loss is associated with prostate cancer recurrence and alterations in tumor DNA methylation profiles.

BACKGROUND

Prostate cancer (PCa) with loss of the tumor suppressor gene has an unfavorable prognosis. DNA methylation profiles associated with loss may provide further insights into the mechanisms underlying these more aggressive, clinically relevant tumors.

METHODS

The cohort included patients with clinically localized PCa. Samples taken from the primary tumor were used to determine genomic deletions using FISH, and to analyze epigenome-wide DNA methylation profiles. Patients were followed for PCa recurrence on average for 8 years after diagnosis.

RESULTS

The study included 471 patients with data on loss, and the frequency of hemi- and homozygous loss was 10.0% and 4.5%, respectively. Loss of was associated with a significantly higher risk of recurrence (any vs. no loss; HR = 1.74; 95% CI: 1.03-2.93). Hazard ratios for hemi- and homozygous loss were 1.39 (95% CI: 0.73-2.64) and 2.84 (95% CI: 1.30-6.19), respectively. Epigenome-wide methylation profiling identified 4,208 differentially methylated CpGs (FDR Q-value < 0.01) in tumors with any versus no loss. There were no genome-wide significant differentially methylated CpGs in homo- versus hemizygous deleted tumors. Tumor methylation data were used to build a methylation signature of loss in our cohort, which was confirmed in TCGA, and included CpGs in , , , , and .

CONCLUSION

Loss of was positively associated with PCa recurrence. Prostate tumors with loss harbor a distinct methylation signature, and these aberrantly methylated CpG sites may mediate tumor progression when is deleted.