Germline variants associated with toxicity to immune checkpoint blockade.
Groha S., Alaiwi SA., Xu W., Naranbhai V., Nassar AH., Bakouny Z., El Zarif T., Saliby RM., Wan G., Rajeh A., Adib E., Nuzzo PV., Schmidt AL., Labaki C., Ricciuti B., Alessi JV., Braun DA., Shukla SA., Keenan TE., Van Allen E., Awad MM., Manos M., Rahma O., Zubiri L., Villani A-C., Fairfax B., Hammer C., Khan Z., Reynolds K., Semenov Y., Schrag D., Kehl KL., Freedman ML., Choueiri TK., Gusev A.
Immune checkpoint inhibitors (ICIs) have yielded remarkable responses but often lead to immune-related adverse events (irAEs). Although germline causes for irAEs have been hypothesized, no individual variant associated with developing irAEs has been identified. We carried out a genome-wide association study of 1,751 patients on ICIs across 12 cancer types. We investigated two irAE phenotypes: (1) high-grade (3-5) and (2) all-grade events. We identified 3 genome-wide significant associations (P < 5 × 10-8) in the discovery cohort associated with all-grade irAEs: rs16906115 near IL7 (combined P = 3.6 × 10-11; hazard ratio (HR) = 2.1); rs75824728 near IL22RA1 (combined P = 3.5 × 10-8; HR = 1.8); and rs113861051 on 4p15 (combined P = 1.2 × 10-8, HR = 2.0); rs16906115 was replicated in 3 independent studies. The association near IL7 colocalized with the gain of a new cryptic exon for IL7, a critical regulator of lymphocyte homeostasis. Patients carrying the IL7 germline variant exhibited significantly increased lymphocyte stability after ICI initiation, which was itself predictive of downstream irAEs and improved survival.