Coordinated Roles of SPOP Mutation and CHD1 Deletion in Prostate Cancer Pathogenesis
Abstract
SPOP mutations occur in 615 percent of cases of prostate cancer (PCa). SPOP mutations are early events that have been found in localized and metastatic stages of PCa but, have shown to be a poor biomarker for risk stratification in patients. Homozygous deletion ofCHD1 is the most common recurrent alteration that occurs mostly in the SPOP mutant subclass. CHD1 loss is commonly subclonal, occurs in 510 percent of cases in PCa, 80 percent of which belong to the mutant SPOP subclass. Tumors carrying combined SPOP mutant; CHD1 loss have distinct gene expression patterns, DNA hypermethylation and highest AR activity compared to other subtypes of PCa. Despite the discovery of this subtype in 2012, molecular mechanisms driving pathogenesis remain to be understood. This stem, in part, from the lack of relevant model systems harboring these specific genetic alterations for use as study tools. Herein, we describe unique genetically engineered mouse models, 3D organoid systems and cell lines that have been developed and deployed in our laboratory to recapitulate clinically observed genotypes in normal prostate cells. Our preliminary data from mouse models supports the tumor suppressor function of SPOP and CHD1. We have also observed a dramatic decrease (by ~50 percent) in the time taken for the development of HG-PIN when CHD1deletion co-occurs with SPOP mutation. This reduction in time to develop HG-PIN suggests that loss of CHD1 is required in SPOP mutant subclass to drive it to an aggressive stage. Additionally, it shows that this subclass of prostate cancer is dependent on androgen receptor(AR) signaling for its growth. This project further aims to elucidate genome wide differences in AR signaling in this subclass of PCa testing our hypothesis suggesting that CHD1 deletion modulates transcriptional programs, specifically AR signaling, to confer a highly aggressive phenotype in SPOP mutant prostate cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 01, 2019
- Accession Number
- AD1089708
Entities
People
- Kaveri Arora
Organizations
- Weill Cornell Medicine