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Predicting immune-related thyroiditis using polygenic risk scores in patients with advanced melanoma
Ahmad A Tarhini1,2, Mohammad Ali Khaksar2, Zhihua Chen3
1Department of Immunology, H Lee Moffitt Cancer Center and Research Center, Tampa, Florida, USA ahmad.tarhini@moffitt.org.
Journal for Immunotherapy of Cancer
|June 19, 2026
Summary
Inherited genetic factors influence thyroid immune toxicity from immune checkpoint inhibitors (ICIs). A custom Polygenic Risk Score (PRS) effectively predicts thyroiditis risk in melanoma patients treated with ipilimumab.
Area of Science:
- Genetics
- Immunology
- Oncology
Background:
- Inherited genetic variations can influence patient responses and toxicity risks associated with immune checkpoint inhibitor (ICI) therapy.
- Thyroid immune toxicity is a known adverse event of ICI treatment.
Purpose of the Study:
- To identify inherited genetic variants associated with thyroiditis risk in melanoma patients treated with ipilimumab.
- To evaluate the predictive performance of Polygenic Risk Scores (PRSs) for thyroiditis in this patient cohort.
Main Methods:
- Genome-wide association study (GWAS) of germline DNA from 744 melanoma patients in a phase 3 adjuvant trial.
- Analysis of single nucleotide polymorphisms (SNPs) and construction of a custom 10-SNP PRS.
- Testing of pre-existing thyroid disease-related PRSs from the Polygenic Score Catalog.
Main Results:
- A custom 10-SNP PRS was significantly associated with thyroiditis risk and severity.
- The lead SNP identified was located in the CNOT6L gene, near CXCL13.
- The custom PRS demonstrated superior discrimination for thyroiditis risk (AUC=0.82) compared to other tested PRSs.
Conclusions:
- Inherited genetic background plays a role in the risk of thyroid immune toxicity following ICI therapy.
- PRS-based approaches can aid in risk-stratified monitoring for patients undergoing immunotherapy.
