Germline variants associated with immunotherapy-related adverse events

Abstract

Immune checkpoint inhibitors (ICIs) have yielded remarkable responses in patients across multiple cancer types, but often lead to immune related adverse events (irAEs). Although a germline cause for irAEs has been hypothesized, no systematic genome wide association study (GWAS) has been performed and no individual variants associated with the overall likelihood of developing irAEs have yet been identified. We carried out a Genome-Wide Association Study (GWAS) of 1,751 patients on ICIs across 12 cancer types, with replication in an independent cohort of 196 patients and independent clinical trial data from 2275 patients. We investigated two irAE phenotypes: (i) high-grade (3-5) events defined through manual curation and (ii) all detectable events (including high-grade) defined through electronic health record (EHR) diagnosis followed by manual confirmation. We identified three genome-wide significant associations (p<5x10-8) in the discovery cohort associated with all-grade irAEs: rs16906115 near IL7 (combined p=1.6x10-11; hazard ratio (HR)=2.1), rs75824728 near IL22RA1 (combined p=6.6x10-9; HR=1.9), and rs113861051 on 4p15 (combined p=1.3x10-8, HR=2.0); with rs16906115 replicating in two independent studies. The association near IL7 colocalized with the gain of a novel cryptic exon for IL7, a critical regulator of lymphocyte homeostasis. Patients carrying the IL7 germline variant exhibited significantly increased lymphocyte stability after ICI initiation than non-carriers, and this stability was predictive of downstream irAEs and improved survival.

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“…irAEs: Summary-level data of irAEs was obtained from a recent GWAS conducted in the Dana-Farber Cancer Institute (DFCI) cohort (27). The study included 1,751 cancer patients of European ancestry who underwent ICIs treatments between 2013 and 2020.…”

“…Additionally, algorithm-based autoimmune-like electronic health records were used to identify 339 patients who experienced any grade irAEs (referred to as all-grade irAEs). Most of these cases were grade 2 or higher events (27). The tumor tissue of these patients was sequenced using the targeted OncoPanel sequencing platform.…”

“…Then, the GWAS was conducted in the DFCI cohort to investigate the association of all variants with the time from the start of ICIs treatment to the occurrence of the two phenotypes of irAEs. For more detailed information, please refer to the original publication (27).…”