Recurrent co-alteration of HDGF and SETDB1 on chromosome 1q drives cutaneous melanoma progression and poor prognosis.
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ABSTRACT:
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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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 patient’s disease that are maintained throughout the end stage of disease. Keywords: genetic modification design
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Project description: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 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 We report the analysis of gene expression profiling of melanoma cell lines obtained from metastsases of a long term survivor melanoma patient and other melanoma cell lines. RNA was amplified and hybridized to 17.5K cDNA arrays.
2010-05-25 | E-GEOD-8778 | biostudies-arrayexpress
Project description:The most common mutation in human melanoma, BRAF(V600E), activates the serine/threonine kinase BRAF and causes excessive activity in the mitogen-activated protein kinase pathway. BRAF(V600E) mutations are also present in benign melanocytic naevi, highlighting the importance of additional genetic alterations in the genesis of malignant tumours. Such changes include recurrent copy number variations that result in the amplification of oncogenes. For certain amplifications, the large number of genes in the interval has precluded an understanding of the cooperating oncogenic events. Here we have used a zebrafish melanoma model to test genes in a recurrently amplified region of chromosome 1 for the ability to cooperate with BRAF(V600E) and accelerate melanoma. SETDB1, an enzyme that methylates histone H3 on lysine 9 (H3K9), was found to accelerate melanoma formation significantly in zebrafish. Chromatin immunoprecipitation coupled with massively parallel DNA sequencing and gene expression analyses uncovered genes, including HOX genes, that are transcriptionally dysregulated in response to increased levels of SETDB1. Our studies establish SETDB1 as an oncogene in melanoma and underscore the role of chromatin factors in regulating tumorigenesis. DNA was enriched from short-term cultures of cells and chromatin immunoprecipitations (ChIPs) were analyzed by Solexa sequencing. ChIPs were performed using an antibody against SetDB1 in WM853.2. Whole cell extracts are provided for WM262, WM451Lu and WM853.2 cells.
2012-03-17 | E-GEOD-36579 | biostudies-arrayexpress
Project description: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 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 patient’s disease that are maintained throughout the end stage of disease. Keywords: genetic modification design
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Project description:The most common mutation in human melanoma, BRAF(V600E), activates the serine/threonine kinase BRAF and causes excessive activity in the mitogen-activated protein kinase pathway. BRAF(V600E) mutations are also present in benign melanocytic naevi, highlighting the importance of additional genetic alterations in the genesis of malignant tumours. Such changes include recurrent copy number variations that result in the amplification of oncogenes. For certain amplifications, the large number of genes in the interval has precluded an understanding of the cooperating oncogenic events. Here we have used a zebrafish melanoma model to test genes in a recurrently amplified region of chromosome 1 for the ability to cooperate with BRAF(V600E) and accelerate melanoma. SETDB1, an enzyme that methylates histone H3 on lysine 9 (H3K9), was found to accelerate melanoma formation significantly in zebrafish. Chromatin immunoprecipitation coupled with massively parallel DNA sequencing and gene expression analyses uncovered genes, including HOX genes, that are transcriptionally dysregulated in response to increased levels of SETDB1. Our studies establish SETDB1 as an oncogene in melanoma and underscore the role of chromatin factors in regulating tumorigenesis.
2012-03-17 | GSE36579 | GEO
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