Genome-wide analysis identify novel germline genetic variations in ADCY1 influencing platinum-based chemotherapy response in non-small cell lung cancer.
- Author:
Chenxue MAO
1
;
Juan CHEN
1
;
Ting ZOU
1
;
Yuankang ZHOU
1
;
Junyan LIU
1
;
Xi LI
1
;
Xiangping LI
1
;
Min LI
2
;
Pinhua PAN
2
;
Wei ZHUO
1
;
Yang GAO
3
;
Shuo HU
4
;
Desheng XIAO
5
;
Lin WU
6
;
Zhan WANG
7
;
Heng XU
8
;
Wen YANG
9
;
Yingjie XU
9
;
Haihua XIAO
10
;
Kazuhiko HANADA
11
;
Wei ZHANG
1
;
Honghao ZHOU
1
;
Jiye YIN
1
;
Zhaoqian LIU
1
Author Information
- Publication Type:Journal Article
- Keywords: ADCY1; GWAS; NSCLC; Pharmacogenomics; Platinum; Precious medicine; SNPs; WES
- From: Acta Pharmaceutica Sinica B 2022;12(3):1514-1522
- CountryChina
- Language:English
- 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.