Comparison of gene mutation profile in different lung adenocarcinoma subtypes by targeted next-generation sequencing

Abstract

Background: Disease prognosis after resection of lung cancer could be affected by pathological subtypes. In this study, we investigated the difference of gene variation and significantly altered pathways between adenocarcinoma in situ (AIS)/microinvasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC) subtypes to reveal the molecular mechanism of prognosis differences.

Methods: Sixty one tumor tissues were subjected to DNA extraction and customized 136 gene targeted next-generation sequencing. Comparisons between groups were performed with two-sided Fisher's exact test for categorical variables and two-tailed unpaired t test for numerical variables.

Results: A total of 402 somatic mutations involved in 70 genes were detected in all these samples, and 74.29% of these genes were mutated in at least two samples. PMS2, ARID1A, EGFR, and POLE were the most frequently mutated genes. ALK_EML4 fusion was observed in one IAC patient and RET_ KIF5B fusion in one AIS patient. A significant higher proportion of patients with TP53 gene mutation was observed in the IAC group (P = 0.0057). The average onset age in IAC group is 62.48 years, which is greater than other subtypes (P = 0.0166). It revealed that mutations in genes involved in the mTOR signaling pathway (56.52% vs 26.32%, P = 0.0288) and Hippo signaling pathway (34.78% vs 10.53%, P = 0.0427) were significantly enriched in IAC subtypes, suggesting the key involvement of mTOR and Hippo signaling pathways in lung tumor development and malignant progression.

Conclusions: This study revealed the heterogeneity of gene mutations and significantly altered pathways between different lung cancer subtypes, suggesting the potential mechanism of different prognosis.

Keywords: Gene mutation Profile; Hippo signaling pathway; Lung adenocarcinoma (LUAD); Next-generation sequencing (NGS); mTOR signaling pathway.