Translation of a Circulating microRNA Signature of Melanoma to a Novel Solid-Tissue Biomarker to Improve Diagnostic Accuracy and Reproducibility.
Abstract Background Successful treatment of cutaneous melanoma depends on early and accurate diagnosis of clinically suspicious melanocytic skin lesions. Currently, histopathology examination of excised skin lesions is considered the ‘gold standard’ for diagnosis of melanoma. Multiple studies have shown the low accuracy and reproducibility of this method, underscoring the urgent need for new diagnostic tools, including disease-specific biomarkers. Previously, a 38-microRNA signature of melanoma (‘Mel38’) was previously identified in plasma and validated as novel circulating biomarker. In this study, Mel38 expression in solid biopsy tissue is examined to determine its ability to contribute to accurate and reproducible melanoma diagnoses.Methods Nanostring digital gene expression profiling was used to apply the Mel38 signature in a cohort of 308 formalin fixed paraffin embedded skin biopsies (‘Mel38’). Genomic data were interrogated using hierarchical clustering, univariate and multivariate statistical approaches. Mel38 classification scores (range 0 to 10) were compared to consensus histopathology results, including MPATH-DX class, AJCC disease stage, histological subtype as well as technical assay factors.Results The Mel38 score can identify high-risk melanomas (MPATH-Dx Class IV) from less-malignant forms of the disease with an area-under-the curve of 0.96 (P < 0.001). The genomic score ranges from 0 to 10 and is positively correlated with the melanoma progression, from benign naevi to metastatic disease (intraclass correlation coefficient: 0.85). Using a score threshold of > 2.3 identifies higher-risk melanomas, associated with poorer outcomes and more intensive suggested clinical actions. Multivariate analysis showed the score to be a significant predictor of malignancy, independent of technical and clinical covariates. Analysis of the Mel38 signature in spitz naevi reveal an intra-subtype profile, in common to both benign and malignant conditions.Conclusion Melanoma-specific circulating microRNAs maintain their association with malignancy when measured in the hypothesized tissue of origin. The Mel38 signature is an accurate and reproducible metric of melanoma status, based on changes in microRNA expression that occur as the disease develops and spreads. Inclusion of the Mel38 score into routine practice would give physicians a genomic assessment of a patient’s disease status. Combining molecular biomarker data with conventional histopathology data may improve diagnostic accuracy, reproducibility, and patient outcomes.