BACKGROUND. The existence of a dichotomy between immunologically active and quiescent phenotypes has been recently recognized in several types of cancer. The activation of a Th1 type of immune signature has been shown to confer better prognosis and likelihood to respond to immunotherapy. However, whether such dichotomy depends on the genetic make-up of individual cancers is not known yet. In melanoma, BRAF and NRAS mutations are frequently acquired during development. We recently proposed a genetic classification of melanoma metastases based on copy number variation and consistency of genes expressed in vivo and in vitro. We found that genes consistently expressed by 15 melanoma cell lines (CMs) and their parental tissues (TMs) were critical for oncogenesis and their respective copy number influenced their expression. Most importantly, these genes were able to categorize melanoma metastases into two divergent phenotypes (TARA class: transcriptional adjustments related to amplification/deletions): one with prevalent expression of cancer testis antigens, enhanced cyclin activity, WNT signaling, and a Th17 immune phenotype (Class A) and the other one with prevalent expression of genes associated with melanoma signaling and with a Th1 immune phenotype (Class B). An intermediate third class (Class C) was further identified. Here, we tested whether these phenotypes might be at least in part explained by BRAF and NRAS mutations in melanoma. METHODS. One-hundred-thirteen melanoma metastases were processed for microarray analysis and BRAF and NRAS sequencing. Allele-specific PCR (AS-PCR) was also performed to exclude low-frequency mutations. RESULTS. Comparison between BRAF and NRAS mutant versus wild type samples identified mostly constituents or regulators of MAPK and related pathways. When testing gene lists discriminative of BRAF, NRAS and MAPK alterations, we found that 112 BRAF-specific transcripts (p<0.01) were able to distinguish the two immune-related phenotypes already described in melanoma, with the poor phenotype associated mostly with BRAF mutation. Noteworthy, such association resulted stronger in samples displaying low BRAF mRNA expression. When testing NRAS mutation and expression, we could not find the same association. Class comparison between BRAF mutant samples displaying high levels of BRAF mRNA expression and wild type samples revealed that there is much more similarity between the two than with the low expressing BRAF mutant samples. To gain further insights concerning this surprising finding we performed functional interpretation analysis of the 6296 genes differentially expressed between BRAF mutants with high and low expression of the same gene; deregulated pathways included IL-2 and JAK/Stat signaling pathways, supporting the immunoregulatory role of BRAF. CONCLUSION. This study suggests that BRAF mutation-related specific transcripts associate with a poor phenotype in melanoma and provide a nest for further investigation.


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