Germline variants associated with toxicity to immune checkpoint blockade

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

doi:10.1038/s41591-022-02094-6

Germline variants associated with toxicity to immune checkpoint blockade

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

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35 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	2584-2591
Number of pages	8
Journal	Nature medicine
Volume	28
Issue number	12
DOIs	https://doi.org/10.1038/s41591-022-02094-6
State	Published - Dec 2022
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1038/s41591-022-02094-6

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Groha, S., Alaiwi, S. A., Xu, W., Naranbhai, V., Nassar, A. H., Bakouny, Z., El Zarif, T., Saliby, R. M., Wan, G., Rajeh, A., Adib, E., Nuzzo, P. V., Schmidt, A. L., Labaki, C., Ricciuti, B., Alessi, J. V., Braun, D. A., Shukla, S. A., Keenan, T. E., ... Gusev, A. (2022). Germline variants associated with toxicity to immune checkpoint blockade. Nature medicine, 28(12), 2584-2591. https://doi.org/10.1038/s41591-022-02094-6

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, AC, Fairfax, B, Hammer, C, Khan, Z, Reynolds, K, Semenov, Y, Schrag, D, Kehl, KL, Freedman, ML, Choueiri, TK & Gusev, A 2022, 'Germline variants associated with toxicity to immune checkpoint blockade', Nature medicine, vol. 28, no. 12, pp. 2584-2591. https://doi.org/10.1038/s41591-022-02094-6

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title = "Germline variants associated with toxicity to immune checkpoint blockade",

abstract = "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.",

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

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

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doi = "10.1038/s41591-022-02094-6",

language = "English (US)",

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T1 - Germline variants associated with toxicity to immune checkpoint blockade

AU - Groha, Stefan

AU - Alaiwi, Sarah Abou

AU - Xu, Wenxin

AU - Naranbhai, Vivek

AU - Nassar, Amin H.

AU - Bakouny, Ziad

AU - El Zarif, Talal

AU - Saliby, Renee Maria

AU - Wan, Guihong

AU - Rajeh, Ahmad

AU - Adib, Elio

AU - Nuzzo, Pier V.

AU - Schmidt, Andrew L.

AU - Labaki, Chris

AU - Ricciuti, Biagio

AU - Alessi, Joao Victor

AU - Braun, David A.

AU - Shukla, Sachet A.

AU - Keenan, Tanya E.

AU - Van Allen, Eliezer

AU - Awad, Mark M.

AU - Manos, Michael

AU - Rahma, Osama

AU - Zubiri, Leyre

AU - Villani, Alexandra Chloe

AU - Fairfax, Benjamin

AU - Hammer, Christian

AU - Khan, Zia

AU - Reynolds, Kerry

AU - Semenov, Yevgeniy

AU - Schrag, Deborah

AU - Kehl, Kenneth L.

AU - Freedman, Matthew L.

AU - Choueiri, Toni K.

AU - Gusev, Alexander

PY - 2022/12

Y1 - 2022/12

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Germline variants associated with toxicity to immune checkpoint blockade

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