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. 2011 Aug 15;20(16):3289-303.
doi: 10.1093/hmg/ddr228. Epub 2011 May 19.

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

Annegien Broeks  1 , 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-Wendtland, Barbara 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; 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, Peter Devilee, Petra E A Huijts, Rob A E M Tollenaar, Christi J Van Asperen, Caroline S Seynaeve, Stephen J Chanock, Jolanta Lissowska, Louise Brinton, Beata Peplonska, Jonine Figueroa, Xiaohong R Yang, Maartje J Hooning, Antoinette Hollestelle, Rogier A Oldenburg, Agnes Jager, Mieke Kriege, Bahar Ozturk, Geert J L H van Leenders, Per Hall, Kamila Czene, Keith Humphreys, Jianjun Liu, Angela Cox, Daniel Connley, Helen E Cramp, Simon S Cross, Sabapathy P Balasubramanian, Malcolm W R Reed, Alison M Dunning, Douglas F Easton, Manjeet K Humphreys, Carlos Caldas, Fiona Blows, Kristy Driver, Elena Provenzano, Jan Lubinski, Anna Jakubowska, Tomasz Huzarski, Tomasz Byrski, Cezary Cybulski, Bohdan Gorski, Jacek Gronwald, Paul Brennan, Suleeporn Sangrajrang, Valerie Gaborieau, Chen-Yang Shen, Chia-Ni Hsiung, Jyh-Cherng Yu, Shou-Tung Chen, Giu-Cheng Hsu, Ming-Feng Hou, Chiun-Sheng Huang, Hoda Anton-Culver, Argyrios Ziogas, Paul D P Pharoah, Montserrat Garcia-Closas
Collaborators, Affiliations

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

Annegien Broeks et al. Hum Mol Genet. .

Abstract

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.

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Figures

Figure 1.
Figure 1.
Association of susceptibility loci with different tumor subtypes: a summary of the findings. The per-allele OR's (ES) are shown. Tumor subtype nomenclature explanation: / = ‘and/or’, & = and. Tumors were classified into four subtypes, two receptor positive or ‘luminal' subtypes: ER+/PR+&HER2− and ER+/PR+&HER2+, and two receptor negative subtypes or ‘non-luminal' ER−&PR−&HER2+ and triple negative tumors (TN: ER−&PR−&HER2−). Cases with TN tumors were further stratified according to the expression of basal markers into the core basal phenotype (CBP) (CK5/6, CK5 or EGFR positive) and the five-negative phenotype (5NP) (CK5/6 or CK5, and EGFR negative).
Figure 2.
Figure 2.
Classification of breast cancer tumors according to the expression of ER, PR, HER2, CK5/6 and EGFR in tumor tissues. Tumor subtype nomenclature explanation: / = ‘and/or’, & = and.
See this image and copyright information in PMC

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