Genetic progression of malignant melanoma

J. Tímár, L. Vizkeleti, V. Doma, T. Barbai, E. Rásó

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Malignant melanoma of the skin is the most aggressive human cancer given that a primary tumor a few millimeters in diameter frequently has full metastatic competence. In view of that, revealing the genetic background of this potential may also help to better understand tumor dissemination in general. Genomic analyses have established the molecular classification of melanoma based on the most frequent driver oncogenic mutations (BRAF, NRAS, KIT) and have also revealed a long list of rare events, including mutations and amplifications as well as genetic microheterogeneity. At the moment, it is unclear whether any of these rare events have role in the metastasis initiation process since the major drivers do not have such a role. During lymphatic and hematogenous dissemination, the clonal selection process is evidently reflected by differences in oncogenic drivers in the metastases versus the primary tumor. Clonal selection is also evident during lymphatic progression, though the genetic background of this immunoselection is less clear. Genomic analyses of metastases identified further genetic alterations, some of which may correspond to metastasis maintenance genes. The natural genetic progression of melanoma can be modified by targeted (BRAF or MEK inhibitor) or immunotherapies. Some of the rare events in primary tumors may result in primary resistance, while further new genetic lesions develop during the acquired resistance to both targeted and immunotherapies. Only a few genetic lesions of the primary tumor are constant during natural or therapy-modulated progression. EGFR4 and NMDAR2 mutations, MITF and MET amplifications and PTEN loss can be considered as metastasis drivers. Furthermore, BRAF and MITF amplifications as well as PTEN loss are also responsible for resistance to targeted therapies, whereas NRAS mutation is the only founder genetic lesion showing any association with sensitivity to immunotherapies. Unfortunately, there are hardly any data on the possible organ-specific metastatic drivers in melanoma. These observations suggest that clinical management of melanoma patients must rely on the genetic analysis of the metastatic lesions to be able to monitor progression-associated changes and to personalize therapies.

Original languageEnglish
Pages (from-to)1-15
Number of pages15
JournalCancer metastasis reviews
DOIs
Publication statusAccepted/In press - Mar 12 2016

Fingerprint

Melanoma
Neoplasm Metastasis
Immunotherapy
Neoplasms
Mutation
Mitogen-Activated Protein Kinase Kinases
Mental Competency
Therapeutics
Maintenance
Skin
Genes
Genetic Background

Keywords

  • Genomics
  • Immunotherapy
  • Melanoma
  • Metastasis
  • Target therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Genetic progression of malignant melanoma. / Tímár, J.; Vizkeleti, L.; Doma, V.; Barbai, T.; Rásó, E.

In: Cancer metastasis reviews, 12.03.2016, p. 1-15.

Research output: Contribution to journalArticle

Tímár, J. ; Vizkeleti, L. ; Doma, V. ; Barbai, T. ; Rásó, E. / Genetic progression of malignant melanoma. In: Cancer metastasis reviews. 2016 ; pp. 1-15.
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