ketendoКлиническая и экспериментальная тиреоидологияClinical and experimental thyroidology1995-54722310-3787Endocrinology Research Centre10.14341/ket12838ketendo-12838Research ArticleОригинальные исследованияOriginal StudiesМолекулярно-генетический профиль пациентов с дифференцированным раком щитовидной железы промежуточной и высокой послеоперационной группы риска рецидиваMolecular Genetic Profile of Patients with Differentiated Thyroid Carcinoma Belonging to the Intermediate and High Postoperative Risk Groups for Recurrencehttps://orcid.org/0009-0002-1632-2197РейнбергМ. В.ReinbergM. V.

Рейнберг Мария Валентиновна, аспирант 

117292, Москва, улица Дм. Ульянова, д. 11 

Maria V. Reinberg, MD

11 Dm.Ulyanova street, 117292, Moscow

mreinberg911@gmail.comhttps://orcid.org/0000-0002-3220-2438СлащукК. Ю.SlashchukK. Yu.

Слащук Константин Юрьевич, к.м.н. 

Москва

Konstantin Yu. Slashchuk, MD, Cand. Sci. (Medicine)

Moscow

slashuk911@gmail.comhttps://orcid.org/0000-0003-2122-2297БондаренкоЕ. В.BondarenkoE. V.

Бондаренко Екатерина Владимировна, к.м.н. 

Москва

Ekaterina V. Bondarenko, MD, Cand. Sci. (Medicine)

Moscow

bondarenko.ekaterina@endocrincentr.ruhttps://orcid.org/0000-0002-9462-8522Першина-МилютинаА. П.Pershina-MiliutinaA. P.

Першина-Милютина Анастасия Павловна

Москва

Anastasiia P. Pershina-Miliutina, MD

Moscow

oa11111998@gmail.comhttps://orcid.org/0009-0005-9875-4541МатросоваА. А.MatrosovaA. A.

Матросова Алина Антоновна 

Москва

Alina A. Matrosova

Moscow

matrosova.alina@endocrincentr.ruhttps://orcid.org/0000-0001-8580-2421АбдулхабироваФ. М.AbdulkhabirovaF. M.

Абдулхабирова Фатима Магомедовна, к.м.н. 

Москва

Fatima M. Abdulkhabirova, MD, Cand. Sci. (Medicine)

Moscow

Abdulkhabirova@endocrincentr.ruhttps://orcid.org/0009-0002-7243-2091МагомедовХ. Х.MagomedovKh. Kh.

Магомедов Хамзат Хаджимурадович 

Москва

Khamzat K. Magomedov, MD

Moscow

hamzat1008@gmail.comhttps://orcid.org/0000-0002-8520-8702ТрошинаЕ. А.TroshinaE. A.

Трошина Екатерина Анатольевна, д.м.н., член-корр. РАН, профессор 

Москва

Ekaterina A. Troshina, MD, Corresponding Member of the Russian Academy of Sciences, Dr. Sci. (Medicine), Professor

Moscow

troshina@inbox.ruНациональный медицинский исследовательский центр эндокринологии им. академика И.И. ДедоваРоссияEndocrinology Research CenterRussian Federation202516062026213415Copyright © Рейнберг М.В., Слащук К.Ю., Бондаренко Е.В., Першина-Милютина А.П., Матросова А.А., Абдулхабирова Ф.М., Магомедов Х.Х., Трошина Е.А., 20262026Рейнберг М.В., Слащук К.Ю., Бондаренко Е.В., Першина-Милютина А.П., Матросова А.А., Абдулхабирова Ф.М., Магомедов Х.Х., Трошина Е.А.Reinberg M.V., Slashchuk K.Y., Bondarenko E.V., Pershina-Miliutina A.P., Matrosova A.A., Abdulkhabirova F.M., Magomedov K.K., Troshina E.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.cet-endojournals.ru/jour/article/view/12838ВВЕДЕНИЕ

ВВЕДЕНИЕ. В структуре дифференцированного рака щитовидной железы на группу промежуточного послеоперационного риска рецидива приходится порядка 35% всех случаев, а на высокий риск рецидива — до 10% случаев; однако оптимальная тактика ведения таких пациентов, целесообразность радиойодтерапии (РЙТ) во всех случаях и факторы ее эффективности остаются неопределенными. Несмотря на хорошую прогностическую изученность мутаций в генах BRAF, TERT, tp53, RAS, их влияние на функциональную активность натрий-йодного симпортера (НЙС), степень дифференцировки клетки и взаимосвязь с РЙТ не определены.

ЦЕЛЬ

ЦЕЛЬ. Оценить связь между мутационным профилем первичной опухоли и клиническими исходами после РЙТ у пациентов с ДРЩЖ промежуточной/высокой группы риска; выделить гены-кандидаты, вероятно ассоциированные с неблагоприятным ответом на проводимое стандартное лечение.

МАТЕРИАЛЫ И МЕТОДЫ

МАТЕРИАЛЫ И МЕТОДЫ. В рамках пилотного поискового исследования было проведено NGS-секвенирование ДНК, полученной из парафиновых блоков первичной опухоли с верифицированным ДРЩЖ (N=28). Ретроспективно проанализированы клинико-анамнестические данные пациентов, соответствующие критериям включения. Проанализированы базы данных MEDLINE, GoogleScholar, STRING на предмет генов-кандидатов, связанных с регуляцией НЙС и неблагоприятным ответом на РЙТ; всего из 68 потенциальных генов-кандитатов в образцах выделена 51 мутация. Проведен статистический анализ на соотношение клинико-анамнестических данных и выделенного молекулярного профиля пациентов с использованием программного обеспечения Statistica v. 12 (TIBCO Software Inc., США).

РЕЗУЛЬТАТЫ

РЕЗУЛЬТАТЫ. Медиана наблюдения составила 22,5 [16; 62] месяца. Медианная численность соматических вариантов из выбранной таргет-панели составила 4,5 [3; 8] (min 1, max 22). Наиболее частые варианты — BRAF, PTEN, PIGU, TG; в группе неблагоприятных исходов отмечалась кластеризация мутаций в генах BRAF, COL5A1, CTNNB1, DUOX2, AKT1, ALK, DUOX2, ERBB2, GLI1, HORMAD2, IYD, NOTCH3, SLC5A8, SMAD3, TSHR. Различие в числе соматических вариантов между группами не достигало значимости (p=0,755); наличие отдаленных метастазов (M1) оказалось сильным предиктором неблагоприятного исхода (p<0,001); влияние сопутствующего аутоиммунного тиреоидита в ткани щитовидной железы не было значимым фактором (p=0,309).

ЗАКЛЮЧЕНИЕ

ЗАКЛЮЧЕНИЕ. Отсутствие значимой разницы в числе соматических вариантов между группами благоприятного и неблагоприятного ответа (p=0,755) при одновременной кластеризации патогенных мутаций в конкретных генах в группе резистентности указывает на то, что ключевым фактором является активация определенных онкогенных сигнальных путей, а не общая геномная нестабильность при данном виде солидных опухолей. Резистентность и неполный ответ на РЙТ могут быть потенциально обусловлены коактивацией нескольких патогенных сигнальных путей, таких как MAPK, PI3K/AKT/mTOR, ТТГ-рТТГ, TGF-β-SMAD3, Sonic Hedgehog, β-catenin/Wnt. Прицельное исследование генов-кандидатов более агрессивного клинического течения ДРЩЖ требует дальнейшего исследования на большей выборке, в том числе с изучением уровня экспрессии их транскриптов.

BACKGROUND

BACKGROUND: Among differentiated thyroid carcinoma (DTC) cases, patients classified into the intermediate and high postoperative risk groups for recurrence account for over at least 35% of all cases. However, the optimal management strategy, the clinical utility of radioiodine therapy (RAIT), and the factors determining its efficacy remain insufficiently elucidated. Although the prognostic significance of mutations in BRAF, TERT, TP53, and RAS genes has been well described, their impact on the functional activity of the sodium–iodide symporter (NIS), the degree of cellular differentiation, and the relationship with RAIT responsiveness has not been clearly established.

AIM

AIM: To assess the relationship between the mutational profile of the primary tumor and clinical outcomes after RAIT in patients with intermediate/high-risk DTC, and to identify candidate genes associated with poor therapeutic response.

MATERIALS AND METHODS

MATERIALS AND METHODS: Next-generation sequencing (NGS) was performed on DNA extracted from formalin-fixed paraffin-embedded (FFPE) samples of primary DTC tumors (N=28). Clinical and anamnestic data of patients meeting inclusion criteria were retrospectively analyzed. The MEDLINE, Google Scholar, and STRING databases were searched for candidate genes implicated in NIS regulation and poor RAIT response. Of the 68 potential genes, 51 distinct mutations were identified in the analyzed samples. Statistical analysis was conducted to evaluate the correlation between clinical characteristics and molecular profiles using Statistica v.12 software (TIBCO Software Inc., USA).

RESULTS

RESULTS: The median follow-up duration was 22.5 [16; 62] months. The median number of somatic variants per patient detected by the targeted sequencing panel was 4.5 [3; 8] (range 1–22). The most frequent variants involved BRAF, PTEN, PIGU, and TG. In the subgroup with unfavorable outcomes, clustering of mutations was observed in BRAF, COL5A1, CTNNB1, DUOX2, AKT1, ALK, ERBB2, GLI1, HORMAD2, IYD, NOTCH3, SLC5A8, SMAD3, and TSHR. The difference in the total number of somatic variants between outcome groups did not reach statistical significance (p=0.755). The presence of distant metastases (M1) emerged as a strong predictor of poor outcome (p<0.001), while coexisting autoimmune thyroiditis had no significant impact (p=0.309).

CONCLUSION

CONCLUSION: The absence of a significant difference in the number of somatic variants between patients with favorable and unfavorable responses (p=0.755), together with the clustering of pathogenic mutations in specific genes in the radioiodine-refractory group, suggests that the activation of specific oncogenic signaling pathways, rather than overall genomic instability, is a key determinant of tumor behavior in this solid tumor type. Resistance or incomplete response to radioiodine therapy may result from the concurrent activation of multiple oncogenic signaling pathways, including MAPK, PI3K/AKT/ mTOR, TSH–TSH receptor, TGF-β/SMAD3, Sonic Hedgehog, and β-catenin/Wnt signaling. Further evaluation of candidate genes implicated in aggressive disease behavior in differentiated thyroid cancer is warranted in larger patient cohorts, with particular emphasis on transcript-level expression analyses.

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The authors declare that there are no conflicts of interest present.