Association of high tumor mutational burden with brain metastases: Insights from a large-scale database analysis

Abstract Background Brain metastases (BrM) are a major cause of cancer-related mortality. To successfully colonize the brain, cancer cells must acquire unique adaptations. We hypothesized that BrM, regardless of their primary tumor origin, share convergent molecular features enabling brain colonization while retaining tumor type–specific alterations. Methods We analyzed genomic data from 150,486 tumor samples, including BrM (N = 4,538), non-brain metastases (non-BrM, N = 43,844), and local biopsies (LB, N = 71,738) across six cancer types: non-small cell lung cancer (NSCLC), colorectal cancer (CRC), breast cancer (BC), esophageal cancer, melanoma, and neuroendocrine tumors (NET). We compared genomic alterations (GA), pathway enrichment, high tumor mutation burden (TMB-high), and high microsatellite instability (MSI-H) across groups. Results Our research revealed that BrM were enriched for TMB-high and exhibited higher median values across all cancer types studied, compared to both LB and non-BrM. Interestingly, MSI-H, despite its known association with TMB-high, was not significantly enriched in BrM. We further showed a consistent enrichment of GA in TP53 in BrM across multiple tumor types. KRAS mutations were enriched in NSCLC and CRC BrM, while GA in TERT were specific to melanoma BrM. Pathway analysis showed that BrM have a higher frequency of GA in genes associated with the ERK-MAPK pathway and, to a lesser extent, the DNA damage response pathway. Conclusions BrM harbor both tumor-specific and shared molecular traits, particularly TMB-high and recurrent TP53/KRAS alterations, potentially reflecting essential adaptations for BrM. These insights provide a molecular framework for developing targeted therapeutic strategies to prevent or treat BrM.