Article open access publication

Shared heritability and functional enrichment across six solid cancers

Nature Communications, Springer Nature, ISSN 2041-1723

Volume 10, 1, 2019

DOI:10.1038/s41467-018-08054-4, Dimensions: pub.1111664801, PMC: PMC6347624, PMID: 30683880,

Authors

Jiang, Xia * (1) (2)
Andrulis, Irene L. (19) (20)
Batra, Jyotsna (29) (30)
Benitez, Javier (32) (33)
Benlloch, Sara (7) (34)
Bien, Stephanie A. (15) (37)
Blomqvist, Carl (38) (39)
Boccia, Stefania (40) (41)
Bojesen, Stig E. (43) (44) (45)
Brauch, Hiltrud (46) (47) (48)
Brunnström, Hans (51) (52)
Burwinkel, Barbara (48) (55)
Cadoni, Gabriella (40) (41)
Campbell, Ian (54) (59)
Campa, Daniele (48) (64)
Chan, Andrew T. (67) (68)
Chen, Chu (15)
Clements, Judith (29) (30)
deFazio, Anna (79) (80)
Fasching, Peter A. (31) (91)
Friedman, Eitan (96) (97)
Gallinger, Steven J. (98) (99) (100)
Garber, Judy (101)
Gayther, Simon A. (88) (94)
Giles, Graham G. (54) (102) (103)
Hall, Per (77) (109)
Haugen, Aage (113)
Heitz, Florian (114) (115)
Høgdall, Estrid (116) (117)
Hulick, Peter J. (119) (120)
Huntsman, David G. (121) (122) (123)
James, Paul (54) (59)
Joshi, Amit D. (2) (67)
Khusnutdinova, Elza (129) (130)
Kim, Jeri (25)
Kjaer, Susanne K. (117) (133)
Knight, Julia A. (20) (100)
Kogevinas, Manolis (32) (134) (135) (136)
Kristensen, Vessela N. (138) (139) (140)
Lam, Stephan (143)
Lambrechts, Diether (71) (144)
Le, Nhu D. (143)
Levine, Douglas A. (148) (149)
Li, Li (5) (150)
Mannermaa, Arto (155) (156)
May, Taymaa (111)
Middha, Pooja (48) (55)
Milne, Roger L. (54) (102)
MacInnis, Robert J. (54) (102)
Muir, Kenneth (90) (163)
Neal, David E. (7) (49) (110)
Newcomb, Polly A. (15) (37)
Newcomb, Lisa F. (15) (37)
Nordestgaard, Børge G. (43) (44) (45)
Olah, Edith (171)
Osorio, Ana (32) (33)
Pashayan, Nora (7) (11)
Phipps, Amanda I. (15) (37)
Ramus, Susan J. (181) (182)
Raskin, Leon (183)
Rennert, Gad (184)
Risch, Angela (187) (188) (189)
Rossing, Mary Anne (15) (37)
Schleutker, Johanna (194) (195) (196)
Sieh, Weiva (190)
Southey, Melissa C. (54) (103)
Stanford, Janet L. (15) (37)
Stone, Jennifer (54) (203)
Tajara, Eloiza H. (206) (207)
Teixeira, Manuel R. (209) (210)
Terry, Kathryn L. (131) (212)
Bjørge, Line (214) (215)
Tischkowitz, Marc (7) (105)
Torres, Diana (48) (217)
Tung, Nadine (219)
Vega, Ana (32) (222)
Wang, Qin (7)
White, Emily (15) (37)
Wichmann, H-Erich (158) (224) (225)
Winqvist, Robert (226) (227)
Wolk, Alicja (1) (228)
Wu, Xifeng (25)
Zheng, Wei (183)
Saxena, Richa (3) (67)
Hung, Rayjean J. (20) (100)
Diergaarde, Brenda (92) (160)
Hsu, Li (15)
Eeles, Rosalind A. (34) (231)
Price, Alkes L. (2) (3)
Kraft, Peter * (2)
Lindström, Sara * (15) (37)

* Corresponding author

Affiliations

Organisations

  1. (1) Karolinska Institute, grid.4714.6
  2. (2) Harvard University, grid.38142.3c
  3. (3) Broad Institute, grid.66859.34
  4. (4) University Hospitals of Cleveland, grid.241104.2
  5. (5) Case Western Reserve University, grid.67105.35
  6. (6) Moffitt Cancer Center, grid.468198.a
  7. (7) University of Cambridge, grid.5335.0
  8. (8) Dartmouth College, grid.254880.3
  9. (9) Cyprus Institute of Neurology and Genetics, grid.417705.0
  10. (10) International Agency For Research On Cancer, grid.17703.32
  11. (11) University College London, grid.83440.3b
  12. (12) Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, 48109, Los Angeles, CA, USA
  13. (13) University of Virginia, grid.27755.32
  14. (14) American Cancer Society, grid.422418.9
  15. (15) Fred Hutchinson Cancer Research Center, grid.270240.3
  16. (16) National Cancer Institute, grid.48336.3a
  17. (17) Vanderbilt University Medical Center, grid.412807.8
  18. (18) Dartmouth–Hitchcock Medical Center, grid.413480.a
  19. (19) Fred ALitwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, 600 University Avenue, M5G1X5, Toronto, ON, Canada
  20. (20) University of Toronto, grid.17063.33
  21. (21) University of California, Irvine, grid.266093.8
  22. (22) NNAlexandrov Research Institute of Oncology and Medical Radiology, Settlement of Lesnoy-2, 223040, Minsk, Belarus
  23. (23) University of Kentucky, grid.266539.d
  24. (24) Queen's University, grid.410356.5
  25. (25) The University of Texas MD Anderson Cancer Center, grid.240145.6
  26. (26) Rutgers, The State University of New Jersey, grid.430387.b
  27. (27) National University Hospital of Iceland, grid.410540.4
  28. (28) University of Iceland, grid.14013.37
  29. (29) Queensland University of Technology, grid.1024.7
  30. (30) Translational Research Institute, grid.489335.0
  31. (31) Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen Nuremberg, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Universitaetsstrasse 21-23, 91054, Erlangen, Germany
  32. (32) Centre for Biomedical Network Research on Rare Diseases, grid.452372.5
  33. (33) Spanish National Cancer Research Centre, grid.7719.8
  34. (34) Institute of Cancer Research, grid.18886.3f
  35. (35) Duke University Hospital, grid.189509.c
  36. (36) University Medical Center Göttingen, grid.411984.1
  37. (37) University of Washington, grid.34477.33
  38. (38) Department of Oncology, Helsinki University Hospital, University of Helsinki, Haartmaninkatu 4, 00290, Helsinki, Finland
  39. (39) Örebro University Hospital, grid.412367.5
  40. (40) Catholic University of the Sacred Heart, grid.8142.f
  41. (41) Istituti di Ricovero e Cura a Carattere Scientifico, grid.414603.4
  42. (42) Hannover Medical School, grid.10423.34
  43. (43) Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev Ringvej 75, 2730, Herlev, Denmark
  44. (44) Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev Ringvej 75, 2730, Herlev, Denmark
  45. (45) University of Copenhagen, grid.5254.6, KU
  46. (46) DrMargarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstr112, 70376, Stuttgart, Germany
  47. (47) University of Tübingen, grid.10392.39
  48. (48) German Cancer Research Center, grid.7497.d
  49. (49) Cancer Research UK Cambridge Institute, grid.470869.4
  50. (50) Catalan Institute of Oncology, grid.418701.b
  51. (51) Department of Genetics and Pathology, Division of Laboratory Medicine, 221 85, Lund, Sweden
  52. (52) Lund University, grid.4514.4
  53. (53) Royal Melbourne Hospital, grid.416153.4
  54. (54) University of Melbourne, grid.1008.9
  55. (55) Heidelberg University, grid.7700.0
  56. (56) Department of Pathology, University of Helsinki and Helsinki University Hospital, Biomedicum Helsinki 4th floor, Haartmaninkatu 8, 00029, Helsinki, Finland
  57. (57) Hospital Clínico San Carlos, grid.411068.a
  58. (58) Section of Genetic Oncology, Department of Laboratory Medicine, University and University Hospital of Pisa, via Roma 67, 56126, Pisa, Italy
  59. (59) Peter MacCallum Cancer Centre, grid.1055.1
  60. (60) Sorbonne Université, GRC N°5 ONCOTYPE-URO, Tenon Hospital, 75020, Paris, France
  61. (61) Tenon Hospital, grid.413483.9
  62. (62) George E. Wahlen Department of VA Medical Center, grid.413886.0
  63. (63) University of Utah, grid.223827.e
  64. (64) University of Pisa, grid.5395.a
  65. (65) Head and Neck Surgery Department, Barretos Cancer Hospital, Pio XII, 1331, Antenor Duarte Villela St, 14784-400, Barretos, SP, Brazil
  66. (66) Hospital de Câncer de Barretos, grid.427783.d
  67. (67) Massachusetts General Hospital, grid.32224.35
  68. (68) Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 181 Longwood Avenue, 02115, Boston, MA, USA
  69. (69) University Cancer Center Hamburg, grid.412315.0
  70. (70) Ghent University, grid.5342.0
  71. (71) KU Leuven, grid.5596.f
  72. (72) Erasmus University Medical Center, grid.5645.2
  73. (73) University of Puerto Rico, Medical Sciences Campus, grid.267034.4
  74. (74) Mayo Clinic, grid.66875.3a
  75. (75) University of Sheffield, grid.11835.3e
  76. (76) Pomeranian Medical University, grid.107950.a
  77. (77) Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Karolinska Univ Hospital, 171 76, Stockholm, Sweden
  78. (78) Temple University Health System, grid.412530.1
  79. (79) University of Sydney, grid.1013.3
  80. (80) Westmead Hospital, grid.413252.3
  81. (81) Leiden University Medical Center, grid.10419.3d
  82. (82) Hospital Universitari Vall d'Hebron, grid.411083.f
  83. (83) Complejo Hospitalario Universitario de Santiago, grid.411048.8
  84. (84) University of California, San Diego, grid.266100.3
  85. (85) University of Bristol, grid.5337.2
  86. (86) University of Westminster, grid.12896.34
  87. (87) University of Southampton, grid.5491.9
  88. (88) University of Southern California, grid.42505.36
  89. (89) Department of Cancer Epidemiology, Clinical Sciences, Lund University, Barngatan 4, Skånes universitetssjukhus, 222 42, Lund, Sweden
  90. (90) University of Manchester, grid.5379.8
  91. (91) University of California, Los Angeles, grid.19006.3e
  92. (92) University of Pittsburgh, grid.21925.3d
  93. (93) University of Liverpool, grid.10025.36
  94. (94) Cedars-Sinai Medical Center, grid.50956.3f
  95. (95) National Centre of Scientific Research Demokritos, grid.6083.d
  96. (96) Sheba Medical Center, grid.413795.d
  97. (97) Tel Aviv University, grid.12136.37
  98. (98) Mount Sinai Hospital, grid.416166.2
  99. (99) Toronto General Hospital, grid.417184.f
  100. (100) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
  101. (101) Dana-Farber Cancer Institute, grid.65499.37
  102. (102) Cancer Council Victoria, grid.3263.4
  103. (103) Monash University, grid.1002.3
  104. (104) University of Kansas Medical Center, grid.412016.0
  105. (105) McGill University, grid.14709.3b
  106. (106) Swedish Medical Center, grid.281044.b
  107. (107) Umeå University, grid.12650.30
  108. (108) Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, 94805, Villejuif, France
  109. (109) Stockholm South General Hospital, grid.416648.9
  110. (110) Nuffield Department of Surgical Sciences, Faculty of Medical Science, John Radcliffe Hospital, University of Oxford, OX1 2JD, Oxford, UK
  111. (111) Princess Margaret Cancer Centre, grid.415224.4
  112. (112) Department of Internal Medicine 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), 01307, Dresden, Germany
  113. (113) National Institute of Occupational Health, grid.416876.a
  114. (114) Department of Gynecology and Gynecologic Oncology, DrHorst Schmidt Kliniken Wiesbaden, Ludwig-Erhard-Straße 100, 65199, Wiesbaden, Germany
  115. (115) Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte/ EvangHuyssens-Stiftung/ Knappschaft GmbH, Henricistrasse 92, 45136, Essen, Germany
  116. (116) Herlev Hospital, grid.411900.d, Capital Region
  117. (117) Danish Cancer Society, grid.417390.8
  118. (118) Seoul National University, grid.31501.36
  119. (119) NorthShore University HealthSystem, grid.240372.0
  120. (120) University of Chicago, grid.170205.1
  121. (121) Department of Molecular Oncology, BC Cancer Agency Research Centre, #3427-600 West 10th Avenue, V5Z 4E6, Vancouver, BC, Canada
  122. (122) University of British Columbia, grid.17091.3e
  123. (123) Vancouver General Hospital, grid.412541.7
  124. (124) NNPetrov Institute of Oncology, Leningradskaya ul, 68, 197758, StPetersburg, Russia
  125. (125) Georgetown University, grid.213910.8
  126. (126) Stanford University, grid.168010.e
  127. (127) Medical University of Sofia, grid.410563.5
  128. (128) Medical University of South Carolina, grid.259828.c
  129. (129) Institute of Biochemistry and Genetics of Ufa Scientific Centre, grid.429129.5
  130. (130) Bashkir State University, grid.77269.3d
  131. (131) Brigham and Women's Hospital, grid.62560.37
  132. (132) Radboud University Nijmegen Medical Centre, grid.10417.33
  133. (133) Department of Gynaecology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100, Copenhagen, Denmark
  134. (134) Centre for Research in Environmental Epidemiology (CREAL), ISGlobal, 08036, Barcelona, Spain
  135. (135) Hospital Del Mar, grid.411142.3
  136. (136) Pompeu Fabra University, grid.5612.0
  137. (137) National Institutes of Health, grid.94365.3d
  138. (138) Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Kirkeveien 166, 0450, Oslo, Norway
  139. (139) Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Kirkeveien 166, 0450, Oslo, Norway
  140. (140) Oslo University Hospital, grid.55325.34
  141. (141) Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, grid.418165.f
  142. (142) Maastricht University Medical Centre, grid.412966.e
  143. (143) BC Cancer Agency, grid.248762.d
  144. (144) Flanders Institute for Biotechnology, grid.11486.3a
  145. (145) Washington State University, grid.30064.31
  146. (146) Carmel Medical Center, grid.413469.d
  147. (147) University Medical Center Hamburg-Eppendorf, grid.13648.38
  148. (148) New York University Langone Medical Center, grid.240324.3
  149. (149) Memorial Sloan Kettering Cancer Center, grid.51462.34
  150. (150) Instituto de Investigación Sanitaria de Santiago, grid.488911.d
  151. (151) Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska Univ Hospital, 171 76, Stockholm, Sweden
  152. (152) Mayo Clinic, grid.417468.8
  153. (153) Istituto Oncologico Veneto, grid.419546.b
  154. (154) University Hospital Ulm, grid.410712.1
  155. (155) Kuopio University Hospital, grid.410705.7
  156. (156) University of Eastern Finland, grid.9668.1
  157. (157) University of Hawaii at Manoa, grid.410445.0
  158. (158) Technical University of Munich, grid.6936.a
  159. (159) Roswell Park Cancer Institute, grid.240614.5
  160. (160) University of Pittsburgh Cancer Institute, grid.478063.e
  161. (161) Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Via Gattamelata 64, 35128, Padua, Italy
  162. (162) Catalan Institute of Oncology, Bellvitge Biomedical Research Institute (IDIBELL), Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP) and University of Barcelona, 08908, Barcelona, Spain
  163. (163) University of Warwick, grid.7372.1
  164. (164) University Health Network, grid.231844.8
  165. (165) Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, 19104, Philadelphia, PA, USA
  166. (166) City Of Hope National Medical Center, grid.410425.6
  167. (167) Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Haartmaninkatu 8, 00290, Helsinki, Finland
  168. (168) Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100, Copenhagen, Denmark
  169. (169) Latvian Biomedical Research and Study Centre, grid.419210.f
  170. (170) University of California, San Francisco, grid.266102.1
  171. (171) National Institute of Oncology, grid.419617.c
  172. (172) Center for Clinical Cancer Genetics, The University of Chicago, 5841S Maryland Ave, 60637, Chicago, IL, USA
  173. (173) University of North Carolina at Chapel Hill, grid.10698.36
  174. (174) University of Surrey, grid.5475.3
  175. (175) Department of Cancer Epidemiology, HLee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, 33612, Tampa, FL, USA
  176. (176) QIMR Berghofer Medical Research Institute, grid.1049.c
  177. (177) Oregon Health & Science University, grid.5288.7
  178. (178) Macedonian Academy of Sciences and Arts, grid.419383.4
  179. (179) Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Via Giacomo Venezian 1, 20133, Milan, Italy
  180. (180) deCODE Genetics (Iceland), grid.421812.c
  181. (181) The Kinghorn Cancer Centre, grid.410697.d
  182. (182) UNSW Sydney, grid.1005.4
  183. (183) Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, 1161 21st Ave S # D3300, 37232, Nashville, TN, USA
  184. (184) Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, 7 Michal Street, 34362, Haifa, Israel
  185. (185) University of Pretoria, grid.49697.35
  186. (186) Yale University, grid.47100.32
  187. (187) Division of Epigenomics and Cancer Risk Factors, DKFZ – German Cancer Research Center, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
  188. (188) German Center for Lung Research, grid.452624.3
  189. (189) University of Salzburg, grid.7039.d
  190. (190) Icahn School of Medicine at Mount Sinai, grid.59734.3c
  191. (191) University Hospital of Heraklion, grid.412481.a
  192. (192) National Institute of Environmental Health Sciences, grid.280664.e
  193. (193) King's College London, grid.13097.3c
  194. (194) Tampere University, grid.502801.e
  195. (195) Turku University Hospital, grid.410552.7
  196. (196) University of Turku, grid.1374.1
  197. (197) Antoni van Leeuwenhoek Hospital, grid.430814.a
  198. (198) Nanjing Medical University, grid.89957.3a
  199. (199) Medical University of Vienna, grid.22937.3d
  200. (200) Aarhus University, grid.7048.b, AU
  201. (201) Aarhus University Hospital, grid.154185.c, Central Denmark Region
  202. (202) Department of Medicine III, University Hospital, LMU Munich, Marchioninistr15, 81377, Munich, Germany
  203. (203) University of Western Australia, grid.1012.2
  204. (204) University of Gothenburg, grid.8761.8
  205. (205) University of South Florida, grid.170693.a
  206. (206) Department of Molecular Biology, School of Medicine of São José do Rio Preto, Av Brig Faria Lima 5416 Vila São Pedro, 15090-000, São José do Rio Preto, SP, Brazil
  207. (207) University of Sao Paulo, grid.11899.38
  208. (208) University of Oviedo, grid.10863.3c
  209. (209) Portuguese Oncology Institute, grid.418711.a
  210. (210) University of Porto, grid.5808.5
  211. (211) Columbia University, grid.21729.3f
  212. (212) Harvard THChan School of Public Health, 221 Longwood Avenue RFB 368, 02115, Boston, MA, USA
  213. (213) Odense University Hospital, grid.7143.1, Southern Denmark Region
  214. (214) Haukeland University Hospital, grid.412008.f
  215. (215) University of Bergen, grid.7914.b
  216. (216) The Ohio State University, grid.261331.4
  217. (217) Pontificia Universidad Javeriana, grid.41312.35
  218. (218) University of Oxford, grid.4991.5
  219. (219) Beth Israel Deaconess Medical Center, grid.239395.7
  220. (220) University of Alberta, grid.17089.37
  221. (221) Universitair Ziekenhuis Leuven, grid.410569.f
  222. (222) Fundación Pública Galega de Medicina Xenómica, grid.443929.1
  223. (223) Division of Cancer Sciences, University of Manchester, Manchester Cancer Research Centre, Manchester Academic Health Science Centre,, The Christie Hospital NHS Foundation Trust, M13 9PL, Manchester, UK
  224. (224) Helmholtz Zentrum Munchen, German Research Center for Environmental Health (GmbH), Institute of Epidemiology, Ingolstadter Landstr1, 85764, Neuherberg, Germany
  225. (225) Ludwig Maximilian University of Munich, grid.5252.0
  226. (226) Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Aapistie 5A, 90220, Oulu, Finland
  227. (227) University of Oulu, grid.10858.34
  228. (228) Uppsala University, grid.8993.b
  229. (229) Memorial University of Newfoundland, grid.25055.37
  230. (230) Magee-Womens Hospital, University of Pittsburgh School of Medicine, 300 Halket St, 15213, Pittsburgh, PA, USA
  231. (231) Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Downs Road, SM2 5NG, Sutton, UK
  232. (232) Centre Hospitalier Universitaire de Québec, grid.411081.d
  233. (233) Baylor College of Medicine, grid.39382.33

Description

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

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