title: 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 BRAFV600 and NRASQ61 mutations in 68% and 24% of samples, respectively. Moreover, we more frequently identified the following alterations related to BRAF status: PIK3CAI391M (44%) and KITD737N (36%) mutations, CTLA4T17A (52%), MC1RV60L (32%) and MITFS473A (60%) polymorphisms. Considering the progression free survival (PFS), statistical analyses showed that BRAFV600 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.
authors: IRCCS Istituto Tumori "Giovanni Paolo II", Molecular Genetics Laboratory, Bari, Italy.
authors: Rosamaria
authors: R
authors: Pinto
authors: IRCCS Istituto Tumori "Giovanni Paolo II", Molecular Genetics Laboratory, Bari, Italy.
authors: Simona
authors: S
authors: De Summa
authors: IRCCS Istituto Tumori "Giovanni Paolo II", Oncology Unit, Bari, Italy.
authors: Sabino
authors: S
authors: Strippoli
authors: IRCCS Istituto Tumori "Giovanni Paolo II", Molecular Genetics Laboratory, Bari, Italy.
authors: Brunella
authors: B
authors: Pilato
authors: IRCCS Istituto Tumori "Giovanni Paolo II", Clinical and Preclinical Pharmacology Laboratory, Bari, Italy.
authors: Amalia
authors: A
authors: Azzariti
authors: University of Bari, Department of Medical Biochemistry, Bari, Italy.
authors: Gabriella
authors: G
authors: Guida
authors: IRCCS Istituto Tumori "Giovanni Paolo II", Oncology Unit, Bari, Italy.
authors: Michele
authors: M
authors: Guida
authors: IRCCS Istituto Tumori "Giovanni Paolo II", Molecular Genetics Laboratory, Bari, Italy.
authors: Stefania
authors: S
authors: Tommasi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D019540:Area Under Curve; D018572:Disease-Free Survival; D005260:Female; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D012372:ROC Curve
chemical_list: D000970:Antineoplastic Agents; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF inhibitors; Ion Torrent; metastatic melanoma; next generation sequencing; progression