Article open access publication

Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33

Human Molecular Genetics, Oxford University Press (OUP), ISSN 1460-2083

Volume 23, 24, 2014

DOI:10.1093/hmg/ddu363, Dimensions: pub.1020025747, PMC: PMC4240198, PMID: 25027329,

Authors

Zhu, Bin (2)
Che, Xu (37)
Ding, Ti (50)
Gu, Jian (77)
Guan, Peng (78)
Hu, Nan (2)
Hu, Wei (2)
Lan, Qing (2)
Lau, Ching C (107)
Li, Donghui (111)
Lim, Wei-Yen (112)
Lin, Jie (77)
Liu, Jianjun (115)
Lu, Da-Ru (118)
Ma, Jing (49)
Orr, Nick (129)
Pu, Xia (77)
Riboli, Elio (133)
Shen, Min (2)
Stattin, Par (116)
Su, Wu-Chou (143)
Sund, Malin (144)
Tan, Wen (113)
Tang, Wei (2)
Vogel, Ulla (152)
Wolk, Alicja (155)
Wu, Chen (113)
Wu, Tangchun (122)
Wu, Xifeng (77)
Wu, Yi-Long (157)
Xu, Jun (158)
Ying, Chen (112)
Yu, Kai (2)

Affiliations

Organisations

  1. (1) Frederick National Laboratory for Cancer Research, grid.418021.e
  2. (2) Division of Cancer Epidemiology and Genetics.
  3. (3) Korle Bu Teaching Hospital, grid.415489.5
  4. (4) Unit of Epidemiology, Institute of Environmental Medicine.
  5. (5) University of Oxford, grid.4991.5
  6. (6) Roswell Park Cancer Institute, grid.240614.5
  7. (7) Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA,
  8. (8) Public Health Division of Gipuzkoa, Basque Regional Health Department, San Sebastian, Spain, CIBERESP, CIBER Epidemiologia y Salud Publica, Madrid, Spain.
  9. (9) Dartmouth College, grid.254880.3
  10. (10) Department of Radiation Sciences, Oncology.
  11. (11) Washington University in St. Louis, grid.4367.6
  12. (12) University of Toronto, grid.17063.33
  13. (13) University of Brescia, grid.7637.5
  14. (14) New York University, grid.137628.9
  15. (15) University of Washington, grid.34477.33
  16. (16) Department of Preventive Medicine, Biostatistics Division, Keck School of Medicine and.
  17. (17) Yale University, grid.47100.32
  18. (18) Division of Cancer Prevention.
  19. (19) University of Milan, grid.4708.b
  20. (20) Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA, International Epidemiology Institute, Rockville, MD, USA.
  21. (21) German Institute of Human Nutrition, grid.418213.d
  22. (22) Mount Sinai Hospital, grid.416167.3
  23. (23) University of Cambridge, grid.5335.0
  24. (24) Institut National de la Sante et de la Recherche Medicale (INSERM) and Institut Gustave Roussy, Villejuif, France.
  25. (25) University of California, San Francisco, grid.266102.1
  26. (26) International Agency For Research On Cancer, grid.17703.32
  27. (27) Westat (United States), grid.280561.8
  28. (28) National Institute for Public Health and the Environment, grid.31147.30
  29. (29) Brigham and Women's Hospital, grid.62560.37
  30. (30) National Institute for Occupational Safety and Health, grid.416809.2
  31. (31) CeRePP, Paris, France, UPMC Univ Paris 06, GRC n°5, ONCOTYPE-URO, Paris, France.
  32. (32) German Cancer Research Center, grid.7497.d
  33. (33) Second Military Medical University, grid.73113.37
  34. (34) Hospital Universitario Ramón y Cajal, grid.411347.4
  35. (35) National Yang Ming University, grid.260770.4
  36. (36) National Institute of Cancer Research.
  37. (37) Department of Abdominal Surgery and.
  38. (38) Genomics Research Center, Academia Sinica, grid.506938.1
  39. (39) China Medical University Hospital, grid.411508.9
  40. (40) Program in Molecular and Genetic Epidemiology.
  41. (41) National Taiwan University Hospital, grid.412094.a
  42. (42) Taipei Veterans General Hospital, grid.278247.c
  43. (43) University of California, Berkeley, grid.47840.3f
  44. (44) Cancer Prevention Institute of California, grid.280669.3
  45. (45) Centre for research in epidemiology and population health, grid.463845.8
  46. (46) University of Colorado Anschutz Medical Campus, grid.430503.1
  47. (47) CeRePP, Paris, France, AP-HP, Department of Urology, Tenon Hospital, GHU-Est, Paris, France, UPMC Univ Paris 06, GRC n°5, ONCOTYPE-URO, Paris, France.
  48. (48) University of Alberta, grid.17089.37
  49. (49) Harvard University, grid.38142.3c
  50. (50) Shanxi Tumor Hospital, grid.440201.3
  51. (51) Department of Urology.
  52. (52) Pitié-Salpêtrière Hospital, grid.411439.a
  53. (53) American Cancer Society, grid.422418.9
  54. (54) Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain.
  55. (55) Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, Bethesda, MD, USA.
  56. (56) Shanghai Cancer Institute, grid.419087.3
  57. (57) Kaiser Permanente, grid.280062.e
  58. (58) University College London, grid.83440.3b
  59. (59) University of Kansas Medical Center, grid.412016.0
  60. (60) Dana-Farber Cancer Institute, grid.65499.37
  61. (61) Complejo Hospitalario Universitario de Santiago, grid.411048.8
  62. (62) Samuel Lunenfeld Research Institute and.
  63. (63) Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotaong University School of Medicine, Shanghai, China.
  64. (64) Institute of Cancer Research, grid.18886.3f
  65. (65) Hospital Universitario de Canarias, grid.411220.4
  66. (66) Nationwide Children's Hospital, grid.240344.5
  67. (67) National Institutes of Health, grid.94365.3d
  68. (68) Information Management Services, grid.280929.8
  69. (69) University of Melbourne, grid.1008.9
  70. (70) Division of Cancer Control and Population Sciences and.
  71. (71) Program in Molecular and Genetic Epidemiology, Department of Nutrition and.
  72. (72) Johns Hopkins University, grid.21107.35
  73. (73) Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada,
  74. (74) Catalan Institute of Oncology, grid.418701.b
  75. (75) Albert Einstein College of Medicine, grid.251993.5
  76. (76) University of Minnesota, grid.17635.36
  77. (77) Department of Epidemiology,
  78. (78) China Medical University, grid.412449.e
  79. (79) University of Southern California, grid.42505.36
  80. (80) Department of Public Health and Clinical Medicine/Nutritional Research.
  81. (81) Channing Laboratory, Department of Medicine.
  82. (82) Center for Cancer Research, grid.417768.b
  83. (83) Istituto Ortopedico Rizzoli, grid.419038.7
  84. (84) Division of Cancer Epidemiology and Genetics, Department of Population Health, New York University Langone Medical Center and Department of Environmental Medicine, New York University Langone Medical Center, New York University Cancer Institute, New York, NY, USA.
  85. (85) Center for Cancer Research and.
  86. (86) Fred Hutchinson Cancer Research Center, grid.270240.3
  87. (87) Seoul National University Hospital, grid.412484.f
  88. (88) National Health Research Institutes, grid.59784.37
  89. (89) Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences and.
  90. (90) Nanjing Medical University, grid.89957.3a
  91. (91) Aichi Cancer Center, grid.410800.d
  92. (92) Rigshospitalet, grid.475435.4, Capital Region
  93. (93) Vermont Cancer Registry, Burlington, VT, USA.
  94. (94) Group Health Cooperative, grid.280243.f
  95. (95) Kyungpook National University, grid.258803.4
  96. (96) Korea University Medical Center, grid.411134.2
  97. (97) Chonnam National University Hwasun Hospital, grid.411602.0
  98. (98) Seoul National University, grid.31501.36
  99. (99) Department of Medicine and.
  100. (100) Center for Research in Environmental Epidemiology, grid.417617.2
  101. (101) Duke NUS Graduate Medical School, grid.428397.3
  102. (102) National Cancer Centre, grid.272242.3
  103. (103) University of Hawaii at Manoa, grid.410445.0
  104. (104) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  105. (105) Ankara Onkoloji Eğitim ve Araştırma Hastanesi, grid.413794.c
  106. (106) Centre National de Génotypage, grid.418135.a
  107. (107) Texas Children's Cancer and Hematology Centers.
  108. (108) Department of Pediatrics, University Clinic of Navarra, Universidad de Navarra, Pamplona, Spain.
  109. (109) Korea National Open University, grid.411128.f
  110. (110) Scott Department of Urology and.
  111. (111) Department of Gastrointestinal Medical Oncology.
  112. (112) National University of Singapore, grid.4280.e
  113. (113) Chinese Academy of Medical Sciences & Peking Union Medical College, grid.506261.6
  114. (114) Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, grid.418165.f
  115. (115) Genome Institute of Singapore, grid.418377.e
  116. (116) Department of Surgical and Perioperative Sciences, Urology and Andrology and.
  117. (117) Institute of Health Carlos III, grid.413448.e
  118. (118) Fudan University, grid.8547.e
  119. (119) Spanish National Cancer Research Centre, grid.7719.8
  120. (120) National Institute for Health and Welfare, grid.14758.3f
  121. (121) Lucile Packard Children's Hospital, grid.414123.1
  122. (122) University of Padua, grid.5608.b
  123. (123) Department of Health Disparities Research, Division of OVP, Cancer Prevention and Population Sciences, and Center for Community-Engaged Translational Research, Duncan Family Institute and.
  124. (124) Mayo Clinic, grid.66875.3a
  125. (125) Huazhong University of Science and Technology, grid.33199.31
  126. (126) Brown University, grid.40263.33
  127. (127) University of Warwick, grid.7372.1
  128. (128) Memorial Sloan Kettering Cancer Center, grid.51462.34
  129. (129) Complex Traits Genetics Team and.
  130. (130) University of Naples Federico II, grid.4691.a
  131. (131) University Medical Center Utrecht, grid.7692.a
  132. (132) Nofer Institute of Occupational Medicine, grid.418868.b
  133. (133) Imperial College London, grid.7445.2
  134. (134) Inha University, grid.202119.9
  135. (135) Karmanos Cancer Institute and Department of Oncology and.
  136. (136) Wayne State University, grid.254444.7
  137. (137) Maine Cancer Registry, Augusta, ME, USA.
  138. (138) Pompeu Fabra University, grid.5612.0
  139. (139) The University of Texas MD Anderson Cancer Center, grid.240145.6
  140. (140) Queen Mary Hospital, grid.415550.0
  141. (141) University Hospital Bonn, grid.15090.3d
  142. (142) Baylor College of Medicine, grid.39382.33
  143. (143) National Cheng Kung University, grid.64523.36
  144. (144) Umeå University, grid.12650.30
  145. (145) Seoul St. Mary's Hospital, grid.414966.8
  146. (146) University of Oviedo, grid.10863.3c
  147. (147) Royal National Orthopaedic Hospital NHS Trust, grid.412945.f
  148. (148) Danish Cancer Society, grid.417390.8
  149. (149) Chiayi Chang Gung Memorial Hospital, grid.454212.4
  150. (150) Cancer Registry Associazione Iblea Ricerca Epidemiologica, Onlus and Asp Ragusa, Ragusa Italy.
  151. (151) Utrecht University, grid.5477.1
  152. (152) National Research Centre for the Working Environment, grid.418079.3
  153. (153) City Of Hope National Medical Center, grid.410425.6
  154. (154) The Arctic University of Norway, grid.10919.30
  155. (155) Karolinska Institute, grid.4714.6
  156. (156) Department of Pathology and.
  157. (157) Guangdong Academy of Medical Sciences, grid.410643.4
  158. (158) University of Hong Kong, grid.194645.b
  159. (159) Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital and.
  160. (160) University of Pittsburgh Cancer Institute, grid.478063.e
  161. (161) Division of Cancer Epidemiology and Genetics, amundadottirl@mail.nih.gov.

Description

Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.

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Times Cited: 70

Field Citation Ratio (FCR): 8

Relative Citation ratio (RCR): 2.42

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