Somatic hypermutation of the YAP oncogene in a human cutaneous melanoma

Xiaomeng Zhang, Jian Zhong Tang, Ismael A. Vergara, Youfang Zhang, Pacman Szeto, Lie Yang, Christopher Mintoff, Andrew Colebatch, Lachlan McIntosh, Katrina A. Mitchell, Evangeline Shaw, Helen Rizos, Georgina V. Long, Nicholas Hayward, Grant A. McArthur, Anthony T. Papenfuss, Kieran F. Harvey, Mark Shackleton

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)1435-1449
Number of pages15
JournalMolecular Cancer Research
Volume17
Issue number7
DOIs
Publication statusPublished - 1 Jul 2019

Cite this

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. / Somatic hypermutation of the YAP oncogene in a human cutaneous melanoma. In: Molecular Cancer Research. 2019 ; Vol. 17, No. 7. pp. 1435-1449.
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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.",
author = "Xiaomeng Zhang and Tang, {Jian Zhong} and Vergara, {Ismael A.} and Youfang Zhang and Pacman Szeto and Lie Yang and Christopher Mintoff and Andrew Colebatch and Lachlan McIntosh and Mitchell, {Katrina A.} and Evangeline Shaw and Helen Rizos and Long, {Georgina V.} and Nicholas Hayward and McArthur, {Grant A.} and Papenfuss, {Anthony T.} and Harvey, {Kieran F.} and Mark Shackleton",
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Zhang, X, Tang, JZ, Vergara, IA, Zhang, Y, Szeto, P, Yang, L, Mintoff, C, Colebatch, A, McIntosh, L, Mitchell, KA, Shaw, E, Rizos, H, Long, GV, Hayward, N, McArthur, GA, Papenfuss, AT, Harvey, KF & Shackleton, M 2019, 'Somatic hypermutation of the YAP oncogene in a human cutaneous melanoma', Molecular Cancer Research, vol. 17, no. 7, pp. 1435-1449. https://doi.org/10.1158/1541-7786.MCR-18-0407

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.; Shackleton, Mark.

In: Molecular Cancer Research, Vol. 17, No. 7, 01.07.2019, p. 1435-1449.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Zhang, Xiaomeng

AU - Tang, Jian Zhong

AU - Vergara, Ismael A.

AU - Zhang, Youfang

AU - Szeto, Pacman

AU - Yang, Lie

AU - Mintoff, Christopher

AU - Colebatch, Andrew

AU - McIntosh, Lachlan

AU - Mitchell, Katrina A.

AU - Shaw, Evangeline

AU - Rizos, Helen

AU - Long, Georgina V.

AU - Hayward, Nicholas

AU - McArthur, Grant A.

AU - Papenfuss, Anthony T.

AU - Harvey, Kieran F.

AU - Shackleton, Mark

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N2 - 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.

AB - 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.

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Zhang X, Tang JZ, Vergara IA, Zhang Y, Szeto P, Yang L et al. Somatic hypermutation of the YAP oncogene in a human cutaneous melanoma. Molecular Cancer Research. 2019 Jul 1;17(7):1435-1449. https://doi.org/10.1158/1541-7786.MCR-18-0407