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

Autor: Liang YX; Department of Cardiothoracic Surgery, First Affiliated Hospital of Huzhou University, Huzhou, Zhejiang, People's Republic of China., Xie YP; Department of Respiratory Medicine, First Affiliated Hospital of Huzhou University, Huzhou, Zhejiang, People's Republic of China., Yu HM; Department of Cardiothoracic Surgery, First Affiliated Hospital of Huzhou University, Huzhou, Zhejiang, People's Republic of China., Zhu WJ; Department of Pathology, The First People's Hospital of Huzhou, Huzhou, Zhejiang, People's Republic of China., Yin CY; Department of Cardiothoracic Surgery, First Affiliated Hospital of Huzhou University, Huzhou, Zhejiang, People's Republic of China., Dong ZH; Department of Respiratory Medicine, First Affiliated Hospital of Huzhou University, Huzhou, Zhejiang, People's Republic of China., Zhang XL; Central Laboratory, Huzhou Key Laboratory of Translational Medicine, First Affiliated Hospital of Huzhou University, Huzhou, Zhejiang, People's Republic of China.
Jazyk: angličtina
Zdroj: The clinical respiratory journal [Clin Respir J] 2024 Aug; Vol. 18 (8), pp. e70006.
DOI: 10.1111/crj.70006
Abstrakt: 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.
(© 2024 The Author(s). The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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