Clinical significance of TMEM229A Q200del mutation in lung adenocarcinoma

Abstract

Lung adenocarcinoma is one of the major histopathological subtype of non-small cell lung cancer (NSCLC), including solid, acinar, lepidic, papillary and micropapillary subtypes. Increasing evidence had showed that micropapillary lung adenocarcinoma was positively associated with higher incidence of metastasis and poorer prognosis, while lepidic lung adenocarcinoma had a relatively better prognosis. However, the key alteration signatures and its role in micropapillary lung adenocarcinoma progression are not exactly determined. Here, 181 patients with lung adenocarcinoma who underwent surgery in the First Affiliated Hospital of Huzhou University from January 2016 and December 2020 were retrospectively enrolled. And three lepidic and three micropapillary lung adenocarcinoma samples were sequenced using whole-exome sequencing. More comprehensively analyze genomic variations between lepidic and micropapillary lung adenocarcinoma was performed. In addition, TMEM229A Q200del mutation was verified using our cohort and The Cancer Genome Atlas-Lung Adenocarcinoma (TCGA-LUAD) datasets. The correlations between TMEM229AQ200del mutation and clinicopathological characteristics of patients with lung adenocarcinoma were further analyzed. The functions of TMEM229A Q200del in H23 cell proliferation and migration were also determined. As expected, the frequency of genomic alteration signatures in patients with micropapillary lung adenocarcinoma was higher than that in lepidic lung adenocarcinoma. Mutations in EGFR, ATXN2, C14orf180, MUC12, NOTCH1 and PKD1L2 were concomitantly detected in three micropapillary and three lepidic lung adenocarcinoma cases. But TMEM229A Q200del mutation was only mutated in lepidic lung adenocarcinoma. Additionally, TMEM229AQ200del mutation was observed in 16 cases (8.8%) of our cohort, while TMEM229A mutations (R76H, Q200del and M346T) accounted for approximately 1.0% of cases in TCGA-LUAD cohorts. Further correlation analysis between TMEM229AQ200del mutation and clinicopathological characteristics suggested that lower frequency of Q200del mutation was significantly associated with gender, positive of lymph node metastasis, advanced TNM stage, positive of cancer thrombus and pathological patterns. Finally, forced overexpression of TMEM229AQ200del markedly suppressed H23 cell proliferation and migration in vitro. In summary, our results demonstrated that TMEM229AQ200del mutation plays a protective role in the progression of lung adenocarcinoma, which could be helpful in developing a novel therapeutic target in lung adenocarcinoma.