Identification of epigenetic drivers of advanced prostate cancer

Division Of Basic Sciences - Nci

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Abstract

Performing epigenomic profiling across disease states facilitates identification of recurrent alterations that are biologically meaningful. For example, identifying differential enhancers between treatment-sensitive versus castration-resistant prostate cancers revealed somatically acquired regulatory elements critical for resistance. These results provided insight into disease progression that could not be obtained through genomic and transcriptomic approaches. We are using a similar strategy to identify enhancers that are activated during relevant disease states in prostate cancer. We are focusing on two disease states associated with poor responses to treatment and represent clinical challenges: 1) localized prostate cancers with an intraductal component and 2) localized prostate cancers with significant residual disease at the time of surgical resection despite neoadjuvant hormone treatment. Using our optimized method to perform epigenomic profiling in FFPE samples, we performed chromatin immunoprecipitation on a cohort of prostate cancers from surgical resections that were annotated based on the presence of an intraductal component. Using the histone mark H3K27ac, we identified enhancers that are enriched in cancers with intraductal carcinoma (IDC). Analysis of the IDC-specific enhancers identified candidate transcription factors that we hypothesize shape the epigenetic landscape of IDC. We are currently performing functional studies to determine if these transcription factors contribute to phenotypes associated with IDC such as invasion and resistance to hormone targeting agents.