title: Low mutational burden of eight genes involved in the MAPK/ERK, PI3K/AKT, and GNAQ/11 pathways in female genital tract primary melanomas.
abstract: Mucosal melanomas exhibit discrete genetic features compared to cutaneous melanoma. Limited studies on gynecological melanomas revealed significant heterogeneity and low mutational burden. To gain further insight into their genetics and DNA repair efficiency, we systematically investigated the status of eight genes whose products are critically involved in the MAPK/ERK, PI3K/AKT, and GNAQ/11 pathways, including BRAF, NRAS, HRAS, KRAS, c-KIT, PI3K, GNAQ, and GNA11, in a series of 16 primary gynecological melanomas, covering all anatomical locations, ranging from stages I to III. Analysis either by real-time PCR coupled with fluorescence melting curve analysis or by PCR followed by direct sequencing, along with studies for DNA mismatch repair status using immunohistochemistry, disclosed that 15 out of the 16 cases displayed wild-type genotypes, with a single case of vulvar primary melanoma, harboring the activating mutation BRAF(V600E). Investigations on whether this could reflect partly an efficient mismatch repair (MMR) mechanism were confirmed by normal expression of hMLH1 and hMSH2, suggesting that the lack of mutations could be explained by the operation of alternative pathogenetic mechanisms modulating downstream effectors of the signaling pathways. Our data suggest the presence of additional genetic components and provide the impetus for systematic approaches to reveal these yet unidentified genetic parameters.
authors.affiliation: First Department of Obstetrics and Gynecology, University of Athens School of Medicine, Alexandra Hospital, 11528 Athens, Greece ; Laboratory of Biology, Department of Basic Medical Sciences, University of Athens School of Medicine, 11527 Athens, Greece ; Laboratory of Cell and Gene Therapy, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece.
authors.forename: Kalliopi I
authors.initials: KI
authors.lastname: Pappa
authors.affiliation: First Department of Obstetrics and Gynecology, University of Athens School of Medicine, Alexandra Hospital, 11528 Athens, Greece.
authors.forename: George D
authors.identifier: 0000-0003-0551-2032
authors.initials: GD
authors.lastname: Vlachos
authors.affiliation: Laboratory of Biology, Department of Basic Medical Sciences, University of Athens School of Medicine, 11527 Athens, Greece ; Laboratory of Cell and Gene Therapy, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Roubelakis
authors.affiliation: First Department of Obstetrics and Gynecology, University of Athens School of Medicine, Alexandra Hospital, 11528 Athens, Greece.
authors.forename: Dimitrios-Efthymios G
authors.initials: DE
authors.lastname: Vlachos
authors.affiliation: Laboratory of Histopathology and Cytopathology, Department of Pathology, Henry Dunant Hospital, 11527 Athens, Greece.
authors.forename: Theodora G
authors.initials: TG
authors.lastname: Kalafati
authors.affiliation: First Department of Obstetrics and Gynecology, University of Athens School of Medicine, Alexandra Hospital, 11528 Athens, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Loutradis
authors.affiliation: Laboratory of Biology, Department of Basic Medical Sciences, University of Athens School of Medicine, 11527 Athens, Greece ; Laboratory of Cell and Gene Therapy, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Anagnou
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D005833:Genital Neoplasms, Female / Q000235:genetics*; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics*; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C554062:GNA11 protein, human; C554061:GNAQ protein, human; D044385:GTP-Binding Protein alpha Subunits; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D043802:GTP-Binding Protein alpha Subunits, Gq-G11