Abstract
Objective:
Single nucleotide polymorphisms (SNPs) in IRF4 and HERC2 are associated with risk for disomy or monosomy of chromosome 3 (D3 or M3) uveal melanoma (UM), respectively. The aim of this study was to assess the association between germline genetics and UM outcome and the potential use of a derived prognostic signature for UM.
Design:
Cohort study from Institut Curie, Paris (France) and Erasmus University Medical Center, Rotterdam (The Netherlands).
Participants:
Patients diagnosed with UM at Institut Curie (N = 2059) and Erasmus University Medical Center (N =576).
Methods:
Impact of IRF4 and HERC2 SNPs on survival was assessed in a cohort of 1339 patients with UM by Kaplan-Meier analysis and Cox proportional hazard regression. Uveal melanoma subtype-specific risk associations with SNPs and iris color were assessed by generalized linear model regression analyses. Classifier of UM subtypes was trained on 560 patients with UM and validated in 2 independent cohorts.
Main Outcome Measures:
We analyzed risk SNPs in the series of patients with UM in relation to tumor and patient characteristics, including eye color, tumor subtype and diameter, and patient outcomes.
Results:
IRF4 rs12203592-T and HERC2 rs12913832-G SNPs were associated with improved and worsened progression-free-survival and overall survival, respectively, mainly through their association with chromosome 3 status. Associations between IRF4 and HERC2 risk SNPs and D3 or M3 subtypes, respectively, were largely independent of their role in determining iris pigmentation. A genetic classifier showed significant results in predicting chromosome 3 status and survival but did not outperform established clinical prognostic features.
Conclusions:
Our study demonstrates that inherited polymorphisms in IRF4 and HERC2 are independently associated with UM subtype and prognosis, although a SNP-based classifier does not yet outperform the established prognostic model.
Single nucleotide polymorphisms (SNPs) in IRF4 and HERC2 are associated with risk for disomy or monosomy of chromosome 3 (D3 or M3) uveal melanoma (UM), respectively. The aim of this study was to assess the association between germline genetics and UM outcome and the potential use of a derived prognostic signature for UM.
Design:
Cohort study from Institut Curie, Paris (France) and Erasmus University Medical Center, Rotterdam (The Netherlands).
Participants:
Patients diagnosed with UM at Institut Curie (N = 2059) and Erasmus University Medical Center (N =576).
Methods:
Impact of IRF4 and HERC2 SNPs on survival was assessed in a cohort of 1339 patients with UM by Kaplan-Meier analysis and Cox proportional hazard regression. Uveal melanoma subtype-specific risk associations with SNPs and iris color were assessed by generalized linear model regression analyses. Classifier of UM subtypes was trained on 560 patients with UM and validated in 2 independent cohorts.
Main Outcome Measures:
We analyzed risk SNPs in the series of patients with UM in relation to tumor and patient characteristics, including eye color, tumor subtype and diameter, and patient outcomes.
Results:
IRF4 rs12203592-T and HERC2 rs12913832-G SNPs were associated with improved and worsened progression-free-survival and overall survival, respectively, mainly through their association with chromosome 3 status. Associations between IRF4 and HERC2 risk SNPs and D3 or M3 subtypes, respectively, were largely independent of their role in determining iris pigmentation. A genetic classifier showed significant results in predicting chromosome 3 status and survival but did not outperform established clinical prognostic features.
Conclusions:
Our study demonstrates that inherited polymorphisms in IRF4 and HERC2 are independently associated with UM subtype and prognosis, although a SNP-based classifier does not yet outperform the established prognostic model.
| Original language | English |
|---|---|
| Article number | 100972 |
| Number of pages | 10 |
| Journal | Ophthalmology Science |
| Volume | 6 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jan 2026 |
Bibliographical note
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