Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Targeted oncology	15	1	2020 Feb	101-113	Target Oncol

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, Sep 2024).
KIT	G498S	missense	unknown	KIT G498S lies within 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, Nov 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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
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