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Updated: Apr 3, 2026
Generation of Tumor Organoids from Genetically Engineered Mouse Models of Prostate Cancer
Published on: June 13, 2019
SPOP mutation leads to genomic instability in prostate cancer
Gunther Boysen1,2,3, Christopher E Barbieri4,5, Davide Prandi6
1Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, United States.
Abstract:
Genomic instability is a fundamental feature of human cancer often resulting from impaired genome maintenance. In prostate cancer, structural genomic rearrangements are a common mechanism driving tumorigenesis. However, somatic alterations predisposing to chromosomal rearrangements in prostate cancer remain largely undefined. Here, we show that SPOP, the most commonly mutated gene in primary prostate cancer modulates DNA double strand break (DSB) repair, and that SPOP mutation is associated with genomic instability. In vivo, SPOP mutation results in a transcriptional response consistent with BRCA1 inactivation resulting in impaired homology-directed repair (HDR) of DSB. Furthermore, we found that SPOP mutation sensitizes to DNA damaging therapeutic agents such as PARP inhibitors. These results implicate SPOP as a novel participant in DSB repair, suggest that SPOP mutation drives prostate tumorigenesis in part through genomic instability, and indicate that mutant SPOP may increase response to DNA-damaging therapeutics.
Insights
SPOP gene mutations in prostate cancer impair DNA repair, leading to genomic instability and increased sensitivity to certain cancer therapies like PARP inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Genomic instability is a hallmark of human cancers, often driven by faulty genome maintenance.
- Structural genomic rearrangements are key drivers of prostate cancer development.
- The specific genetic alterations that predispose prostate cancer to chromosomal rearrangements are not well understood.
Purpose of the Study:
- To investigate the role of SPOP, a frequently mutated gene in prostate cancer, in DNA double-strand break (DSB) repair.
- To determine the association between SPOP mutations and genomic instability in prostate cancer.
- To explore the therapeutic implications of SPOP mutations.
Main Methods:
- Analysis of SPOP gene mutations in primary prostate cancer.
- In vivo studies to assess the transcriptional response to SPOP mutation.
- Evaluation of DNA double-strand break (DSB) repair pathways, including homology-directed repair (HDR).
- Assessment of sensitivity to DNA-damaging agents, such as PARP inhibitors.
Main Results:
- SPOP mutation was found to modulate DNA double-strand break (DSB) repair.
- SPOP mutation is associated with increased genomic instability.
- SPOP-mutated prostate cancer exhibits a transcriptional profile similar to BRCA1 inactivation, indicating impaired homology-directed repair (HDR).
- SPOP mutations sensitize prostate cancer cells to DNA-damaging therapeutics, including PARP inhibitors.
Conclusions:
- SPOP is a novel player in DNA double-strand break (DSB) repair.
- SPOP mutations contribute to prostate tumorigenesis through genomic instability.
- Mutations in SPOP may predict a heightened response to DNA-damaging therapies in prostate cancer.
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