Research Papers:
PTEN loss is associated with prostate cancer recurrence and alterations in tumor DNA methylation profiles
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Abstract
Milan S. Geybels1,2, Min Fang3, Jonathan L. Wright2,4, Xiaoyu Qu3,5, Marina Bibikova6, Brandy Klotzle6, Jian-Bing Fan6,12, Ziding Feng7, Elaine A. Ostrander8, Peter S. Nelson3,9,10 and Janet L. Stanford2,11
1Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
2Division of Public Health Sciences, Fred Hutchison Cancer Research Center, Seattle, Washington, USA
3Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
4Department of Urology, University of Washington School of Medicine, Seattle, Washington, USA
5Department of Cytogenetics, Seattle Cancer Care Alliance, Seattle, Washington, USA
6Department of Oncology, Illumina, Inc., San Diego, California, USA
7Department of Biostatistics, MD Anderson Cancer Center, Houston, Texas, USA
8Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA
9Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
10Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA
11Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA
12Current address: AnchorDx Corp., Guangzhou 510300, People’s Republic of China
Correspondence to:
Milan S. Geybels, email: [email protected]
Janet L. Stanford, email: [email protected]
Keywords: phosphatase with tensin homology, epigenetics, prostate tumor methylation, recurrence and prognosis
Received: April 15, 2017 Accepted: July 08, 2017 Published: September 15, 2017
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 genome-wide 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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