Genomic and Transcriptomic Profiling of Brain Metastases

SIMPLE SUMMARY: Brain metastases (BM) are the most common brain tumors in adults and are the main cause of cancer-associated death. Omics analysis of BM will allow for a better understanding of metastatic progression, prognosis and therapeutic targeting. In this study, BM samples underwent comprehensive molecular profiling with genomics and transcriptomics. Mutational signatures suggested that most mutations were gained prior to metastasis. A novel copy number event centered around the MCL1 gene was found in 75% of all samples. Transcriptomics revealed that melanoma BM formed a distinct cluster in comparison to other subtypes. Poor survival correlated to self-identified black race and absence of radiation treatment but not molecular profiles. These data identify potential new drivers of brain metastatic progression, implicate that melanoma BM are distinctive and likely responsive to unique therapies, and further investigation of sociodemographic and clinical features are needed in BM cohorts. ABSTRACT: Brain metastases (BM) are the most common brain tumors in adults occurring in up to 40% of all cancer patients. Multi-omics approaches allow for understanding molecular mechanisms and identification of markers with prognostic significance. In this study, we profile 130 BM using genomics and transcriptomics and correlate molecular characteristics to clinical parameters. The most common tumor origins for BM were lung (40%) followed by melanoma (21%) and breast (15%). Melanoma and lung BMs contained more deleterious mutations than other subtypes (p < 0.001). Mutational signatures suggested that the bulk of the mutations were gained before metastasis. A novel copy number event centered around the MCL1 gene was found in 75% of all samples, suggesting a broader role in promoting metastasis. Unsupervised hierarchical cluster analysis of transcriptional signatures available in 65 samples based on the hallmarks of cancer revealed four distinct clusters. Melanoma samples formed a distinctive cluster in comparison to other BM subtypes. Characteristics of molecular profiles did not correlate with survival. However, patients with self-identified black race or those who did not receive radiation correlated with poor survival. These data identify potential new drivers of brain metastatic progression. Our data also suggest further investigation of sociodemographic and clinical features is needed in BM cohorts.