Somatic Hypermutation of the YAP Oncogene in a Human Cutaneous Melanoma

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.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. Mutations and methylation changes in Hippo pathway genes in the TCGA melanoma cohort. A, Somatic coding mutations (top) and CN changes (bottom) affecting Hippo pathway genes identified in patients from the TCGA cohort (56), organized horizontally according to the BRAF-, NRAS-, NF1-, TP53-, RAC1-or PTEN-mutant melanoma subtype of each patient and vertically according the mutation frequency in each Hippo pathway gene. Mutations colored by type: amp, amplification; hemi, hemizygous; homo, homozygous; del, deletion. B, top: distributions of methylation values across 473 TCGA patients in 18 known/predicted oncogenes and 33 known/predicted tumor suppressor genes in the Hippo pathway. Bottom: Spearman coefficient values for correlations between methylation and mRNA expression for each gene. C, Methylation versus mRNA expression plots for YAP and TAZ. Each dot represents values for an individual patient. Blue dots, mutated gene; red dots, wild-type gene. r is the Spearman correlation coefficient; Ã , P < 0.001. YAP and Melanoma

YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy

“…[ 157,158 ] Rare activating point mutations in YAP have also been found in melanoma. [ 165 ] Such amplification and translocation events are consistent with Boveri's theory but not sufficient to explain the frequent activation of YAP/TAZ expression and nuclear localization in many solid tumors, suggesting a primary role for other mechanisms including altered upstream signaling during tissue damage and inflammation, consistent with Virchow's theory.…”

The Roles of YAP/TAZ and the Hippo Pathway in Healthy and Diseased Skin

“…In a recent study, YAP protein expression was found to be elevated in benign melanocytic nevi and primary cutaneous melanomas, but YAP was present at only very low levels in normal melanocytes in healthy human skin [151]. Interestingly, more melanocytic cells in nevi and in early stage cutaneous melanomas had higher nuclear YAP abundance compared to cells from metastatic disease [151]. This study also found YAP to be ubiquitously expressed across a panel of melanoma cell lines, while TAZ expression was observed in most but not all cell lines [151].…”

Non-BRAF Mutant Melanoma: Molecular Features and Therapeutical Implications

“…Indeed, they identified seven independent serine to alanine substitutions in YAP gene (called YAP-7SA) from a primary cutaneous melanoma patient carrying BRAF V600E and RAC1 P29S mutation. In vitro study confirmed that YAP-7SA encodes a hyperactive version of the YAP protein (Zhang et al, 2019). Despite the great interest of scientific community toward the role of Hippo pathway in cancer, no drugs and clinical trials direct to YAP in melanoma are described.…”

“…Although the central role of YAP in uveal melanomagenesis is deeply investigated, the role of Hippo/YAP signaling in cutaneous melanoma is less understood. Zhang et al (2019) proved for the first time that YAP hyperactivity is elevated in invasive melanoma cell lines, induce invasion in normally non-invasive melanoma cells, induces spontaneous melanoma metastasis in vivo and promotes melanoma cell invasion by regulating expression of AXL, CYR61 and CRIM1. Moreover, they did not found association between YAP activity and the BRAF/NRAS mutation status.…”