Brain metastases (BMs) are malignancies in the central nervous system with poor prognosis.
Genetic landscapes of the primary tumor sites have been extensively profiled; however,
mutations associated with BMs are poorly understood. In the present study, target
exome sequencing of 560 cancer-associated genes in samples from 52 patients with brain
metastasis from various primary sites was performed. Recurrent mutations for BMs from
distinct origins were identified. There were both genetic homogeneity and heterogeneity
between BMs and primary lung tumor tissues. The mutation rate of the major cancer
driver gene, TP53, was consistently high in both the primary lung cancer sites and
BMs, while some genetic alterations, associated with DNA damage response deficiency,
were specifically enriched in BMs. The mutational signatures enriched in BMs could
serve as actionable targets for treatment. The mutation in the primary site of the
potential brain metastasis driver gene, nuclear mitotic apparatus protein 1 (NUMA1),
affected the progression-free survival time of patients with lung cancer, and patients
with the NUMA1 mutation in BMs had a good prognosis. This suggested that the occurrence
and clinical outcome of brain metastases could be independent of each other.