TY - JOUR
T1 - Epigenome-Wide Tumor DNA Methylation Profiling Identifies Novel Prognostic Biomarkers of Metastatic-Lethal Progression in Men Diagnosed with Clinically Localized Prostate Cancer
AU - Zhao, Shanshan
AU - Geybels, Milan S.
AU - Leonardson, Amy
AU - Rubicz, Rohina
AU - Kolb, Suzanne
AU - Yan, Qingxiang
AU - Klotzle, Brandy
AU - Bibikova, Marina
AU - Hurtado-Coll, Antonio
AU - Troyer, Dean
AU - Lance, Raymond
AU - Lin, Daniel W.
AU - Wright, Jonathan L.
AU - Ostrander, Elaine A.
AU - Fan, Jian-Bing
AU - Feng, Ziding
AU - Stanford, Janet L.
PY - 2017/1/1
Y1 - 2017/1/1
N2 - Purpose: Aside from Gleason sum, few factors accurately identify the subset of prostate cancer patients at high risk for metastatic progression. We hypothesized that epigenetic alterations could distinguish prostate tumors with life-threatening potential.Experimental Design: Epigenome-wide DNA methylation profiling was performed in surgically resected primary tumor tissues from a population-based (n = 430) and a replication (n = 80) cohort of prostate cancer patients followed prospectively for at least 5 years. Metastasis was confirmed by positive bone scan, MRI, CT, or biopsy, and death certificates confirmed cause of death. AUC, partial AUC (pAUC, 95% specificity), and P value criteria were used to select differentially methylated CpG sites that robustly stratify patients with metastatic-lethal from nonrecurrent tumors, and which were complementary to Gleason sum.Results: Forty-two CpG biomarkers stratified patients with metastatic-lethal versus nonrecurrent prostate cancer in the discovery cohort, and eight of these CpGs replicated in the validation cohort based on a significant (P <0.05) AUC (range, 0.66-0.75) or pAUC (range, 0.007-0.009). The biomarkers that improved discrimination of patients with metastatic-lethal prostate cancer include CpGs in five genes (ALKBH5, ATP11A, FHAD1, KLHL8, and PI15) and three intergenic regions. In the validation dataset, the AUC for Gleason sumalone (0.82) significantly increased with the addition of four individual CpGs (range, 0.86-0.89; all P <0.05).Conclusions: Eight differentially methylated CpGs that distinguish patientswithmetastatic-lethal from nonrecurrent tumors were validated. These novel epigenetic biomarkers warrant further investigation as they may improve prognostic classification of patients with clinically localized prostate cancer and provide new insights on tumor aggressiveness. (C) 2016 AACR.
AB - Purpose: Aside from Gleason sum, few factors accurately identify the subset of prostate cancer patients at high risk for metastatic progression. We hypothesized that epigenetic alterations could distinguish prostate tumors with life-threatening potential.Experimental Design: Epigenome-wide DNA methylation profiling was performed in surgically resected primary tumor tissues from a population-based (n = 430) and a replication (n = 80) cohort of prostate cancer patients followed prospectively for at least 5 years. Metastasis was confirmed by positive bone scan, MRI, CT, or biopsy, and death certificates confirmed cause of death. AUC, partial AUC (pAUC, 95% specificity), and P value criteria were used to select differentially methylated CpG sites that robustly stratify patients with metastatic-lethal from nonrecurrent tumors, and which were complementary to Gleason sum.Results: Forty-two CpG biomarkers stratified patients with metastatic-lethal versus nonrecurrent prostate cancer in the discovery cohort, and eight of these CpGs replicated in the validation cohort based on a significant (P <0.05) AUC (range, 0.66-0.75) or pAUC (range, 0.007-0.009). The biomarkers that improved discrimination of patients with metastatic-lethal prostate cancer include CpGs in five genes (ALKBH5, ATP11A, FHAD1, KLHL8, and PI15) and three intergenic regions. In the validation dataset, the AUC for Gleason sumalone (0.82) significantly increased with the addition of four individual CpGs (range, 0.86-0.89; all P <0.05).Conclusions: Eight differentially methylated CpGs that distinguish patientswithmetastatic-lethal from nonrecurrent tumors were validated. These novel epigenetic biomarkers warrant further investigation as they may improve prognostic classification of patients with clinically localized prostate cancer and provide new insights on tumor aggressiveness. (C) 2016 AACR.
KW - BIOCHEMICAL RECURRENCE
KW - RADICAL PROSTATECTOMY
KW - PROMOTER HYPERMETHYLATION
KW - GLEASON SCORE
KW - RISK
KW - GENE
KW - MORTALITY
KW - BIOPSY
KW - ASSOCIATION
KW - SURVIVAL
U2 - 10.1158/1078-0432.CCR-16-0549
DO - 10.1158/1078-0432.CCR-16-0549
M3 - Article
C2 - 27358489
SN - 1078-0432
VL - 23
SP - 311
EP - 319
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -