Mini ReviewOncogenes in melanoma: An update
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.
References (113)
- et al.
MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study
Lancet Oncol.
(2013) MicroRNAs: target recognition and regulatory functions
Cell
(2009)- et al.
P-Rex2, a new guanine-nucleotide exchange factor for Rac
FEBS Lett.
(2004) - et al.
miR-30b/30d regulation of GalNAc transferases enhances invasion and immunosuppression during metastasis
Cancer Cell
(2011) - et al.
Hallmarks of cancer: the next generation
Cell
(2011) - et al.
Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF
Cell
(2010) - et al.
Small molecules and targeted therapies in distant metastatic disease
Ann. Oncol. Suppl.
(2009) - et al.
A landscape of driver mutations in melanoma
Cell
(2012) - et al.
Phospho-ERK staining is a poor indicator of the mutational status of BRAF and NRAS in human melanoma
J. Invest. Dermatol.
(2008) - et al.
microRNAs in cancer management
Lancet Oncol.
(2012)
Intronic miR-211 assumes the tumor suppressive function of its host gene in melanoma
Mol. Cell
The novel ATM-related protein TRRAP is an essential cofactor for the c-Myc and E2F oncoproteins
Cell
Three different human tumor cell lines contain different oncogenes
Cell
Mechanism of activation and inhibition of the HER4/ErbB4 kinase
Structure
Phosphotyrosine signaling networks in epidermal growth factor receptor overexpressing squamous carcinoma cells
Mol. Cell. Proteomics
MicroRNAs (miRNAs) in cancer invasion and metastasis: therapeutic approaches based on metastasis-related miRNAs
J. Mol. Med.
Regulation of MT1-MMP and MMP-2 by the serpin PEDF: a promising new target for metastatic cancer
Cell. Physiol. Biochem.
The implications of clonal genome evolution for cancer medicine
N. Engl. J. Med.
Loss of collagenase-2 confers increased skin tumor susceptibility to male mice
Nat. Genet.
Searching for the ‘melano-miRs’: miR-214 drives melanoma metastasis
EMBO J.
Clonal evolution and therapeutic resistance in solid tumors
Front. Pharmacol.
Targeting protein prenylation for cancer therapy
Nat. Rev. Cancer
Melanoma genome sequencing reveals frequent PREX2 mutations
Nature
Mutational profiling of cancer candidate genes in glioblastoma, melanoma and pancreatic carcinoma reveals a snapshot of their genomic landscapes
Hum. Mutat.
Rac1 GTPase: a “Rac” of all trades
Cell Mol. Life Sci.
Clinical characteristics and outcomes with specific BRAF and NRAS mutations in patients with metastatic melanoma
Cancer
End-joining, translocations and cancer
Nat. Rev. Cancer
KIT as a therapeutic target in metastatic melanoma
J. Am. Med. Assoc.
Improved survival with vemurafenib in melanoma with BRAF V600E mutation
N. Engl. J. Med.
Essential role for oncogenic Ras in tumour maintenance
Nature
Distinct sets of genetic alterations in melanoma
N. Engl. J. Med.
Mutations of the BRAF gene in human cancer
Nature
Analysis of the genome to personalize therapy for melanoma
Oncogene
ErbB receptor tyrosine kinases contribute to proliferation of malignant melanoma cells: inhibition by gefitinib (ZD1839)
Melanoma Res.
Receptor tyrosine kinases and their activation in melanoma
Pigment Cell Melanoma Res.
The clinical significance of BRAF and NRAS mutations in a clinic-based metastatic melanoma cohort
Br. J. Dermatol.
The promyelocytic leukemia zinc finger-microRNA-221/-222 pathway controls melanoma progression through multiple oncogenic mechanisms
Cancer Res.
Tumor heterogeneity and the biology of cancer invasion and metastasis
Cancer Res.
Inhibition of mutated, activated BRAF in metastatic melanoma
N. Engl. J. Med.
From genes to drugs: targeted strategies for melanoma
Nat. Rev. Cancer
Association of ErbB1-4 expression in invasive breast cancer with clinicopathological characteristics and prognosis
Breast Cancer
Systematic identification of genomic markers of drug sensitivity in cancer cells
Nature
Targeting microRNAs in cancer: rationale strategies and challenges
Nat. Rev. Drug Discov.
Intratumor heterogeneity and branched evolution revealed by multiregion sequencing
N. Engl. J. Med.
Clonal evolution in cancer
Nature
Tumor suppressive microRNAs miR-34a/c control cancer cell expression of ULBP2, a stress-induced ligand of the natural killer cell receptor NKG2D
Cancer Res.
The genetics of melanoma: recent advances
Annu. Rev. Genomics Hum. Genet.
Efficient in vivo microRNA targeting of liver metastasis
Oncogene
ASK1 and ASK2 differentially regulate the counteracting roles of apoptosis and inflammation in tumorigenesis
EMBO J.
Imatinib targeting of KIT-mutant oncoprotein in melanoma
Clin. Cancer Res.
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