Journal
ONCOTARGET
Volume 8, Issue 48, Pages 84338-84348Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.20940
Keywords
phosphatase with tensin homology; epigenetics; prostate tumor methylation; recurrence and prognosis
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Funding
- National Cancer Institute, NIH [R01 CA056678, R01 CA092579, K05 CA175147, P50 CA097186]
- Intramural Research Program of the National Human Genome Research Institute
- Fred Hutchinson Cancer Research Center
- Dutch Cancer Society Fellowship [BUIT 2014-6645]
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Background: Prostate cancer (PCa) with loss of the tumor suppressor gene PTEN has an unfavorable prognosis. DNA methylation profiles associated with PTEN 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 PTEN 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 PTEN loss, and the frequency of hemi-and homozygous PTEN loss was 10.0% and 4.5%, respectively. Loss of PTEN was associated with a significantly higher risk of recurrence (any vs. no PTEN 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 PTEN loss. There were no genomewide significant differentially methylated CpGs in homo-versus hemizygous deleted tumors. Tumor methylation data were used to build a methylation signature of PTEN loss in our cohort, which was confirmed in TCGA, and included CpGs in ATP11A, GDNF, JAK1, JAM3, and VAPA. Conclusion: Loss of PTEN was positively associated with PCa recurrence. Prostate tumors with PTEN loss harbor a distinct methylation signature, and these aberrantly methylated CpG sites may mediate tumor progression when PTEN is deleted.
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