Genetic Background Predicts Uveal Melanoma Patients' Outcomes

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.

Cohort study from Institut Curie, Paris (France) and Erasmus University Medical Center, Rotterdam (The Netherlands).

Patients diagnosed with UM at Institut Curie (N = 2059) and Erasmus University Medical Center (N =576).

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.

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.

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.

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.

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.