Association of high tumor mutational burden with brain metastases: analysis of over 150,000 tumor samples from six cancer types

Brain metastases (BrM) are a major cause of cancer-related mortality. To colonize the brain, cancer cells must acquire unique adaptations. Researchers at Tel Aviv Sourasky Medical Center (Israel) investigated the hypothesis that BrM, regardless of their primary tumor origin, share convergent molecular features enabling brain colonization while retaining tumor type-specific alterations. The authors 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: NSCLC, CRC, breast cancer (BC), esophageal cancer, melanoma, and neuroendocrine tumors (NET). The analysis revealed that BrM were enriched for high tumor mutation burden (TMB-H) and exhibited higher median values across all cancer types studies, compared to both non-BrM and LB. Interestingly, high microsatellite instability (MSI-H) was not significantly enriched in BrM. There was a consistent enrichment of genomic alterations in TP53 across multiple tumor types. KRAS mutations were enriched in NSCLC and CRC BrM, while genomic alterations in TERT were specific to melanoma BrM. Pathway analysis showed that BrM have a higher frequency of genomic alteration in genes associated with the ERK-MAPK pathway and the DNA damage response pathway. The authors conclude that BrM harbor both tumor-specific and shared molecular traits.