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.
N1 - Funding Information:
The authors thank Drs. Beatrice Knudson and Xiaotun Zhou for their assistance with the pathology, and the GU Tumor Biorepository, Eastern Virginia Medical School. They also thank all the men who participated in these studies. This work was supported by grants from the NCI (R01 CA056678, R01 CA092579, K05 CA175147, and P50 CA097186), with additional support provided by the Fred Hutchinson Cancer Research Center, the Intramural Program of the National Human Genome Research Institute, the National Institute of Environmental Health Sciences, and the Prostate Cancer Foundation. Illumina, Inc. provided and performed the methylation arrays. M.S. Geybels is the recipient of a Dutch Cancer Society Fellowship (BUIT 2014-6645). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2016 AACR.
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 sum alone (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 patients with metastatic-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.
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 sum alone (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 patients with metastatic-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.
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U2 - 10.1158/1078-0432.CCR-16-0549
DO - 10.1158/1078-0432.CCR-16-0549
M3 - Article
C2 - 27358489
AN - SCOPUS:85010219826
VL - 23
SP - 311
EP - 319
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 1
ER -