Comparative study on the mutational profile of adenocarcinoma and squamous cell carcinoma predominant histologic subtypes in Chinese non-small cell lung cancer patients.

Distinction in the mutational profile between the common histological types, lung adenocarcinoma (LUAD) and squamous cell lung carcinoma (LUSC) has been well-established. However, comprehensive mutation profiles of the predominant histological subtypes within LUAD and LUSC remains elusive. We analyzed the mutational profile of 318 Chinese NSCLC patients of adenocarcinoma and squamous cell carcinoma predominant subtypes from seven hospitals using capture-based ultra-deep sequencing of 68 lung cancer-related genes. Of the 318 NSCLC patients, 215 were diagnosed with LUAD and 103 with LUSC. Adenocarcinoma in situ and acinar adenocarcinoma were the most predominant subtypes of LUAD. On the other hand, keratinizing squamous cell carcinoma was the most predominant subtype of LUSC. Among the LUAD subtypes, EGFR sensitizing mutations were most prevalent in the invasive lepidic subtype. More than half of the patients with preinvasive adenocarcinoma in situ, minimally invasive, acinar, micropapillary and papillary subtypes were also EGFR-mutants. Patients with colloidal, invasive mucinous, and fetal subtypes had the least number of EGFR mutations. Moreover, KRAS mutations were prevalent in patients with invasive mucinous, colloid, enteric and solid subtypes. A total of 90% of the LUSC patients harbor mutations in TP53, wherein all patients except five with nonkeratinizing were TP53 mutants. PIK3CA amplifications were most prevalent in keratinizing, followed by basaloid and nonkeratinizing subtypes. These data suggest that the mutational profiles among the predominant histological subtypes were very distinct, which provided a reliable tool to improve treatment decisions.

Ding Y ，Zhang L ，Guo L ，Wu C ，Zhou J ，Zhou Y ，Ma J ，Li X ，Ji P ，Wang M ，Zhu W ，Shi C ，Li S ，Wu W ，Zhu W ，Xiao D ，Fu C ，He Q ，Sun R ，Mao X ，Lizaso A ，Li B ，Han-Zhang H ，Zhang Z ... -  《-》

Intratumor heterogeneity comparison among different subtypes of non-small-cell lung cancer through multi-region tissue and matched ctDNA sequencing.

Zhang Y ，Chang L ，Yang Y ，Fang W ，Guan Y ，Wu A ，Hong S ，Zhou H ，Chen G ，Chen X ，Zhao S ，Zheng Q ，Pan H ，Zhang L ，Long H ，Yang H ，Wang X ，Wen Z ，Wang J ，Yang H ，Xia X ，Zhao Y ，Hou X ，Ma Y ，Zhou T ，Zhang Z ，Zhan J ，Huang Y ，Zhao H ，Zhou N ，Yi X ，Zhang L ... -  《Molecular Cancer》

A prognosis-related molecular subtype for early-stage non-small lung cell carcinoma by multi-omics integration analysis.

Yang K ，Wu Y 《BMC CANCER》

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

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. 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. 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. 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.

Liang YX ，Xie YP ，Yu HM ，Zhu WJ ，Yin CY ，Dong ZH ，Zhang XL ... -  《-》

The genomic alterations of lung adenocarcinoma and lung squamous cell carcinoma can explain the differences of their overall survival rates.

In the US, lung carcinoma accounted for over 150,000 deaths in 2018 and the advances in increasing survival rates are still limited. In this study, we investigated the cohorts with lung adenocarcinoma (LUAD) or lung squamous cell carcinoma (LUSC) from The Cancer Genome Atlas to figure out the risk factors and genomic alterations that affected their prognosis. The histoclinical factors that differed between LUAD and LUSC were identified and the risk factors affecting the overall survival were figured out for both LUAD and LUSC. Next, the patterns of nucleotides substitutions and the mutational signatures were extracted to illustrate whether different mutational processes performed for them. Finally, the genes that had different frequencies of mutation were identified. LUAD and LUSC presented differences in histoclinical factors including age at the time of diagnosis, sex, smoking history, pathological T classification, and overall survival. This was caused by the distinct genomic alterations including the transition-to-transversion ratios, mutational signatures, and the frequently mutated genes. We proposed that the mutational signature associated with aging could be used to predict the prognosis of patients with LUAD. On the other hand, the AID/APOBEC family was associated with the prognosis of LUSC. Finally, SNTG1 and LRRK2 might be important in LUAD and LUSC, respectively.

Meng F ，Zhang L ，Ren Y ，Ma Q ... -  《-》