Mao Chenxue, Chen Juan, Zou Ting, Zhou Yuankang, Liu Junyan, Li Xi, Li Xiangping, Li Min, Pan Pinhua, Zhuo Wei, Gao Yang, Hu Shuo, Xiao Desheng, Wu Lin, Wang Zhan, Xu Heng, Yang Wen, Xu Yingjie, Xiao Haihua, Hanada Kazuhiko, Zhang Wei, Zhou Honghao, Yin Jiye, Liu Zhaoqian
Departments of Clinical Pharmacology and Pharmacy, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China.
Institute of Clinical Pharmacology, Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Central South University, Changsha 410078, China.
Acta Pharm Sin B. 2022 Mar;12(3):1514-1522. doi: 10.1016/j.apsb.2021.10.007. Epub 2021 Oct 16.
To explore the pharmacogenomic markers that affect the platinum-based chemotherapy response in non-small-cell lung carcinoma (NSCLC), we performed a two-cohort of genome-wide association studies (GWAS), including 34 for WES-based and 433 for microarray-based analyses, as well as two independent validation cohorts. After integrating the results of two studies, the genetic variations related to the platinum-based chemotherapy response were further determined by fine-mapping in 838 samples, and their potential functional impact were investigated by eQTL analysis and cell experiments. We found that a total of 68 variations were significant at < 1 × 10 in cohort 1 discovery stage, of which 3 SNPs were verified in 262 independent samples. A total of 541 SNPs were significant at < 1 × 10 in cohort 2 discovery stage, of which 8 SNPs were verified in 347 independent samples. Comparing the validated SNPs in two GWAS, gene was verified in both independent studies. The results of fine-mapping showed that the G allele carriers of rs2280496 and C allele carriers of rs189178649 were more likely to be resistant to platinum-based chemotherapy. In conclusion, our study found that rs2280496 and rs189178649 in gene were associated the sensitivity of platinum-based chemotherapy in NSCLC patients.
为了探索影响非小细胞肺癌（NSCLC）铂类化疗反应的药物基因组学标志物，我们进行了两项全基因组关联研究（GWAS）队列，包括34项基于全外显子测序（WES）的分析和433项基于微阵列的分析，以及两个独立的验证队列。整合两项研究结果后，在838个样本中通过精细定位进一步确定与铂类化疗反应相关的基因变异，并通过表达定量性状位点（eQTL）分析和细胞实验研究其潜在的功能影响。我们发现，在队列1发现阶段共有68个变异在<1×10时具有显著性，其中3个单核苷酸多态性（SNP）在262个独立样本中得到验证。在队列2发现阶段共有541个SNP在<1×10时具有显著性，其中8个SNP在347个独立样本中得到验证。比较两项GWAS中验证的SNP，在两项独立研究中均验证了该基因。精细定位结果显示，rs2280496的G等位基因携带者和rs189178649的C等位基因携带者更有可能对铂类化疗耐药。总之，我们的研究发现基因中的rs2280496和rs189178649与NSCLC患者铂类化疗的敏感性相关。
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