Prospects for the use of molecular genetic markers to improve diagnostics and targeted therapy of melanoma

Автор: Khripko O.P., Khripko Yu.I., Deulin I.Yu., Koldysheva E.V., Zakharov V.N.

Журнал: Cardiometry @cardiometry

Статья в выпуске: 24, 2022 года.

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Skin melanoma is a highly aggressive malignant neoplasm, the treatment of disseminated forms of which remains a serious problem, despite recent advances in the development of medical drugs based on the inhibition of the BRAF oncogene as well as on the basis of immune response regulators [1]. In addition, the question of identifying prognostic markers of metastasis and diagnostic markers of skin melanoma remains relevant. Despite advances in understanding the pathogenesis of melanoma and the development of various therapies aimed at immune checkpoints, the patient survival remains low in the progressing metastatic disease [2]. Targeted therapy and immune checkpoint inhibitors are used in the treatment of metastatic melanoma.

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Короткий адрес: https://sciup.org/148326334

IDR: 148326334   |   DOI: 10.18137/cardiometry.2022.24.conf.40

Текст статьи Prospects for the use of molecular genetic markers to improve diagnostics and targeted therapy of melanoma

Federal State Budget Scientific Institution "Federal Research Center of Fundamental and Translational Medicine", Novosibirsk, Russia; Novosibirsk Regional Clinical Oncology Center, Novosibirsk, Russia

Skin melanoma is a highly aggressive malignant neoplasm, the treatment of disseminated forms of which remains a serious problem, despite recent advances in the development of medical drugs based on the inhibition of the BRAF oncogene as well as on the basis of immune response regulators [1]. In addition, the question of identifying prognostic markers of metastasis and diagnostic markers of skin melanoma remains relevant. Despite advances in understanding the pathogenesis of melanoma and the development of various therapies aimed at immune checkpoints, the patient survival remains low in the progressing metastatic disease [2]. Targeted therapy and immune checkpoint inhibitors are used in the treatment of metastatic melanoma. Melanoma has intratumoral and intertumoral heterogeneity that further complicates its treatment. The most common melanoma-associated mutation (about 50% of the tumors) is the BRAF gene mutation, which is a replacement for BRAF V600E. This mutation activates MEK/ERK kinase, enhancing melanogenesis [5]. The effect made by the inhibitors on the BRAF mutant serine-threonine kinase demonstrates a pronounced response in melanomas carrying BRAF V600E mutations, contributing both to the regression of tumor foci and an improvement in patient survival [4, 9]. However, resistance to this drug is rapidly developing, preventing its long-term effective use. The mechanisms of the acquired resistance to the BRAF V600E inhibitors include mutations in the N-RAS/MEK-1 genes and overexpression of COT, EGFR, PDGFRβ, IGF1R, and MET [7, 10].

The development of the drug resistance necessitates the use of a combination of some chemotherapeutic agents blocking the MAPK signaling pathway [4, 6]. However, due to multiple genetic and epigenetic modifications as well as due to the tendency of melanomas to a high degree of clone heterogeneity, it is not always possible to achieve the desired therapeutic effect [8]. This necessitates additional molecular genetic examinations of the patient.

The aim of this study was to identify the possible dependence of the stage of the disease on the presence of mutations in the tumor tissue.

Methodology . The examined group included both female (n=13) and male (n=14) patients, the average age of which was 63.5±3.5 and 62.7±3.9 years, respectively. All patients were divided into two groups depending on the disease stage: locally advanced disease (stage I-II) in 14 patients and metastases (stage III-IV) in 13 patients. A molecular genetic study of melanoma samples to identify the presence of BRAF mutations in 17 patients with a histologically confirmed diagnosis was carried out: there were 7 females and 10 males; whose mean age was 65.5±5.1 and 62.3±3.7 years, respectively. All the patients were divided into two groups depending on the stage of the disease, but without regard to their gender: the number of patients with locally advanced disease among them was 9 individuals, and the patients with the presence of metastases were 8 individuals. To confirm the presence of the BRAF V600E mutation, the Real-time-PCR-BRAF-V600E test system was used; the analysis was carried out according to the manufacturer's instructions (Biolink, Russia). In addition to this mutation in 6 tumors (3 men and 3 women), a study was carried out for the presence of a mutation in the c-kit gene; for this purpose the c-kit D816V test system was utilized, according to the manufacturer's instructions (Gene Formula, Russia). Statistics data processing of the correlation of the occurrence with the prevalence of the process was carried out using Pearson's χ2 method.

Results . A positive mutation was detected in 53% of the cases that was consistent with the reference literature data [5]. Moreover, in the presence of metastases (stage III-IV), the mutation rate increased to 75% compared to 33% in the presence of a local process (stage I-II) (χ2=2.951; p=0.086). Mutations in the c-kit gene were not found.

Conclusion . Identification of the mutation in the BRAF gene is important for the purpose of the selection of treatment of melanoma, due to its greater rate in patients with a metastatic process. Moreover, the presence of mutant BRAF alleles may be a negative prognostic sign.

*Our study was performed using the equipment of the Center for Collective Use "Proteomny Analysis", supported by funding from the Ministry of Education and Science of Russia (agreement No. 075-15-2021-691).

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