Genomic alterations dissection revealed MUC4 mutation as a potential driver in lung adenocarcinoma local recurrence

BACKGROUND: Lung adenocarcinoma (LUAD) is the most common histological type of lung cancer, of which genomic alterations play a major role in tumorigenesis. The prognosis of LUAD has been improved these years but nearly half of the patients still develop recurrence even after radical resection. The underlying mechanism driving LUAD recurrence especially genomic alterations is complicated and worth exploring. METHODS: Forty-one primary tumors and 43 recurrent tumors were collected from 41 LUAD patients who received surgery resection after recurrence. Whole exon sequencing (WES) was performed to make genomic landscapes. WES data were aligned to genome and further analyzed for somatic mutation, copy number variation and structure variation. MutsigCV was used to identify significantly mutated genes and recurrence specific genes. RESULTS: Significantly mutated genes including EGFR, MUC4 and TP53 were identified in primary and recurrent tumors. Some were found to be more specifically mutated in recurrent tumors, such as the MUC17, KRAS and ZNF families. In recurrent tumors, ErbB signaling pathway, MAPK pathway and cell cycle pathway were highly activated, which maybe the mechanism driving recurrence. The adjuvant therapy would affect tumor evolution and molecular features during recurrence. MUC4 was highly mutated in this study cohort, and it was a potential driver gene in LUAD recurrence by activating ErbB signaling pathway as a ligand of ERBB2. CONCLUSIONS: Genomic alteration landscape was changing during LUAD recurrence to construct a more suitable environment for the survival of tumor cells. Several potential driver mutations and targets during LUAD recurrence were identified, such as MUC4, and more investigation was needed to verify the specific functions and roles.