Recurrent co‐alteration of HDGF and SETDB1 on chromosome 1q drives cutaneous melanoma progression and poor prognosis. (17th November 2020)

• Record Type: Journal Article
• Authors: Fazio, Maurizio; van Rooijen, Ellen; Mito, Jeffrey K.; Modhurima, Rodsy; Weiskopf, Erika; Yang, Song; Zon, Leonard I.
• Is Part Of: Pigment cell & melanoma research. Volume 34:Number 3(2021)
• Page Start: 641
• Page End: 647
• Publication Date: 2020-11-17
• Subjects: Melanoma -- Periodicals; Chromatophores -- Periodicals; Animal pigments -- Periodicals; 616.99477
• DOI: 10.1111/pcmr.12937
• Languages: English
• ISSNs: 1755-1471

Abstract

Abstract: A progressive increase in copy number variation (CNV) characterizes the natural history of cutaneous melanoma progression toward 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 BRAF V600E ‐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.