Abstract 3937: Investigation of inherited genetic variation for predictors of immune mediated colitis following immune checkpoint inhibitor (ICI) therapy of patients (pts) with melanoma.

Abstract Background: Immune mediated colitis is a common toxicity following ICI therapy of melanoma and can be life threatening. Therefore, predicting the risk of developing colitis may inform the treatment plan and clinical follow up. We hypothesize that inherited genetic variation is an important factor in predisposing pts to this immune related adverse event (irAE). Methods: We conducted genome-wide genotyping on samples from 744 consenting pts enrolled in ECOG-ACRIN E1609 trial (NCT01274338) that tested ipilimumab. We used Illumina Infinium Global Screening Array v.3.0 + Multi-Disease BeadChip with 730059 designed loci. Genotypes were quality controlled, harmonized with the 1000 Genomes Phase 3 (1KGP3) genotypes, and imputed against the hrc-r1.1 reference panel using the Michigan Imputation Server 2, pipeline v2.0.6. We used logistic regression implemented in plink (v2.00a4LM glm with firth fallback) to estimate associations between inherited genetic markers and the occurrence of colitis, adjusting for genetic ancestry. We also calculated the value for 5 published polygenic risk scores (PRS) for inflammatory bowel disease (IBD) listed in PGS-Catalog v20240318 and tested the association with colitis in E1609 pts treating irAE grades as categorical (Kruskal-Wallis test) and as dichotomous (Wilcoxon rank-sum test) variables. IrAEs were graded using CTCAE v.4. Results: There was no significant difference in distribution of the PRS across grade of colitis (Kruskal-Wallis) with any of the 5 PRS. However, all demonstrated stronger differences when irAE grades were dichotomized at >3 vs. other. PRS PGS004253 was most significant in association with grades 4-5 colitis (P = 0.01; AUC 0.73). This PRS (Medha. Nature Commun 2024) was trained in a non-melanoma European population that has a genetic ancestry similar to our melanoma study cohort (Tarhini. AACR 2025) and for which all markers in the PRS were available in our dataset. From our genome-wide association analysis, we identified 10 independent SNPs that were significantly associated with colitis irAE. When combined using log(OR) as weights, these SNPs were significantly associated with the severity of irAE grades, both across irAE grades (Kruskal-Wallis P = 2.5e-26) and when dichotomized as any colitis irAE vs. none (Wilcoxon P = 8.9e-30). In multivariable survival analysis adjusting for primary status (known, unknown) and sex (male, female), our 10-SNP PGS trended towards an association with survival outcomes. Conclusion: Our results support an association between inherited genetic variation and the risk of colitis following ICI, including PRS for IBD selected based on inherited genetic similarity with the population used to train the PRS as well as a novel PRS score computed using 10 SNPs identified from our GWAS analysis. Citation Format: Ahmad A. Tarhini, Zhihua Chen, Mohammad Ali Khaksar, Sandra J. Lee, F. Stephen Hodi, Tingyi Li, Howard Streicher, Vernon K. Sondak, John M. Kirkwood, Xuefeng Wang, Peter A. Kanetsky. Investigation of inherited genetic variation for predictors of immune mediated colitis following immune checkpoint inhibitor (ICI) therapy of patients (pts) with melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3937.