Genetic composition and evolutionary trajectories of brain metastasis in non-small-cell lung cancer

Non-small cell lung cancer (NSCLC) is an aggressive solid malignancy that commonly disseminates to the central nervous system (CNS). Comparative analysis of primary NSCLC and brain metastases (BM) by next-generation sequencing may reveal somatic genetic alterations that drive or favor NSCLC-derived BM.

We performed whole-exome sequencing (WES) in 62 archival samples from 31 paired-matched primary NSCLC sites and corresponding BM. The median age of patients was 66 years; 22 had adenocarcinoma, and 9 had squamous cell carcinoma, 6 patients presented synchronous BM at lung cancer diagnosis, and 22 developed BM after 1-78 months (median 13 months).

Mutations in the RTK-RAS, WNT, NOTCH, and PIK pathways were enriched across all samples. The KMT2D and TP53 genes were the most frequently mutated in the primary tumor and corresponding BM. FAT1, NSD1, and NF1 mutations were among the most frequent alterations newly detected in BM. Non-druggable hotspot alterations in actionable genes, including EGFR, KRAS, ALK, and ROS1, showed various patterns between the two tumor sites.

Our study provides a comprehensive overview of genetic alterations specific to primary NSCLC, unique to BM, and shared between both sites, which may contribute to BM formation affecting various evolutionary trajectories.