Genetic determinants of adverse events in cancer patients receiving immune checkpoint inhibitors.

Abstract

2586 Background: Immune checkpoint inhibitors (ICI) can cause profound immune-related adverse events (irAEs). The host genetic background is likely to play a role in irAEs susceptibility as the phenotype of toxicity varies among patients (pts) and many pts do not develop toxicity despite continued inhibition. Methods: Genotyping was performed for 89 melanoma pts who received ICI using the Infinium Multi-Ethnic Global-8 v1.0 Bead Chip. The genotype data was extracted using PLINK (v1.90b3.34) and processed for quality control including on call rate (>99%), genotyping rate (>95%), minor allele frequency (no less than 5%), and Hardy-Weinberg Equilibrium (p<1x10-6). The pairwise genetic distance was calculated using identity-by-state (IBS matrix) implemented in the genome option of PLINK, and the population-structure-based clustering was carried out using IBS matrix, pairwise population concordance test (p<1x10-3) and phenotype distribution for all pts, resulting in 7 structure groups. In the analytical stage, 602,463 variants in autosomal chromosomes were included for the association test. The test was performed using additive genetic model with exact logistic regression, adjusted for age, sex, and population cluster. Results: 44 pts had arthritis, colitis, hypohysitis, thyroiditis, or multiple irAEs (cases), and 45 did not have irAEs after a minimum of one year of treatment (controls); median age was 64 (23-92) years; 71% were male. A total of 30 variants/single nucleotide polymorphisms (SNPs) had p-value smaller than 10^-5 level were identified. The top variants/SNPs are listed in table. Conclusions: Genetic variants associated with irAEs were identified. Additional larger studies are needed to validate these findings, and to establish their potential functional relevance.[Table: see text]