Details

Autor(en) / Beteiligte

• Groha, Stefan
• Alaiwi, Sarah Abou
• Xu, Wenxin
• Naranbhai, Vivek
• Nassar, Amin H.
• Bakouny, Ziad
• El Zarif, Talal
• Saliby, Renee Maria
• Wan, Guihong
• Rajeh, Ahmad
• Adib, Elio
• Nuzzo, Pier V.
• Schmidt, Andrew L.
• Labaki, Chris
• Ricciuti, Biagio
• Alessi, Joao Victor
• Braun, David A.
• Shukla, Sachet A.
• Keenan, Tanya E.
• Van Allen, Eliezer
• Awad, Mark M.
• Manos, Michael
• Rahma, Osama
• Zubiri, Leyre
• Villani, Alexandra-Chloe
• Fairfax, Benjamin
• Hammer, Christian
• Khan, Zia
• Reynolds, Kerry
• Semenov, Yevgeniy
• Schrag, Deborah
• Kehl, Kenneth L.
• Freedman, Matthew L.
• Choueiri, Toni K.
• Gusev, Alexander

Titel

Germline variants associated with toxicity to immune checkpoint blockade

Ist Teil von

• Nature medicine, 2022-12, Vol.28 (12), p.2584-2591

Ort / Verlag

New York: Nature Publishing Group US

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. A genome-wide association study in large cohorts of patients with different types of cancer treated with immune checkpoint inhibitors identifies genetic variants associated with immune-related adverse events.