Validation of microRNA Liquid Biopsy for Diagnosis and Risk Stratification of Invasive Cutaneous Melanoma.

IMPORTANCE: Non-invasive molecular biomarkers are needed to improve the early, accurate and precise diagnosis of invasive cutaneous melanoma.

OBJECTIVE: To independently validate a previously-identified circulating microRNA signature of melanoma (MEL38). Secondly, to develop of a complementary microRNA signature, optimized for prognostication.

DESIGN, SETTING & PARTICIPANTS: MicroRNA expression profiling was performed on plasma samples from a multi-centre observational case-control study, involving patients with primary or metastatic melanoma, melanoma in-situ, non-melanoma skin cancer, or benign nevi. MicroRNA profiles from patients with length of survival, treatment and sentinel node biopsy data were used to develop the prognostic signature.

MAIN OUTCOMES AND MEASURES: The primary outcome of interest for MEL38 was its association with melanoma status, including area under the curve, binary diagnostic sensitivity and specificity, and incidence-adjusted positive and negative predictive values. The prognostic signature was assessed using rates of survival per risk group and relationship to conventional predictors of outcome.

RESULTS: Circulating microRNA profiles of 372 invasive melanoma patients and 210 control individuals were generated. The average age of all participants was 59, 49% were male. A MEL38 score >5.5 indicated the presence of invasive melanoma. Overall 551/582 (95%) of patients were correctly diagnosed, with 93% sensitivity and 98% specificity. MEL38 score range from 0 to 10 with an area under the curve of 0.98 (95% CI 0.97 to 1.0, P < 0.001).A novel prognostic 12-microRNA signature (MEL12) developed from 232 patients identified low, standard, or high-risk groups, with 94%, 78% and 58% rates of 10-year survival respectively (Log rank P < 0.001). MEL12 prognostic risk groups were significantly associated with clinical staging (Chi square P < 0.001) and SLNB status (P = 0.027). 9/10 patients classified as high-risk by MEL12 had melanoma detected in their sentinel lymph nodes.

CONCLUSION AND RELEVANCE: The circulating MEL38 signature may assist in diagnosing patients with invasive melanoma versus other conditions associated with a lower - or negligible - risk of mortality. A complementary and prognostic MEL12 signature is predictive of SLNB status, clinical stage, and probability of survival. Plasma microRNA profiling may help optimise existing diagnostic pathways as well as enable personalised, risk-informed melanoma treatment decisions.