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Genetic Alterations of Melanoma Brain Metastases: A Systematic Review and Meta-Analysis
Laura Pala1,2, Vincenzo Bagnardi3, Francesca Tettamanzi4
1Division of Melanoma, Sarcomas and Rare Tumors, European Institute of Oncology IRCCS, via Ripamonti 435, 20141, Milan, Italy. laura.pala@gavazzeni.it.
Background:
Data on molecular alterations harbored by melanoma brain metastases (MBMs) are limited, and this has hampered the development of more effective therapeutic strategies. We conducted a systematic review and meta-analysis of all the studies reporting DNA sequencing data of MBMs, in order to identify recurrently mutated genes and molecular pathways significantly enriched for genetic alterations.
Methods:
We searched PubMed, Embase and Scopus for articles published from the inception of each database to June 30, 2021. We included in the analysis all the studies that reported individual patient data on DNA sequencing of MBMs, assessing single nucleotide variants (SNVs) and/or gene copy number variations (CNVs) in at least five tumor samples. Meta-analysis was performed for genes evaluated for SNVs and/or CNVs in at least two studies. Pooled proportions of samples with SNVs and/or CNVs was calculated by applying random-effect models based on the DerSimonian-Laird method. Gene-set enrichment analysis (GSEA) was performed to identify molecular pathways significantly enriched for mutated genes.
Results:
Ten studies fulfilled the inclusion criteria and were included in the analysis, for a total of 531 samples of MBMs evaluated. Twenty-seven genes were found recurrently mutated with a meta-analytic rate of SNVs higher than 5%. GSEA conducted on the list of these 27 recurrently mutated genes revealed vascular endothelial growth factor-activated receptor activity and transmembrane receptor protein tyrosine kinase activity to be among the top 10 gene ontology (GO) molecular functions significantly enriched for mutated genes, while regulation of apoptosis and cell proliferation were among the top 10 significantly enriched GO biological processes. Notably, a high meta-analytic rate of SNVs was found in several actionable cancer-associated genes, such as all the vascular endothelial growth factor (VEGF) receptor isoforms (i.e., Flt1 and Flt2 genes, for both SNV rate: 0.22, 95% CI 0.04-0.49; KDR gene, SNV rate: 0.1, 95% CI 0.05-0.16). Finally, two tumor suppressor genes were characterized by a high meta-analytic rate of CNVs: CDKN2A/B (CNV rate: 0.59, 95% CI 0.23-0.90) and PTEN (CNV rate: 0.31, 95% CI 0.02-0.95).
Conclusion:
MBMs harbored actionable molecular alterations that could be exploited as therapeutic targets to improve the poor prognosis of patients.
Insights
Melanoma brain metastases (MBMs) show actionable molecular alterations, including mutations in VEGF receptor genes and copy number variations in CDKN2A/B and PTEN. These findings highlight potential therapeutic targets for improving patient outcomes.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Limited data exists on molecular alterations in melanoma brain metastases (MBMs), hindering effective therapeutic development.
- Melanoma brain metastases represent a significant clinical challenge with poor patient prognosis.
Approach:
- A systematic review and meta-analysis of DNA sequencing data from MBMs was conducted.
- Included studies reported individual patient data on single nucleotide variants (SNVs) and/or copy number variations (CNVs) in at least five MBM samples.
- Gene-set enrichment analysis (GSEA) identified significantly enriched molecular pathways.
Key Points:
- Twenty-seven genes were recurrently mutated in MBMs.
- Enriched molecular functions included vascular endothelial growth factor-activated receptor activity and tyrosine kinase activity.
- Actionable genes like VEGF receptor isoforms (Flt1, Flt2, KDR) showed high SNV rates.
- Tumor suppressor genes CDKN2A/B and PTEN exhibited high rates of copy number variations.
Conclusions:
- Melanoma brain metastases harbor actionable molecular alterations.
- These alterations represent potential therapeutic targets for improving MBM patient prognosis.
