Genetics and genomics of melanoma

Abstract

The rapidly increasing incidence of melanoma, coupled with its highly aggressive metastatic nature, is of urgent concern. In order to design rational therapies, it is of critical importance to identify the genetic determinants that drive melanoma formation and progression. To date, signaling cascades emanating from the EGF receptor, c-MET and other receptors are known to be altered in melanoma. Important mutations in signaling molecules, such as BRAF and N-RAS, have been identified. In this review, some of the major genetic alterations and signaling pathways involved in melanoma will be discussed. Given the great deal of genetic heterogeneity observed in melanoma, it is likely that many more genetic determinants exist. Through the use of powerful genomic technologies, it is now possible to identify these additional genetic alterations in melanoma. A critical step in this analysis will be culling bystanders from functionally important drivers, as this will highlight genetic elements that will be promising therapeutic targets. Such technologies and the important points to consider in understanding the genetics of melanoma will be reviewed.

Figure 1. CDKN2A encodes two important regulators of melanoma

The CDKN2A gene encodes both p16^INK4A and p14^ARF, which control the RB and p53 pathways, respectively. Germline alterations in CDKN2A are common events in familial melanoma. RB: Retinoblastoma.

Figure 2. Signaling pathways involved in melanoma

Various receptors can activate the ERK and PI3K pathways, both important signaling cascades in melanoma that control cell proliferation and survival. In addition, signaling pathways important for melanocyte regulation may be co-opted in tumors. EGFR: Endothelial growth factor receptor; MMP: Matrix metalloproteinase.

Figure 3. Filtering of genomic alterations identifies genetic determinants of melanoma

The melanoma cancer genome is composed of genomic, epigenomic and transcriptomic alterations found in melanoma. Bystanders may be culled from true genetic drivers of disease through integration of different data sets, cross-species comparison for evolutionarily conserved alterations and analysis in cell lines. These filtering methods have been used successfully to identify MITF and Nedd9 as important regulators of melanoma. All genes of interest must undergo extensive functional and clinicopathological validation in order to identify genetic determinants of melanoma that may serve as therapeutic targets or disease biomarkers.