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.

AMPK promotes survival of c‐Myc‐positive melanoma cells by suppressing oxidative stress

“…A similar trend was observed in analysis of patient‐derived cell lines or tumor samples with low or no C‐MYC expression in melanoma from the primary tumor site and high expression at the site of metastasis. These findings are in agreement with previous reports showing that elevated C‐MYC expression is preferentially observed in metastatic human melanoma patient samples correlating with and caused by copy number gains in C‐MYC at 8q24 (Kraehn et al , ; Gerami et al , ; Pouryazdanparast et al , ,b).…”

Outcomes of Atypical Spitz Tumors With Chromosomal Copy Number Aberrations and Conventional Melanomas in Children

“…16,26,[30][31][32] Among these 6 patients, 1 died of disease within the first year of life, whereas the other 5 are still alive. These tumors consist of sheets or organoid patterns of small-sized to intermediatesized melanocytes with a monotonous cytologic appearance, nuclear atypia, and prominent mitotic activity.…”

Fluorescence In Situ Hybridization for Melanoma Diagnosis

“…The issue of the prognostic assessment of melanoma had been already addressed with the use of the conventional melanoma FISH test, but with overtly conflicting results. 25,44 After preliminary studies about additional probes (Table 6), [48][49][50][51] Gerami et al 61 set up a new melanoma cocktail probe. Eight probes arranged in 2 probe sets (9p21, Cep9, 1q25, and Cep17; 8q24, 7q34, Cep10, and 20q13) were tested in 31 melanomas and 34 nevi (cohort 1), which had been already categorized with the commercially available melanoma FISH test (probe set 1).…”

“…The most optimal combinations of probes belonging to probe sets 1 and 2 were then selected by testing 49 melanomas and 51 nevi (cohort 2); with a logistic regression analysis, 4 combinations of 4 probe parameters were evaluated and, because the statistical differences among the various combinations were marginal, the final combination (probe set 3), including 9p21 (CDKN2a), 6p25 (RREB1), 11q13 (CCND1), and 8q24 (MYC), was chosen on the basis of the results of previous studies. [48][49][50][51] Probe set 3 was then tested in 72 melanomas and 85 nevi (cohort 3) for cutoff determination using receiver operator characteristic curves and exclusively considering criteria requiring $8/30 cells to reduce vulnerability to tetraploidy: the optimal cutoff was thus 29% for all parameters (homozygous deletion of 9p21; 6p25 gain, 11q13 gain, 8q24 gain). Finally, in a validation set of 51 melanomas and 51 nevi, probe set 1 (the commercially available melanoma FISH test) demonstrated a 75% sensitivity and a 96% specificity, whereas the new probe set 3 showed a 94% sensitivity and a 98% specificity.…”