Bidadi Behzad, Liu Duan, Kalari Krishna R, Rubner Matthias, Hein Alexander, Beckmann Matthias W, Rack Brigitte, Janni Wolfgang, Fasching Peter A, Weinshilboum Richard M, Wang Liewei
Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States.
Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States.
Front Pharmacol. 2018 Mar 13;9:158. doi: 10.3389/fphar.2018.00158. eCollection 2018.
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 () 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 ( gene that were significantly associated with neutropenia ( < 1.0E-04). Those three SNPs were trans-expression quantitative trait loci for the expression of ( < 1.0E-04). The minor allele of these SNPs was associated with a decreased mRNA level. Additional functional studies performed with lymphoblastoid cell lines (LCLs) demonstrated that LCLs possessing the minor allele for the SNPs were more sensitive to drug treatment. Knock-down of 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 SNP-dependent cytotoxicity of these chemotherapeutic agents might be related to expression level. In summary, utilizing a pathway-based approach for the analysis of GWAS data, we identified additional SNPs in the gene that were associated with neutropenia and also were correlated with expression.
乳腺癌患者化疗继发的中性粒细胞减少可能危及生命，目前尚无生物标志物可用于预测这些患者发生药物性中性粒细胞减少的风险。我们之前对接受5-氟尿嘧啶、表柔比星和环磷酰胺治疗并纳入SUCCESS-A试验的乳腺癌女性患者的中性粒细胞减少事件进行了全基因组关联研究（GWAS）。在该GWAS中，我们在肿瘤坏死因子超家族成员13B（）基因中鉴定出一个全基因组显著的单核苷酸多态性（SNP）信号，该基因编码细胞因子B细胞激活因子（BAFF）。利用这些现有的GWAS数据，在本研究中，我们通过利用药物的药代动力学和药效学知识以及乳腺癌病理生理学，采用基于通路的分析方法来识别与化疗诱导的中性粒细胞减少的潜在病因相关的其他SNP/基因。我们在透明质酸介导的运动受体（基因中鉴定出三个与中性粒细胞减少显著相关的SNP（<1.0E-04）。这三个SNP是（<1.0E-04）表达的反式表达数量性状位点。这些SNP的次要等位基因与mRNA水平降低相关。对淋巴母细胞系（LCLs）进行的额外功能研究表明，携带这些SNP次要等位基因的LCLs对药物治疗更敏感。在LCLs和HL-60早幼粒细胞中敲低以及用BAFF处理这些细胞可调节细胞对化疗治疗的敏感性。这些结果表明，这些化疗药物的SNP依赖性细胞毒性可能与表达水平有关。总之，利用基于通路的方法分析GWAS数据，我们在基因中鉴定出了与中性粒细胞减少相关且与表达相关的其他SNP。
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