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 BRAFV600E. 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.

Highlights

  • Melanocytic malignancies of the female genital tract constitute rare diseases representing only 2-3% of all human malignant melanomas and 18% of all primary mucosal melanomas [1, 2]

  • UV radiation is considered as the main cause of malignant melanoma concerning the sun-exposed body sites [8, 9], it seems that other mechanisms are capable of initiating melanocyte malignant transformation, leading to tumours with different clinical behaviour

  • To gain insight into the molecular genetics of melanoma of the female genital tract and to its DNA mismatch repair (MMR) status, in the present study we systematically investigated the mutational status of eight genes whose products are critically involved in the mitogen-activated protein kinase (MAPK)/ERK, PI3K/AKT, and GNAQ/11 pathways, such as BRAF, NRAS, HRAS, KRAS, c-KIT, PI3K, GNAQ, and GNA11, by employing either real-time polymerase chain reaction (PCR) coupled with fluorescence melting curve analysis for mutation-specific PCR detection, or PCR followed by direct sequencing techniques, along with studies to determine the DNA MMR status using immunohistochemistry

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Summary

Introduction

Melanocytic malignancies of the female genital tract constitute rare diseases representing only 2-3% of all human malignant melanomas and 18% of all primary mucosal melanomas [1, 2]. UV radiation is considered as the main cause of malignant melanoma concerning the sun-exposed body sites [8, 9], it seems that other mechanisms are capable of initiating melanocyte malignant transformation, leading to tumours with different clinical behaviour. Malignant melanoma of the female genital tract is biologically aggressive, difficult to manage, carrying a poor prognosis and a high incidence of recurrence, while its pathogenesis is still obscure and to a large extend, independent of UV radiation [10]. Functional aberrations and mutations in the MAPK/ERK and PI3K/AKT pathways are thought

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