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Updated: May 31, 2026
Murine Prostate Micro-dissection and Surgical Castration
Published on: May 11, 2016
The mutational landscape of lethal castration-resistant prostate cancer
Catherine S Grasso1, Yi-Mi Wu, Dan R Robinson
1Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Abstract:
Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains and losses, including ETS gene family fusions, PTEN loss and androgen receptor (AR) amplification, which drive prostate cancer development and progression to lethal, metastatic castration-resistant prostate cancer (CRPC). However, less is known about the role of mutations. Here we sequenced the exomes of 50 lethal, heavily pre-treated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment-naive, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPCs (2.00 per megabase) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy number analysis identified disruptions of CHD1 that define a subtype of ETS gene family fusion-negative prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in approximately one-third of CRPCs (commonly through TMPRSS2:ERG fusions), is also deregulated through mutation. Furthermore, we identified recurrent mutations in multiple chromatin- and histone-modifying genes, including MLL2 (mutated in 8.6% of prostate cancers), and demonstrate interaction of the MLL complex with the AR, which is required for AR-mediated signalling. We also identified novel recurrent mutations in the AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC), and showed that mutated FOXA1 represses androgen signalling and increases tumour growth. Proteins that physically interact with the AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX (also known as KDM6A) and ASXL1 were found to be mutated in CRPC. In summary, we describe the mutational landscape of a heavily treated metastatic cancer, identify novel mechanisms of AR signalling deregulated in prostate cancer, and prioritize candidates for future study.
Insights
This study reveals low mutation rates in lethal prostate cancer, identifying key gene mutations like CHD1, ETS2, MLL2, and FOXA1 that drive cancer progression and androgen receptor signaling.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Prostate cancer progression to lethal castration-resistant prostate cancer (CRPC) is driven by genetic alterations like AR amplification and ETS gene fusions.
- The role of specific mutations in CRPC development and progression remains less understood.
- Existing knowledge gaps hinder the identification of novel therapeutic targets for advanced prostate cancer.
Purpose of the Study:
- To characterize the mutational landscape of lethal, metastatic castration-resistant prostate cancer (CRPC).
- To identify novel genetic alterations and pathways deregulated in advanced prostate cancer.
- To investigate the functional impact of identified mutations on androgen receptor signaling and tumor growth.
Main Methods:
- Whole-exome sequencing of 50 lethal metastatic CRPCs and 11 treatment-naive localized prostate cancers.
- Integration of exome copy number analysis with mutation data.
- Functional studies to assess the impact of mutated genes (e.g., FOXA1) on androgen receptor signaling.
Main Results:
- Low overall mutation rates (2.00 per megabase) were observed in heavily treated CRPCs, confirming monoclonal origin.
- Disruptions of CHD1 were identified, defining a subtype of ETS gene family fusion-negative prostate cancer.
- Recurrent mutations in chromatin-modifying genes (MLL2, UTX, ASXL1) and AR-interacting proteins (FOXA1, ERG) were found, impacting AR signaling and tumor growth.
Conclusions:
- The study elucidates the mutational landscape of heavily treated metastatic prostate cancer.
- Novel mechanisms of androgen receptor signaling deregulation, including mutations in MLL2 and FOXA1, are identified.
- These findings prioritize potential therapeutic targets for advanced prostate cancer.
