TY - JOUR
T1 - Somatic hypermutation of the YAP oncogene in a human cutaneous melanoma
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
PY - 2019/7/1
Y1 - 2019/7/1
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. 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.
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. 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.
UR - http://www.scopus.com/inward/record.url?scp=85069267110&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-18-0407
DO - 10.1158/1541-7786.MCR-18-0407
M3 - Article
C2 - 30833299
AN - SCOPUS:85069267110
VL - 17
SP - 1435
EP - 1449
JO - Molecular Cancer Research
JF - Molecular Cancer Research
SN - 1541-7786
IS - 7
ER -