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Genetic Alterations of Melanoma Brain Metastases: A Systematic Review and Meta-Analysis

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Abstract

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.

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Authors and Affiliations

  1. Division of Melanoma, Sarcomas and Rare Tumors, European Institute of Oncology IRCCS, via Ripamonti 435, 20141, Milan, Italy

    Laura Pala, Tommaso De Pas, Elisabetta Pennacchioli, Sara Coppola, Federica Baldini, Damiano Patane’, Maristella Saponara, Paola Queirolo & Fabio Conforti

  2. Oncology Unit, Humanitas Gavazzeni, Via M.Gavazzeni 21, 24125, Bergamo, Italy

    Laura Pala, Tommaso De Pas & Fabio Conforti

  3. Department of Statistics and Quantitative Methods, University of Milan-Bicocca, Milan, Italy

    Vincenzo Bagnardi

  4. Department of Biomedical Sciences, Humanitas University, Milan, Italy

    Francesca Tettamanzi

  5. Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan, Italy

    Massimo Barberis & Giovanni Mazzarol

  6. Department of Neurological Surgery, IRCCS Foundation Neurological Institute “Carlo Besta”, Milan, Italy

    Cecilia Casali

  7. Division of Medical Oncology, European Institute of Oncology, IRCCS, Milan, Italy

    Emilia Cocorocchio

  8. Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy

    Pierfrancesco Ferrucci

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  1. Laura Pala
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Corresponding author

Correspondence to Laura Pala.

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Authors’ contributions

LP, VB, FT, and FC were involved in the conception, design, planning, and management of the study, data acquisition, interpretation of results, drafting the manuscript, and critically reviewing or revising the manuscript for important intellectual content. All other authors supervised the data analysis, provided the interpretation of results, and contributed to the drafting and critical review of the manuscript. All authors approved the final draft. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. The lead author (LP) is the guarantor.

Competing interests

All authors declared no conflicts of interest.

Funding

There was no funding source for this study. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Data availability statement

Detailed extracted data on all included studies are available upon reasonable request to the corresponding author.

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Pala, L., Bagnardi, V., Tettamanzi, F. et al. Genetic Alterations of Melanoma Brain Metastases: A Systematic Review and Meta-Analysis. Mol Diagn Ther 27, 5–13 (2023). https://doi.org/10.1007/s40291-022-00623-0

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