Translation of a circulating miRNA signature of melanoma into a solid tissue assay to improve diagnostic accuracy and precision.

Abstract

Aim: Successful treatment of cutaneous melanoma depends on early and accurate diagnosis of clinically suspicious melanocytic skin lesions. Multiple international studies have described the challenge of providing accurate and reproducible histopathological assessments of melanocytic lesions, highlighting the need for new diagnostic tools including disease-specific biomarkers. Previously, a 38-miRNA signature (MEL38) was identified in melanoma patient plasma and validated as a novel biomarker. In this study, MEL38 expression in solid tissue biopsies representing the benign nevi to metastatic melanoma spectrum is examined. Patients& methods: Nanostring digital gene expression assessment of the MEL38 signature was performed on 308 formalin-fixed paraffin-embedded biopsies of nevi, melanoma insitu and invasive melanoma. Genomic data were interrogated using hierarchical clustering, univariateand multivariate statistical approaches. Classification scores computed from the MEL38 signature were analyzed for their association with demographic data and histopathology results, including MPATH-DX class, AJCC disease stage and tissue subtype. Results: The MEL38 score can stratify higher-risk melanomas (MPATH-Dx class V or more advanced) from lower-risk skin lesions (class I-IV) with an areaunder the curve of 0.97 (p<0.001). The genomic score ranges from 0 to 10 and is positively correlated with melanoma progression, with an intraclass correlation coefficient of 0.85 with stage 0-IV disease. Using an optimized classification threshold of ≥2.7 accurately identifies higher-risk melanomaswith 89% sensitivity and 94% specificity. Multivariate analysis showed the score to be a significant predictor of malignancy, independent of technical and clinical covariates. Application of the MEL38 signature to Spitz nevi reveals an intrasubtype profile, with elements in common to both nevi and melanoma. Conclusion: Melanoma-specific circulating miRNAs 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 miRNA expression that occur as the disease develops and spreads. Inclusion of the MEL38 score into routine practice would provide physicians with previously unavailable, personalized genomic information about their patient's skin lesions. Combining molecular biomarker data with conventional histopathology data may improve diagnostic accuracy, healthcare resource utilization and patient outcomes.