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 W...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 in vitro cell experiments.We found that a total of 68 variations were significant at P<1×10^(-3)in cohort 1 discovery stage,of which 3 SNPs were verified in 262 independent samples.A total of541 SNPs were significant at P<1×10^(-4)in cohort 2 discovery stage,of which 8 SNPs were verified in 347 independent samples.Comparing the validated SNPs in two GWAS,ADCY1 gene was verified in both independent studies.The results of fine-mapping showed that the G allele carriers of ADCY1rs2280496 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 ADCY1 gene were associated the sensitivity of platinum-based chemotherapy in NSCLC patients.展开更多
基金supported by the National Key Research and Development Programs(2016YFC1306900 and 2017ZX09304014,China)National Natural Science Foundation of China(81573508,81874327,81773823,81803640 and 82073943,China)+3 种基金Fundamental Research Funds for the Central Universities of Central South University(2018zzts251,China)The StrategyOriented Special Project of Central South University in China(ZLXD2017003)Youth Science Foundation of Xiangya Hospital,Central South University(2017Q02,China)Hunan Cancer Hospital Climb Plan(YF2020011,China)。
文摘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 in vitro cell experiments.We found that a total of 68 variations were significant at P<1×10^(-3)in cohort 1 discovery stage,of which 3 SNPs were verified in 262 independent samples.A total of541 SNPs were significant at P<1×10^(-4)in cohort 2 discovery stage,of which 8 SNPs were verified in 347 independent samples.Comparing the validated SNPs in two GWAS,ADCY1 gene was verified in both independent studies.The results of fine-mapping showed that the G allele carriers of ADCY1rs2280496 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 ADCY1 gene were associated the sensitivity of platinum-based chemotherapy in NSCLC patients.
