Comprehensive Genetic Landscape of Uveal Melanoma by Whole-Genome Sequencing
| Autor: | Serge Leyvraz, Beryl Royer-Bertrand, Laureen Vallat, Leonidas Zografos, Carlo Rivolta, Giovanni Ciriello, Donata Rimoldi, Nicolo Riggi, Rosanna Pescini-Gobert, Ikram El Zaoui, Ann Schalenbourg, Alexandre Moulin, Matteo Torsello, Robert J. Klein, Franck Raynaud, Daniel E. Speiser, Katarina Cisarova, Michael Nicolas |
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| Rok vydání: | 2016 |
| Předmět: |
Adult
Male Uveal Neoplasms 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 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 0301 basic medicine medicine.medical_specialty Ubiquitin-Protein Ligases Eukaryotic Initiation Factor-1 Uveal Neoplasm Biology medicine.disease_cause 03 medical and health sciences Report Molecular genetics Genetics medicine Melanoma Genetics (clinical) Whole genome sequencing GNA11 Tumor Suppressor Proteins Membrane Proteins Phosphoproteins medicine.disease GTP-Binding Protein alpha Subunits 3. Good health 030104 developmental biology Cutaneous melanoma GTP-Binding Protein alpha Subunits Gq-G11 Melanocytes RNA Splicing Factors Tumor Suppressor p53-Binding Protein 1 Ubiquitin Thiolesterase GNAQ |
| Zdroj: | American journal of human genetics American journal of human genetics, vol. 99, no. 5, pp. 1190-1198 |
| DOI: | 10.1016/j.ajhg.2016.09.008 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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