Молекулярно-генетическая гетерогенность меланомы глаза

Background. Ocular melanoma is the most common cancer of adult eye and is represented by two main subtypes of uveal (UM) and conjunctival (CM) melanoma with distinct clinical (frequency, localization, histology) and genomic features. The objective is to compare molecular and genetic characteristics of tumors in patients with melanoma of the eye. Materials and methods. In this study molecular profiling of 78 tumors including 73 UM (choroidea, ciliar body and iris) and 5 СM, was evaluated. DNA was isolated from tumor cells collected by macrodissection of FEPE sections of tumor biopsies using proteinase K. The following genes were studied by Sanger sequencing: GNAQ, GNA11, KIT, BRAF, NRAS. Results. Mutations in GNAQ and GNA11 were found in 81 % (59/73) of UM, in 42 % (31/73) and 38 % (28/73) of cases correspondently. GNAQ mutations were more frequent in primary UM (63 %), while GNA11 mutations dominated in metastatic UM (42 %). There was а correlation between frequency of GNAQ/GNA11 mutations and histologic type of UM. GNAQ mutations were identified in 55 % of spindle cell UM, while GNA11 mutations were more frequent in epithelioid cell UM (42 %). There were no differences in frequency of GNAQ/GNA11 mutations in UM of patients of different age (younger and elder 50 years). There was no statistically difference in UM patient outcome with GNAQ or GNA11 mutations. We also detected 3 UM with KIT mutations and 2 UM with BRAF mutations. There was no big difference in frequency of «driver mutations» in UM of choroidea, ciliar body and iris. Molecular profiling of conjunctival melanoma (CM) resembles that of cutaneous melanoma of skin: in 3 (60 %) CM BRAF V600E was identified and in 1 (20 %) – NRAS Q61K. Conclusion. Genetic analysis reveals wide diversity of melanoma of eye and is important for it characterization and treatment.Введение. Меланома является наиболее распространенной опухолью глаза у взрослых и представлена 2 основными типами: увеальной (УМ) и конъюнктивальной (КМ), которые отличаются по клиническим (частота распространения, локализация, гистология) и генетическим характеристикам. Цель исследования – сравнительное изучение молекулярно-генетических особенностей опухолей у пациентов с меланомой глаза. Материалы и методы. С использованием метода секвенирования по Сэнгеру для анализа ДНК, выделенной после микродиссекции срезов опухолевых биопсий, проведено сравнительное изучение молекулярного профиля 78 опухолей глаза, среди них 73 УМ (хориоидеи, цилиарного тела и радужки) и 5 КМ. Исследован следующий спектр мутаций: GNAQ, GNA11, KIT, BRAF, NRAS. Результаты. Мутации GNAQ и GNA11 выявлены в 81 % (59/73) УМ, соответственно в 42 % (31/73) и 38 % (28/73). В первичной УМ чаще присутствовали мутации GNAQ (63 %), а в метастатической – GNA11 (42 %). Наблюдались различия в распространенности мутаций GNAQ и GNA11 в зависимости от типа клеток УМ. Мутации GNAQ чаще обнаружены в веретеноклеточных УМ (55 %), а GNA11 – в эпителиоидных УМ (42 %). Не выявлено различий в частоте мутаций GNAQ/GNA11 в зависимости от возраста пациентов (моложе и старше 50 лет), а также в общей выживаемости пациентов УМ с мутациями GNAQ или GNA11. Кроме того, выявлены 3 УМ с мутациями KIT и 2 УМ с мутацией BRAF. В УМ хориоидеи, цилиарного тела и радужки существенных различий в частоте мутаций онкогенов не наблюдалось. Молекулярный профиль КМ отличается от профиля мутаций УМ и сходен с таковым для меланомы кожи: в 3 (60 %) КМ обнаружена мутация BRAF V600E, а в 1 (20 %) – NRAS Q61K. Заключение. Генетический анализ свидетельствует о гетерогенности меланомы глаза и важен для характеристики и лечения заболевания.

Molecular and genetic diversity in melanoma of eye

Background. Ocular melanoma is the most common cancer of adult eye and is represented by two main subtypes of uveal (UM) and conjunctival (CM) melanoma with distinct clinical (frequency, localization, histology) and genomic features. The objective is to compare molecular and genetic characteristics of tumors in patients with melanoma of the eye. Materials and methods. In this study molecular profiling of 78 tumors including 73 UM (choroidea, ciliar body and iris) and 5 СM, was evaluated. DNA was isolated from tumor cells collected by macrodissection of FEPE sections of tumor biopsies using proteinase K. The following genes were studied by Sanger sequencing: GNAQ, GNA11, KIT, BRAF, NRAS. Results. Mutations in GNAQ and GNA11 were found in 81 % (59/73) of UM, in 42 % (31/73) and 38 % (28/73) of cases correspondently. GNAQ mutations were more frequent in primary UM (63 %), while GNA11 mutations dominated in metastatic UM (42 %). There was а correlation between frequency of GNAQ/GNA11 mutations and histologic type of UM. GNAQ mutations were identified in 55 % of spindle cell UM, while GNA11 mutations were more frequent in epithelioid cell UM (42 %). There were no differences in frequency of GNAQ/GNA11 mutations in UM of patients of different age (younger and elder 50 years). There was no statistically difference in UM patient outcome with GNAQ or GNA11 mutations. We also detected 3 UM with KIT mutations and 2 UM with BRAF mutations. There was no big difference in frequency of «driver mutations» in UM of choroidea, ciliar body and iris. Molecular profiling of conjunctival melanoma (CM) resembles that of cutaneous melanoma of skin: in 3 (60 %) CM BRAF V600E was identified and in 1 (20 %) – NRAS Q61K. Conclusion. Genetic analysis reveals wide diversity of melanoma of eye and is important for it characterization and treatment