Copy Number Gains in 11q13 and 8q34 Are Highly Linked to Prognosis in Cutaneous Malignant Melanoma

Abstract

Relating specific genetic alterations to prognosis may help improve prognostication in melanoma, may identify key oncogenic drivers in cancer, and may assist in developing targeted therapies. Characteristic genetic alterations in melanoma include chromosomal copy number aberrations. We evaluated 97 melanomas (55 metastasizing and 42 nonmetastasizing) after a minimum 5-year follow-up in a case-control study using fluorescence in situ hybridization, targeting commonly altered chromosomal loci in melanoma. Eight probes arranged in two panels were used, and 11 parameters were evaluated. Parameters showing a statistically significant difference between the metastasizing and nonmetastasizing groups were evaluated with multivariate logistic regression analysis to compare their prognostic potential with other traditional prognostic markers used by the American Joint Committee on Cancer. Four of 11 parameters evaluated, including CCND1 (alias Bcl-1) gain, CCND1 r-gain, MYC (alias c-myc) gain, and MYC r-gain, had a statistically significant difference in the metastasizing versus nonmetastasizing group. All four parameters maintained statistical significance when evaluated in separate multivariate logistic regression analyses that included the seven currently used American Joint Commission on Cancer prognosticators in melanoma. In multivariate analyses, these four parameters were second only to ulceration in their prognostic potential. Copy number changes at 11q13 and 8q34 harboring CCND1 and MYC, respectively, are highly associated with prognosis. Fluorescence in situ hybridization targeting these loci may be a useful standardized prognostic marker in melanoma skin cancer.

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

“…Recently, we identified a subgroup of melanomas with chromosomal copy number gains involving v-myc myelocytomatosis viral oncogene homolog (MYC; alias c-MYC) at 8q24 having reproducible clinical and histological features including aggressive clinical course, occurrence in non-chronically sun damaged skin, amelanotic clinical appearance, histology showing a nodular or primary dermal growth (Figure 1a), epidermal consumption, cells with irregular nuclear contours, coarse chromatin and infrequent association with a nevus. 1,2 Specifically, 90% of the melanomas in our database having 8q24 copy number gains were clinically and histologically amelanotic (Figure 1b). Halaban et al 3 have proposed that a number of dominantly acting oncogenes, including MYC, may have upstream regulatory effects on genes critical to melanin pigment synthesis.…”

Molecular Approaches for the Diagnostics of Pediatric Pigment Skin Malformations: Four Cases

“…Как и p16 INK4a , циклин D1 реализует свою активность в ядре клетки, но в противопо-ложность p16 INK4a является протоонкогеном [19]. Неоднократно сообщалось об увеличении числа копий гена, кодирующего данный белок, в клетках меланомы кожи взрослых больных [20,21]; увели-чение содержания этого белка в клетках мелано-мы позволило J. Oba и соавт. отличать ее от невусов [22].…”

Molecular techniques for predicting behaviour in melanocytic neoplasms

“…Other case control studies have shown that melanomas with specific chromosomal copy number aberrations such as those with high levels of gains in 11q13 or 8q24 had a significantly worse prognosis than conventional melanomas without these changes. 19,20 While cases with these specific changes clearly have a very poor prognosis and aggressive disease, only a limited percentage of aggressive tumours are identified. Hence, looking at copy number aberrations alone whether by FISH or CGH is unlikely to be a highly accurate method for prognostication of conventional melanomas.…”