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

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 (2015)


Publication Type: Journal article

Publication year: 2015

Journal

Book Volume: 17

Pages Range: 18

DOI: 10.1186/s13058-015-0522-2

Abstract

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.

Authors with CRIS profile

Involved external institutions

Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) Roswell Park Cancer Institute US United States (USA) (US) Mayo Clinic US United States (USA) (US) University of Cambridge GB United Kingdom (GB) Mount Sinai Hospital (MSH) CA Canada (CA) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet NO Norway (NO) Helsingin yliopisto / University of Helsinki FI Finland (FI) Karolinska Institute SE Sweden (SE) University of Eastern Finland FI Finland (FI) Center for Cancer Biology (CCB) (formerly Vesalius Research Center (VRC)) BE Belgium (BE) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) AU Australia (AU) Städtisches Klinikum Karlsruhe DE Germany (DE) Erasmus University Medical Center (MC) NL Netherlands (NL) Erasmus University Rotterdam (EUR) / Erasmus Universiteit Rotterdam NL Netherlands (NL) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven BE Belgium (BE) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven BE Belgium (BE) National Cancer Institute (NCI) US United States (USA) (US) The University of Melbourne AU Australia (AU) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie PL Poland (PL) Klinikum Mittelbaden Baden-Baden Balg DE Germany (DE) Netherlands Cancer Institute (NKI) NL Netherlands (NL) Seoul National University (SNU) / 서울대학교 KR Korea, Republic of (KR) Academia Sinica / 中央研究院 TW Taiwan (TW) Kaohsiung Medical University (KMU) / 高雄醫學大學 TW Taiwan (TW) Ramsay Sime Darby Health Care (RSDHC) MY Malaysia (MY) University of Malaya (UM) / Universiti Malaya MY Malaysia (MY) Kyushu University / 九州大学 JP Japan (JP) Aichi Cancer Center Research Institute JP Japan (JP) Mie University JP Japan (JP) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) ES Spain (ES) University of Southampton GB United Kingdom (GB)

How to cite

APA:

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. https://dx.doi.org/10.1186/s13058-015-0522-2

MLA:

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.

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