Comparison of the somatic genomic landscape between central- and peripheral-type non-small cell lung cancer

Objective: Lung cancer is classified into central and peripheral types based on the anatomic location. The present study aimed to explore the distinct patterns of genomic alterations between central- and peripheral-type nonsmall cell lung cancers (NSCLCs) with negative driver genes and identify potential driver genes and biomarkers to improve therapy strategies for NSCLC. Methods: Whole-exome sequencing (WES) was performed with 182 tumor/control pairs of samples from 145 Chinese NSCLC patients without EGFR, ALK, or ROS1 alterations. Significantly mutated genes (SMGs) and somatic copy number alterations (SCNAs) were identified. Subsequently, tumor mutation burden (TMB), weighted genome integrity index (wGII), copy number alteration (CNA) burden, Shannon diversity index (SDI), intratumor heterogeneity (ITH), neoantigen load (NAL), and clonal variations were evaluated in central- and peripheral-type NSCLCs. Furthermore, mutational signature analysis and survival analysis were performed. Results: TP53 was the most frequently mutated gene in NSCLC and more frequently mutated in central-type NSCLC. Higher wGII, ITH, and SDI were found in central-type lung adenocarcinoma (LUAD) than in peripheral-type LUAD. The NAL of central-type lung squamous cell carcinoma (LUSC) with stage III/IV was significantly higher than that of peripheral-type LUSC. Mutational signature analysis revealed that SBS10b, SBS24, and ID7 were significantly different in central- and peripheral-type NSCLCs. Furthermore, central-type NSCLC was found to evolve at a higher level with fewer clones and more subclones, particularly in centraltype LUSC. Survival analysis revealed that TMB, CNA burden, NAL, subclonal driver mutations, and subclonal mutations were negatively related to the overall survival (OS) and the progression-free survival (PFS) of centraltype LUAD. Conclusions: Central-type NSCLC tended to evolve at a higher level and might suggest a favorable response to immunotherapy. Our study also identified several potential driver genes and promising biomarkers for the prognosis and prediction of chemotherapy responses in NSCLC.