title: Comprehensive Genetic Landscape of Uveal Melanoma by Whole-Genome Sequencing.
abstract: 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.
authors.affiliation: Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, 1011 Lausanne Switzerland; Center for Molecular Diseases, Lausanne University Hospital, 1011 Lausanne, Switzerland.
authors.forename: Beryl
authors.initials: B
authors.lastname: Royer-Bertrand
authors.affiliation: Experimental Pathology, Institute of Pathology, Lausanne University Hospital, 1011 Lausanne, Switzerland.
authors.forename: Matteo
authors.initials: M
authors.lastname: Torsello
authors.affiliation: Ludwig Cancer Research, Department of Oncology, University of Lausanne, 1066 Epalinges, Switzerland.
authors.forename: Donata
authors.initials: D
authors.lastname: Rimoldi
authors.affiliation: Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, 1011 Lausanne Switzerland.
authors.forename: Ikram
authors.initials: I
authors.lastname: El Zaoui
authors.affiliation: Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, 1011 Lausanne Switzerland.
authors.forename: Katarina
authors.initials: K
authors.lastname: Cisarova
authors.affiliation: Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, 1011 Lausanne Switzerland.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Pescini-Gobert
authors.affiliation: Department of Computational Biology, Computational Systems Oncology, University of Lausanne, 1011 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
authors.forename: Franck
authors.initials: F
authors.lastname: Raynaud
authors.affiliation: Jules-Gonin Eye Hospital, Department of Ophthalmology, Fondation Asile des Aveugles, University of Lausanne, 1004 Lausanne, Switzerland.
authors.forename: Leonidas
authors.initials: L
authors.lastname: Zografos
authors.affiliation: Jules-Gonin Eye Hospital, Department of Ophthalmology, Fondation Asile des Aveugles, University of Lausanne, 1004 Lausanne, Switzerland.
authors.forename: Ann
authors.initials: A
authors.lastname: Schalenbourg
authors.affiliation: Ludwig Cancer Research, Department of Oncology, University of Lausanne, 1066 Epalinges, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Speiser
authors.affiliation: Jules-Gonin Eye Hospital, Department of Ophthalmology, Fondation Asile des Aveugles, University of Lausanne, 1004 Lausanne, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Nicolas
authors.affiliation: Jules-Gonin Eye Hospital, Department of Ophthalmology, Fondation Asile des Aveugles, University of Lausanne, 1004 Lausanne, Switzerland.
authors.forename: Laureen
authors.initials: L
authors.lastname: Vallat
authors.affiliation: Formerly Complete Genomics, Mountain View, CA 94043, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Klein
authors.affiliation: Department of Oncology, Lausanne University Hospital, 1011 Lausanne, Switzerland.
authors.forename: Serge
authors.initials: S
authors.lastname: Leyvraz
authors.affiliation: Department of Computational Biology, Computational Systems Oncology, University of Lausanne, 1011 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ciriello
authors.affiliation: Experimental Pathology, Institute of Pathology, Lausanne University Hospital, 1011 Lausanne, Switzerland.
authors.forename: Nicolò
authors.initials: N
authors.lastname: Riggi
authors.affiliation: Jules-Gonin Eye Hospital, Department of Ophthalmology, Fondation Asile des Aveugles, University of Lausanne, 1004 Lausanne, Switzerland.
authors.forename: Alexandre P
authors.initials: AP
authors.lastname: Moulin
authors.affiliation: Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, 1011 Lausanne Switzerland. Electronic address: carlo.rivolta@unil.ch.
authors.forename: Carlo
authors.initials: C
authors.lastname: Rivolta
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D056915:DNA Copy Number Variations; D015977:Eukaryotic Initiation Factor-1 / Q000235:genetics / Q000378:metabolism; D005091:Exons; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008544:Melanocytes / Q000473:pathology; D008545:Melanoma / Q000175:diagnosis / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D000072260:RNA Splicing Factors / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D014604:Uveal Neoplasms / Q000175:diagnosis / Q000235:genetics*; D000096142:Cutaneous Malignant Melanoma; D000098943:Uveal Melanoma
chemical_list: C400134:BAP1 protein, human; C477880:CSMD1 protein, human; D015977:Eukaryotic Initiation Factor-1; C554062:GNA11 protein, human; C554061:GNAQ protein, human; D044385:GTP-Binding Protein alpha Subunits; C088547:KTN1 protein, human; D008565:Membrane Proteins; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; C112491:SF3B1 protein, human; C498301:TP53BP1 protein, human; D025521:Tumor Suppressor Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; C026022:eukaryotic peptide initiation factor-1A; C108062:TTC3 protein, human; D044767:Ubiquitin-Protein Ligases; D043222:Ubiquitin Thiolesterase; D043802:GTP-Binding Protein alpha Subunits, Gq-G11