Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer

Abstract

An increasingly recognized resistance mechanism to androgen receptor (AR)-directed therapy in prostate cancer involves epithelial plasticity, wherein tumor cells demonstrate low to absent AR expression and often neuroendocrine features. The etiology and molecular basis for these “alternative” treatment-resistant cell states remain incompletely understood. Here, by analyzing whole exome sequencing data of metastatic biopsies from patients, we observed significant genomic overlap between castration resistant adenocarcinoma (CRPC-Adeno) and neuroendocrine histologies (CRPC-NE); analysis of serial progression samples points to a model most consistent with divergent clonal evolution. Genome-wide DNA methylation revealed marked epigenetic differences between CRPC-NE and CRPC-Adeno that also designated cases of CRPC-Adeno with clinical features of AR-independence as CRPC-NE, suggesting that epigenetic modifiers may play a role in the induction and/or maintenance of this treatment-resistant state. This study supports the emergence of an alternative, “AR-indifferent” cell state through divergent clonal evolution as a mechanism of treatment resistance in advanced prostate cancer.

Differential impact of RB status on E2F1 reprogramming in human cancer

“…RB loss did not correlate with other clinically relevant alterations including AR amplification or PTEN status (Supplemental Figure 1A; supplemental material available online with this article; https:// doi.org/10.1172/JCI93566DS1), concordant with data from the SU2C/PCF cohort ( Figure 1A) wherein AR amplification was largely observed in RB-intact tumors (30/44 tumors exhibiting AR amplification displayed intact RB). As neuroendocrine prostate cancer (NEPC) is characterized by loss of RB coupled with increased proliferative rates (42)(43)(44), it is of note that tumors within this cohort did not exhibit prevalent neuroendocrine features, as confirmed through pathologic assessment. Additionally, no association was determined between treatment and either RB or Ki67 positivity, suggesting that treatment type did not significantly affect these correlates within this cohort (Supplemental specimens, thus identifying new ways to assign RB status in the clinical setting.…”

LINE-1 methylation status in prostate cancer and non-neoplastic tissue adjacent to tumor in association with mortality

“…Hypermethylation at specific genes is less common but strongly maintained among different metastasis from a patient. 44,45 Gene-specific hypermethylation and global hypomethylation are often considered to coexist in the process of carcinogenesis. 7,9,17 We did not find clear evidence of an association of LINE-1 hypomethylation with GSTP1 and APC hypermethylation, although the inverse association became stronger in more advanced tumors.…”

Role of steroid receptor and coregulator mutations in hormone-dependent cancers

“…In this situation, hormone independence may be achieved by losing dependence on the steroid hormone receptordriven and lineage-defining gene expression programs. Consistent with this idea, it is estimated that 10% of patients with late-stage CRPC (24), and 15% to 20% of patients with ER-positive primary BCa that becomes metastatic lose receptor expression (25). Additionally, the dependency on a specific steroid receptor for gene regulation can be bypassed through the activity of alternative TFs.…”