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

Autor: Middha P; Department of Medicine, University of California San Francisco, San Francisco, CA, USA., Thummalapalli R; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Betti MJ; Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA., Yao L; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA., Quandt Z; Division of Endocrinology and Metabolism, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.; Diabetes Center, University of California San Francisco, San Francisco, CA, USA., Balaratnam K; Princess Margaret Cancer Centre, Toronto, ON, Canada., Bejan CA; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA., Cardenas E; Department of Medicine, University of California San Francisco, San Francisco, CA, USA., Falcon CJ; Fiona and Stanley Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Faleck DM; Gastroenterology, Hepatology & Nutrition Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Gubens MA; Medical Oncology, University of California San Francisco, San Francisco, CA, USA.; Department of Medicine, Weill Cornell Medical Center, New York, NY, USA., Huntsman S; Department of Medicine, University of California San Francisco, San Francisco, CA, USA., Johnson DB; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA., Kachuri L; Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Cancer Institute, Stanford University of Medicine, Stanford, CA, USA., Khan K; Princess Margaret Cancer Centre, Toronto, ON, Canada., Li M; Department of Medicine, University of California San Francisco, San Francisco, CA, USA., Lovly CM; Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, TN, USA., Murray MH; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA., Patel D; Princess Margaret Cancer Centre, Toronto, ON, Canada., Werking K; Department of Thoracic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA., Xu Y; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA., Zhan LJ; Princess Margaret Cancer Centre, Toronto, ON, Canada., Balko JM; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA., Liu G; Princess Margaret Cancer Centre, Temerty School of Medicine, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada., Aldrich MC; Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA., Schoenfeld AJ; Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York., Ziv E; Department of Medicine, University of California San Francisco, San Francisco, CA, USA.; Helen Diller Family Comprehensive Cancer Center, Center for Genes, Environment and Health and Institute for Human Genetics, University of California San Francisco, San Francisco, California.
Jazyk: angličtina
Zdroj: MedRxiv : the preprint server for health sciences [medRxiv] 2023 Sep 13. Date of Electronic Publication: 2023 Sep 13.
DOI: 10.1101/2023.05.15.23289680
Abstrakt: Immune checkpoint inhibitors (ICIs) are a remarkable advancement in cancer therapeutics; however, a substantial proportion of patients develop severe immune-related adverse events (irAEs). Understanding and predicting irAEs is a key to advancing precision immuno-oncology. Immune checkpoint inhibitor-mediated colitis (IMC) is a significant complication from ICI and can have life-threatening consequences. Based on clinical presentation, IMC mimics inflammatory bowel disease, however the link is poorly understood. We hypothesized that genetic susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) may predispose to IMC. We developed and validated polygenic risk scores for CD (PRS CD ) and UC (PRS UC ) in cancer-free individuals and assessed the role of each of these PRSs on IMC in a cohort of 1,316 patients with non-small cell lung cancer who received ICIs. Prevalence of all-grade IMC in our cohort was 4% (55 cases), and for severe IMC, 2.5% (32 cases). The PRS UC predicted the development of all-grade IMC (HR=1.34 per standard deviation [SD], 95% CI=1.02-1.76, P =0.04) and severe IMC (HR=1.62 per SD, 95% CI=1.12-2.35, P =0.01). PRS CD was not associated with IMC or severe IMC. The association between PRS UC and IMC (all-grade and severe) was consistent in an independent pan-cancer cohort of patients treated with ICIs. Furthermore, PRS UC predicted severe IMC among patients treated with combination ICIs (OR = 2.20 per SD, 95% CI = 1.07-4.53, P =0.03). This is the first study to demonstrate the potential clinical utility of a PRS for ulcerative colitis in identifying patients receiving ICI at high risk of developing IMC, where risk reduction and close monitoring strategies could help improve overall patient outcomes.
Databáze: MEDLINE