Background. The correct genome replication is essential for normal cell division to guarantee that genetic information comes changeless through the next cells generations. DNA replication is a strictly regulated and synchronous process and its disturbances could result to mutations appearances. Aberrant time of DNA replication affects on gene expression causes changes of epigenetic modifications and influences on increasing the structural rearrangements leading to enhanced genome disbalance. Replication time failure as asynchronous replication is common for cancerogeneses. The objective of our study was the assessment of asynchronous replication levels in patients with gastric cancer and patients with multiple tumors.Materials and methods. Fluorescence in situ hybridization (FISH) was used for the asynchronous replication of AURKA and TP53 genes analyses. Interphase FISH on lymphocytes of peripheral blood of 37 healthy donors, 19 patients with non-cancer gastrointestinal pathologies, 68 patients with solitary gastric cancer and 39 patients with multiple tumors having gastric cancer and other second synchronous or metachronous tumor was carried out.Results. Values of lymphocytes with asynchronous replication for AURKA were 19.8 ± 0.5 % for control group, 24.7 ± 0.4 % for non-cancer patients, 32.5 ± 0.5 % for gastric cancer patients, 39.5 ± 0.6 % for patients with multiple tumors and 17.3 ± 0.5, 19.5 ± 0.7, 26.1 ± 0.7 and 32.5 ± 0.6 % for TP53 respectively. Differences between cell populations of examined groups had statistical significance with p <0.01 for both studied gene. Also there was statistical difference between gastric cancer patients having distant metastases and gastric cancer patients without metastases for AURKA (34.4 ± 1.0 % vs. 31.7 ± 0.6 %; p = 0.02).Conclusion. High lymphocytes with asynchronous replication level in oncological patients could serve as potential marker of second tumor or possible metastatic process including the earliest stage of it.
Актуальность. По современным представлениям, в патогенезе онкологических заболеваний ведущую роль играют молекулярно-генетические нарушения. Их встречаемость и клиническая значимость при раке слизистой оболочки полости рта (СОПР) недостаточно изучена. Целью исследования было изучение в клетках слущенного эпителия СОПР молекулярно-цитогенетического профиля нарушений хромосом 7, 11 и генов EGFR, CCND1 у больных раком СОПР. Методы. Использован метод флуоресцентной in situ гибридизации (FISH) с применением ДНК-зондов ген/центромера хромосомы: EGFR/CEP7 и CCND1/CEP11. Исследование проводили на мазках с опухоли различной локализации, взятых у 38 больных раком СОПР с различными стадиями заболевания до начала лечения. Контролем служили мазки СОПР 12 клинически здоровых лиц. Результаты. В клетках слущенного эпителия СОПР у здоровых лиц и больных раком наблюдаются клетки с нарушением копийности генов EGFR и/или CCND1 (потеря копии и амплификация), моносомией хромосом 7 и/или 11, а также с их полисомией, представленной в основном трисомией и тетрасомией. У больных выявлены клетки с высокой степенью амплификации исследованных генов и клетки с полисомией, содержащие 5 и более центромер, которые не встречались у здоровых лиц. В группе больных среднегрупповые показатели нарушений статистически значимо (р < 0,01) превышали контрольный уровень для частоты клеток с полисомией хромосомы 7 (26,95% vs 0,67%) и хромосомы 11 (21,15% vs 0,21%), а также амплификации генов EGFR (6,45% vs 0,13%) и CCND1 (14,27% vs 0,83%). Частота клеток с амплификацией генов EGFR и CCND1, а также полисомией хромосом 7 и 11 статистически значимо превышала контрольный уровень у 79%, 79%, 95% и 90% больных, соответственно. Заключение. Установлено, что для больных раком СОПР клинически значимыми нарушениями, выявляемыми в клетках слущенного эпителия СОПР могут быть полисомия хромосом 7, 11 и амплификация генов EGFR, CCND1. Эти нарушения являются показателями нестабильности генома и, вероятно, могут служить не только независимыми прогностическими маркерами прогрессии опухоли, рецидива и метастазов, но также иметь потенциальную прогностическую значимость для оценки индивидуальной радиочувствительности, что позволит персонифицировать методы лечения больных раком СОПР.Background. According to recent conceptions molecular genetic abnormalities play a leading role in the pathogenesis of oncologic diseases. The reoccurrence and clinical significance of these abnormalities in oral squamous cell carcinoma (OSCC) are still unclear. Aim. The aim of this study was to investigate abnormalities in the molecular cytogenetic profile of chromosomes 7, 11 and EGFR, CCND1 genes in exfoliated oral mucosa cells from OSCC patients. Methods. The study used fluorescence in situ hybridization (FISH) with a DNA probe for EGFR/CEP7 and CCND1/CEP11. The study was conducted on tumor smears collected from 38 OSCC patients with different localizations and stages of the disease before treatment. Smears of exfoliated oral mucosa cells from 12 healthy individuals were used as the control. Results. Cells from both healthy subjects and oral cancer patients showed deletions of gene EGFR and/or CCND1, their amplification, and monosomy and polysomy of chromosome 7 and/or 11 represented mainly by trisomy and tetrasomy. Cells with high-grade amplification of the studied genes and polysomic cells containing 5 or more centromeres were found in patients but not in control subjects. In the patient group, the average frequency of abnormalities was significantly higher (р < 0.01) than in control, including the frequencies of chromosome 7 (26.95% vs. 0.67%) and chromosome 11 (21.15% vs 0.21%) polysomy. The same was true for gene EGFR (6.45% vs. 0.13%) and gene CCND1 (14.27% vs. 0.83%) amplifications. The frequencies of cells with EGFR and CCND1 amplifications and chromosome 7 and 11 polysomy were significantly higher than in control for 79%, 79%, 95%, and 90% patients, respectively. Conclusion. The chromosome 7 and 11 polysomy and gene EGFR and CCND1 amplifications detected in exfoliated epithelial cells of oral mucosa may be clinically significant for patients with OSCC. These disorders are markers of genome instability and may serve as prognostic factors for tumor progression, recurrence, and metastases. Moreover, they may also be potentially predictive for individual radiosensitivity, which would help individualizing therapy for patients with OSCC.
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