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Recurrent co-alteration of HDGF and SETDB1 on chromosome 1q drives cutaneous melanoma progression and poor prognosis.

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.

SUBMITTER: Fazio M

PROVIDER: S-EPMC8050117 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:It is generally accepted that human cancers derive from a mutated single cell. However, the genetic steps characterizing various stages of progression remain unclear. Studying a unique case of metastatic melanoma, we observed that cell lines derived from metachronous metastases arising over a decade retained a central core of genetic stability in spite of divergent phenotypes. In the present study we expanded our previous observations comparing these autologous cell lines of clonal derivation with heterologous ones and correlated array Comparative Genomic Hybridization (aCGH) with gene expression profiling to determine their relative contribution to the dynamics of disease progression. aCGH and gene expression profiling were performed on autologous cell lines and heterologous melanoma cell lines originated from other patients. A striking correlation existed between total extent of genetic imbalances, global transcriptional patterns and cellular phenotypes; they did not follow a strict temporal progression but stemmed independently at various time points from a central core of genetic stability best explained according to the cancer stem cell hypothesis; although their contribution was intertwined, genomic imbalances detectable by aCGH contributed only 25% of the transcriptional traits determining autologous tumors distinctiveness. Our study provides important insights about the dynamics of cancer progression and supports the development of targeted anti-cancer therapies against stable genetic factors determining the individuality of each patientâs disease that are maintained throughout the end stage of disease. Keywords: genetic modification design PBMC from a female donor were Ficoll gradient separated and used throughout the study as reference.. Validation of array CGH accuracy was done by obtaining six additional PBMC from female donors and six PBMC from male donors to confirm stability of gene representation in autosomes and sex-determined imbalances within the X and Y chromosome regions. Five melanoma cell lines were generated from distinct cutaneous melanoma metastases that progressively appeared in patient 888. Other melanoma cell lines were generated from cutaneous melanoma metastases from other patients. The melanoma cell line A375 was purchased from the American Type Culture Collection. For each cell line arrayCGh has been performed.

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Recurrent co-alteration of HDGF and SETDB1 on chromosome 1q drives cutaneous melanoma progression and poor prognosis.

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