Differences in Genomic Alterations between Brain Metastases and Primary Tumors

BACKGROUND: Brain metastases (BMs) occur in ∼1/3 of cancer patients and are associated with poor prognosis. Genomic alterations contribute to BM development; however, mutations that predispose and promote BM development are poorly understood. OBJECTIVE: To identify differences in genomic alterations between BM and primary tumors. METHODS: A retrospective cohort of 144 BM patients were tested for genomic alterations (85 lung, 21 breast, 14 melanoma, 4 renal, 4 colon, 3 prostate, 4 others, and 9 unknown carcinomas) by a next-generation sequencing assay interrogating 315 genes. The differences in genomic alterations between BM and primary tumors from COSMIC and TCGA were evaluated by chi-square or Fisher's exact test. Overall survival curves were plotted using the Kaplan-Meier method. RESULTS: The comparison of BM and primary tumors revealed genes that were mutated in BM with increased frequency: TP53, ATR, and APC (lung adenocarcinoma); ARID1A and FGF10 (lung small-cell); PIK3CG, NOTCH3, and TET2 (lung squamous); ERBB2, BRCA2, and AXL1 (breast carcinoma); CDKN2A/B, PTEN, RUNX1T1, AXL, and FLT4 (melanoma); and ATM, AR, CDKN2A/B, TERT, and TSC1 (renal clear-cell carcinoma). Moreover, our results indicate that lung adenocarcinoma BM patients with CREBBP, GPR124, or SPTA1 mutations have a worse prognosis. Similarly, ERBB2, CDK12, or TP53 mutations are associated with worse prognosis in breast cancer BM patients. CONCLUSION: The present study demonstrates significant differences in the frequency of mutations between primary tumors and BM and identifies targetable alterations and genes that correlate with prognosis. Identifying the genomic alterations that are enriched in metastatic central nervous system tumors could help our understanding of BM development and improve patient management.