Article open access publication

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Breast Cancer Research, Springer Nature, ISSN 1465-5411

Volume 17, 1, 2015

DOI:10.1186/s13058-015-0567-2, Dimensions: pub.1045881923, PMC: PMC4478717, PMID: 25925750,

Authors

Blein, Sophie (1) (2) (3)
Bardel, Claire (2) (3) (4)
Osorio, Ana (22) (23)
Benitez, Javier (22) (23)
Segota, Ena (18) (25)
Thelander, Margo (18) (26)
Pensotti, Valeria (18) (29)
Capone, Gabriele L (33) (34)
EMBRACE (7)
Kennedy, M John (52) (53) (54)
Eeles, Ros (60)
Rhiem, Kerstin (69) (70)
Schmutzler, Rita K (69) (70) (78)
Leroux, Dominique (83) (84)
Dreyfus, Hélène (83) (84)
Olah, Edith (102)
Diez, Orland (103)
Teulé, Alex (104)
Agnarsson, Bjarni A (106) (107)
Amadori, Alberto (109) (110)
Teixeira, Manuel R (111) (112)
Robson, Mark (117)
Rennert, Gad (31) (120) (121)
Mulligan, Anna Marie (123) (124)
Glendon, Gord (125) (126)
Andrulis, Irene L (124) (126)
Toland, Amanda Ewart (127) (128) (129)
Zidan, Jamal (135)
Arver, Brita (136)
Arun, Banu K (144)
Mitchell, Gillian (145) (146)
Thomas, Gilles (2) (82)
Mazoyer, Sylvie (1) (2) (3)
Sinilnikova, Olga M (1) (2) (3) (150)
Cox, David G * (1) (2) (3)

* Corresponding author

Affiliations

Organisations

  1. (1) Cancer Center of Lyon, grid.462282.8
  2. (2) Claude Bernard University Lyon 1, grid.7849.2
  3. (3) University of Lyon System, grid.25697.3f
  4. (4) Biometry and Evolutionary Biology Laboratory, grid.462854.9
  5. (5) Grenoble Computer Science Laboratory, grid.462707.0
  6. (6) INRIA Rhône-Alpes, équipe-projet MOAIS, 38334, Saint Ismier, Cedex, France
  7. (7) University of Cambridge, grid.5335.0
  8. (8) QIMR Berghofer Medical Research Institute, grid.1049.c
  9. (9) Laval University, grid.23856.3a
  10. (10) Columbia University, grid.21729.3f
  11. (11) University of Utah, grid.223827.e
  12. (12) Cancer Prevention Institute of California, grid.280669.3
  13. (13) Department of Molecular and Regenerative Medicine, Centre for Innovative Medicine, State Research Institute, Vilnius, Lithuania
  14. (14) Vilnius University Hospital Santariskiu Klinikos, grid.426597.b
  15. (15) Latvian Biomedical Research and Study Centre, grid.419210.f
  16. (16) Beth Israel Deaconess Medical Center, grid.239395.7
  17. (17) University of Pretoria, grid.49697.35
  18. (18) City Of Hope National Medical Center, grid.410425.6
  19. (19) Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  20. (20) Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  21. (21) Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  22. (22) Centre for Biomedical Network Research on Rare Diseases, grid.452372.5
  23. (23) Spanish National Cancer Research Centre, grid.7719.8
  24. (24) Hospital Clínico Universitario Lozano Blesa, grid.411050.1
  25. (25) Holy Cross Hospital, grid.414309.b
  26. (26) John Muir Medical Center, grid.414726.2
  27. (27) FIRC Institute of Molecular Oncology, grid.7678.e
  28. (28) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  29. (29) Cogentech Cancer Genetic Test Laboratory, Via Adamello 16, 20139, Milan, Italy
  30. (30) Centro di Riferimento Oncologico, grid.418321.d
  31. (31) European Institute of Oncology, grid.15667.33
  32. (32) Unit of Hereditary Cancer, Department of Epidemiology, Prevention and Special Functions, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Azienda Ospedaliera Universitaria “San Martino” di Genova, IST Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi, 10, 16132, Genoa, Italy
  33. (33) FiorGen Foundation for Pharmacogenomics, Via Luigi Sacconi 6, 50019, Sesto Fiorentino, Italy
  34. (34) University of Florence, grid.8404.8
  35. (35) Sapienza University of Rome, grid.7841.a
  36. (36) Aristotle University of Thessaloniki, grid.4793.9
  37. (37) National Centre of Scientific Research Demokritos, grid.6083.d
  38. (38) Dana-Farber Cancer Institute, grid.65499.37
  39. (39) German Cancer Research Center, grid.7497.d
  40. (40) St Michael's Hospital, grid.416544.6
  41. (41) North West Thames Regional Genetics Service, Kennedy-Galton Centre, Harrow, UK
  42. (42) Royal Devon and Exeter Hospital, grid.416118.b
  43. (43) Liverpool Womens NHS Foundation Trust, grid.419317.9
  44. (44) Manchester University NHS Foundation Trust, grid.498924.a
  45. (45) Faculty of Medicine, University of Southampton, Southampton University Hospitals NHS Trust, Mailpoint 801, South Academic Block, PAH/G/MP105, Tremona Road, SO16 6YD, Southampton, UK
  46. (46) Institute of Human Genetics, Northern Genetic Service, International Centre for Life, Newcastle upon Tyne Hospitals NHS Trust, Central Parkway, NE1 4EP, Newcastle upon Tyne, UK
  47. (47) Sheffield Children's Hospital, grid.413991.7
  48. (48) Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Old Medical School, Leeds General Infirmary, LS1 3EX, Leeds, UK
  49. (49) Leicester Royal Infirmary, grid.419248.2
  50. (50) Churchill Hospital, grid.415719.f
  51. (51) Guy's Hospital, grid.239826.4
  52. (52) Great Ormond Street Hospital for Children NHS Foundation Trust, grid.424537.3
  53. (53) St. James's Hospital, grid.416409.e
  54. (54) Trinity College Dublin, grid.8217.c
  55. (55) Addenbrooke's Hospital, grid.120073.7
  56. (56) University Hospital of Wales, grid.241103.5
  57. (57) Western General Hospital, grid.417068.c
  58. (58) Belfast City Hospital, grid.412914.b
  59. (59) Queen's University Belfast, grid.4777.3
  60. (60) National Health Service, grid.451052.7
  61. (61) Royal Hospital for Sick Children, grid.415571.3
  62. (62) St George's, University of London, grid.264200.2
  63. (63) West Midlands Regional Genetics Service, Birmingham Women’s Hospital Healthcare NHS Trust, Mindelsohn Way, Edgbaston, B15 2TG, Birmingham, UK
  64. (64) University of Kansas Medical Center, grid.412016.0
  65. (65) Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, 3800 Reservoir Road NW, 20057, Washington, DC, USA
  66. (66) Ghent University Hospital, grid.410566.0
  67. (67) Division of Tumor Genetics, Department of Gynaecology and Obstetrics, University Hospital Klinikum Rechts der Isar, Technische Universität München, Ismaninger Strasse 22, 81675, Munich, Germany
  68. (68) University of Würzburg, grid.8379.5
  69. (69) University Hospital Cologne, grid.411097.a
  70. (70) University of Cologne, grid.6190.e
  71. (71) University Hospital Heidelberg, grid.5253.1
  72. (72) Leipzig University, grid.9647.c
  73. (73) Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Moorenstrasse 5, 40225, Düsseldorf, Germany
  74. (74) Hannover Medical School, grid.10423.34
  75. (75) University Hospital Schleswig-Holstein, grid.412468.d
  76. (76) Department of Gynecology and Obstetrics, University Hospital Carl Gustav Carus of Dresden, Technical University Dresden, Dresden, Germany
  77. (77) Charité, grid.6363.0
  78. (78) German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC), Cologne, Germany
  79. (79) University Hospital Münster, grid.16149.3b
  80. (80) University Hospital Ulm, grid.410712.1
  81. (81) Institute Curie, grid.418596.7
  82. (82) Centre Léon Bérard, grid.418116.b
  83. (83) Centre Hospitalier Universitaire de Grenoble, grid.410529.b
  84. (84) Joseph Fourier University, grid.9621.c
  85. (85) Hôpital René Huguenin, grid.418205.a
  86. (86) Département d’Oncogénétique, Centre Jean Perrin, Université de Clermont-Ferrand, 58 rue Montalembert, BP 392, 63011, Clermont-Ferrand, France
  87. (87) Chris O’Brien Lifehouse, grid.419783.0
  88. (88) University of North Carolina at Chapel Hill, grid.10698.36
  89. (89) Roswell Park Cancer Institute, grid.240614.5
  90. (90) Women & Infants Hospital of Rhode Island, grid.241223.4
  91. (91) Molecular Oncology Laboratory, Health Research Institute of the San Carlos Clinical Hospital (IdISSC), 28040, Madrid, Spain
  92. (92) Helsinki University Central Hospital, grid.15485.3d
  93. (93) Erasmus University Medical Center, grid.5645.2
  94. (94) Radboud University Nijmegen Medical Centre, grid.10417.33
  95. (95) Academic Medical Center, grid.5650.6
  96. (96) Antoni van Leeuwenhoek Hospital, grid.430814.a
  97. (97) VU University Medical Center, grid.16872.3a
  98. (98) University of Groningen, grid.4830.f
  99. (99) Maastricht University Medical Centre, grid.412966.e
  100. (100) Leiden University Medical Center, grid.10419.3d
  101. (101) University Medical Center Utrecht, grid.7692.a
  102. (102) National Institute of Oncology, grid.419617.c
  103. (103) Hospital Universitari Vall d'Hebron, grid.411083.f
  104. (104) Duran i Reynals Hospital, grid.414660.1
  105. (105) Pomeranian Medical University, grid.107950.a
  106. (106) National University Hospital of Iceland, grid.410540.4
  107. (107) University of Iceland, grid.14013.37
  108. (108) Hôpital Civil, Strasbourg, grid.413866.e
  109. (109) University of Padua, grid.5608.b
  110. (110) Istituto Oncologico Veneto, grid.419546.b
  111. (111) Portuguese Oncology Institute, grid.418711.a
  112. (112) University of Porto, grid.5808.5
  113. (113) McGill University, grid.14709.3b
  114. (114) Mayo Clinic, grid.66875.3a
  115. (115) Mayo Clinic, grid.417468.8
  116. (116) National Human Genome Research Institute, grid.280128.1
  117. (117) Memorial Sloan Kettering Cancer Center, grid.51462.34
  118. (118) Department of Obstetrics and Gynecology, Comprehensive Cancer Center Vienna, Medical University of Vienna, Universitätsklinik für Frauenheilkunde, AKH – Wien, Währinger Gürtel 18-20, 1090, Vienna, Austria
  119. (119) National Institutes of Health, grid.94365.3d
  120. (120) National Israeli Cancer Control Center and Department of Community Medicine and Epidemiology, Clalit Health Services Carmel Medical Center, 34361, Haifa, Israel
  121. (121) Technion – Israel Institute of Technology, grid.6451.6
  122. (122) Institute of Oncology NN Petrov, grid.465337.0
  123. (123) St. Michael's Hospital, grid.415502.7
  124. (124) University of Toronto, grid.17063.33
  125. (125) Cancer Care Ontario, grid.419887.b
  126. (126) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
  127. (127) Department of Human Cancer Genetics, 1093 Biomedical Research Tower, 460 West 12th Avenue, 43210, Columbus, OH, USA
  128. (128) James Cancer Hospital, grid.413944.f
  129. (129) The Ohio State University Wexner Medical Center, grid.412332.5
  130. (130) Aalborg Hospital, grid.27530.33, North Denmark Region
  131. (131) Odense University Hospital, grid.7143.1, Southern Denmark Region
  132. (132) Aarhus University Hospital, grid.154185.c, Central Denmark Region
  133. (133) Laboratorio di Genetica Oncologica, Divisione di Anatomia Patologica e di Diagnostica Molecolare ed Ultrastrutturale, Azienda Ospedaliero Universitaria Pisana – Ospedale S Chiara, via Roma 67, 56126, Pisa, Italy
  134. (134) Sheba Medical Center, grid.413795.d
  135. (135) Institute of Oncology, Rivka Ziv Medical Center, Maimonides, 13100, Safed, Israel
  136. (136) Karolinska University Hospital, grid.24381.3c
  137. (137) Umeå University, grid.12650.30
  138. (138) Skåne University Hospital, grid.411843.b
  139. (139) Uppsala University, grid.8993.b
  140. (140) Center for Clinical Cancer Genetics and Global Health, The University of Chicago, 5841 South Maryland Avenue, 60637, Chicago, IL, USA
  141. (141) University of California, San Francisco, grid.266102.1
  142. (142) University of Southern California, grid.42505.36
  143. (143) University of Pennsylvania, grid.25879.31
  144. (144) The University of Texas MD Anderson Cancer Center, grid.240145.6
  145. (145) Peter MacCallum Cancer Centre, grid.1055.1
  146. (146) University of Melbourne, grid.1008.9
  147. (147) Cedars-Sinai Medical Center, grid.50956.3f
  148. (148) Paris Descartes University, grid.10992.33
  149. (149) Moffitt Cancer Center, grid.468198.a
  150. (150) Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon – Centre Léon Bérard, 69373, Lyon, Cedex 08, France

Description

INTRODUCTION: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. METHODS: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. RESULTS: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. CONCLUSIONS: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.

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Times Cited: 14

Field Citation Ratio (FCR): 3.1

Relative Citation ratio (RCR): 0.58

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