Field Matthew G, Durante Michael A, Anbunathan Hima, Cai Louis Z, Decatur Christina L, Bowcock Anne M, Kurtenbach Stefan, Harbour J William
Bascom Palmer Eye Institute, Sylvester Comprehensive Cancer Center and Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida, 33136, USA.
National Heart and Lung Institute, Imperial College London, London, SW3 6LR, UK.
Nat Commun. 2018 Jan 9;9(1):116. 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.
癌症被认为是通过在达尔文选择下进化的基因组畸变的积累而产生的。然而，与转移相关的畸变在肿瘤进化过程中何时出现仍不清楚。葡萄膜黑色素瘤（UM）是最常见的原发性眼癌，经常导致转移性死亡，这与BAP1突变密切相关。因此，UM非常适合用于研究转移能力的克隆进化。在这里，我们使用定制的生物信息学管道分析了151个原发性UM样本的测序数据，以改进BAP1突变的检测并推断基因组畸变之间的克隆关系。令人惊讶的是，我们发现BAP1突变和其他典型的基因组畸变通常在早期的间断爆发中出现，随后是延伸至临床检测时的中性进化。这意味着UM的转移倾向在肿瘤进化早期就“确定下来”了，这可能解释了为什么原发性治疗的进展未能提高生存率。
