2. Academic Validation
  3. A comprehensive evaluation of pathogenic mutations in primary cutaneous melanomas, including the identification of novel loss-of-function variants

A comprehensive evaluation of pathogenic mutations in primary cutaneous melanomas, including the identification of novel loss-of-function variants

  • Sci Rep. 2019 Nov 19;9(1):17050. doi: 10.1038/s41598-019-53636-x.
Ivana Ticha 1,  Jan Hojny 2,  Romana Michalkova 2,  Ondrej Kodet 3 4 5,  Eva Krkavcova 2,  Nikola Hajkova 2,  Kristyna Nemejcova 2,  Michaela Bartu 2,  Radek Jaksa 2,  Miroslav Dura 2 3,  Madiha Kanwal 6,  Andra S Martinikova 6,  Libor Macurek 6,  Petra Zemankova 7,  Zdenek Kleibl 7,  Pavel Dundr 2
Affiliations

Affiliations

  • 1 Institute of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic. ivana.ticha@vfn.cz.
  • 2 Institute of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
  • 3 Department of Dermatology and Venereology, First Faculty of Medicine, Charles University and General Hospital in Prague, Prague, Czech Republic.
  • 4 Institute of Anatomy, First Faculty of Medicine, Charles University, Prague, Czech Republic.
  • 5 BIOCEV, Charles University, First Faculty of Medicine, Vestec, Czech Republic.
  • 6 Cancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
  • 7 Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
PMID: 31745173 DOI: 10.1038/s41598-019-53636-x
Abstract

The most common histological subtypes of cutaneous melanoma include superficial spreading and nodular melanoma. However, the spectrum of somatic mutations developed in those lesions and all potential druggable targets have not yet been fully elucidated. We present the results of a sequence capture NGS analysis of 114 primary nodular and superficial spreading melanomas identifying driver mutations using biostatistical, immunohistochemical and/or functional approach. The spectrum and frequency of pathogenic or likely pathogenic variants were identified across 54 evaluated genes, including 59 novel mutations, and the newly identified TP53 loss-of-function mutations p.(L194P) and p.(R280K). Frequently mutated genes most commonly affected the MAPK pathway, followed by chromatin remodeling, and cell cycle regulation. Frequent aberrations were also detected in the genes coding for proteins involved in DNA repair and the regulation and modification of cellular tight junctions. Furthermore, relatively frequent mutations were described in VEGFR2/KDR/Flk-1 and MET, which represent potential clinically important targets. Those results suggest that with the development of new therapeutic possibilities, not only BRaf testing, but complex molecular testing of cutaneous melanoma may become an integral part of the decision process concerning the treatment of patients with melanoma.

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