Somatic Hypermutation of the YAP Oncogene in a Human Cutaneous Melanoma

作者：Xiaomeng Zhang, Jian Tang, Ismael A. Vergara, Youfang Zhang, Pacman Szeto, Lie Yang, Christopher Mintoff, Andrew J. Colebatch, Lachlan McIntosh, Katrina A. Mitchell, Evangeline Shaw, Helen Rizos, Georgina V. Long, Nicholas K. Hayward, Grant A. McArthur, Anthony T. Papenfuss, Kieran F. Harvey, Mark Shackleton · 发表于：Molecular Cancer Research · 年份：2019 · DOI：10.1158/1541-7786.mcr-18-0407 · 被引用次数：42 · 研究领域：Hippo pathway signaling and YAP/TAZ、Melanoma and MAPK Pathways、Wnt/β-catenin signaling in development and cancer

Abstract Melanoma is usually driven by mutations in BRAF or NRAS, which trigger hyperactivation of MAPK signaling. However, MAPK-targeted therapies are not sustainably effective in most patients. Accordingly, characterizing mechanisms that co-operatively drive melanoma progression is key to improving patient outcomes. One possible mechanism is the Hippo signaling pathway, which regulates cancer progression via its central oncoproteins YAP and TAZ, although is thought to be only rarely affected by direct mutation. As YAP hyperactivation occurs in uveal melanoma, we investigated this oncogene in cutaneous melanoma. YAP protein expression was elevated in most benign nevi and primary cutaneous melanomas but present at only very low levels in normal melanocytes. In patient-derived xenografts and melanoma cell lines, we observed variable reliance of cell viability on Hippo pathway signaling that was independent of TAZ activity and also of classical melanoma driver mutations such as BRAF and NRAS. Finally, in genotyping studies of melanoma, we observed the first ever hyperactivating YAP mutations in a human cancer, manifest as seven distinct missense point mutations that caused serine to alanine transpositions. Strikingly, these mutate four serine residues known to be targeted by the Hippo pathway and we show that they lead to hyperactivation of YAP. Implications: Our studies highlight the YAP oncoprotein as a potential therapeutic target in select subgroups of melanoma patients, al...