Genome-wide association study of germline variants and breast cancer-specific mortality: British Journal of Cancer

M. Escala-Garcia, Q. Guo, T. Dörk, S. Canisius, R. Keeman, J. Dennis, J. Beesley, J. Lecarpentier, M.K. Bolla, Q. Wang, J. Abraham, I.L. Andrulis, H. Anton-Culver, V. Arndt, P.L. Auer, M.W. Beckmann, S. Behrens, J. Benitez, M. Bermisheva, L. BernsteinC. Blomqvist, B. Boeckx, S.E. Bojesen, B. Bonanni, A.-L. Børresen-Dale, H. Brauch, H. Brenner, A. Brentnall, L. Brinton, P. Broberg, I.W. Brock, S.Y. Brucker, B. Burwinkel, C. Caldas, T. Caldés, D. Campa, F. Canzian, A. Carracedo, B.D. Carter, J.E. Castelao, J. Chang-Claude, S.J. Chanock, G. Chenevix-Trench, T.-Y.D. Cheng, S.-F. Chin, C.L. Clarke, E. Cordina-Duverger, F.J. Couch, D.G. Cox, A. Cox, S.S. Cross, K. Czene, M.B. Daly, P. Devilee, J.A. Dunn, A.M. Dunning, L. Durcan, M. Dwek, H.M. Earl, A.B. Ekici, A.H. Eliassen, C. Ellberg, C. Engel, M. Eriksson, D.G. Evans, J. Figueroa, D. Flesch-Janys, H. Flyger, M. Gabrielson, M. Gago-Dominguez, E. Galle, S.M. Gapstur, M. García-Closas, J.A. García-Sáenz, M.M. Gaudet, A. George, V. Georgoulias, G.G. Giles, G. Glendon, D.E. Goldgar, A. González-Neira, G.I.G. Alnæs, M. Grip, P. Guénel, L. Haeberle, E. Hahnen, C.A. Haiman, N. Håkansson, P. Hall, U. Hamann, S. Hankinson, E.F. Harkness, P.A. Harrington, S.N. Hart, J.M. Hartikainen, A. Hein, P. Hillemanns, L. Hiller, B. Holleczek, A. Hollestelle, M.J. Hooning, R.N. Hoover, J.L. Hopper, A. Howell, G. Huang, K. Humphreys, D.J. Hunter, W. Janni, E.M. John, M.E. Jones, A. Jukkola-Vuorinen, A. Jung, R. Kaaks, M. Kabisch, K. Kaczmarek, M.J. Kerin, S. Khan, E. Khusnutdinova, J.I. Kiiski, C.M. Kitahara, J.A. Knight, Y.-D. Ko, L.B. Koppert, V.-M. Kosma, P. Kraft, V.N. Kristensen, U. Krüger, T. Kühl, D. Lambrechts, L. Le Marchand, E. Lee, F. Lejbkowicz, L. Li, A. Lindblom, S. Lindström, M. Linet, J. Lissowska, W.-Y. Lo, S. Loibl, J. Lubiński, M.P. Lux, R.J. MacInnis, M. Maierthaler, T. Maishman, E. Makalic, A. Mannermaa, M. Manoochehri, S. Manoukian, S. Margolin, M.E. Martinez, D. Mavroudis, C. McLean, A. Meindl, P. Middha, N. Miller, R.L. Milne, F. Moreno, A.M. Mulligan, C. Mulot, R. Nassir, S.L. Neuhausen, W.T. Newman, S.F. Nielsen, B.G. Nordestgaard, A. Norman, H. Olsson, N. Orr, V.S. Pankratz, T.-W. Park-Simon, J.I.A. Perez, C. Pérez-Barrios, P. Peterlongo, C. Petridis, M. Pinchev, K. Prajzendanc, R. Prentice, N. Presneau, D. Prokofieva, K. Pylkäs, B. Rack, P. Radice, D. Ramachandran, G. Rennert, H.S. Rennert, V. Rhenius, A. Romero, R. Roylance, E. Saloustros, E.J. Sawyer, D.F. Schmidt, R.K. Schmutzler, A. Schneeweiss, M.J. Schoemaker, F. Schumacher, L. Schwentner, R.J. Scott, C. Scott, C. Seynaeve, M. Shah, J. Simard, A. Smeets, C. Sohn, M.C. Southey, A.J. Swerdlow, A. Talhouk, R.M. Tamimi, W.J. Tapper, M.R. Teixeira, M. Tengström, M.B. Terry, K. Thöne, R.A.E.M. Tollenaar, I. Tomlinson, D. Torres, T. Truong, C. Turman, C. Turnbull, H.-U. Ulmer, M. Untch, C. Vachon, C.J. van Asperen, A.M.W. van den Ouweland, E.M. van Veen, C. Wendt, A.S. Whittemore, W. Willett, R. Winqvist, A. Wolk, X.R. Yang, Y. Zhang, D.F. Easton, P.A. Fasching, H. Nevanlinna, D.M. Eccles, P.D.P. Pharoah, M.K. Schmidt, NBCS Collaborators

Research output: Contribution to journalArticlepeer-review

Abstract

Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10 −8 . For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10 −7 , hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84–0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10 −7 , HR = 1.27, 95% CI = 1.16–1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. Conclusions: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients. © 2019, The Author(s).
Original languageEnglish
Pages (from-to)647-657
Number of pages11
JournalEur. J. Cancer
Volume120
Issue number6
DOIs
Publication statusPublished - 2019

Keywords

  • untranslated RNA
  • estrogen receptor
  • adult
  • Article
  • auts2 gene
  • breast cancer
  • cancer epidemiology
  • cancer mortality
  • cancer patient
  • chromosome 6
  • chromosome 7
  • estrogen receptor negative breast cancer
  • estrogen receptor positive breast cancer
  • female
  • galnt17 gene
  • gene cluster
  • gene frequency
  • genome-wide association study
  • germline mutation
  • human
  • major clinical study
  • meta analysis (topic)
  • mortality risk
  • priority journal
  • recurrence free survival
  • single nucleotide polymorphism
  • survival time
  • tumor gene
  • young adult
  • Bayes theorem
  • breast tumor
  • Caucasian
  • genetic variation
  • genetics
  • meta analysis
  • metabolism
  • mortality
  • prognosis
  • proportional hazards model
  • Bayes Theorem
  • Breast Neoplasms
  • Chromosomes, Human, Pair 7
  • European Continental Ancestry Group
  • Female
  • Genetic Variation
  • Genome-Wide Association Study
  • Humans
  • Prognosis
  • Proportional Hazards Models
  • Receptors, Estrogen

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