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The immune-related role of BRAF in melanoma

Sara Tomei, Davide Bedognetti, Valeria De Giorgi, Michele Sommariva, Sara Civini, Jennifer Reinboth, Muna Al Hashmi, Maria Libera Ascierto, Qiuzhen Liu, Ben D. Ayotte, Andrea Worschech, Lorenzo Uccellini, Paolo A. Ascierto, David Stroncek, Giuseppe Palmie

Original Research Article
Molecular Oncology, In Press, Uncorrected Proof, Available online 6 August 2014

Editor's comments:
The role of oncogenes BRAF and NRAS has been extensively described with regard to their ability to promote tumor growth. It is not yet clear their role to influence the modulation of the immune response against the tumor. In this study it was investigated the correlation between the presence NRAS or BRAF mutation, the gene expression profile and the presence of one of the two different immune phenotypes, the Th17 and the Th1, which were previously connected to different classes of prognosis. According to this study, the BRAF mutation was associated with a worse prognosis immunophenotype, while there was no clear correlation between the mutation of NRAS and the context of tumor immunology. Despite the great interest of these results, it remains unclear what are the mechanisms that underlie this association and what are the possible clinical implications.

Abstract

Background
The existence of a dichotomy between immunologically active and quiescent tumor 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. BRAF and NRAS mutations are commonly acquired during melanoma progression. Here we explored the role of BRAF and NRAS mutations in influencing the immune phenotype based on a classification previously identified by our group.

Methods
One-hundred-thirteen melanoma metastases underwent microarray analysis and BRAF and NRAS genotyping. Allele-specific PCR was also performed in order 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 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 was stronger in samples displaying low BRAF mRNA expression. However, when testing NRAS mutations, we were not able to find the same association.

Conclusion
This study suggests that BRAF mutation-related specific transcripts associate with a poor phenotype in melanoma and provide a nest for further investigation.