Abstract
Neutropenia secondary to chemotherapy in breast cancer patients can be life-threatening and there are no biomarkers available to predict the risk of drug-induced neutropenia in those patients. We previously performed a genome-wide association study (GWAS) for neutropenia events in women with breast cancer who were treated with 5-fluorouracil, epirubicin and cyclophosphamide and recruited to the SUCCESS-A trial. A genome-wide significant single-nucleotide polymorphism (SNP) signal in the tumor necrosis factor superfamily member 13B (TNFSF13B) gene, encoding the cytokine B-cell activating factor (BAFF), was identified in that GWAS. Taking advantage of these existing GWAS data, in the present study we utilized a pathway-based analysis approach by leveraging knowledge of the pharmacokinetics and pharmacodynamics of drugs and breast cancer pathophysiology to identify additional SNPs/genes associated with the underlying etiology of chemotherapy-induced neutropenia. We identified three SNPs in the hyaluronan mediated motility receptor (HMMR) gene that were significantly associated with neutropenia (p < 1.0E-04). Those three SNPs were trans-expression quantitative trait loci for the expression of TNFSF13B (p < 1.0E-04). The minor allele of these HMMR SNPs was associated with a decreased TNFSF13B mRNA level. Additional functional studies performed with lymphoblastoid cell lines (LCLs) demonstrated that LCLs possessing the minor allele for the HMMR SNPs were more sensitive to drug treatment. Knock-down of TNFSF13B in LCLs and HL-60 promyelocytic cells and treatment of those cells with BAFF modulated the cell sensitivity to chemotherapy treatment. These results demonstrate that HMMR SNP-dependent cytotoxicity of these chemotherapeutic agents might be related to TNFSF13B expression level. In summary, utilizing a pathway-based approach for the analysis of GWAS data, we identified additional SNPs in the HMMR gene that were associated with neutropenia and also were correlated with TNFSF13B expression.
Highlights
Breast cancer is the most common invasive cancer in women worldwide and approximately 1.3 million cases are diagnosed worldwide annually (Ferlay et al, 2015)
We took advantage of GWAS data that we had generated in the SUCCESS-A trial, and utilized a pathwaybased approach to identify additional biomarkers and underlying biology for chemotherapy-induced neutropenia (CIN) in breast cancer patients
SNPs in genes involved in PK and PD pathways for the chemotherapy agents that were used to treat patients, and were involved in disease risk were associated with neutropenia events
Summary
Breast cancer is the most common invasive cancer in women worldwide and approximately 1.3 million cases are diagnosed worldwide annually (Ferlay et al, 2015). Administration of chemotherapy regimens such as cytotoxic agents potentially leads to life-threatening adverse drug effects, of which the most common adverse event is chemotherapy-induced neutropenia (CIN) (Fontanella et al, 2014) This adverse event is common in breast cancer patients receiving adjuvant chemotherapy and affects more than 50% of patients (Holmes et al, 2002; Therasse et al, 2003). Sub-classification of patients at increased risk of CIN may allow for improved treatment modifications, such as G-CSF support, dose reduction, or use of chemotherapy regimens with a lower risk of myelosuppression Clinical risk factors such as older age, poor nutrition and prior chemotherapy have been associated with increased risk of febrile neutropenia (Aapro et al, 2006). Other predictors for CIN risk are urgently needed which may help to improve the individualized care of breast cancer patients during adjuvant chemotherapy
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