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.

中文翻译：

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1q 染色体上 HDGF 和 SETDB1 的反复共同改变导致皮肤黑色素瘤进展和不良预后

拷贝数变异 (CNV) 的逐渐增加是皮肤黑色素瘤进展到疾病后期的自然史的特征，但我们对染色体臂水平 CNV 的遗传驱动因素的理解仍然有限。为了确定候选进展驱动因素，我们挖掘了 TCGA SKCM 数据集，并将HDGF确定为反复扩增的基因，其高 mRNA 表达与患者生存率低相关。通过在斑马鱼BRAF ^V600E驱动的 MiniCoopR 黑色素瘤模型中黑色素细胞特异性过度表达，我们发现HDGF可加速体内黑色素瘤的发展。与对照 EGFP 肿瘤相比，HDGF 的转录分析显示内皮/血管生成途径的激活。我们使用内皮kdrl:mCherry报告系验证了这一观察结果，该报告系显示 HDGF 可以增加肿瘤脉管系统。HDGF经常与已建立的黑色素瘤驱动程序SETDB1共同改变。这两个基因都位于染色体 1q 上，在高达 13% 的转移性黑色素瘤中观察到它们的共同扩增。两种基因均扩增和/或过度表达的 TCGA 患者的黑色素瘤特异性生存率较差。我们在 MiniCoopR 模型中测试了 HDGF 和 SETDB1 的共表达，这导致比任一基因单独表达更快、更具侵袭性的黑色素瘤发展。我们的工作确定HDGF和SETDB1的共同扩增是黑色素瘤进展和患者预后不良的功能驱动因素。