Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium.

Annegien Broeks, Marjanka K. Schmidt, Mark E. Sherman, Fergus J Couch, John L. Hopper, Gillian S. Dite, Carmel Apicella, Letitia D. Smith, Fleur Hammet, Melissa C. Southey, Laura J. Van 't Veer, Renate de Groot, Vincent T H B M Smit, Peter A. Fasching, Matthias W. Beckmann, Sebastian Jud, Arif B. Ekici, Arndt Hartmann, Alexander Hein, Ruediger Schulz-WendtlandBarbara Burwinkel, Frederik Marme, Andreas Schneeweiss, Hans Peter Sinn, Christof Sohn, Sandrine Tchatchou, Stig E. Bojesen, Børge G. Nordestgaard, Henrik Flyger, David D. Ørsted, Diljit Kaur-Knudsen, Roger L. Milne, Jose I Arias Pérez, Pilar Zamora, Primitiva Menéndez Rodríguez, Javier Benítez, Hiltrud Brauch, Christina Justenhoven, Yon Dschun Ko, Network Genica Network, Ute Hamann, Hans Peter Fischer, Thomas Brüning, Beate Pesch, Jenny Chang-Claude, Shan Wang-Gohrke, Michael Bremer, Johann H. Karstens, Peter Hillemanns, Thilo Dörk, Heli A. Nevanlinna, Tuomas Heikkinen, Päivi Heikkilä, Carl Blomqvist, Kristiina Aittomäki, Kirsimari Aaltonen, Annika Lindblom, Sara Margolin, Arto Mannermaa, Veli Matti Kosma, Jaana M. Kauppinen, Vesa Kataja, Päivi Auvinen, Matti Eskelinen, Ylermi Soini, Georgia Chenevix-Trench, Amanda B. Spurdle, Jonathan Beesley, Xiaoqing Chen, Helene Holland, kConFab, AOCS, Diether Lambrechts, Bart Claes, Thijs Vandorpe, Patrick Neven, Hans Wildiers, Dieter Flesch-Janys, Rebecca Hein, Thomas Löning, Matthew Kosel, Zachary S. Fredericksen, Xianshu Wang, Graham G. Giles, Laura Baglietto, Gianluca Severi, Catriona McLean, Christopher A. Haiman, Brian E. Henderson, Loic Le Marchand, Laurence N. Kolonel, Grethe Grenaker Alnæs, Vessela Kristensen, Anne Lise Børresen-Dale, David J. Hunter, Susan E. Hankinson, Irene L. Andrulis, Anna Marie Mulligan, Frances P. O'Malley

Research output: Contribution to journalArticle

131 Scopus citations


Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations with ER+ than ER- tumors for six of the eight loci identified in GWAS: rs2981582 (10q26) (P-heterogeneity = 6.1 × 10(-18)), rs3803662 (16q12) (P = 3.7 × 10(-5)), rs13281615 (8q24) (P = 0.002), rs13387042 (2q35) (P = 0.006), rs4973768 (3p24) (P = 0.003) and rs6504950 (17q23) (P = 0.002). The two candidate loci, CASP8 (rs1045485, rs17468277) and TGFB1 (rs1982073), were most strongly related with the risk of PR negative tumors (P = 5.1 × 10(-6) and P = 4.1 × 10(-4), respectively), as previously suggested. Four of the eight loci identified in GWAS were associated with triple negative tumors (P ≤ 0.016): rs3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P ≤ 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor stratification might help in the identification and characterization of novel risk factors for breast cancer subtypes. This may eventually result in further improvements in prevention, early detection and treatment.

Original languageEnglish (US)
Pages (from-to)3289-3303
Number of pages15
JournalHuman Molecular Genetics
Issue number16
StatePublished - Aug 15 2011


ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Broeks, A., Schmidt, M. K., Sherman, M. E., Couch, F. J., Hopper, J. L., Dite, G. S., Apicella, C., Smith, L. D., Hammet, F., Southey, M. C., Van 't Veer, L. J., de Groot, R., Smit, V. T. H. B. M., Fasching, P. A., Beckmann, M. W., Jud, S., Ekici, A. B., Hartmann, A., Hein, A., ... O'Malley, F. P. (2011). Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium. Human Molecular Genetics, 20(16), 3289-3303. https://doi.org/10.1093/hmg/ddr228