Abstract 1572: Transformation from melanocytes or nevi into melanoma: models based on a transcriptome meta-analysis
Authors: Ortega-Bernal Daniel , Rangel-Escareño Claudia , Arechaga-Ocampo Elena , Rosa Claudia H. Gonzalez-De la 
Published: July 2017

Abstract
Background
Melanoma is the most aggressive skin cancer due to its ability to rapidly metastasize and resist radio- and chemotherapy. The frequency of this disease has increased 400% worldwide in the last 30 years. There are 2 ways to develop melanoma: direct transformation of melanocytes into melanoma and the nevus as an intermediary. Here, we used a computational strategy based on transcriptome meta-analysis to identify the pathways involved in the 2 possible ways by which cells may transform to melanoma.
Methods
Affymetrix HU 133A Plus 2.0 microarray files (50 in total) were collected from the Gene Expression Omnibus database for the meta-analysis, representing melanocytes, nevi and stage I, II, and III melanoma. Differential expression was analyzed using linear models and the limma library. The analysis focused on 3 comparisons: nevi vs. melanocytes; melanoma vs. nevi; and melanoma vs. melanocytes. Transcripts with a log fold change of &lt;-1/&gt;1 (B-statistic &gt;3) were included in the study. Functional enrichment analysis identified the most deregulated pathway. Genes resulting from the intersection of the melanoma vs. nevi and melanoma vs. melanocytes comparisons were used as possible biomarkers of transformation and analyzed by IPA.
Gene signature identification
In melanoma vs. nevi comparison, 1881 expressed genes were differentially expressed, of which only 888 were used to generate the transformation model and to perform functional enrichment. Consistent with the phenomenon of malignant transformation, we identified 3 pathways associated with cell cycle checkpoint control that exhibited decreased activity. Conversely, the pathways that exhibited increased activity, Estrogen-mediated S-phase Entry and Cyclins and Cell Cycle Regulation, promote cell cycle progression. In melanoma vs. Melanocytes comparison, 4112 expressed genes were differentially expressed (2310 downregulated and 1802 upregulated), 1099 of which intersected with the nevi vs. melanocytes comparison. The 682 genes intersecting the melanoma vs. nevi comparison were removed. Thus, 2331 genes were used to perform enrichment analysis. The main result was the decreased activity of the cAMP-mediated signaling pathway. The intersection of both comparisons (682 genes), was used to identify 22 genes upregulated whose product is a secreted protein. Two of these genes were previously reported as potential biomarkers in neoplasia, cytokines CXCL8 and CXCL16, supporting the quality of our analysis.
Conclusions
Our analysis, in agreement with previously reported results, identify CXCL8 as biomarker of melanoma, and also identified new biomarkers, including CXCL16, MMP19, BIVM, and FAM60A. A better understanding of the specific molecular alterations causally involved in this disease may lead to new biomarkers and pathways involved in the transformation for this currently incurable malignancy.
Citation Format: Daniel Ortega-Bernal, Claudia Rangel-Escareño, Elena Arechaga-Ocampo, Claudia H. Gonzalez-De la Rosa. Transformation from melanocytes or nevi into melanoma: models based on a transcriptome meta-analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1572. doi:10.1158/1538-7445.AM2017-1572