Epigenetic and transcriptional analysis reveals a core transcriptional program conserved in clonal prostate cancer metastases.

Tesa M Severson,Angelo M De Marzo,Jonathan W Simons,Srinivasan Yegnasubramanian,Wilbert Zwart,Matthew L Freedman,Michael C Haffner,Yanyun Zhu,Tracy Jones,Andries M Bergman,Lodewyk Wessels,William G Nelson

doi:10.1002/1878-0261.12923

Abstract

The epigenomic regulation of transcriptional programs in metastatic prostate cancer is poorly understood. We studied the epigenomic landscape of prostate cancer drivers using transcriptional profiling and ChIP‐seq in four clonal metastatic tumors derived from a single prostate cancer patient. Our epigenomic analyses focused on androgen receptor (AR), which is a key oncogenic driver in prostate cancer, the AR pioneer factor FOXA1, chromatin insulator CCCTC‐Binding Factor, as well as for modified histones H3K27ac and H3K27me3. The vast majority of AR binding sites were shared among healthy prostate, primary prostate cancer, and metastatic tumor samples, signifying core AR‐driven transcriptional regulation within the prostate cell lineage. Genes associated with core AR‐binding events were significantly enriched for essential genes in prostate cancer cell proliferation. Remarkably, the metastasis‐specific active AR binding sites showed no differential transcriptional output, indicating a robust transcriptional program across metastatic samples. Combined, our data reveal a core transcriptional program in clonal metastatic prostate cancer, despite epigenomic differences in the AR cistrome.

Highlights

In metastatic castration-resistant prostate cancer, under the selective pressure of low circulating testosterone levels, tumors typically respond by restoring the Androgen Receptor (AR) pathway by means of activating mutations or splice variants of the AR [1,2,3,4], amplification of the gene itself [5,6], or its associated enhancer [7]
To determine whether differences in metastatic niche are associated with alterations in the epigenome and transcriptome, we investigated multiple metastasis samples from a single patient, which share a high concordance in driver gene alterations [15]
Genomic analyses revealed a high level of shared driver gene alterations including mutations in Phosphatase And Tensin Homolog (PTEN), Speckle Type BTB/POZ Protein (SPOP), and Tumor Protein P53 (TP53), copy number alterations including a highlevel copy number gain of the AR locus and structural rearrangements such as an inversion of the ATRX Chromatin Remodeler (ATRX) locus in all metastases (Fig. 1B)

Summary

Introduction

In metastatic castration-resistant prostate cancer (mCRPC), under the selective pressure of low circulating testosterone levels, tumors typically respond by restoring the Androgen Receptor (AR) pathway by means of activating mutations or splice variants of the AR [1,2,3,4], amplification of the gene itself [5,6], or its associated enhancer [7]. The genomic landscape of mCRPC is heterogenous, numerous studies have demonstrated that genomic driver alterations are shared between different metastatic sites in a given patient [12,13,14,15,16]. These findings establish that distant metastases likely arise from a single cell clone in the primary tumor and show a high level of genetic similarity, irrespective of their anatomic location [15,17]. For genomic analyses in mCRPC, a biopsy procedure is performed on an accessible metastatic lesion [20,21] and the question remains whether sampling bias would impact the clinical decision-making process

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Results

Conclusion