全基因组测序和实验验证揭示 TMEM229A Q200del 突变在肺腺癌中的作用

IF 1.9 4区 医学 Q3 RESPIRATORY SYSTEM
Yi-Xian Liang, Yan-Ping Xie, Huan-Ming Yu, Wen-Juan Zhu, Cheng-Yi Yin, Zhao-Hui Dong, Xi-Lin Zhang
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引用次数: 0

摘要

简介肺腺癌(LUAD)是非小细胞肺癌(NSCLC)的主要组织病理学类型之一,包括实性、尖锐性、鳞状、乳头状和微乳头状亚型。越来越多的证据表明,微乳头状 LUAD 与较高比例的驱动基因突变、较高的转移发生率和较差的预后呈正相关,而鳞状 LUAD 的预后相对较好。然而,微乳头状 LUAD 进展过程中的新型基因变化及其内在机制尚未确切确定:方法:选取2020年1月至2022年12月在湖州大学附属第一医院接受手术治疗的181例LUAD患者为研究对象。采用全外显子组测序技术,对 3 例优势鳞状上皮细胞和 3 例优势微乳头状上皮细胞 LUAD 组织样本进行了测序。对鳞状上皮癌和微乳头状上皮癌的基因组变异和差异进行了全面分析。此外,还利用我们的队列和TCGA-LUAD数据集验证了TMEM229A Q200del突变。研究还进一步分析了TMEM229A Q200del突变与LUAD患者临床病理特征之间的相关性。研究还确定了TMEM229A Q200del对NSCLC细胞增殖和迁移的功能和机制:结果:微乳头状 LUAD 患者的基因组变化频率高于鳞状 LUAD 患者。在三例占优势的微乳头状LUAD和三例占优势的鳞状LUAD病例中,同时检测到了表皮生长因子受体(EGFR)、ATXN2、C14orf180、MUC12、NOTCH1和PKD1L2的突变。TMEM229A Q200del突变仅在鳞状LUAD中出现。此外,TMEM229A Q200del突变发生在16例(8.8%)患者中,在我们的队列中未发现TMEM229A R76H和M346T突变,而在TCGA-LUAD队列中,TMEM229A突变(R76H、M346T和Q200del)仅发生在1.0%的患者中。TMEM229A Q200del突变与临床病理特征之间的进一步相关性分析表明,较低频率的Q200del突变与淋巴结转移阳性、TNM分期晚期、癌栓阳性和病理特征显著相关。最后,体外过表达 TMEM229A Q200del 可抑制 NSCLC 细胞的增殖和迁移。从机理上讲,过表达TMEM229A和TMEM229A Q200del都会降低磷酸化(p)-ERK和p-AKT(Ser473)的表达水平,而且与TMEM229A组相比,TMEM229A Q200del组p-ERK蛋白水平的降低更为明显:我们的研究结果表明,TMEM229A Q200del突变体可能通过使ERK通路失活而在LUAD的进展过程中发挥保护作用,为LUAD提供了一个潜在的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Whole-Exome Sequencing and Experimental Validation Unveil the Roles of TMEM229A Q200del Mutation in Lung Adenocarcinoma

Whole-Exome Sequencing and Experimental Validation Unveil the Roles of TMEM229A Q200del Mutation in Lung Adenocarcinoma

Introduction

Lung adenocarcinoma (LUAD) is one of the major histopathological types of non-small cell lung cancer (NSCLC), including solid, acinar, lepidic, papillary and micropapillary subtypes. Increasing evidence has shown that micropapillary LUAD is positively associated with a higher percentage of driver gene mutations, a higher incidence of metastasis and a poorer prognosis, while lepidic LUAD has a relatively better prognosis. However, the novel genetic change and its underlying mechanism in the progression of micropapillary LUAD have not been exactly determined.

Methods

A total of 181 patients with LUAD who underwent surgery at the First Affiliated Hospital of Huzhou University from January 2020 to December 2022 were enrolled. Three predominant lepidic and three predominant micropapillary LUAD tissue samples were carried out using whole-exome sequencing. Comprehensive analysis of genomic variations and the difference between lepidic and micropapillary LUAD was performed. In addition, the TMEM229A Q200del mutation was verified using our cohort and TCGA-LUAD datasets. The correlations between the TMEM229A Q200del mutation and the clinicopathological characteristics of patients with LUAD were further analyzed. The functions and mechanisms of TMEM229A Q200del on NSCLC cell proliferation and migration were also determined.

Results

The frequency of genomic changes in patients with micropapillary LUAD was higher than that in patients with lepidic LUAD. Mutations in EGFR, ATXN2, C14orf180, MUC12, NOTCH1, and PKD1L2 were concomitantly detected in three predominant micropapillary and three predominant lepidic LUAD cases. The TMEM229A Q200del mutation was only mutated in lepidic LUAD. Additionally, the TMEM229A Q200del mutation had occurred in 16 (8.8%) patients, and not found TMEM229A R76H and M346T mutations in our cohort, while TMEM229A mutations (R76H, M346T, and Q200del) occurred only in 1.0% of the TCGA-LUAD cohort. Further correlation analysis between the TMEM229A Q200del mutation and clinicopathological characteristics suggested that a lower frequency of the Q200del mutation was significantly associated with positive lymph node metastasis, advanced TNM stage, positive cancer thrombus, and pathological features. Finally, overexpression of TMEM229A Q200del suppressed NSCLC cell proliferation and migration in vitro. Mechanistically, overexpression of TMEM229A and TMEM229A Q200del both reduced the expression level of phosphorylated (p)-ERK and p-AKT (Ser473), and the reduced protein level of p-ERK in the TMEM229A Q200del group was more pronounced compared to the TMEM229A group.

Conclusion

Our results demonstrated that the TMEM229A Q200del mutant may play a protective role in the progression of LUAD via inactivating ERK pathway, providing a potential therapeutic target in LUAD.

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来源期刊
Clinical Respiratory Journal
Clinical Respiratory Journal 医学-呼吸系统
CiteScore
3.70
自引率
0.00%
发文量
104
审稿时长
>12 weeks
期刊介绍: Overview Effective with the 2016 volume, this journal will be published in an online-only format. Aims and Scope The Clinical Respiratory Journal (CRJ) provides a forum for clinical research in all areas of respiratory medicine from clinical lung disease to basic research relevant to the clinic. We publish original research, review articles, case studies, editorials and book reviews in all areas of clinical lung disease including: Asthma Allergy COPD Non-invasive ventilation Sleep related breathing disorders Interstitial lung diseases Lung cancer Clinical genetics Rhinitis Airway and lung infection Epidemiology Pediatrics CRJ provides a fast-track service for selected Phase II and Phase III trial studies. Keywords Clinical Respiratory Journal, respiratory, pulmonary, medicine, clinical, lung disease, Abstracting and Indexing Information Academic Search (EBSCO Publishing) Academic Search Alumni Edition (EBSCO Publishing) Embase (Elsevier) Health & Medical Collection (ProQuest) Health Research Premium Collection (ProQuest) HEED: Health Economic Evaluations Database (Wiley-Blackwell) Hospital Premium Collection (ProQuest) Journal Citation Reports/Science Edition (Clarivate Analytics) MEDLINE/PubMed (NLM) ProQuest Central (ProQuest) Science Citation Index Expanded (Clarivate Analytics) SCOPUS (Elsevier)
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