A compact VEGF signature associated with distant metastases and poor outcomes
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE3521 | GEO | 2009/03/31
SECONDARY ACCESSION(S): PRJNA93569
REPOSITORIES: GEO
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Project description:Results When compared with each other, primary tumors and regional metastases showed statistically indistinguishable gene expression patterns. Supervised analyses comparing patients with distant metastases versus primary tumors or regional metastases showed that the distant metastases were distinct and distinguished by the lack of expression of fibroblast/mesenchymal genes, and by the high expression of a 13-gene profile (that is, the âvascular endothelial growth factor (VEGF) profileâ) that included VEGF, ANGPTL4, ADM and the monocarboxylic acid transporter SLC16A3. At least 8 out of 13 of these genes contained HIF1α binding sites, many are known to be HIF1α-regulated, and expression of the VEGF profile correlated with HIF1α IHC positivity. The VEGF profile also showed prognostic significance on tests of sets of patients with breast and lung cancer and glioblastomas, and was an independent predictor of outcomes in primary breast cancers when tested in models that contained other prognostic gene expression profiles and clinical variables. Conclusions These data identify a compact in vivo hypoxia signature that tends to be present in distant metastasis samples, and which portends a poor outcome in multiple tumor types. Microarrays and immunohistochemistry were used to analyze primary breast tumors, regional (lymph node) metastases, and distant metastases in order to identify biological features associated with distant metastases.
2009-03-31 | E-GEOD-3521 | biostudies-arrayexpress
Project description:The identification of novel tumor-specific markers may improve understanding of melanoma progression and prognostic accuracy. Whole genome expression profiling of 46 primary melanomas, 12 metastases, and 16 normal skin samples using Affymetrix U133 PLUS 2.0 array generated gene lists including both known and new melanoma genes. The molecular genetic alterations contributing to the pathogenesis of melanoma are incompletely defined and few independent prognostic features have been identified beyond the pathologic characteristics of the primary tumor. Early stage melanoma is frequently curable, in contrast to the inferior prognosis of melanomas with regional lymph nodes involvement and the incurability of distant metastatic disease. The identification of novel tumor-specific markers may improve our understanding of melanoma progression and prognostic accuracy. To find differentially expressed genes that can distinguish melanoma from normal tissue, we performed a whole genome expression profiling of 46 primary melanoma samples, 12 regional or distant metastases, and 16 normal skin samples using Affymetrix U133 2.0 Plus array. Our study generated lists of differentially expressed genes in melanoma and identified novel prognostic marker HMGA2. It is a novel, highly overexpressed melanoma gene associated with poor prognosis. The overexpression of HMGA2 is strongly associated with regional and distant metastases and serves as an independent predictor of disease-free survival and overall survival in melanoma.
2012-06-08 | GSE15605 | GEO
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:The identification of novel tumor-specific markers may improve understanding of melanoma progression and prognostic accuracy. Whole genome expression profiling of 46 primary melanomas, 12 metastases, and 16 normal skin samples using Affymetrix U133 PLUS 2.0 array generated gene lists including both known and new melanoma genes. The molecular genetic alterations contributing to the pathogenesis of melanoma are incompletely defined and few independent prognostic features have been identified beyond the pathologic characteristics of the primary tumor. Early stage melanoma is frequently curable, in contrast to the inferior prognosis of melanomas with regional lymph nodes involvement and the incurability of distant metastatic disease. The identification of novel tumor-specific markers may improve our understanding of melanoma progression and prognostic accuracy. To find differentially expressed genes that can distinguish melanoma from normal tissue, we performed a whole genome expression profiling of 46 primary melanoma samples, 12 regional or distant metastases, and 16 normal skin samples using Affymetrix U133 2.0 Plus array. Our study generated lists of differentially expressed genes in melanoma and identified novel prognostic marker HMGA2. It is a novel, highly overexpressed melanoma gene associated with poor prognosis. The overexpression of HMGA2 is strongly associated with regional and distant metastases and serves as an independent predictor of disease-free survival and overall survival in melanoma. Melanoma samples were obtained through an IRB-approved protocol using informed consent at the University of Michigan Multidisciplinary Melanoma Clinic. A portion of pigmented lesions clinically suspicious for melanoma and known melanoma were sampled by punch biopsy at the time of excision. The punch biopsy was bisected; half was sent to for clinical diagnosis and the other half along with adjacent normal skin when available immediately snap-frozen in liquid nitrogen. Snap-frozen tissue was embedded in OCT (TissueTek) followed by frozen sectioning and H&E slide preparation. The slides were evaluated by dermatopathologist who identified areas with greater than 70% tumor cellularity, which were sampled for RNA extraction. Primary melanomas and melanoma metastases were derived from different patients. Metastatic samples included lymph nodes (n=8), subcutaneous soft tissue (n=2), spleen (n=1), and small intestine (n=1).
2012-06-07 | E-GEOD-15605 | biostudies-arrayexpress
Project description:Lymph node involvement is a major prognostic variable in breast cancer. Whether the molecular mechanisms that drive breast cancer cells to colonize lymph nodes are shared with their capacity to form distant metastases is yet to be established. In a transcriptomic survey aimed at identifying molecular factors associated with lymph node involvement of ductal breast cancer, we found that luminal differentiation, assessed by the expression of estrogen receptor (ER) and/or progesterone receptor (PR) and GATA3, was only infrequently lost in node-positive primary tumors and in matched lymph node metastases. The transcription factor GATA3 critically determines luminal lineage specification of mammary epithelium and is widely considered a tumor and metastasis suppressor in breast cancer. Strong expression of GATA3 and ER in a majority of primary node-positive ductal breast cancer was corroborated by quantitative RT-PCR and immunohistochemistry in the initial sample set, and by immunohistochemistry in an additional set from 167 patients diagnosed of node-negative and positive primary infiltrating ductal breast cancer, including 102 samples from loco-regional lymph node metastases matched to their primary tumors, as well as 37 distant metastases. These observations suggest that loss of luminal differentiation is not a major factor driving the ability of breast cancer cells to colonize regional lymph nodes. The transcriptomic study comprises 16 samples from Lymph node metastasis from infiltrating ductal breast carcinoma, 18 samples from Primary node-positive infiltrating ductal,7 samples from Primary node-negative infiltrating ductal and 3 samples from Unaffected lymph node were included. Their RNA was isolated and prepared for hybridization to human Affymetrix GeneChip arrays.
2013-03-05 | E-GEOD-44408 | biostudies-arrayexpress
Project description: Lymph node involvement is a major prognostic variable in breast cancer. Whether the molecular mechanisms that drive breast cancer cells to colonize lymph nodes are shared with their capacity to form distant metastases is yet to be established. In a transcriptomic survey aimed at identifying molecular factors associated with lymph node involvement of ductal breast cancer, we found that luminal differentiation, assessed by the expression of estrogen receptor (ER) and/or progesterone receptor (PR) and GATA3, was only infrequently lost in node-positive primary tumors and in matched lymph node metastases. The transcription factor GATA3 critically determines luminal lineage specification of mammary epithelium and is widely considered a tumor and metastasis suppressor in breast cancer. Strong expression of GATA3 and ER in a majority of primary node-positive ductal breast cancer was corroborated by quantitative RT-PCR and immunohistochemistry in the initial sample set, and by immunohistochemistry in an additional set from 167 patients diagnosed of node-negative and –positive primary infiltrating ductal breast cancer, including 102 samples from loco-regional lymph node metastases matched to their primary tumors, as well as 37 distant metastases. These observations suggest that loss of luminal differentiation is not a major factor driving the ability of breast cancer cells to colonize regional lymph nodes.
2013-03-05 | GSE44408 | GEO
Project description:The majority of patients with squamous cell lung cancer (SCC) die because of metastatic disease. The genomic mechanisms underlying this metastatic behaviour are underexposed. We analyzed a cohort of patients with primary squamous cell carcinoma (SCC) using array-based comparative genomic hybridization (aCGH) to identify which genomic aberrations were related metastatic behaviour. The cohort consisted of 34 patients with a follow-up of at least 5 years, including 15 without any metastases, 8 with metastases in regional lymph nodes only, and 11 with metastases exclusively in distant organs within two years after surgery. Common alterations observed in at least 40% of all SCC were gains at 3q13-q29, 5p11-p15, 8q24, 19q13, 20p12-p13, 22q11-q13, and losses at 3p12-p14, 3p24, 4p15, 4q33-q35, 5q14-q23, 5q31-q35, 8p21-p22, 9p21-p24. Amplifications were observed at 2p15-p16, 3q24-q29, 8p11-p12, 8q23-q24, and 12p12, containing candidate oncogenes such as BCL11A, REL, ECT2, PIK3CA, ADAM9, MYC, and KRAS. Gains at 7q36, 8p12, 10q22, 12p12, loss at 4p14 and homozygous deletions at 4q33-q34.1 occurred significantly more frequent in SCC from patients with lymph node metastases. SCC from patients with distant metastases showed a significantly higher frequency of gain at 8q22-q24 and loss of 8p23 and 13q21, and a significantly lower frequency of gain at 2p12 and 2p16 and loss at 11q25 as compared to SCC from patients without metastases. In conclusion, we identified specific genomic aberrations in primary SCC that are related to lymph node or distant metastases. These loci can be further explored for their potential use as predictive or prognostic markers.
2008-10-01 | GSE12280 | GEO
Project description:Small intestinal neuroendocrine tumors (SI-NETs) arise from serotonin-producing enterochromaffin cells. SI-NETs are often well-differentiated tumors and most patients have regional or distant metastases at initial presentation. MicroRNAs (miRs) are post-transcriptional regulators which are important in diverse biological processes and can function as tumor suppressor genes or oncogenes. This study aims to identify an exclusive SI-NETs miR profile that may have a critical role in development, diagnosis, prognosis and progression of these malignancies. Five human NET cell lines, one octreotide-treated CNDT2.5 cells, one microdissected normal enterochromaffin cells, three snap-frozen normal ileum specimens and 15 SI-NET specimens at different stage of malignancy, five primary tumors, five mesentery metastases and five liver metastases, were included in this study. Total RNA was hybridized onto Affymetrix GeneChipM-BM-. miR arrays for genome-wide profiling. Array data summarization, normalization, and quality control were performed using miRNA QC Tool software.
2013-03-01 | E-GEOD-33568 | 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.
2014-07-01 | GSE43934 | GEO
Project description:Small intestinal neuroendocrine tumors (SI-NETs) arise from serotonin-producing enterochromaffin cells. SI-NETs are often well-differentiated tumors and most patients have regional or distant metastases at initial presentation. MicroRNAs (miRs) are post-transcriptional regulators which are important in diverse biological processes and can function as tumor suppressor genes or oncogenes. This study aims to identify an exclusive SI-NETs miR profile that may have a critical role in development, diagnosis, prognosis and progression of these malignancies.
2012-11-08 | E-MTAB-862 | biostudies-arrayexpress