Meta-Analysis

. 2024 Mar 26;15(1):2568.

doi: 10.1038/s41467-023-44512-4.

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

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, Affiliations

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.

PMID: 38531883
PMCID: PMC10966072
DOI: 10.1038/s41467-023-44512-4

Meta-Analysis

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

Pooja Middha et al. Nat Commun. 2024.

. 2024 Mar 26;15(1):2568.

doi: 10.1038/s41467-023-44512-4.

Authors

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.

PMID: 38531883
PMCID: PMC10966072
DOI: 10.1038/s41467-023-44512-4

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.

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Conflict of interest statement

J.M.B. receives research support from Genentech/Roche and Incyte Corporation, has received advisory board payments from AstraZeneca and Mallinckrodt, and is an inventor on patents regarding immunotherapy targets and biomarkers in cancer. The remaining authors declare no other competing interests.

Figures

**Fig. 1. Overview of the analytical pipeline.**
Development and validation of the polygenic risk scores (PRSs) for ulcerative colitis and Crohn’s disease was conducted in cancer-free individuals using UK Biobank and BioVU. LDPred2 method was used to tune the parameters for the PRS for ulcerative colitis and Crohn’s disease (PRS_UC, PRS_CD) in 70% of the UK Biobank, using the summary statistics from the largest genome-wide association study of UC and CD. The PRSs were then tested in the remaining 30% of the UK Biobank and validated in BioVU. In the next step, the role of PRS_UC and PRS_CD on all-grade and severe immune checkpoint inhibitor-mediated colitis (IMC) was evaluated in a cohort of 1316 non-small cell lung cancer patients who received at least one dose of immune checkpoint inhibitor therapy. Furthermore, replication was conducted using 873 pan-cancer patients treated with immune checkpoint inhibitors obtained from BioVU. Finally, associations of all-grade and severe IMC along with PRS_UC and PRS_CD on progression-free survival (PFS) and overall survival (OS) were assessed. Figure created with BioRender.com.

**Fig. 2. Cumulative incidence curves of all-grade and severe immune checkpoint inhibitor-mediated colitis by polygenic risk score of ulcerative colitis in the GeRI cohort.**
Cumulative incidence curves of a All-grade immune checkpoint inhibitor-mediated colitis (IMC) and b Severe IMC by categories of polygenic risk score of ulcerative colitis (PRS_UC) in the entire GeRI cohort. Cumulative incidence curves are unadjusted, and PRS_UC is categorized as ≤10th percentile (low genetic risk), 10–90th percentile (average genetic risk), and >90th percentile (high genetic risk). The p-values included on each plot are the results of a log-rank test for the difference between the curves (two-sided). Underneath each set of curves is the number of study participants at risk beyond that time point for each of the PRS groups. Source data are provided as a Source Data file.

**Fig. 3. Immune checkpoint inhibitor-mediated colitis (IMC) as a predictor of overall survival (OS) in the entire GeRI cohort.**
a All-grade IMC and b Severe IMC. Kaplan–Meier survival curves are unadjusted with 90-day landmark and compare those who had an IMC (all-grade or severe) with those who did not have an IMC (No IMC). The p-values in the graph represent the log-rank p-values (two-sided), and the dotted line represents the median survival time. Underneath each set of curves is the number of study participants at risk beyond that time point for the IMC and No IMC groups. Source data are provided as a Source Data file.

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Update of

Polygenic risk score for ulcerative colitis predicts immune checkpoint inhibitor-mediated colitis.
Middha P, Thummalapalli R, Betti MJ, Yao L, Quandt Z, Balaratnam K, Bejan CA, Cardenas E, Falcon CJ, Faleck DM; Princess Margaret Lung Group; Gubens MA, Huntsman S, Johnson DB, Kachuri L, Khan K, Li M, Lovly CM, Murray MH, Patel D, Werking K, Xu Y, Zhan LJ, Balko JM, Liu G, Aldrich MC, Schoenfeld AJ, Ziv E. Middha P, et al. medRxiv [Preprint]. 2023 Sep 13:2023.05.15.23289680. doi: 10.1101/2023.05.15.23289680. medRxiv. 2023. Update in: Nat Commun. 2024 Mar 26;15(1):2568. doi: 10.1038/s41467-023-44512-4. PMID: 37292751 Free PMC article. Updated. Preprint.

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

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

Authors

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Abstract

Conflict of interest statement

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