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Introduction
Tumor heterogeneity is a driver of treatment resistance in cancer and therefore represents a major obstacle for the development of precision medicine and targeted therapies. While prostate cancer typically arises as an androgen receptor (AR)-driven adenocarcinoma, reflecting its luminal prostate cell of origin1, up to 15–20% of castration resistant prostate cancer (CRPC) tumors acquire alternative lineage programs as a mechanism of treatment resistance including transformation to a poorly differentiated small cell/neuroendocrine prostate cancer (NEPC) with loss of AR-dependence and morphologic features often indistinguishable from small cell carcinomas arising from other sites2, 3–4. Clinically, the diagnosis of NEPC is typically made through a single site metastatic biopsy, and patients with biopsy-confirmed NEPC histology are recommended to receive small cell carcinoma -directed therapies. However, there can be heterogeneity observed, sometimes with both NEPC and adenocarcinoma features present within tumors, and treatment efficacy can vary depending on the metastatic site and underlying phenotype.
The transcriptomic changes that distinguish castration-resistant NEPC from adenocarcinoma (CRPC-Adeno) are driven in part by underlying epigenetic alterations2,5, 6, 7, 8–9. DNA methylation, histone marks, and chromatin accessibility are all epigenetic alterations, each contributing to transcriptional changes that can impact cell lineage and tumor phenotype. While it has been shown that global DNA methylation, H3K27ac and H3K27me3 histone patterns can begin to subtype phenotypic variants of CRPC5,6,9, 10, 11–12, their extent of overlap and degree of diversity across metastases within and between patients has not been fully characterized.
Here, we perform comprehensive multi-omic profiling of metastatic CRPC tumors, including rapid autopsy cases with multiple anatomic sites from individual patients, to investigate the extent of epigenetic heterogeneity across metastases. We conduct integrated analyses of DNA methylation, RNA sequencing, and histone modifications (H3K27ac and H3K27me3) to understand the epigenetic mechanisms underlying phenotypic diversity. Additionally, we explore the regulatory networks driving tumor lineage programs and expression of therapeutic targets, with particular focus on cases exhibiting intraindividual heterogeneity.
Results
Patient-specific epigenetic signatures in metastatic CRPC
We evaluated 98 tumor tissue samples from 35 patients with metastatic CRPC (9 NEPC and 26 CRPC-Adeno); tissues from 21 patients were obtained at the time of rapid autopsy (8 NEPC, 13 CRPC-Adeno) where multiple anatomic sites were assessed (median 4 sites per patient) (Fig....