Genomic profiling reveals SMARCA4 mutations are associated with shorter overall and intracranial progression free survival in melanoma brain metastasis patients

Abstract

Purpose: Melanoma brain metastases (MBMs) are a common, lethal complication of metastatic melanoma. Despite improvements in treatments, subsets of MBM patients experience rapid decline, and few prognostic biomarkers have been identified. An improved understanding of the molecular features specifically associated with MBM overall survival (OS) and intracranial progression free survival (PFS) could facilitate the development of more effective clinical management strategies. Experimental Design: We established an initial cohort of 102 MBMs, 970 unmatched melanoma extracranial metastases (ECMs), and 569 unmatched melanoma primaries with available targeted exome sequencing data covering 182 genes and a validation cohort of 50 MBMs with SMARCA4 genomically profiled. Kaplan-Meier analysis, log-rank test, and Cox proportional hazards model were used to evaluate associations between pathogenic genomic alterations and OS and intracranial PFS. We evaluated 14 MBMs and 19 ECMs with paired RNA sequencing and whole exome sequencing data to identify genotype-transcriptome correlations. Results: Of 43 genes significantly mutated amongst MBMs, only pathogenic mutations in SMARCA4 significantly associated with shorter OS and intracranial PFS on univariable and multivariable analyses in MBM patients but not from first ECM or primary tumor diagnosis. SMARCA4 mutations significantly associated with enrichment of oxidative phosphorylation (OXPHOS) and depletion of immune signaling gene sets. Conclusions: Pathogenic SMARCA4 mutations independently predict an association with shorter OS and intracranial PFS in MBM patients and associate with expression of pathways known to mediate melanoma virulence. These findings add to our understanding of MBM pathogenesis and suggest their potential use as prognostic biomarkers and possible therapeutic opportunities.