Acta Pharmaceutica Sinica B (Mar 2022)
Genome-wide analysis identify novel germline genetic variations in ADCY1 influencing platinum-based chemotherapy response in non-small cell lung cancer
- 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
Affiliations
- Chenxue Mao
- 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
- Juan Chen
- 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
- Ting Zou
- 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
- Yuankang Zhou
- 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
- Junyan Liu
- 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
- Xi Li
- 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
- Xiangping Li
- 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
- Min Li
- Department of Respiratory, Xiangya Hospital, Central South University, Changsha 410008, China
- Pinhua Pan
- Department of Respiratory, Xiangya Hospital, Central South University, Changsha 410008, China
- Wei Zhuo
- 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
- Yang Gao
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
- Shuo Hu
- Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha 410008, China
- Desheng Xiao
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, China
- Lin Wu
- Department of Thoracic Medicine, Hunan Cancer Hospital, Changsha 410014, China
- Zhan Wang
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital, Changsha 410014, China
- Heng Xu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610000, China
- Wen Yang
- Department of Molecular and Cellular Biochemistry, School of Medicine, Shanghai Jiaotong University, Shanghai 200025, China
- Yingjie Xu
- Department of Molecular and Cellular Biochemistry, School of Medicine, Shanghai Jiaotong University, Shanghai 200025, China
- Haihua Xiao
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
- Kazuhiko Hanada
- Department of Pharmacometrics and Pharmacokinetics Meiji Pharmaceutical University, Tokyo 204-8588, Japan
- Wei Zhang
- 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
- Honghao Zhou
- 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
- Jiye Yin
- 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; Corresponding authors. Tel.: +86 731 89753845, fax: +86 731 82354476 (Zhaoqian Liu); +86 731 84805380, fax: +86 731 82354476 (Jiye Yin).
- Zhaoqian Liu
- 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; Corresponding authors. Tel.: +86 731 89753845, fax: +86 731 82354476 (Zhaoqian Liu); +86 731 84805380, fax: +86 731 82354476 (Jiye Yin).
- Journal volume & issue
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Vol. 12,
no. 3
pp. 1514 – 1522
Abstract
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.
