Mutational landscapes of brain metastases across various histological subtypes of lung cancer.

Knowledge of the genetic landscape of lung cancer brain metastases (BM) is limited due to the scarcity of intracranial samples. Here, we investigated the genetic features of 142 BM by next-generation sequencing in various lung cancer histological subtypes (19 small-cell lung cancer (SCLC), 123 non-small-cell lung cancer (NSCLC), including 79 lung adenocarcinomas (LUAD), 31 squamous carcinomas (LUSC), and 13 large-cell lung carcinomas (LCLC). TP53, H3F3A, and PMS2 genes were mutated in over 20% of BM cases, irrespective of primary lung cancer histology. LUAD-BM harbored a broad repertoire of mutated proto-oncogenes with tyrosine kinase activity and was significantly associated with APOBEC enrichment and mutations in PTEN, EGFR, and NF1 genes. TP53 and RB1 were the most frequently mutated suppressor genes in SCLC-BM. Gene Ontology analysis indicated that SCLC-BM and LCLC-BM were associated with deregulated glial proliferation processes. These findings provide a comprehensive genomic characterization of BM from various lung cancer histologies.