Baptiste Louveau1,2,3, Fanélie Jouenne1,2,3, Céleste Lebbe2,3,4, Samia Mourah5,6,7, Pauline Têtu4, Aurélie Sadoux1, Aurélia Gruber1, Eddie Lopes1, Julie Delyon2,3,4, Kevin Serror8, Oren Marco8, Laetitia Da Meda4, Aminata Ndiaye9, Alban Lermine9, Nicolas Dumaz3, Maxime Battistella2,3,10, Barouyr Baroudjian4. 1. Department of Pharmacology and Solid Tumor Genomics, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, 1 Avenue Claude Vellefaux, 75475, Paris Cedex 10, France. 2. Université de Paris, Paris, France. 3. INSERM UMR-S 976, Team 1, Human Immunology Pathophysiology and Immunotherapy (HIPI), Paris, France. 4. Department of Dermatology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France. 5. Department of Pharmacology and Solid Tumor Genomics, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, 1 Avenue Claude Vellefaux, 75475, Paris Cedex 10, France. samia.mourah@aphp.fr. 6. Université de Paris, Paris, France. samia.mourah@aphp.fr. 7. INSERM UMR-S 976, Team 1, Human Immunology Pathophysiology and Immunotherapy (HIPI), Paris, France. samia.mourah@aphp.fr. 8. Department of Plastic, Reconstructive and Esthetic Surgery, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France. 9. MOABI-APHP Bioinformatics Platform-WIND-DSI, Assistance Publique-Hôpitaux de Paris, Paris, France. 10. Department of Pathology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France.
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.
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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Authors: Jedd D Wolchok; Vanna Chiarion-Sileni; Rene Gonzalez; Piotr Rutkowski; Jean-Jacques Grob; C Lance Cowey; Christopher D Lao; John Wagstaff; Dirk Schadendorf; Pier F Ferrucci; Michael Smylie; Reinhard Dummer; Andrew Hill; David Hogg; John Haanen; Matteo S Carlino; Oliver Bechter; Michele Maio; Ivan Marquez-Rodas; Massimo Guidoboni; Grant McArthur; Celeste Lebbé; Paolo A Ascierto; Georgina V Long; Jonathan Cebon; Jeffrey Sosman; Michael A Postow; Margaret K Callahan; Dana Walker; Linda Rollin; Rafia Bhore; F Stephen Hodi; James Larkin Journal: N Engl J Med Date: 2017-09-11 Impact factor: 91.245
Authors: Alan E Siroy; Genevieve M Boland; Denái R Milton; Jason Roszik; Silva Frankian; Jared Malke; Lauren Haydu; Victor G Prieto; Michael Tetzlaff; Doina Ivan; Wei-Lien Wang; Carlos Torres-Cabala; Jonathan Curry; Sinchita Roy-Chowdhuri; Russell Broaddus; Asif Rashid; John Stewart; Jeffrey E Gershenwald; Rodabe N Amaria; Sapna P Patel; Nicholas E Papadopoulos; Agop Bedikian; Wen-Jen Hwu; Patrick Hwu; Adi Diab; Scott E Woodman; Kenneth D Aldape; Rajyalakshmi Luthra; Keyur P Patel; Kenna R Shaw; Gordon B Mills; John Mendelsohn; Funda Meric-Bernstam; Kevin B Kim; Mark J Routbort; Alexander J Lazar; Michael A Davies Journal: J Invest Dermatol Date: 2014-08-22 Impact factor: 8.551