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Title: Somatic hypermutation of the YAP oncogene in a human cutaneous melanoma.
Austin Authors: 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;Shackleton, Mark
Affiliation: Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
The Walter and Eliza Hall Institute, Melbourne, Victoria, Australia
Department of Mathematics and Statistics, University of Melbourne, Melbourne, Victoria, Australia
Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia
Melanoma Institute of Australia, Sydney, NSW, Australia
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
Alfred Health, Melbourne, Victoria, Australia
School of Medicine, Tsinghua University, Beijing, China
School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia
Central Clinical School, Monash University, Melbourne, Victoria, Australia
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
Issue Date: Jul-2019 2019-03-04
Publication information: Molecular cancer research : MCR 2019; 17(7): 1435-1449
Abstract: Melanoma is usually driven by mutations in BRAF or NRAS that trigger hyperactivation of mitogen-activated protein kinase (MAPK) signalling. 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 signalling 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 signalling 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 sub-groups of melanoma patients, although successful treatment with anti-YAP therapies will depend on identification of biomarkers additional to YAP protein expression.
DOI: 10.1158/1541-7786.MCR-18-0407
ORCID: 0000-0002-2094-9198
PubMed URL: 30833299
Type: Journal Article
Appears in Collections:Journal articles

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