Germline variants associated with toxicity to immune checkpoint blockade.

TitleGermline variants associated with toxicity to immune checkpoint blockade.
Publication TypeJournal Article
Year of Publication2022
AuthorsGroha S, Alaiwi SAbou, Xu W, Naranbhai V, Nassar AH, Bakouny Z, Zarif TEl, Saliby RMaria, Wan G, Rajeh A, Adib E, Nuzzo PV, Schmidt AL, Labaki C, Ricciuti B, Alessi JVictor, 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
JournalNat Med
Date Published2022 Dec
KeywordsCognition, Genome-Wide Association Study, Germ Cells, Immune Checkpoint Inhibitors, Interleukin-7, Retrospective Studies

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.

Alternate JournalNat Med
PubMed ID36526723
PubMed Central IDPMC10958775
Grant ListR21 HG010748 / HG / NHGRI NIH HHS / United States
K23 AR080791 / AR / NIAMS NIH HHS / United States
T32 CA009172 / CA / NCI NIH HHS / United States
R50 CA211482 / CA / NCI NIH HHS / United States
201488/Z/16/Z / WT_ / Wellcome Trust / United Kingdom
L30 CA264747 / CA / NCI NIH HHS / United States
P30 CA006516 / CA / NCI NIH HHS / United States
R01 CA244569 / CA / NCI NIH HHS / United States
R01 CA227237 / CA / NCI NIH HHS / United States
P50 CA101942 / CA / NCI NIH HHS / United States
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