Article open access publication

PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS

Journal of Medical Genetics, BMJ, ISSN 0022-2593

Volume 53, 12, 2016

DOI:10.1136/jmedgenet-2016-103839, Dimensions: pub.1025022032, PMC: PMC5200636, PMID: 27595995,

Authors

Fasching, Peter A (18) (19)
Haeberle, Lothar (19) (20)
Tomlinson, Ian (25) (26)
Marme, Federik (28) (29)
Burwinkel, Barbara (29) (30)
Yang, Rongxi (29) (30)
Guénel, Pascal (31) (32)
Truong, Thérèse (31) (32)
Menegaux, Florence (31) (32)
Sanchez, Marie (31) (32)
Bojesen, Stig (33) (34)
Nielsen, Sune F (33) (34)
Benitez, Javier (36) (37)
Brauch, Hiltrud (30) (44) (45)
Mannermaa, Arto (50) (51)
Kataja, Vesa (50) (51)
Kosma, Veli-Matti (50) (51)
Wauters, Els (53) (54)
Smeets, Dominiek (53) (54)
Zheng, Wei (62)
Andrulis, Irene (64) (65)
Knight, Julia A (64) (65)
Hall, Per (49)
Torres, Diana (30) (77)
Orr, Nick (23)
Eeles, Rosalind (23) (88)
Weischer, Maren (93) (94)
Neal, David (5) (95)
Stanford, Janet L (97) (98)
Maier, Christiane (101) (102)
Kibel, Adam S (103) (104)
Park, Jong (105)
Teixeira, Manuel R (108) (109)
Rossing, Mary Anne (97) (98)
Modugno, Francesmary (100) (116)
du Bois, Andreas (118) (119)
Heitz, Florian (118) (119)
Harter, Philipp (118) (119)
Kommoss, Stefan (119) (120)
Høgdall, Estrid (121) (123)
Bernard, Loris (124) (125)
Liang, Dong (127)
Lu, Karen H (128)
Wu, Xifeng (128)
Dao, Fanny (11)
Poole, Elizabeth M (63) (132)
Stampfer, Meir (63) (132)
Tworoger, Shelley S (63) (132)
Bjorge, Line (134) (135)
Salvesen, Helga B (134) (135)
Aben, Katja K H (136) (137) (138)
Bean, Yukie (138)
Brooks-Wilson, Angela (139) (140)
Kelemen, Linda E (141) (142)
Le, Nhu D (140)
Dicks, Ed (5)
Paul, James (149)
Sieh, Weiva (151)
Cai, Hui (62)
Lin, Hui-Yi (105)
Chen, Y Ann (105)
Tsai, Ya-Yu (105)
Chen, Zhihua (105)
Menon, Usha (154)
Wu, Anna H (58)
Pike, Malcolm C (11) (58)
Winship, Ingrid (155) (156)
Giles, Graham G (1) (157)
Milne, Roger L (1) (157)

Affiliations

Organisations

  1. (1) University of Melbourne, grid.1008.9
  2. (2) Huntsman Cancer Institute, grid.479969.c
  3. (3) University of Oulu, grid.10858.34
  4. (4) Mayo Clinic, grid.66875.3a
  5. (5) University of Cambridge, grid.5335.0
  6. (6) Program in Cancer Genetics, Department of Human Genetics and Oncology, Lady Davis Institute, and Research Institute, McGill University Health Centre, McGill University, Montreal, Canada
  7. (7) University of Pretoria, grid.49697.35
  8. (8) Helsinki University Central Hospital, grid.15485.3d
  9. (9) Hannover Medical School, grid.10423.34
  10. (10) Ghent University Hospital, grid.410566.0
  11. (11) Memorial Sloan Kettering Cancer Center, grid.51462.34
  12. (12) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  13. (13) FIRC Institute of Molecular Oncology, grid.7678.e
  14. (14) Antoni van Leeuwenhoek Hospital, grid.430814.a
  15. (15) Australian Breast Cancer Tissue Bank, University of Sydney at the Westmead Institute for Medical Research, NSW, Australia
  16. (16) Centre for Cancer Research, University of Sydney at the Westmead Institute for Medical Research, NSW, Australia
  17. (17) University of Newcastle Australia, grid.266842.c
  18. (18) University of California, Los Angeles, grid.19006.3e
  19. (19) University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
  20. (20) Unit of Biostatistics, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
  21. (21) Institute of Human Genetics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany
  22. (22) London School of Hygiene & Tropical Medicine, grid.8991.9
  23. (23) Institute of Cancer Research, grid.18886.3f
  24. (24) King's College London, grid.13097.3c
  25. (25) Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, UK and Oxford NIHR Biomedical Research Centre, Headington, OX3 7LE
  26. (26) University of Oxford, grid.4991.5
  27. (27) University Hospital Galway, grid.412440.7
  28. (28) National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany
  29. (29) Heidelberg University, grid.7700.0
  30. (30) German Cancer Research Center, grid.7497.d
  31. (31) French Institute of Health and Medical Research, grid.7429.8
  32. (32) University of Paris-Sud, grid.5842.b
  33. (33) Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark
  34. (34) Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark
  35. (35) Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark
  36. (36) Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain
  37. (37) Spanish National Cancer Research Centre, grid.7719.8
  38. (38) Hospital Universitario La Paz, grid.81821.32
  39. (39) Hospital Monte Naranco, grid.414858.4
  40. (40) University of California, Irvine, grid.266093.8
  41. (41) City Of Hope National Medical Center, grid.410425.6
  42. (42) Cancer Prevention Institute of California, grid.280669.3
  43. (43) Krebsregister Saarland, grid.482902.5
  44. (44) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  45. (45) University of Tübingen, grid.10392.39
  46. (46) Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University, Bochum (IPA), Germany
  47. (47) Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany
  48. (48) N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus
  49. (49) Karolinska Institute, grid.4714.6
  50. (50) Kuopio University Hospital, grid.410705.7
  51. (51) University of Eastern Finland, grid.9668.1
  52. (52) QIMR Berghofer Medical Research Institute, grid.1049.c
  53. (53) Flanders Institute for Biotechnology, grid.11486.3a
  54. (54) KU Leuven, grid.5596.f
  55. (55) Universitair Ziekenhuis Leuven, grid.410569.f
  56. (56) University Medical Center Hamburg-Eppendorf, grid.13648.38
  57. (57) The Alfred Hospital, grid.1623.6
  58. (58) University of Southern California, grid.42505.36
  59. (59) University of Hawaii at Manoa, grid.410445.0
  60. (60) University of Oslo, grid.5510.1
  61. (61) Oslo University Hospital, grid.55325.34
  62. (62) Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
  63. (63) Harvard University, grid.38142.3c
  64. (64) Mount Sinai Hospital, grid.416166.2
  65. (65) University of Toronto, grid.17063.33
  66. (66) University Health Network, grid.231844.8
  67. (67) Department of Oncology, Oulu University Hospital, University of Oulu, Oulu, Finland
  68. (68) Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, Finland
  69. (69) Department of Pathology, Oulu University Hospital, University of Oulu, Oulu, Finland
  70. (70) Leiden University Medical Center, grid.10419.3d
  71. (71) Erasmus University Medical Center, grid.5645.2
  72. (72) National Cancer Institute, grid.48336.3a
  73. (73) Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, grid.418165.f
  74. (74) University of Southampton, grid.5491.9
  75. (75) Genome Institute of Singapore, grid.418377.e
  76. (76) University of Sheffield, grid.11835.3e
  77. (77) Pontificia Universidad Javeriana, grid.41312.35
  78. (78) Klinikum Mittelbaden, grid.506801.a
  79. (79) Städtisches Klinikum Karlsruhe, grid.419594.4
  80. (80) Pomeranian Medical University, grid.107950.a
  81. (81) Medical University of Warsaw, grid.13339.3b
  82. (82) The Ohio State University, grid.261331.4
  83. (83) Roswell Park Cancer Institute, grid.240614.5
  84. (84) National Centre of Scientific Research Demokritos, grid.6083.d
  85. (85) Centre d’innovation Genome Quebec et University McGill Montreal Quebec, Canada
  86. (86) McGill University, grid.14709.3b
  87. (87) Centre Hospitalier Universitaire de Québec, grid.411081.d
  88. (88) Royal Marsden NHS Foundation Trust, grid.5072.0
  89. (89) University of Warwick, grid.7372.1
  90. (90) Department of Medical Biochemistry and Genetics, University of Turku, and Tyks Microbiology and Genetics, Department of Medical Genetics, Turku University Hospital, Turku, Finland
  91. (91) Tampere University, grid.502801.e
  92. (92) Herlev Hospital, grid.411900.d, Capital Region
  93. (93) Department of Human Genetics University of Utah, Salt Lake City, UT, USA and Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark
  94. (94) University of Utah, grid.223827.e
  95. (95) Cancer Research UK Cambridge Institute, grid.470869.4
  96. (96) University of Bristol, grid.5337.2
  97. (97) Fred Hutchinson Cancer Research Center, grid.270240.3
  98. (98) University of Washington, grid.34477.33
  99. (99) International Epidemiology Institute, grid.419344.f
  100. (100) University of Pittsburgh, grid.21925.3d
  101. (101) University Hospital Ulm, grid.410712.1
  102. (102) University of Bonn, grid.10388.32
  103. (103) Brigham and Women’s Hospital/Dana-Farber Cancer Institute, 45 Francis Street-ASB II-3, Boston, MA 02115
  104. (104) Washington University in St. Louis, grid.4367.6
  105. (105) Moffitt Cancer Center, grid.468198.a
  106. (106) Medical University of Sofia, grid.410563.5
  107. (107) Queensland University of Technology, grid.1024.7
  108. (108) Portuguese Oncology Institute, grid.418711.a
  109. (109) University of Porto, grid.5808.5
  110. (110) University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Universitaetsstrasse 21-23, 91054 Erlangen, Germany
  111. (111) University Hospital Erlangen, Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Universitaetsstrasse 21-23, 91054 Erlangen, German
  112. (112) Dartmouth College, grid.254880.3
  113. (113) University of Ulm, grid.6582.9
  114. (114) Cedars-Sinai Medical Center, grid.50956.3f
  115. (115) Department of Gynecology and Obstetrics, Friedrich Schiller University, Jena University Hospital, Jena, Germany
  116. (116) University of Pittsburgh Department of Epidemiology, University of Pittsburgh Graduate School of Public Health and Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute Pittsburgh PA USA
  117. (117) The University of Texas Health Science Center at Houston, grid.267308.8
  118. (118) Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte/ Evang. Huyssens-Stiftung/ Knappschaft GmbH, Essen, Germany
  119. (119) Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany
  120. (120) Universitätsklinikum Tübingen, grid.411544.1
  121. (121) Danish Cancer Society, grid.417390.8
  122. (122) Rigshospitalet, grid.475435.4, Capital Region
  123. (123) University of Copenhagen, grid.5254.6, KU
  124. (124) European Institute of Oncology, grid.15667.33
  125. (125) Department of Experimental Oncology, Istituto Europeo di Oncologia (IEO), Milan, Italy and Cogentech Cancer Genetic Test Laboratory, Milan, Italy
  126. (126) University of Kansas Medical Center, grid.412016.0
  127. (127) Texas Southern University, grid.264771.1
  128. (128) The University of Texas MD Anderson Cancer Center, grid.240145.6
  129. (129) Duke University Hospital, grid.189509.c
  130. (130) Duke University, grid.26009.3d
  131. (131) Brigham and Women's Hospital, grid.62560.37
  132. (132) Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School
  133. (133) Rutgers, The State University of New Jersey, grid.430387.b
  134. (134) Haukeland University Hospital, grid.412008.f
  135. (135) University of Bergen, grid.7914.b
  136. (136) Radboud University Nijmegen Medical Centre, grid.10417.33
  137. (137) Netherlands Comprehensive Cancer Organisation, grid.470266.1
  138. (138) Oregon Health & Science University, grid.5288.7
  139. (139) Simon Fraser University, grid.61971.38
  140. (140) BC Cancer Agency, grid.248762.d
  141. (141) Department of Public Health Sciences, College of Medicine, Medical University of South Carolina, SC, USA
  142. (142) Medical University of South Carolina, grid.259828.c
  143. (143) University of New Mexico, grid.266832.b
  144. (144) Gyn Clinic, Rigshospitalet, University of Copenhagen, Denmark
  145. (145) Department of Pathology, Rigshospitalet, University of Copenhagen, Denmark
  146. (146) Department of Oncology, Rigshospitalet, University of Copenhagen, Denmark
  147. (147) Peter MacCallum Cancer Centre, grid.1055.1
  148. (148) University of Glasgow, grid.8756.c
  149. (149) Beatson West of Scotland Cancer Centre, grid.422301.6
  150. (150) Department of Gynaecological Oncology, Glasgow Royal Infirmary
  151. (151) Stanford University, grid.168010.e
  152. (152) University of South Florida, grid.170693.a
  153. (153) Public Health Ontario, grid.415400.4
  154. (154) University College London, grid.83440.3b
  155. (155) Department of Medicine, The University of Melbourne Health, Australia
  156. (156) Royal Melbourne Hospital, grid.416153.4
  157. (157) Cancer Council Victoria, grid.3263.4

Description

BACKGROUND: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. METHODS: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. RESULTS: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. CONCLUSIONS: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

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Times Cited: 81

Field Citation Ratio (FCR): 23.88

Relative Citation ratio (RCR): 4.22

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