Dataset Information

Expression analysis of genes and pathways associated with liver metastases of the uveal melanoma.

ABSTRACT: BACKGROUND: Uveal melanoma is an aggressive cancer which has a high percentage metastasizing to the liver, with a worse prognosis. Identification of patients at high risk of metastases may provide information for early detection of metastases and treatment. METHODS: Expression profiling of ocular tumor tissues from 46 liver metastatic uveal melanoma samples and 45 non-metastatic uveal melanoma samples were got from GEO database. Bioinformatic analyses such as the Gene Oncology and Kyoto Encyclopedia of Genes and Genomes were used to identify genes and pathways specifically associated with liver metastases of the uveal melanoma. RESULTS: A total of 1138 probes were differentially expressed in two group samples. All differential gene interactions in the Signal-Net were analyzed. Of them, 768 probes were up-regulated and 370 down-regulated. They mainly participated in 125 GO terms and 16 pathways. Of the genes differentially expressed between two group cancers, HTR2B, CHL1, the ZNF family, YWHAZ and FYN were the most significantly altered. CONCLUSIONS: Bioinformatics may help excavate and analyze large amounts of data in microarrays by means of rigorous experimental planning, scientific statistical analysis and collection of complete data about liver metastases of uveal melanoma patients. In the present study, a novel differential gene expression pattern was constructed and advanced study will provide new targets for diagnosis and mechanism of uveal melanoma liver metastases.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC4015751 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Expression analysis of genes and pathways associated with liver metastases of the uveal melanoma.

Zhang Yuanyuan Y Yang Yong Y Chen Lei L Zhang Jianhong J

BMC medical genetics 20140305

<h4>Background</h4>Uveal melanoma is an aggressive cancer which has a high percentage metastasizing to the liver, with a worse prognosis. Identification of patients at high risk of metastases may provide information for early detection of metastases and treatment.<h4>Methods</h4>Expression profiling of ocular tumor tissues from 46 liver metastatic uveal melanoma samples and 45 non-metastatic uveal melanoma samples were got from GEO database. Bioinformatic analyses such as the Gene Oncology and K ...[more]

PMID: 24597767

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Project description:The profound disparity in response to immune checkpoint blockade (ICB) by cutaneous melanoma (CM) and uveal melanoma (UM) patients is not well understood. Therefore, we characterized metastases of CM and UM from the same metastatic site (liver), in order to dissect the potential underlying mechanism in differential response on ICB. Tumor liver samples from CM (n=38) and UM (n=28) patients were analyzed at the genomic (whole exome sequencing), transcriptional (RNA sequencing) and protein (immunohistochemistry and GeoMx Digital Spatial Profiling) level. Comparison of CM and UM metastases from the same metastatic site revealed that, although originating from the same melanocyte lineage, CM and UM differed in somatic mutation profile, copy number profile, tumor mutational burden (TMB) and consequently predicted neoantigens. A higher melanin content and higher expression of the melanoma differentiation antigen MelanA was observed in liver metastases of UM patients. No difference in B2M and human leukocyte antigen-DR (HLA-DR) expression was observed. A higher expression of programmed cell death ligand 1 (PD-L1) was found in CM compared with UM liver metastases, although the majority of CM and UM liver metastases lacked PD-L1 expression. There was no difference in the extent of immune infiltration observed between CM and UM metastases, with the exception of a higher expression of CD163 (p<0.0001) in CM liver samples. While the extent of immune infiltration was similar for CM and UM metastases, the ratio of exhausted CD8 T cells to cytotoxic T cells, to total CD8 T cells and to Th1 cells, was significantly higher in UM metastases. While TMB was different between CM and UM metastases, tumor immune infiltration was similar. The greater dependency on PD-L1 as an immune checkpoint in CM and the identification of higher exhaustion ratios in UM may both serve as explanations for the difference in response to ICB. Consequently, in order to improve current treatment for metastatic UM, reversal of T cell exhaustion beyond programmed cell death 1 blockade should be considered.

Project description:This study reports the role played by the mutation status of Uveal Melanoma (UM) in relation to hepatic metastatic patterns as seen on imaging modalities. Radiological images were obtained from 123 patients treated at the Erasmus Medical Center Rotterdam or the Rotterdam Eye Hospital. Radiological images were derived from either computed tomography or magnetic resonance imaging. Hepatic metastatic patterns were classified by counting the number of metastases found in the liver. Miliary metastatic pattern (innumerable small metastases in the entire liver) was analyzed separately. Mutation status was determined in 85 patients. Median disease-free survival (DFS) and survival with metastases differed significantly between each of the metastatic patterns (respectively, p = 0.009, p < 0.001), both in favor of patients with less hepatic metastases. The mutation status of the primary tumor was not correlated with any hepatic tumor profiles (p = 0.296). Of the patients who had a solitary metastasis (n = 18), 11 originated from a primary BAP1-mutated tumors and one from a primary SF3B1-mutated tumor. Of the patients who had a miliary metastasis pattern (n = 24), 17 had a primary BAP1-mutated tumor and two had a primary SF3B1-mutated tumor. Chromosome 8p loss was significantly more in patients with more metastases (p = 0.045). Moreover, the primary UMs of patients with miliary metastases harbored more chromosome 8p and 1p loss, compared to patients with single solitary metastasis (p = 0.035 and p = 0.026, respectively). In conclusion, our study shows that there is an inverse correlation of the number of metastasis with the DFS and metastasized survival, indicating separate growth patterns. We also revealed that the number and type of metastases is irrelevant to the prognostic mutation status of the tumor, showing that both BAP1- and SF3B1-mutated UM can result in solitary and miliary metastases, indicating that other processes lay ground to the different metastatic patterns.

Dataset Information

Expression analysis of genes and pathways associated with liver metastases of the uveal melanoma.

Publications

Expression analysis of genes and pathways associated with liver metastases of the uveal melanoma.

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