Melanocortin 1 receptor (MC1R) expression as a marker of progression in melanoma

Abstract

Melanocortin-1 receptor (MC1R) plays a critical role in human pigmentation and DNA repair mechanisms. MC1R-targeting agents are being investigated in clinical trials in melanoma patients, yet large studies investigating the rate and degree of MC1R expression in primary and metastatic human melanoma tissue are lacking. Using tissue microarrays containing three large cohorts of 225 cases of benign nevi, 189 with primary melanoma, and 271 with metastatic melanoma, we applied quantitative immunofluorescence and immunohistochemistry to comprehensively study MC1R protein expression. We show a stepwise elevation of MC1R expression in different stages of melanoma progression (nevi, primary, metastasis). Higher MC1R expression was seen in deeper (>1 mm) primary lesions, ulcerated lesions, and mucosal melanomas compared to cutaneous melanomas and was associated with shorter survival in primary and metastatic tumors. On multi-variable analysis, Breslow thickness, ulceration, male sex, and chronic sun exposure were independent predictors of worse overall survival in the primary melanoma cohort. In the metastatic melanoma cohort, MC1R expression and mucosal melanomas were independent predictors of inferior overall survival. Our data suggest that MC1R might be a valuable drug target in aggressive melanoma. Additional studies are warranted to determine its functional significance in melanoma progression and its utility as a predictive biomarker in patients receiving MC1R-directed therapies.

The Keratinocyte in the Picture Cutaneous Melanoma Microenvironment

“…Moreover, MC1R variants correlate with poor response to BRAF inhibitors [ 57 ]. As part of the “qualitative” consideration concerning non-synonymous genomic variants, very recently, high MC1R levels of expression in primary and metastatic melanoma have been associated with poor prognosis [ 58 ]. Inverting the viewpoint, paradoxically a possible explanation for this observation might reside in the overexpression of DNA repair and anti-apoptosis pathways that support the persistence of highly injured cells [ 59 ].…”