Genetically regulated expression underlies cellular sensitivity to chemotherapy in diverse populations
Genetically regulated expression underlies cellular sensitivity to chemotherapy in diverse populations
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DOI：
10.1093/hmg/ddab029
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发表时间：
2021-02-11
影响因子：
3.5
通讯作者：
Wheeler, Heather E.
中科院分区：
文献类型：
--
作者：
Mulford, Ashley J.;Wing, Claudia;Wheeler, Heather E.
大多数癌症化疗药物在一部分患者中无效;因此，重要的是要考虑遗传变异在药物反应中的作用。不同祖先的1000个基因组计划群体中的淋巴母细胞样细胞系（LCL）是确定遗传因素如何影响细胞毒性变化的有用模型。在我们的研究中，来自不同血统的三个1000基因组项目群体的LCL之前用浓度不断增加的八种化疗药物进行了治疗，并在每个剂量下测量了细胞生长抑制，其中半最大抑制浓度（IC 50）或剂量下面积-反应曲线（AUC）作为我们对每种药物的表型。我们进行了全基因组关联研究（GWAS）和全转录组关联研究（TWAS）内和跨祖先人群。我们确定了GWAS中的四个独特位点和TWAS中的三个基因与祖先群体内和跨祖先群体的化疗诱导的细胞毒性显著相关。在依托泊苷TWAS中，STARD 5表达的增加与依托泊苷IC 50的降低相关（P = 8.5 × 10 - 8）。在肺癌细胞系A549中的功能研究显示，STARD 5表达的敲低导致暴露72（P=0.033）和96 h（P=0.0001）后对依托泊苷的敏感性降低。通过识别与祖先群体中细胞毒性相关的基因座和基因，我们努力了解影响化疗药物有效性的遗传因素，并为未来癌症治疗的发展做出贡献。
Most cancer chemotherapeutic agents are ineffective in a subset of patients; thus, it is important to consider the role of genetic variation in drug response. Lymphoblastoid cell lines (LCLs) in 1000 Genomes Project populations of diverse ancestries are a useful model for determining how genetic factors impact the variation in cytotoxicity. In our study, LCLs from three 1000 Genomes Project populations of diverse ancestries were previously treated with increasing concentrations of eight chemotherapeutic drugs, and cell growth inhibition was measured at each dose with half-maximal inhibitory concentration (IC50) or area under the dose-response curve (AUC) as our phenotype for each drug. We conducted both genome-wide association studies (GWAS) and transcriptome-wide association studies (TWAS) within and across ancestral populations. We identified four unique loci in GWAS and three genes in TWAS to be significantly associated with the chemotherapy-induced cytotoxicity within and across ancestral populations. In the etoposide TWAS, increased STARD5 predicted expression associated with decreased etoposide IC50 (P = 8.5 x 10(-8)). Functional studies in A549, a lung cancer cell line, revealed that knockdown of STARD5 expression resulted in the decreased sensitivity to etoposide following exposure for 72 (P=0.033) and 96 h (P=0.0001). By identifying loci and genes associated with cytotoxicity across ancestral populations, we strive to understand the genetic factors impacting the effectiveness of chemotherapy drugs and to contribute to the development of future cancer treatment.