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Published on: May 18, 2018
Genetic Profiling of Advanced Melanoma: Candidate Mutations for Predicting Sensitivity and Resistance to Targeted
Magdalena Olbryt1, Wojciech Pigłowski2,3, Marcin Rajczykowski4
1Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie Institute, Oncology Center Gliwice Branch, Wybrzeze Armii Krajowej 15, Gliwice, Poland. Magdalena.Olbryt@io.gliwice.pl.
Background:
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.
Objective:
We aimed to validate the predictive significance of selected genes in advanced melanoma patients before treatment with BRAF/MEK inhibitors.
Patients And Methods:
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.
Results:
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.
Conclusions:
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.
Insights
Genetic alterations in advanced melanoma predict treatment response to targeted therapies. Identifying these mutations, including pathogenic variants and those of unknown significance, can help personalize melanoma treatment strategies and overcome resistance.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Molecularly targeted therapy has transformed advanced melanoma treatment.
- Acquired and intrinsic resistance lead to relapse or lack of benefit in a significant portion of patients.
- Melanoma's genetic heterogeneity is a primary driver of treatment resistance.
Purpose of the Study:
- To validate the predictive significance of selected genes in advanced melanoma patients before BRAF/MEK inhibitor therapy.
- To identify genetic markers associated with treatment response and resistance.
Main Methods:
- Next-generation sequencing (Ion Torrent platform) of DNA from 37 pre-treatment advanced melanoma samples.
- Analysis of 23 key melanoma genes using an AmpliSeq Custom Panel.
- Validation of genomic alterations using Sanger sequencing.
Main Results:
- Non-BRAF genetic alterations were found in 75.7% (28/37) of samples.
- Mutations were identified in multiple genes including PTEN, CDK4, CTNNB1, and MITF.
- A significant association was observed between pathogenic mutations and time to progression.
Conclusions:
- Gene panel sequencing can identify pathogenic mutations with potential predictive value for melanoma targeted therapy.
- Further validation in larger cohorts is warranted.
- Investigating the role of specific mutations (e.g., CDK4, PTEN, CTNNB1, MITF, KIT) in BRAF/MEK inhibitor resistance is crucial.
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