{"title":"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","authors":"Yi-Xian Liang, Yan-Ping Xie, Huan-Ming Yu, Wen-Juan Zhu, Cheng-Yi Yin, Zhao-Hui Dong, Xi-Lin Zhang","doi":"10.1111/crj.70006","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Introduction</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>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 <i>TMEM229A</i> Q200del mutation was verified using our cohort and TCGA-LUAD datasets. The correlations between the <i>TMEM229A</i> Q200del mutation and the clinicopathological characteristics of patients with LUAD were further analyzed. The functions and mechanisms of <i>TMEM229A</i> Q200del on NSCLC cell proliferation and migration were also determined.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>The frequency of genomic changes in patients with micropapillary LUAD was higher than that in patients with lepidic LUAD. Mutations in <i>EGFR</i>, <i>ATXN2</i>, <i>C14orf180</i>, <i>MUC12</i>, <i>NOTCH1</i>, and <i>PKD1L2</i> were concomitantly detected in three predominant micropapillary and three predominant lepidic LUAD cases. The <i>TMEM229A</i> Q200del mutation was only mutated in lepidic LUAD. Additionally, the <i>TMEM229A</i> Q200del mutation had occurred in 16 (8.8%) patients, and not found <i>TMEM229A</i> R76H and M346T mutations in our cohort, while <i>TMEM229A</i> mutations (R76H, M346T, and Q200del) occurred only in 1.0% of the TCGA-LUAD cohort. Further correlation analysis between the <i>TMEM229A</i> 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 <i>TMEM229A</i> 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.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>Our results demonstrated that the <i>TMEM229A</i> Q200del mutant may play a protective role in the progression of LUAD via inactivating ERK pathway, providing a potential therapeutic target in LUAD.</p>\n </section>\n </div>","PeriodicalId":55247,"journal":{"name":"Clinical Respiratory Journal","volume":"18 8","pages":""},"PeriodicalIF":1.9000,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/crj.70006","citationCount":"0","resultStr":"{\"title\":\"Whole-Exome Sequencing and Experimental Validation Unveil the Roles of TMEM229A Q200del Mutation in Lung Adenocarcinoma\",\"authors\":\"Yi-Xian Liang, Yan-Ping Xie, Huan-Ming Yu, Wen-Juan Zhu, Cheng-Yi Yin, Zhao-Hui Dong, Xi-Lin Zhang\",\"doi\":\"10.1111/crj.70006\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Introduction</h3>\\n \\n <p>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.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>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 <i>TMEM229A</i> Q200del mutation was verified using our cohort and TCGA-LUAD datasets. The correlations between the <i>TMEM229A</i> Q200del mutation and the clinicopathological characteristics of patients with LUAD were further analyzed. The functions and mechanisms of <i>TMEM229A</i> Q200del on NSCLC cell proliferation and migration were also determined.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>The frequency of genomic changes in patients with micropapillary LUAD was higher than that in patients with lepidic LUAD. Mutations in <i>EGFR</i>, <i>ATXN2</i>, <i>C14orf180</i>, <i>MUC12</i>, <i>NOTCH1</i>, and <i>PKD1L2</i> were concomitantly detected in three predominant micropapillary and three predominant lepidic LUAD cases. The <i>TMEM229A</i> Q200del mutation was only mutated in lepidic LUAD. Additionally, the <i>TMEM229A</i> Q200del mutation had occurred in 16 (8.8%) patients, and not found <i>TMEM229A</i> R76H and M346T mutations in our cohort, while <i>TMEM229A</i> mutations (R76H, M346T, and Q200del) occurred only in 1.0% of the TCGA-LUAD cohort. Further correlation analysis between the <i>TMEM229A</i> 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 <i>TMEM229A</i> 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.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusion</h3>\\n \\n <p>Our results demonstrated that the <i>TMEM229A</i> Q200del mutant may play a protective role in the progression of LUAD via inactivating ERK pathway, providing a potential therapeutic target in LUAD.</p>\\n </section>\\n </div>\",\"PeriodicalId\":55247,\"journal\":{\"name\":\"Clinical Respiratory Journal\",\"volume\":\"18 8\",\"pages\":\"\"},\"PeriodicalIF\":1.9000,\"publicationDate\":\"2024-08-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1111/crj.70006\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Respiratory Journal\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/crj.70006\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"RESPIRATORY SYSTEM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Respiratory Journal","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/crj.70006","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"RESPIRATORY SYSTEM","Score":null,"Total":0}
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.
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,
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