Punctuated evolution of canonical genomic aberrations in uveal melanoma

• Published in: Nature communications 2018-01, Vol.9 (1), p.116-116, Article 116
• Main Authors: Field, Matthew G., Durante, Michael A., Anbunathan, Hima, Cai, Louis Z., Decatur, Christina L., Bowcock, Anne M., Kurtenbach, Stefan, Harbour, J. William
• Format: Article
• Language: English
• Subjects: 38/23; 38/39; 45/91; 631/67/1484; 631/67/69; Aberration; Biological evolution; Cancer; Cluster Analysis; Data processing; DNA Copy Number Variations; DNA Methylation; Evolution; Evolution, Molecular; Eye diseases; Humanities and Social Sciences; Humans; Melanoma; Melanoma - genetics; Metastases; Metastasis; multidisciplinary; Mutation; Science; Science (multidisciplinary); Tumor Suppressor Proteins - genetics; Ubiquitin Thiolesterase - genetics; Uveal Neoplasms - genetics; Whole Exome Sequencing
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-02428-w

Cancer is thought to arise through the accumulation of genomic aberrations evolving under Darwinian selection. However, it remains unclear when the aberrations associated with metastasis emerge during tumor evolution. Uveal melanoma (UM) is the most common primary eye cancer and frequently leads to metastatic death, which is strongly linked to BAP1 mutations. Accordingly, UM is ideally suited for studying the clonal evolution of metastatic competence. Here we analyze sequencing data from 151 primary UM samples using a customized bioinformatic pipeline, to improve detection of BAP1 mutations and infer the clonal relationships among genomic aberrations. Strikingly, we find BAP1 mutations and other canonical genomic aberrations usually arise in an early punctuated burst, followed by neutral evolution extending to the time of clinical detection. This implies that the metastatic proclivity of UM is “set in stone” early in tumor evolution and may explain why advances in primary treatment have not improved survival. Uveal melanoma (UM), the most common primary eye cancer, is strongly linked to mutations in the tumor suppressor BAP1 . Here, the authors analyze 151 primary UM samples to find that BAP1 and other canonical genomic aberrations arise in an early punctuated burst followed by neutral tumor evolution.