Comprehensive Genetic Landscape of Uveal Melanoma by Whole-Genome Sequencing

Royer-Bertrand, Beryl and Torsello, Matteo and Rimoldi, Donata and El Zaoui, Ikram and Cisarova, Katarina and Pescini-Gobert, Rosanna and Raynaud, Franck and Zografos, Leonidas and Schalenbourg, Ann and Speiser, Daniel and Nicolas, Michael and Vallat, Laureen and Klein, Robert and Leyvraz, Serge and Ciriello, Giovanni and Riggi, Nicolò and Moulin, Alexandre P. and Rivolta, Carlo. (2016) Comprehensive Genetic Landscape of Uveal Melanoma by Whole-Genome Sequencing. American Journal of Human Genetics, 99 (5). pp. 1190-1198.

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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.
Faculties and Departments:03 Faculty of Medicine
09 Associated Institutions > Institute of Molecular and Clinical Ophthalmology Basel (IOB)
UniBasel Contributors:Rivolta, Carlo
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:02 Mar 2021 14:17
Deposited On:02 Mar 2021 14:17

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