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Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy
- Source :
- Breast Cancer Research : BCR, Breast Cancer Research, 17. BioMed Central Ltd.
- Publisher :
- Springer Nature
-
Abstract
- Introduction 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). Methods 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. Results Three independent SNPs in TGFBR2 and IL12B were associated with OS (P C) (per allele hazard ratio (HR) 1.54 (95% confidence interval (CI) 1.22 to 1.95), P = 3.08 × 10−4) was not found in ER-negative patients without chemotherapy or ER-positive patients with chemotherapy (P for interaction A) with poorer OS (HR 1.50 (95% CI 1.21 to 1.86), P = 1.81 × 10−4), and rs2853694 (A > C) with improved OS (HR 0.73 (95% CI 0.61 to 0.87), P = 3.67 × 10−4). 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 × 10−5) without study heterogeneity. Conclusions 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.
- Subjects :
- Oncology
medicine.medical_treatment
Estrogen receptor
32 Biomedical and Clinical Sciences
Genome-wide association study
Kaplan-Meier Estimate
0302 clinical medicine
Medizinische Fakultät
Surgical oncology
Antineoplastic Combined Chemotherapy Protocols
2.1 Biological and endogenous factors
Prospective cohort study
health care economics and organizations
Cancer
2 Aetiology
Medicine(all)
0303 health sciences
Interleukin-12 Subunit p40
Hazard ratio
Genomics
Middle Aged
Prognosis
Tumor Burden
3. Good health
3204 Immunology
Treatment Outcome
Receptors, Estrogen
030220 oncology & carcinogenesis
Female
4.2 Evaluation of markers and technologies
Signal Transduction
Research Article
Adult
medicine.medical_specialty
Breast Neoplasms
Single-nucleotide polymorphism
Protein Serine-Threonine Kinases
Polymorphism, Single Nucleotide
Immunomodulation
03 medical and health sciences
Breast cancer
SDG 3 - Good Health and Well-being
Internal medicine
Breast Cancer
Genetics
Biomarkers, Tumor
medicine
Humans
ddc:610
Neoplasm Staging
030304 developmental biology
Chemotherapy
business.industry
Receptor, Transforming Growth Factor-beta Type II
3211 Oncology and Carcinogenesis
medicine.disease
Cancer research
Neoplasm Grading
4 Detection, screening and diagnosis
business
Receptors, Transforming Growth Factor beta
Subjects
Details
- Language :
- English
- ISSN :
- 1465542X and 14655411
- Volume :
- 17
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Breast Cancer Research
- Accession number :
- edsair.doi.dedup.....a1286fdbfb19ae232189499121971d57
- Full Text :
- https://doi.org/10.1186/s13058-015-0522-2