Genomic characterisation of pulmonary subsolid nodules: mutational landscape and radiological features.

Background Lung adenocarcinomas (LUADs) that radiologically display as subsolid nodules (SSNs) exhibit more indolent biological behavior than solid LUADs. SSNs, commonly encompassing preinvasive and invasive but early-stage adenocarcinomas, can be categorised as pure ground-glass nodules (pGGNs) and part-solid nodules (PSNs). The genomic characteristics of SSNs remain poorly understood. Methods We subjected 154 SSN samples from 120 treatment-naive Chinese patients to whole exome sequencing. Clinical parameters and radiological features of these SSNs were collected. The genomic landscape of SSNs and differences from that of advanced stage LUADs were defined. We also investigated the intratumor heterogeneity and clonal relationship of multifocal SSNs and conducted radiogenomic analysis to link imaging and molecular characteristics of SSNs. Fisher9s exact and Wilcoxon rank sum tests were used in the statistical analysis. Results The median somatic mutation rate across the SSN cohort was 1.12 mutations/Mb. Mutations in EGFR were the most prominent and significant variation, followed by those in RBM10, TP53, STK11, and KRAS. The differences between SSNs and advanced-stage LUADs at a genomic level were unraveled. Branched evolution and remarkable genomic heterogeneity were demonstrated in SSNs. Although multi-centric origin was predominant, we also detected early metastatic events among multifocal SSNs. Using radiogenomic analysis, we found that higher ratios of solid components in SSNs were accompanied by significantly higher mutation frequencies in EGFR, TP53, RBM10, and ARID1B, suggesting that these genes play roles in the progression of LUADs. Conclusions Our study provides the first comprehensive description of the mutational landscape and radiogenomic mapping of SSNs.