口腔黏膜白斑和鳞状细胞癌患者种系突变的前瞻性观察研究

N. A. Karpuk, S. Rubnikovich, O. C. Mazur, I. V. Zhyltsov, I. Karpuk, A. Mikhalenka
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With the knowledge of such variants, it would become possible to develop PCR (polymerase chain reaction) and NGS (next-generation sequencing) test systems for the detection of clinically significant germline mutations.Objectives — to identify pathogenic germline genetic variants in patients with oral mucosal leukoplakia accompanied by grade 1 epithelial dysplasia, as well as oral mucosal squamous cell carcinoma, using new-generation sequencing.Methods. Study design: prospective, observational, cross-sectional, without a control group. The sample included patients (48 persons) of either sex (18 years of age or older) with the following proven and morphologically confirmed diagnoses: oral mucosal leukoplakia accompanied by grade 1 squamous intraepithelial neoplasia of epithelium (24 people) and oral mucosal squamous cell carcinoma (24 people), who sought medical care at the Vitebsk Regional Clinical Dental Center and Vitebsk Regional Clinical Oncological Center in 2019–2020. 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引用次数: 0

摘要

背景致力于口腔粘膜白斑和鳞状细胞癌分子遗传学的研究数量很少,而所获得的结果通常是初步的。我们可以假设存在与口腔粘膜白斑和鳞状细胞癌发展有关的区域特异性致病基因变异。有了这些变体的知识,就有可能开发PCR(聚合酶链式反应)和NGS(下一代测序)检测系统来检测具有临床意义的种系突变。目的——利用新一代测序技术,鉴定口腔黏膜白斑伴1级上皮发育不良和口腔黏膜鳞状细胞癌患者的致病性种系遗传变异。方法。研究设计:前瞻性、观察性、横断面,无对照组。样本包括具有以下经证实和形态学证实诊断的患者(48人),无论性别(18岁或以上):口腔粘膜白斑伴1级鳞状上皮内瘤变(24人)和口腔粘膜鳞状细胞癌(24人,他于2019-2020年在维捷布斯克地区临床牙科中心和维捷布克地区临床肿瘤中心寻求医疗护理。定量评估了与这些疾病发展有关的已鉴定的致病性和推测致病性遗传变异。这项研究是在白俄罗斯国家科学院遗传学和细胞学研究所的共享核心设施GENOME进行的。为了从血液样本中分离脱氧核糖核酸(DNA),使用QIAamp DNA FFPE组织试剂盒(Qiagen,德国)。DNA文库的制备和测序通过Illumina NextSeq 550测序系统(Illumina,股份有限公司,USA)使用Illumina Next DNA Exome试剂盒(USA)进行。根据现行指南,使用Illumina BaseSpace专业软件(美国)和银河项目(国际非营利项目银河社区)进行生物信息学分析。使用专门的软件包Statistica 12(StatSoft,股份有限公司,美国)和MedCalc 18.9.1(MedCalc software,Ltd,比利时)对获得的数据进行统计处理第一次。两组患者外显子组中独特种系遗传变异的总数都很高,但大多数都没有致病性。在检查的患者中,发现大多数种系突变仅定位于19个外显子组基因:MAP2K3、DNAH5、HSPG2、OBSCN、SYNE1、HLA-DRB1、HLA-DQA1、HLA-DQB1、HLA-A、HLA-B、PKD1L2、TTN、AHNAK2、PDE4DIP、MUC3A、MUC4、MUC12、MUC16和MUC17。在两个临床组中,在负责糖蛋白-粘蛋白家族合成的MUC3A、MUC4、MUC12和MUC16中检测到最大数量的遗传变异(>总数的40%)。结论口腔粘膜白斑和鳞状细胞癌可由MUC3A、MUC4、MUC12和MUC16的致病性变体引起。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Germline mutations in patients with oral mucosal leukoplakia and squamous cell carcinoma: a prospective observational study
Background. The number of studies devoted to the molecular genetics of oral mucosal leukoplakia and squamous cell carcinoma is small, while the obtained results are usually preliminary in nature. We can assume the existence of region-specific pathogenic genetic variants involved in the development of oral mucosal leukoplakia and squamous cell carcinoma. With the knowledge of such variants, it would become possible to develop PCR (polymerase chain reaction) and NGS (next-generation sequencing) test systems for the detection of clinically significant germline mutations.Objectives — to identify pathogenic germline genetic variants in patients with oral mucosal leukoplakia accompanied by grade 1 epithelial dysplasia, as well as oral mucosal squamous cell carcinoma, using new-generation sequencing.Methods. Study design: prospective, observational, cross-sectional, without a control group. The sample included patients (48 persons) of either sex (18 years of age or older) with the following proven and morphologically confirmed diagnoses: oral mucosal leukoplakia accompanied by grade 1 squamous intraepithelial neoplasia of epithelium (24 people) and oral mucosal squamous cell carcinoma (24 people), who sought medical care at the Vitebsk Regional Clinical Dental Center and Vitebsk Regional Clinical Oncological Center in 2019–2020. The identified pathogenic and presumably pathogenic genetic variants involved in the development of these diseases were quantitatively assessed. The study was conducted at the Shareable Core Facilities GENOME of the Institute of Genetics and Cytology of the National Academy of Sciences of Belarus. In order to isolate deoxyribonucleic acid (DNA) from blood samples, a QIAamp DNA FFPE Tissue Kit (Qiagen, Germany) was used. The preparation of DNA libraries and sequencing were carried out by means of an Illumina NextSeq 550 sequencing system (Illumina, Inc., USA) using an Illumina Nextera DNA Exome kit (USA). Bioinformatic analysis was conducted using Illumina BaseSpace specialized software (USA) and Galaxy Project (Galaxy Community, an international non-profit project) in accordance with current guidelines. The obtained data were statistically processed employing specialized software packages Statistica 12 (StatSoft, Inc., USA) and MedCalc 18.9.1 (MedCalc Software, Ltd, Belgium).Results. Next-generation whole-exome sequencing of deoxyribonucleic acid samples isolated from the blood of patients with oral mucosal leukoplakia and squamous cell carcinoma has been conducted in the Republic of Belarus for the first time. The total number of unique germline genetic variants in the exome of both groups of patients was shown to be very high, yet most of them were not pathogenic. In the examined patients, the majority of germline mutations were found to be localized only in 19 exome genes: MAP2K3, DNAH5, HSPG2, OBSCN, SYNE1, HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-A, HLA-B, PKD1L2, TTN, AHNAK2, PDE4DIP, MUC3A, MUC4, MUC12, MUC16, and MUC17. In both clinical groups, the greatest number of genetic variants (> 40% of the total number) was detected in MUC3A, MUC4, MUC12, and MUC16, responsible for the synthesis of the glycoprotein mucin family.Conclusion. Oral mucosal leukoplakia and squamous cell carcinoma can arise from the pathogenic variants of MUC3A, MUC4, MUC12, and MUC16.
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