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Pathologic and gene expression features of metastatic melanomas to the brain.

ABSTRACT: The prognosis of metastatic melanomas to the brain (MBM) is variable with prolonged survival in a subset. It is unclear whether MBM differ from extracranial metastases (EcM) and primary melanomas (PrM).To study the biology of MBM, histopathologic analysis of tumor blocks from patients' craniotomy samples and whole-genome expression profiling (WGEP) with confirmatory immunohistochemistry were performed.High mononuclear infiltrate and low intratumoral hemorrhage were associated with prolonged overall survival (OS). Pathway analysis of WGEP data from 29 such craniotomy tumor blocks demonstrated that several immune-related BioCarta gene sets were associated with prolonged OS. WGEP analysis of MBM in comparison with same-patient EcM and PrM showed that MBM and EcM were similar, but both differ significantly from PrM. Immunohistochemical analysis revealed that peritumoral CD3? and CD8? cells were associated with prolonged OS.MBMs are more similar to EcM compared with PrM. Immune infiltrate is a favorable prognostic factor for MBM.

SUBMITTER: Hamilton R

PROVIDER: S-EPMC3901051 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Pathologic and gene expression features of metastatic melanomas to the brain.

Hamilton Ronald R Krauze Michal M Romkes Marjorie M Omolo Bernard B Konstantinopoulos Panagiotis P Reinhart Todd T Harasymczuk Malgorzata M Wang YangYang Y Lin Yan Y Ferrone Soldano S Whiteside Theresa T Bortoluzzi Stephanie S Werley Jonette J Nukui Tomoko T Fallert-Junecko Beth B Kondziolka Douglas D Ibrahim Joseph J Becker Dorothea D Kirkwood John J Moschos Stergios S

Cancer 20130521 15

<h4>Background</h4>The prognosis of metastatic melanomas to the brain (MBM) is variable with prolonged survival in a subset. It is unclear whether MBM differ from extracranial metastases (EcM) and primary melanomas (PrM).<h4>Methods</h4>To study the biology of MBM, histopathologic analysis of tumor blocks from patients' craniotomy samples and whole-genome expression profiling (WGEP) with confirmatory immunohistochemistry were performed.<h4>Results</h4>High mononuclear infiltrate and low intratum ...[more]

PMID: 23695963

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Project description:The molecular biology of metastatic potential in melanoma has been studied many times previously and changes in the expression of many genes have been linked to metastatic behaviour. What is lacking is a systematic characterization of the regulatory relationships between genes whose expression is related to metastatic potential. Such a characterization would produce a molecular taxonomy for melanoma which could feasibly be used to identify epigenetic mechanisms behind changes in metastatic behaviour. To achieve this we carried out three separate DNA microarray analyses on a total of 86 cultures of melanoma. Significantly, multiple testing correlation revealed that previous reports describing correlations of gene expression with activating mutations in BRAF or NRAS were incorrect and that no gene expression patterns correlate with the mutation status of these MAPK pathway components. Instead, we identified three different sample cohorts (A, B and C) and found that these cohorts represent melanoma groups of differing metastatic potential. Cohorts A and B were susceptible to TGFbeta-mediated inhibition of proliferation and had low motility. Cohort C was resistant to TGFb and demonstrated high motility. Meta-analysis of the data against previous studies linking gene expression and phenotype confirmed that cohorts A and C represent transcription signatures of weakly and strongly metastatic melanomas, respectively. Gene expression co-regulation suggested that signalling via TGFbeta-type and Wnt pathways underwent considerable change between cohorts. These results suggest a model for the transition from weakly to strongly metastatic melanomas in which TGFbeta-type signalling upregulates genes expressing vasculogenic/extracellular matrix remodeling factors and Wnt signal inhibitors, coinciding with a downregulation of genes downstream of Wnt signalling. Experiment Overall Design: In this (Zürich) data set three melanocyte cultures and twelve melanoma cultures were analyzed.

Dataset Information

Pathologic and gene expression features of metastatic melanomas to the brain.

Publications

Pathologic and gene expression features of metastatic melanomas to the brain.

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