Human Genetics

, Volume 135, Issue 7, pp 741–756 | Cite as

Assessing the genetic architecture of epithelial ovarian cancer histological subtypes

  • Gabriel Cuellar-Partida
  • Yi Lu
  • Suzanne C. Dixon
  • Australian Ovarian Cancer Study
  • Peter A. Fasching
  • Alexander Hein
  • Stefanie Burghaus
  • Matthias W. Beckmann
  • Diether Lambrechts
  • Els Van Nieuwenhuysen
  • Ignace Vergote
  • Adriaan Vanderstichele
  • Jennifer Anne Doherty
  • Mary Anne Rossing
  • Jenny Chang-Claude
  • Anja Rudolph
  • Shan Wang-Gohrke
  • Marc T. Goodman
  • Natalia Bogdanova
  • Thilo Dörk
  • Matthias Dürst
  • Peter Hillemanns
  • Ingo B. Runnebaum
  • Natalia Antonenkova
  • Ralf Butzow
  • Arto Leminen
  • Heli Nevanlinna
  • Liisa M. Pelttari
  • Robert P. Edwards
  • Joseph L. Kelley
  • Francesmary Modugno
  • Kirsten B. Moysich
  • Roberta B. Ness
  • Rikki Cannioto
  • Estrid Høgdall
  • Claus Høgdall
  • Allan Jensen
  • Graham G. Giles
  • Fiona Bruinsma
  • Susanne K. Kjaer
  • Michelle A. T. Hildebrandt
  • Dong Liang
  • Karen H. Lu
  • Xifeng Wu
  • Maria Bisogna
  • Fanny Dao
  • Douglas A. Levine
  • Daniel W. Cramer
  • Kathryn L. Terry
  • Shelley S. Tworoger
  • Meir Stampfer
  • Stacey Missmer
  • Line Bjorge
  • Helga B. Salvesen
  • Reidun K. Kopperud
  • Katharina Bischof
  • Katja K. H. Aben
  • Lambertus A. Kiemeney
  • Leon F. A. G. Massuger
  • Angela Brooks-Wilson
  • Sara H. Olson
  • Valerie McGuire
  • Joseph H. Rothstein
  • Weiva Sieh
  • Alice S. Whittemore
  • Linda S. Cook
  • Nhu D. Le
  • C. Blake Gilks
  • Jacek Gronwald
  • Anna Jakubowska
  • Jan Lubiński
  • Tomasz Kluz
  • Honglin Song
  • Jonathan P. Tyrer
  • Nicolas Wentzensen
  • Louise Brinton
  • Britton Trabert
  • Jolanta Lissowska
  • John R. McLaughlin
  • Steven A. Narod
  • Catherine Phelan
  • Hoda Anton-Culver
  • Argyrios Ziogas
  • Diana Eccles
  • Ian Campbell
  • Simon A. Gayther
  • Aleksandra Gentry-Maharaj
  • Usha Menon
  • Susan J. Ramus
  • Anna H. Wu
  • Agnieszka Dansonka-Mieszkowska
  • Jolanta Kupryjanczyk
  • Agnieszka Timorek
  • Lukasz Szafron
  • Julie M. Cunningham
  • Brooke L. Fridley
  • Stacey J. Winham
  • Elisa V. Bandera
  • Elizabeth M. Poole
  • Terry K. Morgan
  • Ellen L. Goode
  • Joellen M. Schildkraut
  • Celeste L. Pearce
  • Andrew Berchuck
  • Paul D. P. Pharoah
  • Penelope M. Webb
  • Georgia Chenevix-Trench
  • Harvey A. Risch
  • Stuart MacGregor
Original Investigation

Abstract

Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease (\(h^{ 2}_{\rm{g}}\) = 8.8 ± 1.1 %), endometrioid (\(h^{ 2}_{\rm{g}}\) = 3.2 ± 1.6 %), clear cell (\(h^{ 2}_{\rm{g}}\) = 6.7 ± 3.3 %) and all EOC (\(h^{ 2}_{\rm{g}}\) = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.

Supplementary material

439_2016_1663_MOESM1_ESM.docx (2.1 mb)
Supplementary material 1 (DOCX 2190 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Gabriel Cuellar-Partida
    • 1
    • 2
  • Yi Lu
    • 1
  • Suzanne C. Dixon
    • 3
    • 44
  • Australian Ovarian Cancer Study
    • 4
    • 5
  • Peter A. Fasching
    • 7
    • 8
  • Alexander Hein
    • 8
  • Stefanie Burghaus
    • 8
  • Matthias W. Beckmann
    • 8
  • Diether Lambrechts
    • 9
    • 10
  • Els Van Nieuwenhuysen
    • 11
  • Ignace Vergote
    • 11
  • Adriaan Vanderstichele
    • 11
  • Jennifer Anne Doherty
    • 12
  • Mary Anne Rossing
    • 13
    • 14
  • Jenny Chang-Claude
    • 15
    • 83
  • Anja Rudolph
    • 15
  • Shan Wang-Gohrke
    • 16
  • Marc T. Goodman
    • 17
    • 18
  • Natalia Bogdanova
    • 19
  • Thilo Dörk
    • 20
  • Matthias Dürst
    • 21
  • Peter Hillemanns
    • 22
  • Ingo B. Runnebaum
    • 21
  • Natalia Antonenkova
    • 23
  • Ralf Butzow
    • 24
  • Arto Leminen
    • 25
  • Heli Nevanlinna
    • 25
  • Liisa M. Pelttari
    • 25
  • Robert P. Edwards
    • 26
    • 27
  • Joseph L. Kelley
    • 26
  • Francesmary Modugno
    • 26
    • 27
    • 28
  • Kirsten B. Moysich
    • 29
  • Roberta B. Ness
    • 30
  • Rikki Cannioto
    • 29
  • Estrid Høgdall
    • 31
    • 32
  • Claus Høgdall
    • 36
  • Allan Jensen
    • 31
  • Graham G. Giles
    • 33
    • 34
    • 35
  • Fiona Bruinsma
    • 35
  • Susanne K. Kjaer
    • 31
    • 36
  • Michelle A. T. Hildebrandt
    • 37
  • Dong Liang
    • 38
  • Karen H. Lu
    • 39
  • Xifeng Wu
    • 37
  • Maria Bisogna
    • 40
  • Fanny Dao
    • 40
  • Douglas A. Levine
    • 40
  • Daniel W. Cramer
    • 41
  • Kathryn L. Terry
    • 41
    • 42
  • Shelley S. Tworoger
    • 42
    • 43
  • Meir Stampfer
    • 42
    • 43
  • Stacey Missmer
    • 41
    • 42
    • 43
  • Line Bjorge
    • 45
    • 46
  • Helga B. Salvesen
    • 45
    • 46
  • Reidun K. Kopperud
    • 45
    • 46
  • Katharina Bischof
    • 45
    • 46
  • Katja K. H. Aben
    • 47
    • 48
  • Lambertus A. Kiemeney
    • 47
  • Leon F. A. G. Massuger
    • 49
  • Angela Brooks-Wilson
    • 50
    • 51
  • Sara H. Olson
    • 52
  • Valerie McGuire
    • 53
  • Joseph H. Rothstein
    • 53
  • Weiva Sieh
    • 53
  • Alice S. Whittemore
    • 53
  • Linda S. Cook
    • 54
  • Nhu D. Le
    • 55
  • C. Blake Gilks
    • 56
  • Jacek Gronwald
    • 57
  • Anna Jakubowska
    • 57
  • Jan Lubiński
    • 57
  • Tomasz Kluz
    • 58
  • Honglin Song
    • 59
  • Jonathan P. Tyrer
    • 59
  • Nicolas Wentzensen
    • 60
  • Louise Brinton
    • 60
  • Britton Trabert
    • 60
  • Jolanta Lissowska
    • 61
  • John R. McLaughlin
    • 62
  • Steven A. Narod
    • 63
  • Catherine Phelan
    • 64
  • Hoda Anton-Culver
    • 65
    • 66
  • Argyrios Ziogas
    • 65
  • Diana Eccles
    • 67
  • Ian Campbell
    • 5
  • Simon A. Gayther
    • 68
  • Aleksandra Gentry-Maharaj
    • 69
  • Usha Menon
    • 69
  • Susan J. Ramus
    • 68
  • Anna H. Wu
    • 68
  • Agnieszka Dansonka-Mieszkowska
    • 70
  • Jolanta Kupryjanczyk
    • 70
  • Agnieszka Timorek
    • 71
  • Lukasz Szafron
    • 70
  • Julie M. Cunningham
    • 72
  • Brooke L. Fridley
    • 73
  • Stacey J. Winham
    • 74
  • Elisa V. Bandera
    • 75
  • Elizabeth M. Poole
    • 43
  • Terry K. Morgan
    • 76
    • 77
  • Ellen L. Goode
    • 78
  • Joellen M. Schildkraut
    • 79
  • Celeste L. Pearce
    • 68
    • 80
  • Andrew Berchuck
    • 81
  • Paul D. P. Pharoah
    • 6
    • 59
  • Penelope M. Webb
    • 3
    • 44
  • Georgia Chenevix-Trench
    • 4
  • Harvey A. Risch
    • 82
  • Stuart MacGregor
    • 1
  1. 1.Statistical Genetics, QIMR Berghofer Medical Research InstituteHerstonAustralia
  2. 2.School of Medicine, University of QueenslandSt LuciaAustralia
  3. 3.Gynaecological Cancers GroupQIMR Berghofer Medical Research InstituteHerstonAustralia
  4. 4.Cancer Genetics, QIMR Berghofer Medical Research InstituteHerstonAustralia
  5. 5.Research DivisionPeter MacCallum Cancer CentreEast MelbourneAustralia
  6. 6.Department of Public Health and Primary Care, The Centre for Cancer Genetic EpidemiologyUniversity of CambridgeCambridgeUK
  7. 7.Division of Hematology and Oncology, Department of MedicineUniversity of California at Los Angeles, David Geffen School of MedicineLos AngelesUSA
  8. 8.Department of Gynecology and ObstetricsFriedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, University Hospital ErlangenErlangenGermany
  9. 9.Laboratory for Translational Genetics, Department of OncologyUniversity of LeuvenLeuvenBelgium
  10. 10.Vesalius Research Center, VIBLouvainBelgium
  11. 11.Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer InstituteUniversity Hospitals LeuvenLouvainBelgium
  12. 12.Section of Biostatistics and Epidemiology, Department of Community and Family Medicine, Geisel School of MedicineDartmouth CollegeHanoverUSA
  13. 13.Department of EpidemiologyUniversity of WashingtonSeattleUSA
  14. 14.Program in Epidemiology, Division of Public Health SciencesFred Hutchinson Cancer Research CenterSeattleUSA
  15. 15.Division of Cancer EpidemiologyGerman Cancer Research CenterHeidelbergGermany
  16. 16.Department of Obstetrics and GynecologyUniversity of UlmUlmGermany
  17. 17.Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical CenterLos AngelesUSA
  18. 18.Department of Biomedical Sciences, Cedars-Sinai Medical CenterCommunity and Population Health Research InstituteLos AngelesUSA
  19. 19.Radiation Oncology Research UnitHannover Medical SchoolHannoverGermany
  20. 20.Gynaecology Research UnitHannover Medical SchoolHannoverGermany
  21. 21.Department of GynecologyJena-University Hospital-Friedrich Schiller UniversityJenaGermany
  22. 22.Clinics of Obstetrics and GynaecologyHannover Medical SchoolHannoverGermany
  23. 23.N.N. Alexandrov National Cancer Centre of BelarusMinskBelarus
  24. 24.Department of PathologyUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
  25. 25.Department of Obstetrics and GynecologyUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
  26. 26.Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive SciencesUniversity of Pittsburgh School of MedicinePittsburghUSA
  27. 27.Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer InstitutePittsburghUSA
  28. 28.Department of EpidemiologyUniversity of Pittsburgh Graduate School of Public HealthPittsburghUSA
  29. 29.Department of Cancer Prevention and ControlRoswell Park Cancer InstituteBuffaloUSA
  30. 30.The University of Texas School of Public HealthHoustonUSA
  31. 31.Department of Virus, Lifestyle and GenesDanish Cancer Society Research CenterCopenhagenDenmark
  32. 32.Molecular Unit, Department of Pathology, Herlev HospitalUniversity of CopenhagenCopenhagenDenmark
  33. 33.Department of Epidemiology and Preventive MedicineMonash UniversityMelbourneAustralia
  34. 34.Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneMelbourneAustralia
  35. 35.Cancer Epidemiology Centre, Cancer Council VictoriaMelbourneAustralia
  36. 36.Department of Gynaecology, RigshospitaletUniversity of CopenhagenCopenhagenDenmark
  37. 37.Department of EpidemiologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  38. 38.College of Pharmacy and Health SciencesTexas Southern UniversityHoustonUSA
  39. 39.Department of Gynecologic OncologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  40. 40.Gynecology Service, Department of SurgeryMemorial Sloan Kettering Cancer CenterNew YorkUSA
  41. 41.Obstetrics and Gynecology Epidemiology CenterBrigham and Women’s HospitalBostonUSA
  42. 42.Department of Epidemiology Harvard TH Chan School of Public HealthBostonUSA
  43. 43.Channing Division of Network MedicineBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA
  44. 44.School of Public HealthUniversity of QueenslandHerstonAustralia
  45. 45.Department of Gynecology and ObstetricsHaukeland University HospitalBergenNorway
  46. 46.Department of Clinical Science, Centre for Cancer BiomarkersUniversity of BergenBergenNorway
  47. 47.Radboud University Medical Centre, RADBOUD Institute for Health SciencesNijmegenThe Netherlands
  48. 48.Netherlands Comprehensive Cancer OrganisationUtrechtThe Netherlands
  49. 49.Department of Obstetrics and GynaecologyRadboud University Medical Center, Radboud Institute for Molecular Life SciencesNijmegenThe Netherlands
  50. 50.Canada’s Michael Smith Genome Sciences Centre, BC Cancer AgencyVancouverCanada
  51. 51.Department of Biomedical Physiology and KinesiologySimon Fraser UniversityBurnabyCanada
  52. 52.Department of Epidemiology and BiostatisticsMemorial Sloan Kettering Cancer CenterNew YorkUSA
  53. 53.Department of Health Research and Policy-EpidemiologyStanford University School of MedicineStanfordUSA
  54. 54.Division of Epidemiology and Biostatistics, Department of Internal MedicineUniversity of New MexicoAlbuquerqueUSA
  55. 55.Cancer Control Research, BC Cancer AgencyVancouverCanada
  56. 56.Pathology and Laboratory MedicineUniversity of British ColumbiaVancouverCanada
  57. 57.Department of Genetics and Pathology, International Hereditary Cancer CenterPomeranian Medical UniversitySzczecinPoland
  58. 58.Faculty of Medicine, Institute of Midwifery and Emergency Medicine, Clinic of Obstetrics and Gynecology, Frederick Chopin Clinical Provincial Hospital No 1University of RzeszówRzeszowPoland
  59. 59.Department of Oncology, The Centre for Cancer Genetic EpidemiologyUniversity of CambridgeCambridgeUK
  60. 60.Division of Cancer Epidemiology and GeneticsNational Cancer InstituteBethesdaUSA
  61. 61.Department of Cancer Epidemiology and Prevention The Maria Sklodowska-Curie Memorial Cancer Center and Institute of OncologyWarsawPoland
  62. 62.Public Health OntarioTorontoCanada
  63. 63.Women’s College Research Institute, University of TorontoTorontoCanada
  64. 64.Department of Cancer EpidemiologyMoffitt Cancer CenterTampaUSA
  65. 65.Department of EpidemiologyUniversity of California IrvineIrvineUSA
  66. 66.Center for Cancer Genetics Research and Prevention, School of MedicineUniversity of California IrvineIrvineUSA
  67. 67.Faculty of MedicineUniversity of SouthamptonSouthamptonUK
  68. 68.Department of Preventive Medicine, Keck School of MedicineUniversity of Southern California Norris Comprehensive Cancer CenterLos AngelesUSA
  69. 69.Women’s Cancer, Institute for Women’s HealthUniversity College LondonLondonUK
  70. 70.Department of Pathology and Laboratory DiagnosticsThe Maria Sklodowska-Curie Memorial Cancer Center and Institute of OncologyWarsawPoland
  71. 71.Department of Obstetrics, Gynaecology and Oncology, IInd Faculty of MedicineWarsaw Medical University and Brodnowski HospitalWarsawPoland
  72. 72.Division of Experimental Pathology, Department of Laboratory Medicine and PathologyMayo ClinicRochesterUSA
  73. 73.Department of BiostatisticsUniversity of KansasKansas CityUSA
  74. 74.Division of Biomedical Statistics and Informatics, Department of Health Sciences ResearchMayo ClinicRochesterUSA
  75. 75.Rutgers Cancer Institute of New JerseyNew BrunswickUSA
  76. 76.Department of Pathology and ObstetricsOHSUPortlandUSA
  77. 77.Department of GynaecologyOHSUPortlandUSA
  78. 78.Division of Epidemiology, Department of Health Science ResearchMayo ClinicRochesterUSA
  79. 79.Department of Public Health SciencesUniversity of VirginiaVirginiaUSA
  80. 80.Department of EpidemiologyUniversity of Michigan School of Public HealthAnn ArborUSA
  81. 81.Duke Cancer Institute, Duke University Medical CenterDurhamUSA
  82. 82.Department of Chronic Disease EpidemiologyYale School of Public HealthNew HavenUSA
  83. 83.University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-EppendorfHamburgGermany

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