Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy

Journal article

Publication Details

Author(s): Lei J, Rudolph A, Moysich KB, Rafiq S, Behrens S, Goode EL, Pharoah PP, Seibold P, Fasching P, Andrulis IL, Kristensen VN, Couch FJ, Hamann U, Hooning MJ, Nevanlinna H, Eilber U, Bolla MK, Dennis J, Wang Q, Lindblom A, Mannermaa A, Lambrechts D, Garcia-Closas M, Hall P, Chenevix-Trench G, Shah M, Luben R, Haeberle L, Ekici AB, Beckmann M, Knight JA, Glendon G, Tchatchou S, Alnaes GIG, Borresen-Dale AL, Nord S, Olson JE, Hallberg E, Vachon C, Torres D, Ulmer HU, Ruediger T, Jager A, Van Deurzen CH, Tilanus-Linthorst MM, Muranen TA, Aittomaki K, Blomqvist C, Margolin S, Kosma VM, Hartikainen JM, Kataja V, Hatse S, Wildiers H, Smeets A, Figueroa J, Chanock SJ, Lissowska J, Li J, Humphreys K, Phillips KA, Linn S, Cornelissen S, Van Den Broek SAJ, Kang D, Choi JY, Park SK, Yoo KY, Hsiung CN, Wu PE, Hou MF, Shen CY, Teo SH, Taib NAM, Yip CH, Ho GF, Matsuo K, Ito H, Iwata H, Tajima K, Dunning AM, Benitez J, Czene K, Sucheston LE, Maishman T, Tapper WJ, Eccles D, Easton DF, Schmidt MK, Chang-Claude J
Journal: Breast Cancer Research
Publication year: 2015
Volume: 17
Pages range: 18
ISSN: 1465-542X


Tumor lymphocyte infiltration is associated with clinical response to chemotherapy in estrogen receptor (ER) negative breast cancer. To identify variants in immunosuppressive pathway genes associated with prognosis after adjuvant chemotherapy for ER-negative patients, we studied stage I-III invasive breast cancer patients of European ancestry, including 9,334 ER-positive (3,151 treated with chemotherapy) and 2,334 ER-negative patients (1,499 treated with chemotherapy).We pooled data from sixteen studies from the Breast Cancer Association Consortium (BCAC), and employed two independent studies for replications. Overall 3,610 single nucleotide polymorphisms (SNPs) in 133 genes were genotyped as part of the Collaborative Oncological Gene-environment Study, in which phenotype and clinical data were collected and harmonized. Multivariable Cox proportional hazard regression was used to assess genetic associations with overall survival (OS) and breast cancer-specific survival (BCSS). Heterogeneity according to chemotherapy or ER status was evaluated with the log-likelihood ratio test.Three independent SNPs in TGFBR2 and IL12B were associated with OS (P <10?³) solely in ER-negative patients after chemotherapy (267 events). Poorer OS associated with TGFBR2 rs1367610 (G > C) (per allele hazard ratio (HR) 1.54 (95% confidence interval (CI) 1.22 to 1.95), P = 3.08 × 10??) was not found in ER-negative patients without chemotherapy or ER-positive patients with chemotherapy (P for interaction <10-3). Two SNPs in IL12B (r² = 0.20) showed different associations with ER-negative disease after chemotherapy: rs2546892 (G > A) with poorer OS (HR 1.50 (95% CI 1.21 to 1.86), P = 1.81 × 10??), and rs2853694 (A > C) with improved OS (HR 0.73 (95% CI 0.61 to 0.87), P = 3.67 × 10??). Similar associations were observed with BCSS. Association with TGFBR2 rs1367610 but not IL12B variants replicated using BCAC Asian samples and the independent Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer Study and yielded a combined HR of 1.57 ((95% CI 1.28 to 1.94), P = 2.05 × 10??) without study heterogeneity.TGFBR2 variants may have prognostic and predictive value in ER-negative breast cancer patients treated with adjuvant chemotherapy. Our findings provide further insights into the development of immunotherapeutic targets for ER-negative breast cancer.

FAU Authors / FAU Editors

Beckmann, Matthias Prof. Dr.
Lehrstuhl für Geburtshilfe und Frauenheilkunde
Ekici, Arif Bülent Dr. rer. nat.
Humangenetisches Institut
Fasching, Peter PD Dr.
Professur für Translationale Frauenheilkunde und Geburtshilfe

External institutions with authors

Academia Sinica / 中央研究院
Aichi Cancer Center Research Institute
Center for Cancer Biology (CCB) (formerly Vesalius Research Center (VRC))
Deutsches Krebsforschungszentrum (DKFZ)
Erasmus University Medical Center
Erasmus University Rotterdam (EUR) / Erasmus Universiteit Rotterdam
Helsingin yliopisto / University of Helsinki
Kaohsiung Medical University (KMU) / 高雄醫學大學
Karolinska Institute
Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven
Klinikum Mittelbaden Baden-Baden Balg
Kyushu University / 九州大学
Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie
Mayo Clinic
Mie University
Mount Sinai Hospital (MSH)
National Cancer Institute (NCI)
Netherlands Cancer Institute (NKI)
Oslo University Hospital / Oslo Universitetssykehus
QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research)
Ramsay Sime Darby Health Care (RSDHC)
Roswell Park Cancer Institute
Seoul National University (SNU) / 서울대학교
Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO)
Städtisches Klinikum Karlsruhe
The University of Melbourne
University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven
University of Cambridge
University of Eastern Finland
University of Malaya (UM) / Universiti Malaya
University of Southampton

How to cite

Lei, J., Rudolph, A., Moysich, K.B., Rafiq, S., Behrens, S., Goode, E.L.,... Chang-Claude, J. (2015). Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy. Breast Cancer Research, 17, 18.

Lei, Jieping, et al. "Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy." Breast Cancer Research 17 (2015): 18.


Last updated on 2019-21-07 at 07:59

Share link