Evaluation of gene expression profiling beyond Breslow thickness and ulceration for prediction of distant metastases in early-stage melanoma: the population-based Dutch Early-Stage Melanoma (D-ESMEL) study

PurposeDespite their central role in the current staging system, Breslow thickness and ulceration do not fully identify early-stage melanoma patients who will develop distant metastases. We assessed whether gene expression profiling (GEP) improves prediction of distant metastases beyond standard staging factors in early-stage melanoma. MethodsData were derived from the population-based Dutch Early-Stage Melanoma (D-ESMEL) study, including a matched discovery set of 442 stage I/II melanomas (221 case-control pairs) and a validation cohort of 308 melanomas nested within 5,815 patients. The discovery set was used to identify genes associated with distant metastases, independent of age, sex, Breslow thickness, and ulceration. The validation cohort was partitioned into model development and independent validation subsets. Candidate genes from the discovery set were used to develop and validate a GEP model, evaluated by weighted area under the curve (AUC) and concordance index (C-index). ResultsRNA sequencing succeeded for 356 melanomas in the discovery set, 200 in the model development subset, and 94 melanomas in the independent validation subset. Differential gene expression analyses and modeling identified 558 candidate genes. In the independent validation subset, the GEP model achieved a weighted AUC of 0.77 (95% CI, 0.66-0.86) and weighted C-index of 0.79 (95% CI, 0.69-0.88), comparable to the clinical model based on Breslow thickness and ulceration (weighted AUC 0.82 (95% CI, 0.73-0.90), weighted C-index 0.84 (95% CI, 0.76-0.91)). Integration of GEP with the clinical model did not improve accuracy. Gene set enrichment analyses showed enrichment of proliferative and stress-related pathways. ConclusionWhile GEP captured biologically relevant signals, its predictive accuracy for distant metastases was comparable to that of Breslow thickness and ulceration in a population-based early-stage melanoma cohort.