Comprehensive Genetic Landscape of Uveal Melanoma by Whole-Genome Sequencing.

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3 novembre 2016

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Serveur académique Lausannois

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info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ajhg.2016.09.008

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info:eu-repo/semantics/altIdentifier/pmid/27745836

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info:eu-repo/semantics/altIdentifier/eissn/1537-6605

Ce document est lié à :
info:eu-repo/semantics/altIdentifier/urn/urn:nbn:ch:serval-BIB_035A22A1A6AE3

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Serveur Académique Lausannois

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Université de Lausanne et CHUV

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info:eu-repo/semantics/openAccess , Copying allowed only for non-profit organizations , https://serval.unil.ch/disclaimer

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Adult; Aged; Aged, 80 and over; Case-Control Studies; DNA Copy Number Variations; Eukaryotic Initiation Factor-1/genetics; Eukaryotic Initiation Factor-1/metabolism; Exons; Female; GTP-Binding Protein alpha Subunits/genetics; GTP-Binding Protein alpha Subunits/metabolism; GTP-Binding Protein alpha Subunits, Gq-G11/genetics; GTP-Binding Protein alpha Subunits, Gq-G11/metabolism; Genome-Wide Association Study; Humans; Male; Melanocytes/pathology; Melanoma/diagnosis; Melanoma/genetics; Membrane Proteins/genetics; Membrane Proteins/metabolism; Middle Aged; Mutation; Phosphoproteins/genetics; Phosphoproteins/metabolism; RNA Splicing Factors/genetics; RNA Splicing Factors/metabolism; Skin Neoplasms; Tumor Suppressor Proteins/genetics; Tumor Suppressor Proteins/metabolism; Tumor Suppressor p53-Binding Protein 1/genetics; Tumor Suppressor p53-Binding Protein 1/metabolism; Ubiquitin Thiolesterase/genetics; Ubiquitin Thiolesterase/metabolism; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/metabolism; Uveal Neoplasms/diagnosis; Uveal Neoplasms/genetics

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Melanocytic tumor Malignant melanoma

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B. Royer-Bertrand et al., « Comprehensive Genetic Landscape of Uveal Melanoma by Whole-Genome Sequencing. », Serveur académique Lausannois, ID : 10.1016/j.ajhg.2016.09.008

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Uveal melanoma (UM) is a rare intraocular tumor that, similar to cutaneous melanoma, originates from melanocytes. To gain insights into its genetics, we performed whole-genome sequencing at very deep coverage of tumor-control pairs in 33 samples (24 primary and 9 metastases). Genome-wide, the number of coding mutations was rather low (only 17 variants per tumor on average; range 7-28), thus radically different from cutaneous melanoma, where hundreds of exonic DNA insults are usually detected. Furthermore, no UV light-induced mutational signature was identified. Recurrent coding mutations were found in the known UM drivers GNAQ, GNA11, BAP1, EIF1AX, and SF3B1. Other genes, i.e., TP53BP1, CSMD1, TTC28, DLK2, and KTN1, were also found to harbor somatic mutations in more than one individual, possibly indicating a previously undescribed association with UM pathogenesis. De novo assembly of unmatched reads from non-coding DNA revealed peculiar copy-number variations defining specific UM subtypes, which in turn could be associated with metastatic transformation. Mutational-driven comparison with other tumor types showed that UM is very similar to pediatric tumors, characterized by very few somatic insults and, possibly, important epigenetic changes. Through the analysis of whole-genome sequencing data, our findings shed new light on the molecular genetics of uveal melanoma, delineating it as an atypical tumor of the adult for which somatic events other than mutations in exonic DNA shape its genetic landscape and define its metastatic potential.

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