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Chenxue Mao, Juan Chen, Ting Zou, Yuankang Zhou, Junyan Liu, Xi Li, Xiangping Li, Min Li, Pinhua Pan, Wei Zhuo, Yang Gao, Shuo Hu, Desheng Xiao, Lin Wu, Zhan Wang, Heng Xu, Wen Yang, Yingjie Xu, Haihua Xiao, Kazuhiko Hanada, Wei Zhang, Honghao Zhou, Jiye Yin, Zhaoqian Liu. Genome-wide analysis identify novel germline genetic variations in ADCY1 influencing platinum-based chemotherapy response in non-small cell lung cancer[J]. Acta Pharmaceutica Sinica B, 2022, 12(3): 1514-1522

Genome-wide analysis identify novel germline genetic variations in ADCY1 influencing platinum-based chemotherapy response in non-small cell lung cancer
Chenxue Maoa,b, Juan Chena,b, Ting Zoua,b, Yuankang Zhoua,b, Junyan Liua,b, Xi Lia,b, Xiangping Lia, Min Lic, Pinhua Panc, Wei Zhuoa,b, Yang Gaod, Shuo Hue, Desheng Xiaof, Lin Wug, Zhan Wangh, Heng Xui, Wen Yangj, Yingjie Xuj, Haihua Xiaok, Kazuhiko Hanadal, Wei Zhanga,b, Honghao Zhoua,b, Jiye Yina,b, Zhaoqian Liua,b
a. 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;
b. Institute of Clinical Pharmacology, Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Central South University, Changsha 410078, China;
c. Department of Respiratory, Xiangya Hospital, Central South University, Changsha 410008, China;
d. Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha 410008, China;
e. Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha 410008, China;
f. Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, China;
g. Department of Thoracic Medicine, Hunan Cancer Hospital, Changsha 410014, China;
h. Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital, Changsha 410014, China;
i. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610000, China;
j. Department of Molecular and Cellular Biochemistry, School of Medicine, Shanghai Jiaotong University, Shanghai 200025, China;
k. Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China;
l. Department of Pharmacometrics and Pharmacokinetics Meiji Pharmaceutical University, Tokyo 204-8588, Japan
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 of 541 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 ADCY1 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 ADCY1 gene were associated the sensitivity of platinum-based chemotherapy in NSCLC patients.
Key words:    Pharmacogenomics    NSCLC    Platinum    GWAS    WES    ADCY1    Precious medicine    SNPs   
Received: 2021-06-20     Revised: 2021-09-02
DOI: 10.1016/j.apsb.2021.10.007
Funds: This work was supported by the National Key Research and Development Programs (2016YFC1306900 and 2017ZX09304-014, China), National Natural Science Foundation of China (81573508, 81874327, 81773823, 81803640 and 82073943, China), Fundamental Research Funds for the Central Universities of Central South University (2018zzts251, China), The Strategy-Oriented Special Project of Central South University in China (ZLXD2017003), Youth Science Foundation of Xiangya Hospital, Central South University (2017Q02, China) and Hunan Cancer Hospital Climb Plan (YF2020011, China).
Corresponding author: Jiye Yin,;Zhaoqian Liu,;
Author description:
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Chenxue Mao
Juan Chen
Ting Zou
Yuankang Zhou
Junyan Liu
Xi Li
Xiangping Li
Min Li
Pinhua Pan
Wei Zhuo
Yang Gao
Shuo Hu
Desheng Xiao
Lin Wu
Zhan Wang
Heng Xu
Wen Yang
Yingjie Xu
Haihua Xiao
Kazuhiko Hanada
Wei Zhang
Honghao Zhou
Jiye Yin
Zhaoqian Liu

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