Lightning Talk GENEMAPPERS 2026

Genetic predisposition for inflammatory bowel disease predicts immune checkpoint inhibitors–induced colitis in patients with melanoma (#17)

Hadis Ghajari 1 2 , Nurudeen Adegoke 3 4 5 , Stuart MacGregor 1 , Huanwei Wang 1 , Dale R Nyholt 2 , Ines Silva 3 4 5 , Georgina V Long 3 4 5 6 7 , Alexander M Menzies 3 4 6 7 , Serigne Lo 3 4 5 , Mathias Seviiri 1 2 8 , Matthew H Law 1 2 8
  1. QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
  2. Queensland University of Technology, School of Biomedical Sciences and Centre for Genomics and Personalised Health, Faculty of Health, Brisbane, Australia, Brisbane , QLD, Australia
  3. Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
  4. Faculty of Medicine and Health, University of Sydney, NSW 2006, Australia, Sydney, NSW, Australia
  5. Charles Perkins Centre, The University of Sydney, NSW 2006, Australia, Sydney, NSW, Australia
  6. Mater Hospital, North Sydney, NSW 2060, Australia, Sydney, NSW, Australia
  7. Royal North Shore Hospital, St Leonards, NSW 2065, Australia, Sydney, NSW, Australia
  8. University of Queensland, School of Biomedical Sciences, Faculty of Health, Medicine and Behavioural Sciences, Brisbane, Australia, Brisbane, QLD, Australia

Immune checkpoint inhibitors (ICIs) are standard treatment for advanced melanoma, markedly improving survival. However, they are associated with immune-related adverse events (irAEs). Colitis is a common irAE that can lead to hospitalization or even death1. Histological studies revealed some similarities between ICI-induced colitis and inflammatory bowel diseases (IBD), such as ulcerative colitis (UC) and Crohn’s disease (CD)2. Understanding genetic predisposition to ICI-induced colitis is crucial for clarifying its pathology and identifying those at risk. 

We conducted genome-wide association studies (GWAS) for UC and CD using 90% of the UK Biobank (UKBB)3 cohort. Meta-analyses were performed combining UKBB, the Million Veteran Program4 and FinnGen5, forming our discovery cohorts for polygenic risk scores (PRSs). Discovery GWAS included 17,263 UC cases and 1,336,274 controls, and 19,573 CD cases and 1,233,508 controls. PRSs were validated in the remaining 10% of the UKB cohort and tested in patients with colitis irAEs (106 ICI_induced colitis cases and 1,305 controls) genotyped in two phases from the Melanoma Institute Australia Biospecimen Bank (MIA 1 and 2). 

In the UKBB, the PRSs incorporating age and sex demonstrated strong predictive performance for both UC and CD, with ORs per SD of 2.29 (95% CI 2.05, 2.55) and 2.15 (1.87, 2.46), respectively. The areas under the receiver operating characteristic curve were 0.736 (95% CI: 0.710–0.763) for UC and 0.707 (95% CI: 0.671–0.744) for CD. Fixed-effect meta-analysis of MIA 1 and 2 showed significant associations between UC- and CD-derived PRSs and ICI-induced colitis (UC PRS: OR = 1.30, 95% CI 1.07–1.58, P = 0.006; CD PRS: OR = 1.24, 95% CI 1.02–1.51, P = 0.03).

Genetic susceptibility to IBD, particularly UC, increases the risk of ICI-induced colitis, supporting shared immunogenetic pathways between IBD and irAEs. Identifying high-risk individuals could guide precision immunotherapy and closer monitoring to mitigate severe irAEs.

  1. 1. Losurdo, G. et al. Checkpoint Inhibitor-Induced Colitis: An Update. Biomedicines 11, (2023). 2. Chen, J. H., Pezhouh, M. K., Lauwers, G. Y. & Masia, R. Histopathologic Features of Colitis Due to Immunotherapy With Anti-PD-1 Antibodies. Am J Surg Pathol 41, 643–654 (2017). 3. Bycroft, C. et al. The UK Biobank resource with deep phenotyping and genomic data. Nature 562, 203–209 (2018). 4. Hunter-Zinck, H. et al. Measuring genetic variation in the multi-ethnic Million Veteran Program (MVP). bioRxiv (2020) doi:10.1101/2020.01.06.896613. 5. Kurki, M. I. et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature 613, 508–518 (2023).