Abstract 4570: Functional analysis of gene expression profiling of primary and metastatic melanoma: Possible implications from BRAF mutant and wild-type cell lines
Authors: Richard Essner, Ke Wei Gong, Bartosz Chmielowski, Richard Finn, William D. Tap, Dennis Slamon
Journal: Cancer Research (2012)

Abstract Metastatic melanoma is largely refractory to existing therapies and has a very poor prognosis. Despite the recent development of new therapies, the median survival rate is only 6-9 months and 5-year survival is less than 5%. Better understanding of melanoma biology, specifically the gene expression profile between primary and metastatic melanoma, may provide useful information for developing new therapeutic approaches to this disease. The gene expression profile from 89 primary and metastatic melanoma tissues was investigated by cDNA microarray. 8261 differentially expressed genes were identified between primary and metastatic melanoma at a statistical level p &amp;lt;0.01 and false discovery rate (FDR) of 5%. Panther Pathway Classification showed that the 8261 differentially expressed genes were enriched with genes which were involved in cytoskeletal regulation by Rho GTPase, inflammation mediated by chemokine and cytokine signaling pathways, Notch signalling pathways, p53 and angiogenesis pathways. The primary melanoma microarrays were analyzed according to the thickness of tumour. Group A: the thickness of a tumour less than 2.0 mm, 20 microarrays. Group B: the thickness of a tumour was equal or more than 2.0 mm, 11 microarrays. 981 genes were identified as differentially expressed between Group A and Group B at statistical level p&amp;lt;0.01 and FDR=5%. 657 out of 981 differentially expressed genes were shared with the 8261 differentially expressed genes. We believed these 657 genes were related to malignant potential of melanoma; they were enriched with genes which were involved in apoptosis, cell adhesion, cell cycle regulation and immune system processing. 218 out of the 657 genes overlapped with a published gene list (308 genes) which have been implicated in melanoma metastases. We further evaluated the expression of the transcription factor gene: ETV1. Ets variant 1 (ETV1) gene expression was significantly increased in metastatic melanoma and in primary melanoma with tumour thickness equal or more than 2.0 mm. We investigated the ETV1 expression in human melanoma cell lines. ETV1 mRNA level in 7 BRAF inhibitor sensitive cell lines was significantly lower than that in 6 BRAF inhibitor resistant cell lines (0.230±0.057 vs 0.927±0.6, p&amp;lt;0.0001). The ETV1 expression in BRAF-induced resistant melanoma cell lines was significantly (p&amp;lt;0.05) higher than in their parental cell lines. While a variety of genes are differentially expressed in primary and metastatic melanoma, the transcription factor–ETV1 gene may be an important target for study and as a therapeutic target as its expression may be associated with BRAF inhibitor resistance in melanoma cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4570. doi:1538-7445.AM2012-4570