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

Broeks A, Schmidt MK, Sherman ME, Couch FJ, Hopper JL, Dite GS, Apicella C, Smith LD, Hammet F, Southey MC, Van 'T Veer LJ, De Groot R, Smit VTHBM, Fasching PA, Beckmann M, Jud S, Ekici AB, Hartmann A, Hein A, Schulz-Wendtland R, Burwinkel B, Marme F, Schneeweiss A, Sinn HP, Sohn C, Tchatchou S, Bojesen SE, Nordestgaard BG, Flyger H, Orsted DD, Kaur-Knudsen D, Milne RL, Perez JIA, Zamora P, Menendez Rodriguez P, Benitez J, Brauch H, Justenhoven C, Ko YD, Hamann U, Fischer HP, Bruening T, Pesch B, Chang-Claude J, Wang-Gohrke S, Bremer M, Karstens JH, Hillemanns P, Doerk T, Nevanlinna HA, Heikkinen T, Heikkila P, Blomqvist C, Aittomaki K, Aaltonen K, Lindblom A, Margolin S, Mannermaa A, Kosma VM, Kauppinen JM, Kataja V, Auvinen P, Eskelinen M, Soini Y, Chenevix-Trench G, Spurdle AB, Beesley J, Chen X, Holland H, Lambrechts D, Claes B, Vandorpe T, Neven P, Wildiers H, Flesch-Janys D, Hein R, Loening T, Kosel M, Fredericksen ZS, Wang X, Giles GG, Baglietto L, Severi G, Mclean C, Haiman CA, Henderson BE, Le Marchand L, Kolonel LN, Alnaes GG, Kristensen V, Borresen-Dale AL, Hunter DJ, Hankinson SE, Andrulis IL, Mulligan AM, O'Malley FP, Devilee P, Huijts PEA, Tollenaar RAEM, Van Asperen CJ, Seynaeve CS, Chanock SJ, Lissowska J, Brinton L, Peplonska B, Figueroa J, Yang XR, Hooning MJ, Hollestelle A, Oldenburg RA, Jager A, Kriege M, Ozturk B, Van Leenders GJLH, Hall P, Czene K, Humphreys K, Liu J, Cox A, Connley D, Cramp HE, Cross SS, Balasubramanian SP, Reed MWR, Dunning AM, Easton DF, Humphreys MK, Caldas C, Blows F, Driver K, Provenzano E, Lubinski J, Jakubowska A, Huzarski T, Byrski T, Cybulski C, Gorski B, Gronwald J, Brennan P, Sangrajrang S, Gaborieau V, Shen CY, Hsiung CN, Yu JC, Chen ST, Hsu GC, Hou MF, Huang CS, Anton-Culver H, Ziogas A, Pharoah PDP, Garcia-Closas M (2011)

Publication Type: Journal article

Publication year: 2011

Journal

Book Volume: 20

Pages Range: 3289-3303

Journal Issue: 16

DOI: 10.1093/hmg/ddr228

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 ER1 than ER2 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.

Authors with CRIS profile

Involved external institutions

University of Copenhagen Denmark (DK) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) Spain (ES) University of Toronto Canada (CA) University of Sheffield United Kingdom (GB) University of Cambridge United Kingdom (GB) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) Tri-Service General Hospital (TSGH) / 三軍總醫院 Taiwan (TW) National Taiwan University Hospital (NTUH) / 國立台灣大學醫學院附設醫院 Taiwan (TW) University of California Irvine United States (USA) (US) The University of Melbourne Australia (AU) Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI / NKI-AVL) Netherlands (NL) Universitätsklinikum Heidelberg Germany (DE) Institut für Prävention und Arbeitsmedizin der Deutschen Gesetzlichen Unfallversicherung, Institut der Ruhr-Universität Bochum (IPA) Germany (DE) Universität Ulm Germany (DE) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven Belgium (BE) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Mayo Clinic United States (USA) (US) International Agency for Research on Cancer (IARC) France (FR) National Cancer Institute (NCI) United States (USA) (US) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Helsingin yliopisto / University of Helsinki Finland (FI) University of Eastern Finland Finland (FI) Kuopio University Hospital / Pohjois-Savon sairaanhoitopiiri Finland (FI) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet Norway (NO) Erasmus University Medical Center (MC) Netherlands (NL) University of California Los Angeles (UCLA) United States (USA) (US) Albertinen-Krankenhaus Germany (DE) Karolinska Institute Sweden (SE) Vaasa Central Hospital / Vaasan Keskussairaala Finland (FI) Cancer Council Victoria Australia (AU) The Alfred Hospital Australia (AU) University of Hawaii (U.H.) United States (USA) (US) Brigham and Women's Hospital (BWH) United States (USA) (US) Leiden University Netherlands (NL) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie Poland (PL) Erasmus University Rotterdam (EUR) / Erasmus Universiteit Rotterdam Netherlands (NL) Genome Institute of Singapore Singapore (SG) Hospital Monte Naranco Spain (ES) Robert-Bosch-Krankenhaus Germany (DE) University of Southern California (USC) United States (USA) (US) Mount Sinai Hospital (MSH) Canada (CA) Nofer Institute of Occupational Medicine (NIOM) Poland (PL) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) Academia Sinica / 中央研究院 Taiwan (TW) Changhua Christian Hospital Taiwan (TW) Kaohsiung Medical University (KMU) / 高雄醫學大學 Taiwan (TW) Hospital Universitario La Paz Spain (ES) Evangelisches Krankenhaus Oberhausen Germany (DE)

How to cite

APA:

Broeks, A., Schmidt, M.K., Sherman, M.E., Couch, F.J., Hopper, J.L., Dite, G.S.,... Garcia-Closas, M. (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

MLA:

Broeks, Annegien, et al. "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 (2011): 3289-3303.

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