Polygenic risk score for ulcerative colitis predicts immune checkpoint inhibitor-mediated colitis

Pooja Middha, Rohit Thummalapalli, Michael J. Betti, Lydia Yao, Zoe Quandt, Karmugi Balaratnam, Cosmin A. Bejan, Eduardo Cardenas, Christina J. Falcon, David M. Faleck, Matthew A. Gubens, Scott Huntsman, Douglas B. Johnson, Linda Kachuri, Khaleeq Khan, Min Li, Christine M. Lovly, Megan H. Murray, Devalben Patel, Kristin Werking, Yaomin Xu, Luna Jia Zhan, Justin M. Balko, Geoffrey Liu, Melinda C. Aldrich, Adam J. Schoenfeld and Elad Ziv ()
Additional contact information
Pooja Middha: University of California San Francisco
Rohit Thummalapalli: Memorial Sloan Kettering Cancer Center
Michael J. Betti: Vanderbilt University Medical Center
Lydia Yao: Vanderbilt University Medical Center
Zoe Quandt: University of California San Francisco
Karmugi Balaratnam: Princess Margaret Cancer Centre
Cosmin A. Bejan: Vanderbilt University Medical Center
Eduardo Cardenas: University of California San Francisco
Christina J. Falcon: Fiona and Stanley Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center
David M. Faleck: Memorial Sloan Kettering Cancer Center
Matthew A. Gubens: University of California San Francisco
Scott Huntsman: University of California San Francisco
Douglas B. Johnson: Vanderbilt University Medical Center
Linda Kachuri: Stanford University School of Medicine
Khaleeq Khan: Princess Margaret Cancer Centre
Min Li: University of California San Francisco
Christine M. Lovly: Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center
Megan H. Murray: Vanderbilt University Medical Center
Devalben Patel: Princess Margaret Cancer Centre
Kristin Werking: Vanderbilt University Medical Center
Yaomin Xu: Vanderbilt University Medical Center
Luna Jia Zhan: Princess Margaret Cancer Centre
Justin M. Balko: Vanderbilt University Medical Center
Geoffrey Liu: Princess Margaret Cancer Centre
Melinda C. Aldrich: Vanderbilt University Medical Center
Adam J. Schoenfeld: Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center
Elad Ziv: University of California San Francisco

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: Abstract Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event of treatment with immune checkpoint inhibitors (ICI). We hypothesize that genetic susceptibility to Crohn’s disease (CD) and ulcerative colitis (UC) predisposes to IMC. In this study, we first develop a polygenic risk scores for CD (PRSCD) and UC (PRSUC) in cancer-free individuals and then test these PRSs on IMC in a cohort of 1316 patients with ICI-treated non-small cell lung cancer and perform a replication in 873 ICI-treated pan-cancer patients. In a meta-analysis, the PRSUC predicts all-grade IMC (ORmeta=1.35 per standard deviation [SD], 95% CI = 1.12–1.64, P = 2×10−03) and severe IMC (ORmeta=1.49 per SD, 95% CI = 1.18–1.88, P = 9×10−04). PRSCD is not associated with IMC. Furthermore, PRSUC predicts severe IMC among patients treated with combination ICIs (ORmeta=2.20 per SD, 95% CI = 1.07–4.53, P = 0.03). Overall, PRSUC can identify patients receiving ICI at risk of developing IMC and may be useful to monitor patients and improve patient outcomes.

Date: 2024
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DOI: 10.1038/s41467-023-44512-4

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