Somatic hypermutation of the YAP oncogene in a human cutaneous melanoma

Zhang, Xiaomeng, Tang, Jian Zhong, Vergara, Ismael A., Zhang, Youfang, Szeto, Pacman, Yang, Lie, Mintoff, Christopher, Colebatch, Andrew, McIntosh, Lachlan, Mitchell, Katrina A., Shaw, Evangeline, Rizos, Helen, Long, Georgina V., Hayward, Nicholas, McArthur, Grant A., Papenfuss, Anthony T., Harvey, Kieran F,, and Shackleton, Mark (2019) Somatic hypermutation of the YAP oncogene in a human cutaneous melanoma. Molecular Cancer Research, 17 (7). pp. 1435-1449.

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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.

Item ID: 75277
Item Type: Article (Research - C1)
ISSN: 1557-3125
Copyright Information: © 2019 American Association for Cancer Research.
Funders: National Health and Medical Research Council of Australia (NHMRC)
Projects and Grants: NHMRC 1078220, NHMRC 1054618, NHMRC 1116955, NHMRC 628735
Date Deposited: 17 Aug 2022 00:39
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3211 Oncology and carcinogenesis > 321103 Cancer genetics @ 100%
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