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Dear Editor, We have previously shown that the functional melanoma risk variant rs12203592 in the I IRF4 i gene (interferon regulatory factor-4) was associated with increased Breslow thickness, an important prognostic indicator for melanoma.[1] In line with this, a recent study found evidence for an association between the minor T allele of this single-nucleotide polymorphism (SNP) and melanoma-specific survival in patients from two European hospitals.[2] We therefore sought to extend our previous work and replicate these hospital-based findings by investigating the association of rs12203592 with melanoma-specific survival, overall and by anatomical site. A mediation analysis found that 70-2% of the observed association between rs12203592*T and melanoma-specific survival was mediated through Breslow thickness, with significant natural indirect effects identified (HR 1-13, 95% CI 1-06-1-20; I P i < 0-001). Our results suggest that I IRF4 i rs12203592 is associated with poorer melanoma-specific survival, largely mediated through Breslow thickness, reinforcing our previous findings related to rs12203592*T and tumour thickness.[1] This variant's adverse effect on survival may occur through its functional effect on I IRF4 i expression. [Extracted from the article]