Research InstituteMount Sinai HospitalTorontoCanada
  82. 82.Women’s College Research InstituteUniversity of TorontoTorontoCanada
  83. 83.Department of Epidemiology, Center for Cancer Genetics Research and Prevention, School of MedicineUniversity of California-IrvineIrvineUSA
  84. 84.Gynaecological Cancer Research Centre, Women’s Cancer, Elizabeth Garrett Anderson Institute for Women’s HealthUniversity College LondonLondonUK
  85. 85.Department of Preventive Medicine, Keck School of MedicineUniversity of Southern California Norris Comprehensive Cancer CenterLos AngelesUSA
  86. 86.Department of Pathology, The Maria Sklodowska-Curie Memorial Cancer CenterInstitute of OncologyWarsawPoland
  87. 87.Division of Epidemiology and Biostatistics, Department of Internal MedicineUniversity of New MexicoAlbuquerqueUSA
  88. 88.Department of Community Health Sciences, Faculty of MedicineUniversity of CalgaryCalgaryCanada
  89. 89.Cancer Control ResearchBC Cancer AgencyVancouverCanada
  90. 90.Department of Biomedical Physiology and KinesiologySimon Fraser UniversityBurnabyCanada

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