A two-stage genome-wide association study to identify novel genetic loci associated with irAEs in lung cancer patients receiving PD-1/PD-L1 inhibitors

Abstract

Use of immune checkpoint inhibitors (ICIs) has significantly improved patients' survival, especially in lung cancer. However, immunotherapy-related adverse events (irAEs) frequently occur and negatively impact patients' quality of life. While investigations into genetic predictors of irAEs remain ongoing, no robust genetic loci predictive of these toxicities have been definitively established to date. To investigate the pharmacogenomic markers related to irAEs of PD-1/PD-L1 inhibitors in lung cancer patients, we collected blood specimens from 1467 patients. After rigorous screening and quality control procedures, 785 of these patients were enrolled in a two-stage genome-wide association study (GWAS). The study comprised an initial discovery phase, in which 455 patients underwent microarray-based analysis, and a subsequent validation phase with an independent cohort of 330 patients. Of 688,783 SNPs genotyped using whole genome-wide microarray screening, 52 SNPs were validated using MassARRAY system. The potential impact of significant variants investigated by eQTL analysis. We identified three novel SNPs that are significantly associated with irAEs of PD-1/PD-L1 inhibitor treatments in these lung cancer patients in both discovery and validation cohorts, rs192921786 (discovery: P = 4.09 × 10^-7, OR = 9.57; validation: P = 0.043, OR = 4.42) for pneumonitis, rs2498632 (discovery: P = 1.85 × 10^-6, OR = 0.50; validation: P = 0.021, OR = 0.65) for anemia and rs17080141 (discovery: P = 9.11 × 10^-7, OR = 3.16; validation: P = 0.027, OR = 1.86) for thrombocytopenia. Lung cancer patients with rs192921786 T allele, rs2498632 C allele, and rs17080141 A allele were more likely to suffer immunotherapy related pneumonitis, anemia and thrombocytopenia, respectively. In conclusion, rs192921786, rs2498632 and rs17080141 are novel candidate risk loci for pneumonitis, anemia, and thrombocytopenia in lung cancer patients receiving immunotherapy. These findings warrant further investigation and validation to assess their potential as predictive biomarkers.

Keywords: Anemia; GWAS; Lung cancer; PD-1/PD-L1 inhibitors; Pharmacogenomics; Pneumonitis; Thrombocytopenia; irAEs.