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

Milan S. Geybels*, Min Fang, Jonathan L. Wright, Xiaoyu Qu, Marina Bibikova, Brandy Klotzle, Jian-Bing Fan, Ziding Feng, Elaine A. Ostrander, Peter S. Nelson, Janet L. Stanford*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

20 Citations (Web of Science)

Abstract

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.

Original languageEnglish
Pages (from-to)84338-84348
Number of pages11
JournalOncotarget
Volume8
Issue number48
DOIs
Publication statusPublished - 13 Oct 2017

Keywords

  • phosphatase with tensin homology
  • epigenetics
  • prostate tumor methylation
  • recurrence and prognosis
  • RADICAL PROSTATECTOMY
  • SUPPRESSOR PTEN
  • ERG EXPRESSION
  • PATHWAY
  • RISK
  • PROGRESSION
  • DELETION
  • PI3K
  • IDENTIFICATION
  • PROGNOSIS

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