Abstract

Lung cancer is one of the cancer types with the highest mortality worldwide. The most frequently mutated genes known to be clinically important in lung cancers are EGFR, BRAF, and KRAS genes. Therefore, the therapeutic agents developed are directed against variants that cause over-activation of the EGFR–KRAS–BRAF–BRAF–MEK/ERK signalling pathway. However, different responses of patients to Tyrosine Kinase Inhibitors (TKIs) suggest that new prognostic biomarkers should be defined and epigenetic mechanisms may be related to this situation. Methods: In this study, sequence analyses of AGO2, DICER, and DROSHA genes involved in miRNA biogenesis and EGFR, KRAS, and BRAF genes were performed in 35 patients with sporadic lung cancer. Results: We found variations in genes involved in miRNA biogenesis that have not been previously reported in the literature. In addition, we found 4 different variants in the EGFR gene that have been described in the literature. In addition, a statistically significant association was found between the presence of mutations in at least one of the genes involved in miRNA biogenesis and metastasis (p:0.02). Conclusions: In conclusion, genomic dysregulation of key miRNA biogenesis genes may be one of the possible reasons for the differential response of patients to therapeutic agents and the development of metastasis in EGFR wild type tumours.

中文翻译：

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35个散发性肺癌肿瘤miRNA调控基因的变异分析

摘要

肺癌是全球死亡率最高的癌症类型之一。已知在肺癌中具有临床重要性的最常见突变基因是EGFR、BRAF和KRAS基因。因此，开发的治疗药物针对导致 EGFR-KRAS-BRAF-BRAF-MEK/ERK 信号通路过度激活的变异。然而，患者对酪氨酸激酶抑制剂（TKI）的不同反应表明应该定义新的预后生物标志物，表观遗传机制可能与这种情况有关。方法：本研究对 35 例散发性肺癌患者进行了参与 miRNA 生物发生的AGO2、DICER和DROSHA基因以及EGFR、KRAS和BRAF基因的序列分析。结果：我们发现了之前文献中未报道过的参与 miRNA 生物合成的基因变异。此外，我们还发现了文献中描述的EGFR基因的 4 种不同变异。此外，至少一个参与 miRNA 生物发生和转移的基因中的突变存在之间存在统计学上显着的关联 (p:0.02)。结论： 总之，关键 miRNA 生物合成基因的基因组失调可能是患者对治疗药物反应差异和 EGFR 野生型肿瘤发生转移的可能原因之一。