Abstract
Background
Tumor molecular deciphering is crucial in clinical management. Pan-cancer next-generation sequencing panels have moved towards exhaustive molecular characterization. However, because of treatment resistance and the growing emergence of pharmacological targets, tumor-specific customized panels are needed to guide therapeutic strategies.
Objective
The objective of this study was to present such a customized next-generation sequencing panel in melanoma.
Methods
Melanoma patients with somatic molecular profiling performed as part of routine care were included. High-throughput sequencing was performed with a melanoma tailored next-generation sequencing panel of 64 genes involved in molecular classification, prognosis, theranostic, and therapeutic resistance. Single nucleotide variants and copy number variations were screened, and a comprehensive molecular analysis identified clinically relevant alterations.
Results
Four hundred and twenty-one melanoma cases were analyzed (before any treatment initiation for 94.8% of patients). After bioinformatic prioritization, we uncovered 561 single nucleotide variants, 164 copy number variations, and four splice-site mutations. At least one alteration was detected in 368 (87.4%) lesions, with BRAF, NRAS, CDKN2A, CCND1, and MET as the most frequently altered genes. Among patients with BRAFV600 mutated melanoma, 44.5% (77 of 173) harbored at least one concurrent alteration driving potential resistance to mitogen-activated protein kinase inhibitors. In patients with RAS hotspot mutated lesions and in patients with neither BRAFV600 nor RAS hotspot mutations, alterations constituting potential pharmacological targets were found in 56.9% (66 of 116) and 47.7% (63 of 132) of cases, respectively.
Conclusions
Our tailored next-generation sequencing assay coupled with a comprehensive analysis may improve therapeutic management in a significant number of patients with melanoma. Updating such a panel and implementing multi-omic approaches will further enhance patients’ clinical management.
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Acknowledgements
The authors thank the patients who agreed to participate in the study, the Société Française de Dermatologie (SFD) for their support and Kirsten Dumaz for English proofreading. Baptiste Louveau was supported by La Fondation de l’Avenir (Bourse Legs Cancérologie).
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No external funding was used in the preparation of this article.
Conflict of interest
Barouyr Baroudjian declares honoraria from BMS, MSD, Novartis, and Pierre Fabre and travel accommodations from BMS and Pierre Fabre. Maxime Battistella declares a consulting role for Innate Pharma and Kyowa Kirin, honoraria from BMS and Takeda, travel accommodations from Roche, and research funding from Takeda and Kyowa Kirin. Julie Delyon declares travel accommodations from Pierre Fabre and Roche. Céleste Lebbe declares a consulting role for Amgen, BMS, MSD, Novartis, and Roche, research funding from BMS and Roche, honoraria from Amgen, BMS, Incyte, MSD, Novartis, Pfizer, Pierre Fabre, and Roche, and travel accommodations from BMS. Samia Mourah declares a consulting role for Novartis, Biocartis, and Roche and research funding from Roche, Novartis, BMS, and Biocartis. Laetitia Da Meda, Nicolas Dumaz, Aurélia Gruber, Fanélie Jouenne, Alban Lermine, Eddie Lopes, Baptiste Louveau, Oren Marco, Aminata Ndiaye, Aurélie Sadoux, Kevin Serror, and Pauline Têtu have no conflicts of interest that are directly relevant to the content of this article.
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The INSERM Research Ethics Committee has confirmed that no ethical approval is legally required for this retrospective study.
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Informed consent was obtained from all individual participants included in the study.
Data availability and material
Sequencing data analyzed in this study have been deposited in the NCBI Sequence Read Archive (SRA). The accession number is PRJNA647798.
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Author contributions
Conceptualization: SM, CL. Data curation: BL, FJ, AS, AG, EL, AN, AL. Formal analysis: BL, FJ. Investigation: BL, FJ, PT, AS, AG, EL, MB. Methodology: BL, FJ. Project administration: CL, SM. Resources: PT, JD, KS, OM, LDM, MB, BB. Software: AN, AL. Supervision: CL, SM. Validation: BL, FJ, CL, SM. Visualization: BL, FJ. Writing original draft: BL, FJ. Writing review and editing: ND, CL, SM.
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Louveau, B., Jouenne, F., Têtu, P. et al. A Melanoma-Tailored Next-Generation Sequencing Panel Coupled with a Comprehensive Analysis to Improve Routine Melanoma Genotyping. Targ Oncol 15, 759–771 (2020). https://doi.org/10.1007/s11523-020-00764-4
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DOI: https://doi.org/10.1007/s11523-020-00764-4