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Ref Type Journal Article
PMID (31980996)
Authors Olbryt M, Pigłowski W, Rajczykowski M, Pfeifer A, Student S, Fiszer-Kierzkowska A
Title Genetic Profiling of Advanced Melanoma: Candidate Mutations for Predicting Sensitivity and Resistance to Targeted Therapy.
Journal Targeted oncology
Vol 15
Issue 1
Date 2020 Feb
URL
Abstract Text Molecularly targeted therapy has revolutionized the treatment of advanced melanoma. However, despite its high efficiency, a majority of patients experience relapse within 1 year of treatment because of acquired resistance, and approximately 10-25% patients gain no benefit from these agents owing to intrinsic resistance. This is mainly caused by the genetic heterogeneity of melanoma cells.We aimed to validate the predictive significance of selected genes in advanced melanoma patients before treatment with BRAF/MEK inhibitors.Archival DNA derived from 37 formalin-fixed paraffin-embedded pre-treatment advanced melanoma samples of patients treated with targeted therapy was used for next-generation sequencing analysis using the Ion Torrent platform. The AmpliSeq Custom Panel comprised coding sequences or hot spots of 23 melanoma genes: ATM, BRAF, CDK4, CDKN2A, CTNNB1, EGFR, HOXD8, HRAS, IDH1, KIT, KRAS, MAP3K8, MAP2K1, MAP2K2, MITF, MYC, NF1, NRAS, PAX5, PIK3R1, PTEN, RAC1, and RB1. The sequences were evaluated for genomic alterations and further validated using Sanger sequencing.Our analysis revealed non-BRAF genetic alterations in 28 out of 37 samples (75.7%). Genetic changes were identified in PTEN, CDK4, CDKN2A, CTNNB1, EGFR, HOXD8, HRAS, KIT, MAP2K1, MAP2K2, MITF, MYC, NF1, PAX5, RAC1, and RB1. Fifteen known pathogenic mutations (single nucleotide variants or indels) and 11 variants of unknown significance were detected. Statistical analysis revealed an association between the presence of pathogenic mutations and time to progression during treatment with combination therapy.Pathogenic mutations identified by gene panel sequencing have potential predictive value for targeted therapy of melanoma and are worth further validation in a larger series of cases. The role of some known mutations (e.g. CDK4R24, PTEN c.801 + 1G > A, CTNNB1S45F) as well as variants of unknown significance identified in this study (e.g. MITFR316K, KITG498S) in the generation of resistance to BRAF/MEK inhibitors should be further investigated.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
BRAF S602T missense unknown BRAF S602T lies within the protein kinase domain of the Braf protein (UniProt.org). S602T has been identified in sequencing studies (PMID: 24433452, PMID: 31980996), but has not been biochemically characterized and therefore, its effect on Braf protein function is unknown (PubMed, Nov 2021).
KIT G498S missense unknown KIT G498S lies within the Ig-like C2-type domain 5 (exon 9) of the Kit protein (UniProt.org). G498S has been identified in the scientific literature (PMID: 31980996) but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Oct 2021).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600K MAP2K1 P124L melanoma predicted - resistant Dabrafenib + Trametinib Case Reports/Case Series Actionable In a clinical case study, Tafinlar (dabrafenib) and Mekinist (trametinib) combination treatment resulted in disease progression within one month in a metastatic melanoma patient harboring BRAF V600K and MAP2K1 P124L (PMID: 31980996). 31980996
BRAF V600E PTEN del melanoma predicted - resistant Dabrafenib Case Reports/Case Series Actionable In a clinical case study, Tafinlar (dabrafenib) treatment in a metastatic melanoma patient harboring BRAF V600E and PTEN deletion resulted in disease progression after 2.8 months following an initial partial response (PMID: 31980996). 31980996
BRAF V600E PTEN Y27C melanoma predicted - resistant Vemurafenib Case Reports/Case Series Actionable In a clinical case study, Zelboraf (vemurafenib) treatment in a metastatic melanoma patient harboring BRAF V600E and PTEN Y27C resulted in disease progression after 2.3 months following an initial partial response (PMID: 31980996). 31980996