Unknown,Transcriptomics,Genomics,Proteomics

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Comparative genomic hybridization of human primary melanomas

ABSTRACT: Malignant melanoma is an aggressive heterogeneous disease for which new biomarkers for diagnosis and clinical outcome are needed. We investigated by array-CGH the presence of DNA gains and losses to provide better genomic profile of primary malignant melanoma and to explore the possibility to distinguish metastatic from non metastatic melanomas using this technology. High resolution array-CGH (Agilent Technologies, Palo Alto, CA), with more than 40.000 probes, has been used to analyze 20 frozen tissues of vertical growth phase primary melanoma with a minimum follow-up time of 36 months. Eight patients developed nodal metastatic disease and twelve did not. For results validation, 83 additional melanoma samples with similar clinical characteristics were analysed by FISH. DNA copy number aberrations (CNA) were observed in 19 out of 20 cases. The most frequent changes were complete or partial losses in chromosomes 9 (12 cases, 60%) and 10 (9 cases, 45%), partial gains or trisomies of chromosome 7 (10 cases, 50%); and monosomy of chromosome 19 (7 cases, 35%). Sixty-four recurrent aberrant regions (SORIs) were precisely delimited and used as variables for clustering. Unsupervised Cluster analysis allowed the segregation of samples into two genomic groups that naturally fitted with the metastatic condition of the cases. Four of these aberrant regions were chosen for their biological interest and were confirmed as aberrant using FISH technique on fixed paraffin embedded tissues. Conclusion: Supervised classification allowed obtaining aberrations useful to separate samples with different clinical outcome. Obtained results are useful to improve the knowledge about melanoma tumorigenesis but unfortunately cannot be used as a marker for metastatic progression. Experiment Overall Design: Comparative experiment: pheripheral blood pool of ten healthy female donors: CONTROL vs. 20 Primary Vertigal Growth Phase Melanoma samples.

ORGANISM(S): Homo sapiens

SUBMITTER: Juan Cigudosa

PROVIDER: E-GEOD-11109 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

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Comparative genomic hybridization of human primary melanomas

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