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Elife. 2015 Sep 16;4. pii: e09207. doi: 10.7554/eLife.09207.

SPOP mutation leads to genomic instability in prostate cancer.

Author information

1
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, United States.
2
Division of Clinical Studies, Institute of Cancer Research, London, United Kingdom.
3
The Royal Marsden, London, United Kingdom.
4
Department of Urology, Weill Cornell Medical College, New York, United States.
5
Sandra and Edward Meyer Cancer Center, Weill Cornell Medical College, New York, United States.
6
Centre for Integrative Biology, University of Trento, Trento, Italy.
7
Department of Surgery, Weill Cornell Medical College, New York, United States.
8
HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, United States.
9
Institute for Precision Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, United States.
10
Department of 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.

KEYWORDS:

DNA repair; SPOP; cancer genomics; cell biology; human; human biology; medicine; mouse; prostate cancer; zebrafish

Comment in

PMID:
26374986
PMCID:
PMC4621745
DOI:
10.7554/eLife.09207
[Indexed for MEDLINE]
Free PMC Article

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