title: Epigenome-Wide Tumor DNA Methylation Profiling Identifies Novel Prognostic Biomarkers of Metastatic-Lethal Progression in Men Diagnosed with Clinically Localized Prostate Cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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. Clin Cancer Res; 23(1); 311-9. ©2016 AACR.
authors.affiliation: National Institute of Environmental Health Sciences, Biostatistics and Computational Biology Branch, Research Triangle Park, Durham, North Carolina.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Division of Public Health Sciences, Fred Hutchison Cancer Research Center, Seattle, Washington.|Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.
authors.forename: Milan S
authors.initials: MS
authors.lastname: Geybels
authors.affiliation: Division of Public Health Sciences, Fred Hutchison Cancer Research Center, Seattle, Washington.
authors.forename: Amy
authors.initials: A
authors.lastname: Leonardson
authors.affiliation: Division of Public Health Sciences, Fred Hutchison Cancer Research Center, Seattle, Washington.
authors.forename: Rohina
authors.initials: R
authors.lastname: Rubicz
authors.affiliation: Division of Public Health Sciences, Fred Hutchison Cancer Research Center, Seattle, Washington.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kolb
authors.affiliation: MD Anderson Cancer Center, Department of Biostatistics, Houston, Texas.
authors.forename: Qingxiang
authors.initials: Q
authors.lastname: Yan
authors.affiliation: Illumina, Inc., San Diego, California.
authors.forename: Brandy
authors.initials: B
authors.lastname: Klotzle
authors.affiliation: Illumina, Inc., San Diego, California.
authors.forename: Marina
authors.initials: M
authors.lastname: Bibikova
authors.affiliation: Department of Urologic Sciences, University of British Columbia, and the Prostate Center, Vancouver General Hospital, Vancouver, Canada.
authors.forename: Antonio
authors.initials: A
authors.lastname: Hurtado-Coll
authors.affiliation: Departments of Pathology, Microbiology, and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia.
authors.forename: Dean
authors.initials: D
authors.lastname: Troyer
authors.affiliation: Department of Urology, Eastern Virginia Medical School, Norfolk, Virginia.
authors.forename: Raymond
authors.initials: R
authors.lastname: Lance
authors.affiliation: Division of Public Health Sciences, Fred Hutchison Cancer Research Center, Seattle, Washington.|Department of Urology, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Lin
authors.affiliation: Division of Public Health Sciences, Fred Hutchison Cancer Research Center, Seattle, Washington.|Department of Urology, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Wright
authors.affiliation: Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland.
authors.forename: Elaine A
authors.initials: EA
authors.lastname: Ostrander
authors.affiliation: Illumina, Inc., San Diego, California.
authors.forename: Jian-Bing
authors.initials: JB
authors.lastname: Fan
authors.affiliation: MD Anderson Cancer Center, Department of Biostatistics, Houston, Texas.
authors.forename: Ziding
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Division of Public Health Sciences, Fred Hutchison Cancer Research Center, Seattle, Washington. jstanfor@fredhutch.org.|Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stanford
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D014408:Biomarkers, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D018450:Disease Progression; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality* / Q000628:therapy; D012372:ROC Curve; D012008:Recurrence; D015203:Reproducibility of Results
chemical_list: D014408:Biomarkers, Tumor