Abstract 5708: The DNA methylation landscape of prostate cancer brain metastases

Abstract

Abstract Introduction: Improved survival in prostate cancer through more effective therapies has also led to an increase in the diagnosis of metastases to infrequent locations such as the brain. In the largest cohort of prostate cancer brain metastases (PCBM) yet studied, we investigated the DNA methylation landscape of PCBM. Methods: Using Illumina EPIC arrays, we profiled the DNA methylation landscapes of 95 metastatic samples from 42 patients, with multi-regional analysis of the metastases from 31 patients. We compared DNA methylation profiles from metastases to the primary prostate cancer (PCa) samples of 18 of these patients. Multi-regional data was obtained for 15 of these. We performed unsupervised analyses of DNA methylation profiles across sample types, and identified differentially methylated CpG sites and regions (DMRs) between PCBM and PCa samples, and PCBM/PCa samples and normal prostate tissue. We integrated our data with targeted-RNA sequencing and whole exome sequencing (WES). Results: We highlight the epigenetic heterogeneity present in different regions of the PCBM from patients for which multi-regional data were available. While substantial DNA methylation changes were detected in PCa compared to normal prostate tissue, epigenetic dysregulation was strikingly more pronounced in PCBM samples. DNA methylation changes in PCBM involved striking hypermethylation particularly enriched at CpG islands, and associated with activity of the PRC2 complex. We observed a marked distinction of the methylation profiles of SPOP mutant and TMPRSS2-ERG samples. SPOP mutant samples acquired substantially more epigenetic aberrations, particularly enriched at CpG islands which were hypermethylated genome-wide compared to TMPRSS2-ERG PCBM samples, as well as SPOP mutant PCa samples. These changes were strongly associated with the activity of EZH2 and MYC, both of which were overexpressed specifically in SPOP mutant PCBM. TMPRSS2-ERG samples showed fewer DNA methylation changes, but those detected were associated with targets of the SP1 transcription factor. Conclusion: We show that epigenetic heterogeneity is present in different regions of PCBM. While the distinct methylation landscapes of SPOP mutant and TMPRSS2-ERG PCa has been previously reported, we show that metastasis-specific DNA methylation changes emerge in each of these settings. These observations suggest that the acquisition of DNA methylation changes may be an important feature of PCBM, and may help to improve our understanding of the processes driving the occurrence of these rare metastases. Citation Format: John Gallon, Antonio Rodriguez-Calero, Sina Maletti, Charlotte Ng, Mark Rubin, Salvatore Piscuoglio. The DNA methylation landscape of prostate cancer brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5708.