Somatic Hypermutation of the YAP Oncogene in a Human Cutaneous Melanoma
| Autor: | Helen Rizos, Evangeline Shaw, Lachlan McIntosh, Mark Shackleton, Jian-Zhong Tang, Katrina A. Mitchell, Grant A. McArthur, Andrew J. Colebatch, Xiaomeng Zhang, Kieran F. Harvey, Georgina V. Long, Lie Yang, Nicholas K. Hayward, Pacman Szeto, Christopher P. Mintoff, Ismael A. Vergara, Youfang Zhang, Anthony T. Papenfuss |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Neuroblastoma RAS viral oncogene homolog Cancer Research Mutation Hippo signaling pathway Oncogene Melanoma Somatic hypermutation Cancer Biology medicine.disease medicine.disease_cause 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Oncology 030220 oncology & carcinogenesis Cutaneous melanoma medicine Cancer research neoplasms Molecular Biology |
| Zdroj: | Molecular Cancer Research. 17:1435-1449 |
| ISSN: | 1557-3125 1541-7786 |
| Popis: | 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, although successful treatment with anti-YAP therapies will depend on identification of biomarkers additional to YAP protein expression. |
| Databáze: | OpenAIRE |
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