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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.

frontiers in pharmacology

Pathway-Based Analysis of Genome-Wide Association Data Identified SNPs in HMMR as Biomarker for Chemotherapy- Induced Neutropenia in Breast Cancer Patients