The role of 8q24 copy number gains and c-MYC expression in amelanotic cutaneous melanoma

Abstract

Cutaneous melanomas may be quite heterogeneous in their clinical, histological and molecular findings. Correlating these features may help identify distinctive subgroups of melanomas and improve our overall understanding and prognostication of melanoma. We recently identified a subgroup of melanomas with increased chromosomal copy number gains in 8q24 at MYC having several distinctive clinical and histopathological characteristics, including an aggressive clinical course and an amelanotic clinical and histological appearance. It has been postulated that oncogenes such as MYC may have regulatory effects on genes critical to melanin pigment synthesis, specifically microphthalmia-associated transcription factor (MITF), which is known to have a key role in regulating the expression of tyrosinase (TYR), an important enzyme in the production of melanin pigment. We investigated the possible mechanism underlying the amelanotic appearance of melanomas with gains in 8q24 by evaluating the relationship between melanomas with and without 8q24 copy number gains and c-MYC, MITF and TYR protein expression. Immunohistochemical analysis of c-MYC, MITF and TYR was performed on 36 melanomas with gains in 8q24 and 40 melanomas without gains in 8q24. The melanomas with gains of 8q24 correlated with elevated c-MYC protein expression and melanomas without gains in 8q24 showed significantly decreased c-MYC protein expression. A direct relationship between the presence of gains in 8q24 and decreased MITF expression, as well as between c-MYC and TYR protein expression was also observed. Our results suggest that MYC can have a role in the pigmentary pathway of melanoma. In amelanotic melanomas with gains in 8q24, downregulation of TYR and other melanocyte-specific genes may be mediated by MYC leading to transcriptional suppression of MITF. As MITF is a frequently used marker to establish melanocytic lineage in melanoma, our study also raises the important clinical consideration that amelanotic melanomas, especially those with gains in 8q24 may lack expression of MITF.