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Front. Pharmacol. | doi: 10.3389/fphar.2018.00158

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

 Behzad Bidadi1,  Duan Liu1,  Krishna R. Kalari2, Matthias Rubner3,  Alexander Hein3, Matthias W. Beckmann3, Brigitte Rack4, Wolfgang Janni5, Peter A. Fasching3,  Richard M. Weinshilboum1 and  Liewei Wang1*
  • 1Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Minnesota, United States
  • 2Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic Minnesota, United States
  • 3University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, University of Erlangen-Nuremberg, Germany
  • 4Department of Gynecology and Obstetrics, Ludwig-Maximilians-Universität München, Germany
  • 5Department of Gynecology and Obstetrics, Universitätsklinikum Ulm, Germany

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 in the SUCCESS-A trial. A genome-wide significant 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 the advantage of these existing GWAS data, in the present study, we utilized a pathway-based analysis approach by leveraging the knowledge of pharmacokinetics and pharmacodynamics of drugs and breast cancer pathophysiology to identify additional SNPs/genes and underlying etiology of the 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-eQTLs for 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 the lymphoblastoid cell lines (LCLs) demonstrated that LCLs possessing the minor allele of 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 modulate the cell sensitivity to chemotherapy treatment. These results demonstrate that HMMR SNP-dependent cytotoxicity of these chemotherapeutic agents might be related to the TNFSF13B expression level. In summary, utilizing a pathway-based approach for analysis of GWAS data, we identified additional SNPs in the HMMR gene were associated with neutropenia that were also correlated with TNFSF13B expression.

Keywords: breast cancer, Neutropenia, HMMR, TNFSF13B, GWAS

Received: 23 Oct 2017; Accepted: 13 Feb 2018.

Edited by:

Rick Kittles, Irell & Manella Graduate School of Biological Sciences, City of Hope, United States

Reviewed by:

Ming Ta Michael Lee, Geisinger Health System, United States
Ken Batai, University of Arizona, United States  

Copyright: © 2018 Bidadi, Liu, Kalari, Rubner, Hein, Beckmann, Rack, Janni, Fasching, Weinshilboum and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: MD, PhD. Liewei Wang, Mayo Clinic Minnesota, Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Rochester, MN, United States,