DNA methylation analysis of melanoma progression to brain metastasis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE44661 | GEO | 2013/09/19
SECONDARY ACCESSION(S): PRJNA190805
REPOSITORIES: GEO
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Project description:Melanoma is one of the most aggressive and treatment-resistant cancers. It represents the most life-threatening neoplasm of the skin, and its incidence has been increasing for the last three decades. Melanoma evolves from the local transformation of melanocytes to primary tumors, which can metastasize to multiple organs. Brain metastases represent one of the most significant causes of death in cutaneous melanoma patients. Despite aggressive multi-modality threapy, patients with melanoma brain metastasis have a median survival of less than a year, with a majority of these patients dying as a result of their intracranial disease. To identify alterations in gene expression related to brain metastasis, we used Affymetrix expression arrays to assess differentially expressed genes in melanocytes, lymph node metastases, and brain metastases. Total RNA from twenty-two specimens representing normal melanocytes (n=3), melanoma lymph node metastasis (n=12), and melanoma brain metastasis (n=7) was extracted and analyzed by Affymetrix expression arrays. Melanocytes specimens were used as control samples. Melanocytes were acquired from Invitrogen (LifeTechnologies). Metastatic melanoma specimens were taken from different patients, established as cell lines in the John Wayne Cancer Institute. Early passages (less than 6) were used to perform expression analysis.
2013-09-19 | E-GEOD-44660 | biostudies-arrayexpress
Project description:Melanoma is one of the most aggressive and treatment-resistant cancers. It represents the most life-threatening neoplasm of the skin, and its incidence has been increasing for the last three decades. Melanoma evolves from the local transformation of melanocytes to primary tumors, which can metastasize to multiple organs. Brain metastases represent one of the most significant causes of death in cutaneous melanoma patients. Despite aggressive multi-modality threapy, patients with melanoma brain metastasis have a median survival of less than a year, with a majority of these patients dying as a result of their intracranial disease. We aimed to find brain metastasis-specific molecular markers. To identify alterations in DNA methylation related to brain metastasis, we used Illumina 450K BeadChips to assess differentially methylated regions in melanocytes, primary melanomas, lymph node metastases, and brain metastases. Bisulphite-converted DNA from 40 specimens was hybridised to the Illumina Infinium 450k Human Methylation BeadChip.
2013-09-19 | E-GEOD-44661 | biostudies-arrayexpress
Project description:Melanoma is one of the most aggressive and treatment-resistant cancers. It represents the most life-threatening neoplasm of the skin, and its incidence has been increasing for the last three decades. Melanoma evolves from the local transformation of melanocytes to primary tumors, which can metastasize to multiple organs. Brain metastases represent one of the most significant causes of death in cutaneous melanoma patients. Despite aggressive multi-modality threapy, patients with melanoma brain metastasis have a median survival of less than a year, with a majority of these patients dying as a result of their intracranial disease. To identify alterations in gene expression related to brain metastasis, we used Affymetrix expression arrays to assess differentially expressed genes in melanocytes, lymph node metastases, and brain metastases.
2013-09-19 | GSE44660 | GEO
Project description:Comparison between the copy number of differentially methylated sites between lymph node metastasis from melanoma patients with good prognosis and melanoma brain metastasis. All samples are taken from different patients, and were established as cell lines in the John Wayne Cancer Institute. Sixteen metastatic melanomas were run on Affymetrix Genome-Wide Human SNP Array 6.0. Lymph node metastases and brain metastases genetic copy number variations were compared.
2013-09-19 | E-GEOD-44019 | biostudies-arrayexpress
Project description:Circulating tumor cells (CTCs) are critical in the development of distant organ tumor metastasis, and are associated with advanced cancer stage and poor patient outcome. Here, we present the first genome-wide nucleotide-level characterization of CTCs. Our single-nucleotide polymorphism (SNP) analysis in patients with melanoma involved: 1) global comparative genomic analysis of CTCs and matched regional metastases, 2) identification of key genomic aberrations in CTCs, 3) verification of these target genes in aggressive distant tumor metastases, and 4) evidence of selective expression and functional consequence of CTC-associated genes in melanomas. We report 131 aberrant loci in CTCs that are potentially pro-metastatic, and show that such expression of a 5-marker gene panel (CSMD2, CNTNAP5, FLJ14051, ADAM6, TRPM2) in melanomas confers prognostic utility. Successful treatment of melanoma requires understanding of the metastatic process and identification of patients with tumors most likely to develop aggressive metastatic disease. Melanomas are heterogeneous, and CTCs have long been recognized as vehicles for cancer spread, representing particularly aggressive tumor clones that can evolve into successful clinical metastases. Elucidation of genomic aberrations in CTCs will aid in the development of prognostic biomarkers and therapeutic strategies to target CTCs to prevent or control distant cancer spread. This study provides the first detailed genomic confirmation of the close relation between CTCs and tumor metastases, and illustrates how CTCs can be utilized as a novel approach and rational source for identification of pro-metastatic genes in cancer research. Three individual patient cohorts were utilized in the study. CNV and LOH loci were evaluated initially in metastatic melanoma patients (n=13) in a discovery cohort. SNP loci that harbored CNV/LOH in CTCs were then separately verified for: (a) presence in distant organ metastasis (AJCC Stage IV melanoma) (n=27), and (b) relevance to prognosis in regional melanoma metastasis (AJCC Stage III melanoma) (n=35). The first discovery patient cohort group was utilized for capture of CTCs, and consisted of peripheral blood mononuclear cell (PBMC) and tumor specimens from metastatic melanoma patients (n=13). CTC-related loci were verified in a second cohort of patients with Stage IV distant organ metastases (n=27), including 15 brain, 4 lung, and 8 gastrointestinal (bowel, liver) metastases. The third patient cohort consisted of early passage (<12) established melanoma cell lines derived from 35 regional melanoma metastases (Stage III) for evaluation of the prognostic utility of the CTC-associated aberrant loci.
2014-07-01 | E-GEOD-43934 | biostudies-arrayexpress
Project description:Development of melanoma brain metastasis is caused by an interaction between tumor cells and normal cells in the brain microenvironment. miRNAs delivered by exosomes derived from the tumor cells seem to prime the brain microenvironment, prior to extravasation of tumor cells into the brain. We investigated miRNA in exosomes extracted from normal (astrocytes, melanocytes) and metastatic melanoma cells (brain, skin and lymph node metastasis). We have discovered that miR-146a-5p is an important player in brain metastatic development: this miRNA was highly upregulated in exosomes from melanoma brain metastasis cells, compared to normal cells.
2023-09-29 | E-MTAB-11798 | biostudies-arrayexpress
Project description:An improved understanding of the molecular pathogenesis of brain metastases, one of the most common and devastating complications of advanced melanoma, may identify and prioritize rational therapeutic approaches for this disease. In particular, the identification of molecular differences between brain and extracranial metastases would support the need for the development of organ-specific therapeutic approaches. Hotspot mutations, copy number variations (CNV), global mRNA expression patterns, and protein expression and activation, quantitatively analyzed by molecular inversion probe arrays, microarrays and reverse phase protein array (RPPA) were evaluated in pairs of melanoma brain metastases and extracranial metastases from patients who had undergone surgical resection for both types of tumors. Seventy-two samples from 52 brain (except for patient 01, who had a spinal cord metastasis) and extracranial metastases of melanoma were analyzed. Available biological replicates (different parts of the same tumor) were included.
2014-05-08 | E-GEOD-50493 | biostudies-arrayexpress
Project description:Brain metastasis is a significant cause of morbidity and mortality in multiple cancer types and represents an unmet clinical need. The mechanisms that mediate metastatic cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the highest rate of brain metastasis among common cancer types, is an ideal model to study how cancer cells adapt to the brain parenchyma. We utilized pairs of brain metastasis-derived (BM) and non-brain metastasis-derived (NBM) melanoma short term cultures (STCs) obtained from the same patient. We performed TMT based multiplexed analysis of these cell lines using off-line fractionation to increase our proteomics coverage. Our unbiased proteomics analysis of these melanoma short-term cultures revealed that proteins implicated in neurodegenerative pathologies are differentially expressed in melanoma cells explanted from brain metastases compared to those derived from extracranial metastases. We showed that melanoma cells require amyloid beta for growth and survival in the brain parenchyma. Melanoma-secreted A beta activates surrounding astrocytes to a pro-metastatic, anti-inflammatory phenotype and prevents phagocytosis of melanoma by microglia. Finally, we demonstrate that pharmacological inhibition of Abeta decreases brain metastatic burden.
2022-02-10 | MSV000088814 | MassIVE
Project description:An improved understanding of the molecular pathogenesis of brain metastases, one of the most common and devastating complications of advanced melanoma, may identify and prioritize rational therapeutic approaches for this disease. In particular, the identification of molecular differences between brain and extracranial metastases would support the need for the development of organ-specific therapeutic approaches. Hotspot mutations, copy number variations (CNV), global mRNA expression patterns, and protein expression and activation, quantitatively analyzed by mass-array genotyping, molecular inversion probe arrays, microarrays and reverse phase protein array (RPPA) were evaluated in pairs of melanoma brain metastases and extracranial metastases from patients who had undergone surgical resection for both types of tumors. Somatic copy number variation (CNV) in 47 melanoma brain metastases (BM, except for patient 01, who had a spinal cord metastasis) and extracranial metastases (EM) were analyzed by molecular inversion probe (MIP) array (Affymetrix OncoScan FFPE Express 2.0). DNA were extracted from regions with >70% viable tumor cells from formalin-fixed and paraffin-embedded (FFPE) tissues. Of the 47 tumor samples, 22 were matched BM and EM from the same patients. In addition, 24 DNA samples from normal tissues were included as diploid controls.
2014-05-08 | E-GEOD-50495 | biostudies-arrayexpress
Project description:We established a model of human melanoma metastasis to identify differentially expressed genes in brain metastasis, compared to cutaneous melanoma from which they were developed. Such genes may control brain metastasis. The identification and characterization of these genes would advance the understanding of the metastatic process and may lead to new diagnostics and therapeutic approach. Brain metastases occur in almost 40% of melanoma patients. The median survival of such patients does not exceed a few months. Very little information is available on mechanisms underlying the progression of melanoma towards brain metastasis. The function, and significance of the various factors involved in melanoma progression must be deciphered using relevant models. Currently, most human melanoma brain metastasis models consist of xenografted cells inoculated into immune-deficient mice mainly by intracarotid or intra-cardiac administration. We generated a reproducible melanoma brain metastasis model, consisting of brain-metastasizing variants and local, sub-dermal variants that originate from the same melanomas thus sharing a common genetic background. The brain metastasizing variants were obtained by intra-cardiac inoculation. One of the brain metastasizing variants when inoculated sub-dermally yielded spontaneous brain dormant micrometastasis. Cells from the spontaneous brain micrometastasis when removed from the brain microenvironment proliferate very well in vitro and generate tumors in the skin being the orthotopic organ site. The brain metastasis and micro-metastasis cells expressed higher levels of ANGPTL4, COX-2, MMP1, MMP2 and PRAME and lower levels of CLDN1, CYR61 and IL-6R than the cutaneous variants. These gene products may be involved in melanoma brain metastasis and may serve as novel brain metastasis biomarkers and targets for therapy. 8 Samples (arrays) were analyzed. We generated pairwise comparisons between cutaneous and brain metastatic variants of the same genetic background, using Partek Genomics Suite, in the three melanoma models. Genes with pM-bM-^IM-$5% and a fold-change difference of M-bM-^IM-%1.25 or <-1.25 were selected.
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