Pathway-Based Analysis of Genome-Wide Association Data Identified SNPs in HMMR as Biomarker for Chemotherapy- Induced Neutropenia in Breast Cancer Patients
Behzad Bidadi, Duan Liu, Krishna R. Kalari, Matthias Rubner, Alexander Hein, Matthias W. Beckmann, Brigitte Rack, Wolfgang Janni, Peter A. Fasching, Richard M. Weinshilboum, Liewei Wang
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 ofTNFSF13B(p< 1.0E-04). The minor allele of theseHMMRSNPs was associated with a decreasedTNFSF13BmRNA level. Additional functional studies performed with lymphoblastoid cell lines (LCLs) demonstrated that LCLs possessing the minor allele for theHMMRSNPs were more sensitive to drug treatment. Knock-down ofTNFSF13Bin LCLs and HL-60 promyelocytic cells and treatment of those cells with BAFF modulated the cell sensitivity to chemotherapy treatment. These results demonstrate thatHMMRSNP-dependent cytotoxicity of these chemotherapeutic agents might be related toTNFSF13Bexpression level. In summary, utilizing a pathway-based approach for the analysis of GWAS data, we identified additional SNPs in theHMMRgene that were associated with neutropenia and also were correlated withTNFSF13Bexpression.
Pharmacology, Toxicology and Pharmaceutical Science
2
7%
Neuroscience
1
3%
Other
1
3%
Unknown
7
23%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 30 March 2018.
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