Here, we define a novel biomarker for increased genomic instability in clinically localized prostate cancer, provide the first mechanism by which SPOP mutations induce these alterations, and also suggest that similar to other cancers with impaired HDR, this distinct class of cancer may benefit from treatment with clinically established DNA damaging therapeutics, providing a rationale for genotype-based clinical trials. The gene discussed is SPOP; the disease is cancer.