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; Princess Margaret Lung Group; 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; Elad Ziv

doi:10.1038/s41467-023-44512-4

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

Nat Commun. 2024 Mar 26;15(1):2568. doi: 10.1038/s41467-023-44512-4.

Authors

Pooja Middha¹, Rohit Thummalapalli², Michael J Betti³, Lydia Yao⁴, Zoe Quandt^{5

6}, Karmugi Balaratnam⁷, Cosmin A Bejan⁸, Eduardo Cardenas¹, Christina J Falcon⁹, David M Faleck¹⁰; Princess Margaret Lung Group; Matthew A Gubens^{11

12}, Scott Huntsman¹, Douglas B Johnson¹³, Linda Kachuri^{14

15}, Khaleeq Khan⁷, Min Li¹, Christine M Lovly¹⁶, Megan H Murray⁴, Devalben Patel⁷, Kristin Werking¹⁷, Yaomin Xu⁴, Luna Jia Zhan⁷, Justin M Balko¹³, Geoffrey Liu^{7

18

19}, Melinda C Aldrich³, Adam J Schoenfeld²⁰, Elad Ziv^{21

22

23

24}

Collaborators

Princess Margaret Lung Group:
Natasha B Leighl, Penelope A Bradbury, Frances A Shepherd, Adrian G Sacher, Lawson Eng

Affiliations

¹ Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
² Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
³ Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁴ Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁵ Division of Endocrinology and Metabolism, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
⁶ Diabetes Center, University of California San Francisco, San Francisco, CA, USA.
⁷ Princess Margaret Cancer Centre, Toronto, ON, Canada.
⁸ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁹ Fiona and Stanley Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁰ Gastroenterology, Hepatology & Nutrition Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹¹ Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
¹² Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
¹³ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁴ Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA.
¹⁵ Stanford Cancer Institute, Stanford University of Medicine, Stanford, CA, USA.
¹⁶ Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, TN, USA.
¹⁷ Department of Thoracic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁸ Temerty School of Medicine, Toronto, ON, Canada.
¹⁹ Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
²⁰ Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
²¹ Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Elad.Ziv@ucsf.edu.
²² Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. Elad.Ziv@ucsf.edu.
²³ Center for Genes, Environment and Health, University of California San Francisco, San Francisco, CA, USA. Elad.Ziv@ucsf.edu.
²⁴ Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA. Elad.Ziv@ucsf.edu.

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 (PRS_CD) and UC (PRS_UC) 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 PRS_UC predicts all-grade IMC (OR_meta=1.35 per standard deviation [SD], 95% CI = 1.12-1.64, P = 2×10^-03) and severe IMC (OR_meta=1.49 per SD, 95% CI = 1.18-1.88, P = 9×10^-04). PRS_CD is not associated with IMC. Furthermore, PRS_UC predicts severe IMC among patients treated with combination ICIs (OR_meta=2.20 per SD, 95% CI = 1.07-4.53, P = 0.03). Overall, PRS_UC can identify patients receiving ICI at risk of developing IMC and may be useful to monitor patients and improve patient outcomes.

Publication types

Meta-Analysis

MeSH terms

Carcinoma, Non-Small-Cell Lung*
Colitis*
Colitis, Ulcerative* / genetics
Crohn Disease* / genetics
Genetic Risk Score
Humans
Immune Checkpoint Inhibitors
Lung Neoplasms*

Substances

Immune Checkpoint Inhibitors

Abstract

Publication types

MeSH terms

Substances

Grants and funding