The next generation of metastatic melanoma: uncovering the genetic variants for anti-BRAF therapy response

Abstract

Metastatic melanoma (MM) is a highly aggressive cancer with a median overall survival of 6–9 months, notwithstanding the numerous efforts in development of new therapeutic approaches. To this aim we tested the clinical applicability of the Ion Torrent Personal Genome Machine to simultaneously screen MM patients in order to individuate new or already known SNPs and mutations able to predict the duration of response to BRAF inhibitors. An Ampliseq Custom Panel, including 11 crucial full length genes involved in melanoma carcinogenesis and therapy response pathways, was created and used to analyze 25 MM patients. We reported BRAF^V600 and NRAS^Q61 mutations in 68% and 24% of samples, respectively. Moreover, we more frequently identified the following alterations related to BRAF status: PIK3CA^I391M (44%) and KIT^D737N (36%) mutations, CTLA4^T17A (52%), MC1R^V60L (32%) and MITF^S473A (60%) polymorphisms. Considering the progression free survival (PFS), statistical analyses showed that BRAF^V600 patients without any of these more frequent alterations had a higher median PFS. Protein structure changes seem to be due to these variants by in silico analysis. In conclusion, a Next-Generation Sequencing approach with custom panel may provide new information to evaluate tumor-specific therapeutic susceptibility and individual prognosis to improve the care of MM patients.