Elsevier

European Journal of Cell Biology

Volume 93, Issues 1–2, January–February 2014, Pages 1-10
European Journal of Cell Biology

Mini Review
Oncogenes in melanoma: An update

https://doi.org/10.1016/j.ejcb.2013.12.002Get rights and content

Abstract

Melanoma is a highly aggressive tumour with poor prognosis in the metastatic stage. BRAF, NRAS, and KIT are three well-known oncogenes involved in melanoma pathogenesis. Targeting of mutated BRAF kinase has recently been shown to significantly improve overall survival of metastatic melanoma patients, underscoring the particular role of this oncogene in melanoma biology. However, recurrences regularly occur within several months, which supposedly involve further oncogenes. Moreover, oncogenic driver mutations have not been described for up to 30% of all melanomas. In order to obtain a more complete picture of the mutational landscape of melanoma, more recent studies used high-throughput DNA sequencing technologies. A number of new oncogene candidates such as MAPK1/2, ERBB4, GRIN2A, GRM3, RAC1, and PREX2 were identified. Their particular role in melanoma biology is currently under investigation. Evidence for the functional relevance of some of these new oncogene candidates has been provided in in vitro and in vivo experiments. However, these findings await further validation in clinical studies. This review provides an overview on well-known melanoma oncogenes and new oncogene candidates, based on recent high-throughput sequencing studies. The list of genes discussed herein is of course not complete but highlights some of the most significant of recent findings in this area. The new candidates may support more individualized treatment approaches for metastatic melanoma patients in the future.

Introduction

Oncogenes are genes implicated in tumour development and tumour progression with their counterparts termed tumour suppressor genes. In principle, activation of proto-oncogenes by various genetic aberrations like point mutations, gene amplifications, and translocations results in a gain-of-function for the individual gene (Vicente-Dueñas et al., 2013). By this means, they exert a dominant activity over their normal gene variants. In contrast, genetic aberrations of tumour suppressor genes result in a loss-of-function. Normally, the pro-tumorigenic effect is due to a loss of one allele with a subsequent mutational inactivation of the second allele. The first description of oncogenes and their putative role in cancer development was provided in the 1980s, when it was shown that transfer of chemically treated DNA was able to transform benign fibroblasts (Murray et al., 1981). At present, the principle of oncogenic control of malignant tumours is widely accepted. However, the mere gene-centric view is currently challenged by the fact that above oncogenic mutations, the differentiation stage of cells may significantly contribute to tumour pathogenesis, which is reflected by the cancer stem cell hypothesis (Marusyk et al., 2012). Moreover, oncogenes may require a secondary inactivation of other pro-apoptotic genes or pathways such as mouse double minute2 (MDM2)-p14ARF-p53 tumour suppressor pathways to induce a malignant transformation (Shortt and Johnstone, 2012).

The genetic changes that lead to oncogene induction are variable. In the majority of cases, activating point mutations modify the resulting protein leading to enhanced and uncontrolled activity, as described for RAS and RAF oncogenes (Hanahan and Weinberg, 2011, Shortt and Johnstone, 2012). Moreover, genomic translocations may put a constitutive active promoter close to the proto-oncogene, and thereby relieve the normal control of the proto-oncogene with the consequence of its continuous expression. A classical example is Burkitt lymphoma, where the MYC gene comes under the control of the promoter of the active immunoglobulin heavy chain cluster. Translocations may also produce chimeric fusion proteins such as the BCR-ABL fusion protein in chronic myeloid leukaemia (CML), which leads to a continuously active ABL kinase and subsequent cellular proliferation. High treatment responses to ABL kinase inhibitors such as imatinib and its derivatives with five-year survival rates of 90% support the particular role for this fusion protein for CML development, maintenance and progression. Gene translocations have also been described for solid tumours such a prostate and pancreatic cancer (Bunting and Nussenzweig, 2013), but their role in these cancers has not yet been analyzed in more detail. Gene or chromosomal amplifications constitute a further mechanism for oncogene activation.

These principle mechanisms of oncogene activation are also active in melanoma (Hill et al., 2013). In this review article, we review the current knowledge about well-known (classical) oncogenes and new oncogene candidates in melanoma, the latter based on more recent high-throughput sequencing studies (Kunz et al., 2013). Recent discoveries regarding the role of oncogenic microRNAs, also called oncomirs, are also included (Kunz, 2013). Many of the more recent findings may in the near future be validated in pre-clinical settings and may even lead to new treatment modalities using specifically targeted small molecule inhibitors (see Fig. 1 and Table 1).

Section snippets

BRAF/NRAS

In recent years, significant progress has been made in the understanding of the genetic basis of sporadic, non-familial melanoma (Miller and Mihm, 2006, Hill et al., 2013, Wangari-Talbot and Chen, 2013). In a seminal work in 2002, Davies and co-workers demonstrated that a majority of melanomas harbour a particular mutation in the serine/threonine kinase BRAF, which was also found in other tumour entities but with dramatically lower incidences (Davies et al., 2002). More than 60% of melanoma

MAP kinases

In search for new putative driver genes for melanoma, a series of studies have been recently published using high-throughput sequencing technology including automated capillary sequencing and next generation sequencing (NGS). MEK1 and MEK2 are direct downstream targets of the RAS-RAF-MAPK cascade. In a relatively small study on a set of seven melanoma cell lines from metastatic melanomas, all samples harboured mutations in this pathway (Nikolaev et al., 2011). Two melanoma samples with

MicroRNAs as oncogene and tumour suppressor gene candidates in melanoma

The term microRNA (miRNA) is used for small, 21–23 nt non-coding RNA molecules, which negatively regulate gene expression by binding to the 3′-untranslated region (3′-UTR) of mRNAs (Bartel, 2009). By this means, they mediate either degradation or inhibition of translation into protein. Based on more recent data, target mRNA degradation appears to be the most prevalent activity of miRNAs. At least 1000 miRNAs exist in the human genome.

In a seminal miRNA expression study of 540 human samples in

Clonality and intra-tumour heterogeneity

Interpretation of oncogenic mutations in cancers is hampered by the fact that primary tumours and metastases are a heterogeneous collection of different tumour cell clones (Fidler, 1978, Parisi et al., 2012, Sakaizawa et al., 2012, Greaves and Maley, 2012, Aparicio and Caldas, 2013). These clones are responsible for so-called intra-tumour heterogeneity. Due to the availability of high-throughput sequencing techniques intra-tumour heterogeneity may currently be analyzed on a molecular level and

Conclusions

Taken together, the plethora of new candidate oncogenes in melanoma opens interesting future perspectives for new treatment approaches, which may even use combinations of targeted inhibitors for a more individualized treatment of melanoma patients. In a recent study, genetic information has been used as a basis for large-scale testing of drug sensitivity of a panel of 700 different cancer lines (Garnett et al., 2012, Yang et al., 2013). The database generated based on these experiments (The

Acknowledgement

M.K. is supported by funding of the Deutsche Krebshilfe, Melanomverbund, Grant No. 109716.

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