Purpose: Brain metastases occur in approximately 8-10% of patients with cancer, and the incidence has increased over the past decades. The most common primary tumors responsible for brain metastases are lung cancer, melanoma, renal cell carcinoma (RCC), breast cancer and colorectal cancer, and the prognosis is still very poor with an overall 2-year survival rate of 8%. The precise mechanisms by which genomic and transcriptional abnormalities drive the formation of brain metastases remains unclear. Here, we conducted comprehensive genomic and transcriptional analysis with paired primary tumor tissue (or extracranial metastasis tissue) and brain metastasis tissue using whole-exome sequencing (WES), mRNA-Seq and global methylation profiling.

Methods: All patient samples were collected at the University of Texas MD Anderson Cancer Center. Frozen, paired brain metastasis tissue and primary tumor tissue (or extracranial metastasis tissue) and white blood cells were acquired from RCC (n=12), breast cancer (n=17), lung cancer (n=15) and cutaneous melanoma (n=14) patients. DNA and RNA were extracted from regions of frozen tissue with at least 70% viable tumor cells and peripheral blood leukocytes. Libraries for WES and mRNA-Seq were prepared and sequenced on the Illumina HiSeq4000 platform. For methylation profiling, DNA was subjected to bisulfite conversion and analyzed using Illumina Infinium MethylationEPIC Beadchip arrays.

Results: Genome-wide hypermutation due to POLE or POLD1 mutations was observed in one breast cancer patient and two lung cancer patients. Two of these cases acquired the hypermutation during development to brain metastasis. Somatic mutations or methylation of VHL gene were identified in 81.8% of RCC patients, and two patients had somatic VHL mutations in brain metastases only. Interestingly, Gene Set Enrichment Analysis revealed significant enrichment for hypoxia pathway transcripts in the RCC brain metastases relative to primary tumors. The most common alterations in breast and lung cancer patients were TP53 mutations with frequencies of 50.0% and 73.3%, followed by ERBB2 alterations (43.8%) in breast cancer patients and mutually exclusive alterations of EGFR (33.3%) and KRAS (26.7%) in lung cancer patients. Mutually exclusive alterations of NRAS (42.9%) and BRAF (42.9%) were also observed in melanoma patients. Gene expression and epigenetic analysis revealed characteristics of brain metastases depending on primary cancer types.

Conclusions: Comprehensive genomic analysis of brain metastases from four different cancer types revealed that brain metastasis tissue has unique genomic, transcriptional and epigenetic profiles according to histopathology groups. Therefore, the therapeutic strategies should be designed based at least in part on tumor histiogenesis.

Citation Format: Kazutaka Fukumura, Xizeng Mao, Xingzhi Song, Grant M. Fischer, Jie Yang, Erik P. Sulman, Michael A. Davies, Jianhua Zhang, Jason T. Huse. Comprehensive genomic analysis of brain metastases from multiple cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3406.