Article open access publication

Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers

PLoS ONE, Public Library of Science (PLoS), ISSN 1932-6203

Volume 10, 4, 2015

DOI:10.1371/journal.pone.0120020, Dimensions: pub.1044278974, PMC: PMC4382299, PMID: 25830658,

Authors

Chu, Carol (32)
Friedman, Eitan (92) (93)
Esteller, Manel (3) (101) (102)
Sinilnikova, Olga M (105) (106)
Robson, Mark (113)
Kauff, Noah (113)
Lee, Adam (4)

* Corresponding author

Affiliations

Organisations

  1. (1) Hereditary Cancer Program, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Catalonia, Spain
  2. (2) University of Cambridge, grid.5335.0
  3. (3) Institut d'Investigació Biomédica de Bellvitge, grid.418284.3
  4. (4) Mayo Clinic, grid.66875.3a
  5. (5) Breast Cancer and Systems Biology Unit, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Catalonia, Spain
  6. (6) University of Barcelona, grid.5841.8
  7. (7) University of Dhaka, grid.8198.8
  8. (8) Department of Pathology, University Hospital of Bellvitge, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Catalonia, Spain
  9. (9) Hereditary Cancer Program, Catalan Institute of Oncology (ICO), Girona Biomedical Research Institute (IDIBGI), Hospital Josep Trueta, Girona, Catalonia, Spain
  10. (10) Spanish National Cancer Research Centre, grid.7719.8
  11. (11) Hospital de Sant Pau, grid.413396.a
  12. (12) Helsinki University Central Hospital, grid.15485.3d
  13. (13) The University of Texas MD Anderson Cancer Center, grid.240145.6
  14. (14) The Ohio State University, grid.261331.4
  15. (15) Cedars-Sinai Medical Center, grid.50956.3f
  16. (16) National Cancer Institute, grid.48336.3a
  17. (17) University of California, San Francisco, grid.266102.1
  18. (18) University of Toronto, grid.17063.33
  19. (19) University of Pennsylvania, grid.25879.31
  20. (20) University of Iceland, grid.14013.37
  21. (21) Pomeranian Medical University, grid.107950.a
  22. (22) Ghent University, grid.5342.0
  23. (23) Hospital Universitari Vall d'Hebron, grid.411083.f
  24. (24) Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  25. (25) Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  26. (26) Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  27. (27) Hospital Clínico San Carlos, grid.411068.a
  28. (28) Glan Clwyd Hospital, grid.415564.7
  29. (29) Singleton Hospital, grid.415947.a
  30. (30) National Health Service, grid.451052.7
  31. (31) Manchester Academic Health Science Centre, grid.462482.e
  32. (32) Yorkshire Regional Genetics Service, Leeds, United Kingdom
  33. (33) North West Thames Regional Genetics Service, Kennedy-Galton Centre, Harrow, United Kingdom
  34. (34) Addenbrooke's Hospital, grid.120073.7
  35. (35) West Midlands Regional Genetics Service, Birmingham Women’s Hospital Healthcare National Health Service (NHS) Trust, Edgbaston, Birmingham, United Kingdom
  36. (36) University of Porto, grid.5808.5
  37. (37) Antoni van Leeuwenhoek Hospital, grid.430814.a
  38. (38) Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, Netherlands
  39. (39) Erasmus University Medical Center, grid.5645.2
  40. (40) University Medical Center Utrecht, grid.7692.a
  41. (41) Radboud University Nijmegen Medical Centre, grid.10417.33
  42. (42) Leiden University Medical Center, grid.10419.3d
  43. (43) VU University Medical Center, grid.16872.3a
  44. (44) Maastricht University Medical Centre, grid.412966.e
  45. (45) Academic Medical Center, grid.5650.6
  46. (46) Division of Gynecologic Oncology, NorthShore University HealthSystem, University of Chicago, Chicago, Illinois, United States of America
  47. (47) Peter MacCallum Cancer Centre, grid.1055.1
  48. (48) Roswell Park Cancer Institute, grid.240614.5
  49. (49) Central Connecticut Cancer Consortium, Hartford Hospital/Helen and Harry Gray Cancer Center, Hartford, Connecticut, United States of America
  50. (50) University of North Carolina System, grid.410711.2
  51. (51) Yale University, grid.47100.32
  52. (52) University Hospital Cologne, grid.411097.a
  53. (53) Leipzig University, grid.9647.c
  54. (54) Department of Gynecology and Obstetrics, Division of Tumor Genetics, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany
  55. (55) Ludwig Maximilian University of Munich, grid.5252.0
  56. (56) University Hospital Schleswig-Holstein, grid.412468.d
  57. (57) Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
  58. (58) University Hospital Heidelberg, grid.5253.1
  59. (59) University Hospital Ulm, grid.410712.1
  60. (60) Hannover Medical School, grid.10423.34
  61. (61) University of Münster, grid.5949.1
  62. (62) Department of Gynecology and Obstetrics, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
  63. (63) Charité, grid.6363.0
  64. (64) University of Würzburg, grid.8379.5
  65. (65) Vejle Sygehus, grid.417271.6, Southern Denmark Region
  66. (66) Aalborg Hospital, grid.27530.33, North Denmark Region
  67. (67) Aarhus University Hospital, grid.154185.c, Central Denmark Region
  68. (68) Odense University Hospital, grid.7143.1, Southern Denmark Region
  69. (69) Masaryk Memorial Cancer Institute, grid.419466.8
  70. (70) Italian Association for Cancer Research, grid.429138.5
  71. (71) European Institute of Oncology, grid.15667.33
  72. (72) Istituti di Ricovero e Cura a Carattere Scientifico, grid.414603.4
  73. (73) Sapienza University of Rome, grid.7841.a
  74. (74) Istituto Oncologico Veneto, grid.419546.b
  75. (75) Hôpitaux Universitaires de Strasbourg, grid.412220.7
  76. (76) Centre Hospitalier Universitaire de Québec, grid.411081.d
  77. (77) Medical University of Vienna, grid.22937.3d
  78. (78) Cancer Prevention Institute of California, grid.280669.3
  79. (79) Dana-Farber Cancer Institute, grid.65499.37
  80. (80) City Of Hope National Medical Center, grid.410425.6
  81. (81) Columbia University, grid.21729.3f
  82. (82) Columbia University Medical Center, grid.239585.0
  83. (83) Temple University Health System, grid.412530.1
  84. (84) University of Utah, grid.223827.e
  85. (85) Vilnius University Hospital Santariskiu Klinikos, grid.426597.b
  86. (86) University of Pretoria, grid.49697.35
  87. (87) National Centre of Scientific Research Demokritos, grid.6083.d
  88. (88) Center for Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America
  89. (89) University of Kansas Medical Center, grid.412016.0
  90. (90) National Institute of Oncology, grid.419617.c
  91. (91) Technion – Israel Institute of Technology, grid.6451.6
  92. (92) Sheba Medical Center, grid.413795.d
  93. (93) Tel Aviv University, grid.12136.37
  94. (94) Karolinska University Hospital, grid.24381.3c
  95. (95) Linköping University, grid.5640.7
  96. (96) Skåne University Hospital, grid.411843.b
  97. (97) Institute of Oncology NN Petrov, grid.465337.0
  98. (98) German Cancer Research Center, grid.7497.d
  99. (99) QIMR Berghofer Medical Research Institute, grid.1049.c
  100. (100) St. Joseph Hospital, grid.416692.e
  101. (101) Catalan Institution for Research and Advanced Studies, grid.425902.8
  102. (102) Department of Physiological Sciences II, School of Medicine, University of Barcelona, L’Hospitalet del Llobregat, Catalonia, Spain
  103. (103) Paris Descartes University, grid.10992.33
  104. (104) Institute Curie, grid.418596.7
  105. (105) Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon–Centre Léon Bérard, Lyon, France
  106. (106) Cancer Center of Lyon, grid.462282.8
  107. (107) Centre Léon Bérard, grid.418116.b
  108. (108) Centre Hospitalier Métropole Savoie, grid.418064.f
  109. (109) UniCancer Group, grid.418189.d
  110. (110) Hôpital Avicenne, grid.413780.9
  111. (111) Département d'Oncogénétique, Centre Jean Perrin, Université de Clermont-Ferrand, Clermont-Ferrand, France
  112. (112) University of British Columbia, grid.17091.3e
  113. (113) Memorial Sloan Kettering Cancer Center, grid.51462.34
  114. (114) Mayo Clinic, grid.417468.8

Description

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

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