Skip to content
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Menu
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Menu
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Germline variants associated with toxicity to immune checkpoint blockade
Nature Medicine, Volume 28, No. 12, Year 2022
Notification
URL copied to clipboard!
Description
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. © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
Authors & Co-Authors
Groha, Stefan M.
United States, Boston
Dana-farber Cancer Institute
United States, Cambridge
Massachusetts Institute of Technology
United States, Boston
Harvard Medical School
Naranbhai, Vivek
United States, Boston
Dana-farber Cancer Institute
Nassar, Amin H.
United States, Boston
Dana-farber Cancer Institute
United States, Boston
Brigham and Women's Hospital
Bakouny, Ziad
United States, Boston
Dana-farber Cancer Institute
United States, Boston
Brigham and Women's Hospital
El-Zarif, Talal
United States, Boston
Dana-farber Cancer Institute
Saliby, Renee Maria
United States, Boston
Dana-farber Cancer Institute
Adib, Elio
United States, Boston
Dana-farber Cancer Institute
United States, Boston
Brigham and Women's Hospital
Labaki, Chris
United States, Boston
Dana-farber Cancer Institute
Ricciuti, Biagio
United States, Boston
Dana-farber Cancer Institute
Braun, David A.
United States, Boston
Dana-farber Cancer Institute
United States, New Haven
Yale School of Medicine
Shukla, Sachet A.
United States, Cambridge
Massachusetts Institute of Technology
United States, Boston
Dana-farber Cancer Institute
Keenan, Tanya E.
United States, Cambridge
Massachusetts Institute of Technology
United States, Boston
Dana-farber Cancer Institute
van Allen, Eliezer M.
United States, Cambridge
Massachusetts Institute of Technology
United States, Boston
Dana-farber Cancer Institute
Awad, Mark M.
Italy, Genoa
Università Degli Studi Di Genova
Rahma, Osama E.
United States, Boston
Dana-farber Cancer Institute
United States, Boston
Brigham and Women's Hospital
Zubiri, Leyre
United States, Boston
Massachusetts General Hospital
Villani, Alexandra Chloé
United States, Cambridge
Massachusetts Institute of Technology
United States, Boston
Harvard Medical School
United States, Boston
Massachusetts General Hospital
Fairfax, Benjamin Peter
United Kingdom, Oxford
University of Oxford
Reynolds, Kerry Lynn
United States, Boston
Harvard Medical School
United States, Boston
Massachusetts General Hospital
Schrag, Deborah H.
United States, Boston
Dana-farber Cancer Institute
Kehl, Kenneth L.
United States, Boston
Dana-farber Cancer Institute
Freedman, Matthew Lee
United States, Cambridge
Massachusetts Institute of Technology
United States, Boston
Dana-farber Cancer Institute
Choueiri, Toni K.
United States, Boston
Harvard Medical School
United States, Boston
Dana-farber Cancer Institute
United States, Boston
Brigham and Women's Hospital
Gusev, Alexander
United States, Boston
Dana-farber Cancer Institute
United States, Cambridge
Massachusetts Institute of Technology
United States, Boston
Harvard Medical School
United States, Boston
Brigham and Women's Hospital
Statistics
Citations: 39
Authors: 24
Affiliations: 9
Identifiers
Doi:
10.1038/s41591-022-02094-6
ISSN:
10788956
Research Areas
Cancer
Environmental
Genetics And Genomics
Study Design
Cohort Study