Translation of a circulating microRNA signature of melanoma into a solid tissue assay with the potential to improve diagnostic precision and reproducibility [post]

Ryan Van Laar, Samuel King, Richard McCoy, Mirette Saad, Sian Fereday, Ingrid Winship, Catherine Uzzell, Anthony Landgren
2021 unpublished
Background: 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-microRNA signature ("MEL38") was identified in melanoma patient plasma and validated as a novel
more » ... idated as a novel biomarker. In this study, MEL38 expression in solid tissue biopsies representing the benign naevi to metastatic melanoma spectrum is examined. Methods: Nanostring digital gene expression assessment of the MEL38 signature was performed on 308 formalin fixed paraffin embedded biopsies of naevi, melanoma in-situ and invasive melanoma. Genomic data were interrogated using hierarchical clustering, univariate, and multivariate statistical approaches. Classification scores computed from the MEL38 signature were analysed 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 area-under-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 to IV disease. Using an optimised classification threshold of ≥2.7 accurately identifies higher-risk melanomas, associated with poorer outcomes and more intensive suggested clinical actions with 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 naevi reveal an intra-subtype profile, with elements of the profile in common to both naevi and melanoma. 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 provide physicians with previously unavailable, personalised genomic information about their patient's skin lesions. Combining molecular biomarker data with conventional histopathology data may improve diagnostic accuracy, healthcare resource utilisation, and patient outcomes.
doi:10.21203/rs.3.rs-77357/v5 fatcat:qpyb4icvzvf4jeko256yi2k75i