Genome-wide analysis identify novel germline genetic variations in ADCY1 influencing platinum-based chemotherapy response in non-small cell lung cancer

Release time:2022-03-12

Impact Factor:14.907

DOI number:10.1016/j.apsb.2021.10.007

Affiliation of Author(s):中南大学湘雅医院

Teaching and Research Group:临床药理研究所

Journal:Acta Pharmaceutica Sinica B

Key Words:ADCY1; GWAS; NSCLC; Pharmacogenomics; Platinum; Precious medicine; SNPs; WES

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.

Co-author:Ting Zou, Yuan-Kang Zhou, Jun-Yan Liu, Xi Li, Xiang-Ping Li, Min Li, Pin-Hua Pan, Wei Zhuo, Yang Gao, Shuo Hu, De-Sheng Xiao, Lin Wu, Zhan Wang, Heng Xu, Wen Yang, Ying-Jie Xu, Hai-Hua Xiao, Kazuhiko Hanada, Wei Zhang, Hong-Hao Zhou

First Author:Chen-Xue Mao, Juan Chen

Indexed by:Article

Correspondence Author:Ji-Ye Yin, Zhao-Qian Liu

Discipline:Medicine

First-Level Discipline:Pharmaceutical Science

Volume:12

Issue:3

Page Number:1514-1522

ISSN No.:2211-3835

Translation or Not:no

Date of Publication:2022-03-12

Included Journals:SCI

Links to published journals:https://www.sciencedirect.com/science/article/pii/S2211383521003993?via%3Dihub