WES cutaneous and uveal melanoma liver metastases
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ABSTRACT:
PROVIDER: EGAS00001004795 | EGA |
REPOSITORIES: EGA
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Project description:RNA sequencing analyses of tumor liver metastases from untreated cutaneous melanoma (CM) and uveal melanoma (UM) patients.
| EGAS00001004794 | EGA
Project description:Cutaneous melanoma (CM) and uveal melanoma (UM) both originate from the melanocytic lineage but are primarily driven by distinct oncogenic drivers, BRAF/NRAS or GNAQ/GNA11 respectively. The melanocytic master transcriptional regulator, MITF, is essential for both CM development and maintenance, but its role in UM is largely unexplored. Here, we use zebrafish models to dissect the key UM oncogenic signaling events, and establish the role of MITF in UM tumors. Remarkably, mitfa deficiency was profoundly UM promoting, dramatically accelerating the onset and progression of tumors induced by Tg(mitfa:GNAQQ209L);tp53M214K/M214K. To further explore the role of MITF in GNAQ-driven tumorigenesis, we performed phospho-proteomics and total proteomics on 5 zebrafish GNAQ Tg(mitfa:GNAQQ209L);tp53M214K/M214K tumors and 5 zebrafish GNAQ Tg(mitfa:GNAQQ209L);tp53M214K/M214K;mitfa-/- tumors.
2023-03-11 | PXD030527 | Pride
Project description:Cutaneous melanoma (CM) and uveal melanoma (UM) both originate from the melanocytic lineage but are primarily driven by distinct oncogenic drivers, BRAF/NRAS or GNAQ/GNA11 respectively. The melanocytic master transcriptional regulator, MITF, is essential for both CM development and maintenance, but its role in UM is largely unexplored. Here, we use zebrafish models to dissect the key UM oncogenic signaling events, and establish the role of MITF in UM tumors. Using a melanocytic lineage expression system, we showed that patient-derived mutations of GNAQ (GNAQQ209L) or its upstream CYSLTR2 receptor (CYSLTR2L129Q) both drive UM when combined with a cooperating mutation, tp53M214K/M214K. The tumor-initiating potential of the major GNAQ/11 effector pathways, YAP and PLCβ-ERK, was also investigated in this system, and thus showed that while activated YAP (YAPAA) induced UM with high potency, the patient-derived PLC4 mutation (PLCB4D630Y) very rarely yielded UM tumors in the tp53M214K/M214K context. Remarkably, mitfa deficiency was profoundly UM promoting, dramatically accelerating the onset and progression of tumors induced by Tg(GNAQQ209L);tp53M214K/M214K or Tg(CYSLTR2L129Q);tp53M214K/M214K. Moreover, mitfa loss was sufficient to cooperate with GNAQQ209L to drive tp53-wildtype UM development, and allowed Tg(PLCB4D630Y);tp53M214K/M214K melanocyte lineage cells to readily form tumors. Notably, all of the mitfa-/- UM tumors, including those arising in Tg(mitfa:PLCB4D630Y);tp53M214K/M214K;mitfa-/- fish, displayed nuclear YAP while lacking hyperactive ERK indicative of PLCβ signaling. Collectively, these data show that YAP signaling is the major mediator of UM, and that MITF acts as bona fide tumor suppressor in UM, in direct opposition to its essential role in CM.
2022-04-27 | GSE190802 | GEO
Project description:Metastatic uveal melanoma (MUM) is chemoresistant and usually fatal within one year of diagnosis. There is an urgent need to better understand disease pathogenesis, in order to determine key drivers of the metastatic process that could be effectively targeted by therapy. Gene copy number variations occurring in a rare cohort of 13 metastatic and six matched primary, formalin-fixed, paraffin-embedded uveal melanoma samples were identified using the Affymetrix Genome-Wide Human SNP 6.0 Array. Gross chromosomal abnormalities commonly seen in primary UM and associated with the development of metastasis were observed in the MUMs. The most common CNVs were gene amplifications on chromosome 8q, especially in the region 8q24.3. Interestingly, deletions on chromosome 3 were detected at a lower frequency. Genomic profiles of PUM-MUM pairs varied in their degree of similarity and complexity. No genes were altered being unique to either all PUMs or all MUMs of the pairs, but 135 gene CNVs were consistently shared. Of these genes, 125 were amplifications located on chr. 8q24.3. Five genes in the region 8q24.3 and two genes on chromosome 3 were selected for validation by immunohistochemistry because of their known function in cancer (BCL6, C-MYC, E2F5, PTP4A3, SNAI2, and WISP1), or known importance in UM pathology (BAP1). The functional effect of these CNVs on protein expression was confirmed; amplified genes showed increased expression and deleted genes reduced expression. To conclude, our data demonstrate frequent amplification of chromosome 8q in MUMs, suggesting that genes facilitating the expansion of UM in the metastatic niche occur in this region. Furthermore, validation of a range of amplified 8q genes at the protein level strongly indicates the CNVs may be functional and, contribute to MUM biology. 19 samples in total: 13 metastatic uveal melanoma (MUMs) and in six cases their paired primary UM (PUMs)
2016-05-18 | E-GEOD-69614 | biostudies-arrayexpress
Project description:Uveal melanoma (UM) is the most common intraocular tumor in adults, and its pathogenesis is only partly understood. UM can develop de novo from normal choroidal melanocytes (NCMs) or from pre-existing nevi that stem from NCMs and are thought to harbour UM-initiating mutations, most commonly in GNAQ or GNA11. However, there is a complete lack of commercially available NCM cell lines and no detailed protocol for developing oncogene-mutated CM line (MutCM) to study UM development. The purpose of this study was to establish and characterize premalignant CM models from human donor eyes to recapitulate the cell populations at the origin of UM.
2024-11-25 | PXD047179 | Pride
Project description:Uveal melanoma (UM) is the most common intraocular tumor in adults, and its pathogenesis is only partly understood. UM can develop de novo from normal choroidal melanocytes (NCMs) or from pre-existing nevi that stem from NCMs and are thought to harbour UM-initiating mutations, most commonly in GNAQ or GNA11. However, there is a complete lack of commercially available NCM cell lines and no detailed protocol for developing oncogene-mutated CM line (MutCM) to study UM development. The purpose of this study was to establish and characterize premalignant CM models from human donor eyes to recapitulate the cell populations at the origin of UM.
2024-11-25 | GSE273527 | GEO
Project description:Genome wide DNA methylation profiling of primary uveal melanoma cells, normal uveal melanocytes, neural crest stem cells, embryonic stem cells and uveal melanoma cell lines. The Illumina Infinium 27k Human DNA methylation Beadchip Rev B was used to obtain DNA methylation profiles across approximately 27,000 CpGs in the samples. Samples included 58 primary UM, 3 NUM and NCSC controls and 2 cell lines.
2013-02-14 | GSE44296 | GEO
Project description:Genome wide DNA methylation profiling of primary uveal melanoma cells, normal uveal melanocytes, neural crest stem cells, embryonic stem cells and uveal melanoma cell lines. The Illumina Infinium 27k Human DNA methylation Beadchip Rev B was used to obtain DNA methylation profiles across approximately 27,000 CpGs in the samples. Samples included 58 primary UM, 3 NUM and NCSC controls and 2 cell lines. Bisulphite converted DNA from the 63 samples were hybridised to the Illumina Infinium 27k Human Methylation Beadchip Rev B
2013-02-14 | E-GEOD-44296 | biostudies-arrayexpress
Project description:Despite advances in surgery and radiotherapy of uveal melanoma (UM), many patients develop distant metastases that poorly respond to therapy. Improved therapies for the metastatic disease are therefore urgently needed. Expression of the epidermal growth factor receptor (EGFR), a target of kinase inhibitors and humanized antibodies in use for several cancers, had been reported. 48 human UMs were analyzed by expression profiling. Evidence for signaling in tumors was obtained through the application of a UM-specific EGF signature. The EGFR specific kinase inhibitor, Gefitinib, and the humanized monoclonal antibody, Cetuximab, were tested for their effect on EGFR signaling. Natural killer cell mediated antibody-dependent cellular cytotoxicity (ADCC) and TNF-alpha release was analyzed for Cetuximab. EGFR appears suited as a novel molecular drug target for therapy of uveal melanoma. Gene expression profiles of 19 unique samples from uveal melanoma patients were measured.
2013-11-18 | E-GEOD-51880 | biostudies-arrayexpress
Project description:Purpose: Epigenetic mechanisms and alterations in uveal melanoma (UM) development are still not well understood. In this pilot study, histone posttranslational modifications (PTMs), which are epigenetic mechanisms regulating gene expression, were analyzed in UM formalin-fixed paraffin-embedded (FFPE) tissues and control tissue as well as in UM cell lines and healthy melanocytes to provide a deeper insight into the pathogenesis of UM and the potentially prognostic relevance of these molecular markers. Methods: FFPE tissue of UM (n=24) and normal choroid (n=4) as well as human UM cell lines (n=7), human skin melanocytes (n=6) and uveal melanocytes (n=2), were analyzed by a quantitative mass spectrometry (MS) approach.
2024-02-14 | PXD043551 | Pride