Stepwise evolutionary genomics of early-stage lung adenocarcinoma manifesting as pure, heterogeneous and part-solid ground-glass nodules.

BACKGROUND: This study was designed to unravel the genomic landscape and evolution of early-stage subsolid lung adenocarcinomas (SSN-LUADs) manifesting as pure ground-glass nodules (pGGNs), heterogeneous ground-glass nodules (HGGNs) and part-solid nodules (PSNs).
METHODS: Samples subjected to either broad-panel next-generation sequencing (NGS) or whole-exome sequencing (WES) were included. Clinicopathologic and genomic features were compared among pGGN, HGGN and PSN, while tumour evolutionary trajectories and mutational signatures were evaluated in the entire cohort.
RESULTS: In total, 247 SSN-LUAD samples subjected to broad-panel NGS and 125 to WES were identified. Compared with PSNs, HGGNs had significantly lower tumour mutation count (P < 0.001), genomic alteration count (P < 0.001), and intra-tumour heterogeneity (P = 0.005). Statistically significant upward trends were observed in alterations involving driver mutations and oncogenic pathways from pGGNs to HGGNs to PSNs. EGFR mutation was proved to be a key early event in the progression of SSN-LUADs, with subsequently two evolutionary trajectories involving either RBM10 or TP53 mutation in the cancer-evolution models.
CONCLUSIONS: This study provided evidence for unravelling the previously unknown genomic underpinnings associated with SSN-LUAD evolution from pGGN to HGGN to PSN, proving that HGGN was an intermediate SSN form between pGGN and PSN genetically.