ZFIN ID: ZDB-PUB-201020-41
Recurrent co-alteration of HDGF and SETDB1 on chromosome 1q drives cutaneous melanoma progression and poor prognosis
Fazio, M., van Rooijen, E., Mito, J.K., Modhurima, R., Weiskopf, E., Yang, S., Zon, L.I.
Date: 2020
Source: Pigment cell & melanoma research   34(3): 641-647 (Other)
Registered Authors: van Rooijen, Ellen, Zon, Leonard I.
Keywords: none
MeSH Terms: none
PubMed: 33064882 Full text @ Pigment Cell Melanoma Res.
A progressive increase in copy number variation (CNV) characterizes the natural history of cutaneous melanoma progression towards later disease stages, but our understanding of genetic drivers underlying chromosomal arm-level CNVs remains limited. To identify candidate progression drivers, we mined the TCGA SKCM dataset and identified HDGF as a recurrently amplified gene whose high mRNA expression correlates with poor patient survival. Using melanocyte specific overexpression in the zebrafish BRAFV600E -driven MiniCoopR melanoma model, we show that HDGF accelerates melanoma development in vivo. Transcriptional analysis of HDGF compared to control EGFP tumors showed the activation of endothelial/angiogenic pathways. We validated this observation using an endothelial kdrl:mCherry reporter line which showed HDGF to increases tumor vasculature. HDGF is frequently co-altered with the established melanoma driver SETDB1. Both genes are located on chromosome 1q and their co-amplification is observed in up to 13% of metastatic melanoma. TCGA patients with both genes amplified and/or overexpressed have a worse melanoma specific survival. We tested co-expression of HDGF and SETDB1 in the MiniCoopR model, which resulted in faster and more aggressive melanoma development than either gene individually. Our work identifies the co-amplification of HDGF and SETDB1 as a functional driver of melanoma progression and poor patient prognosis.