口腔白斑体细胞突变致病性的前瞻性观察研究

N. A. Karpuk, S. Rubnikovich, I. V. Zhyltsov, O. C. Mazur, I. Karpuk, A. Mikhalenka
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引用次数: 0

摘要

背景绝大多数口腔粘膜恶性肿瘤是指鳞状细胞癌。口腔黏膜鳞状细胞癌的发展往往受到先前潜在恶性疾病的促进,其中口腔白斑占主导地位。客观的探讨口腔黏膜白斑体细胞突变致病性的临床意义。方法。研究材料包括24份白斑患者口腔粘膜异常上皮的样本。QIAamp DNA FFPE组织试剂盒(Qiagen,Germany)用于从样品中提取脱氧核糖核酸(DNA)。使用IlluminaNextSeq 550测序仪和TruSight进行DNA测序™ 与NextSeq一起使用的肿瘤学500 DNA试剂盒(Illumina,USA)。所有生物样品的DNA提取、DNA文库的制备和测序都是严格按照各自试剂盒提供的指南逐步进行的。根据现行指南,使用特定软件Illumina Base Space(Illumina,USA)和银河项目(银河社区,一个非营利国际项目)进行生物信息学分析。研究的期望功率占90%。两个比例Z检验是通过Statistica 12(StatSoft,股份有限公司)的样本量计算进行的,设置选项为“单尾假说”,因为最初假设致病(致癌)基因变异发生在口腔黏膜组织中的频率远高于用于序列比对的人类参考基因组。后果本研究中单独或联合鉴定的TP53、KRAS、APC、NRAs和BRAF基因的致病性体细胞突变极有可能(危险比3000-11000)与口腔粘膜白斑和低度上皮发育不良的发展有关。与上皮发育不良相关的致病性和可能致病性遗传变异的多样性,以及并非所有患者都会出现许多变异的事实,表明相同组织类型的口腔粘膜发育不良可能在不同突变的影响下发展。结论本研究中单独或联合鉴定的TP53、KRAS、APC、NRAS和BRAF基因的致病性和可能的致病性变体极有可能(危险比3000-11000)与白斑和低度上皮发育不良的发展有关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Clinical Significance of Pathogenicity of Somatic Mutations in Oral Leukoplakia: a Prospective Observational Study
Background. The vast majority of malignant neoplasms of the oral mucosa refer to squamous cell carcinomas. The development of squamous cell carcinoma of the oral mucosa is often promoted by previous potentially malignant diseases, with oral leukoplakia dominating among them.Objective. To determine the clinical significance of the pathogenicity of somatic mutations in oral mucosal leukoplakia.Methods. The study material included 24 samples of abnormal epithelium of the oral mucosa from leukoplakia patients. QIAamp DNA FFPE Tissue Kit (Qiagen, Germany) was used for deoxyribonucleic acid (DNA) extraction from the samples. DNA sequencing was performed using IlluminaNextSeq 550 sequencer and TruSight™ Oncology 500 DNA Kit For Use with NextSeq (Illumina, USA). All DNA extractions from biological samples, preparation and sequencing of DNA libraries were performed step-by-step in strict accordance with the guidelines provided with the respective reagent kits. Bioinformatics analysis was carried out using specific software Illumina Base Space (Illumina, USA) and Galaxy Project (The Galaxy Community, a non-profit international project) according to current guidelines. The desired power of the study accounted for 90%. Two Proportions Z test was performed by means of The Sample Size Calculation of Statistica 12 (StatSoft, Inc.) with the set option “one-tailed hypothesis”, because it was initially assumed that pathogenic (oncogenic) genetic variants occur in the tissue of oral leukoplakia much more frequently than in the human reference genome used for sequence alignment.Results. The pathogenic somatic mutations in the TP53, KRAS, APC, NRAs and BRAF genes, identified in this study, alone or in combination, are highly likely (hazard ratio 3000-11000) to be associated with the development of oral mucosal leukoplakia and low-grade epithelial dysplasia. The multiplicity of pathogenic and likely pathogenic genetic variants associated with epithelial dysplasia, as well as the fact that a number of variants do not occur in all patients, suggests that the same histotype of oral mucosal dysplasia may develop under the influence of different mutations.Conclusion. The pathogenic and likely pathogenic variants of the TP53, KRAS, APC, NRAS and BRAF genes, identified in this study, alone or in combination, are highly likely (hazard ratio 3000–11000) to be associated with the development of leukoplakia and low-grade epithelial dysplasia.
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