RNA expression signatures as predictors of prognosis in thin and thick primary cutaneous melanoma.

e21602 Background: Risk stratification of primary cutaneous melanoma based on Breslow thickness remains clinically imperfect, particularly in thin tumors (≤1 mm), where a subset progresses unexpectedly. Previously, targeted RT-PCR analyses of established tissue RNA markers demonstrated prognostic utility mainly in thick melanoma, with no robust markers identified for thin tumors, prompting an unbiased RNA sequencing approach to address this gap.Objectives: Identify RNA expression signatures associated with prognosis in thin (≤1 mm) and thick (≥4 mm) primary cutaneous melanoma. Methods: RNA-seq was performed on primary tumor tissue from 51 thin and 65 thick melanomas after hybrid-capture library preparation and deep sequencing (NovaSeq 6000, S4). Expression was quantified for 18,146 genes, including full coding regions of 17,702 protein-coding genes (54,142 transcripts), using a standardized four-step pipeline with stringent filtering. Analyses were performed by clinical outcome (regional recurrence and/or distant metastases and/or death) and to build classifiers distinguishing thin vs thick melanoma. Results: In thin melanoma, 69 genes were differentially expressed by outcome; a 10-marker panel (BAIAP2L1, DMRT3, ENSG00000305404, HOXA11-AS, MGP, MIR1183, MUC6, NBPF17P, NANOS3, TMEM191C) showed the best prognostic performance (AUROC 0.835). In thick melanoma, 26 prognostic genes were identified; a 6-marker panel (EEF1A1P16, HSPA8P5, IBSP, MEX3B, MMP3, VAMP2) achieved AUROC 0.93. A shared 4-marker signature (MMP3, RGS1, SPP1, VAMP2) performed consistently across thin and thick tumors (AUROC 0.80). A 5-marker classifier (ALOX12, COL22A1, KRT10-AS1, S100B, SPP1) distinguished thin vs thick melanomas (AUROC 0.96), supporting distinct transcriptional programs linked to thickness and progression biology. Conclusions: RNA profiling reveals substantial prognostic heterogeneity within thin melanoma and identifies multigene signatures that may refine risk stratification beyond Breslow thickness. Divergent prognostic panels in thin vs thick tumors suggest distinct mechanisms of progression and support development of clinically deployable RNA-based assays for risk-adapted management.These signatures identify biologically aggressive subsets within thin melanoma that may warrant intensified surveillance or consideration of adjuvant strategies.