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

// Milan S. Geybels 1, 2 , Min Fang 3 , Jonathan L. Wright 2, 4 , Xiaoyu Qu 3, 5 , Marina Bibikova 6 , Brandy Klotzle 6 , Jian-Bing Fan 6, 12 , Ziding Feng 7 , Elaine A. Ostrander 8 , Peter S. Nelson 3, 9, 10 and Janet L. Stanford 2, 11 1 Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands 2 Division of Public Health Sciences, Fred Hutchison Cancer Research Center, Seattle, Washington, USA 3 Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA 4 Department of Urology, University of Washington School of Medicine, Seattle, Washington, USA 5 Department of Cytogenetics, Seattle Cancer Care Alliance, Seattle, Washington, USA 6 Department of Oncology, Illumina, Inc., San Diego, California, USA 7 Department of Biostatistics, MD Anderson Cancer Center, Houston, Texas, USA 8 Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA 9 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA 10 Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA 11 Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA 12 Current address: AnchorDx Corp., Guangzhou 510300, People’s Republic of China Correspondence to: Milan S. Geybels, email: mgeybels@fredhutch.org Janet L. Stanford, email: jstanfor@fredhutch.org 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.