title: Heterogeneous patterns of DNA methylation-based field effects in histologically normal prostate tissue from cancer patients.
abstract: Prostate cancer (PC) diagnosis is based on histological evaluation of prostate needle biopsies, which have high false negative rates. Here, we investigated if cancer-associated epigenetic field effects in histologically normal prostate tissue may be used to increase sensitivity for PC. We focused on nine genes (AOX1, CCDC181 (C1orf114), GABRE, GAS6, HAPLN3, KLF8, MOB3B, SLC18A2, and GSTP1) known to be hypermethylated in PC. Using quantitative methylation-specific PCR, we analysed 66 malignant and 134 non-malignant tissue samples from 107 patients, who underwent ultrasound-guided prostate biopsy (67 patients had at least one cancer-positive biopsy, 40 had exclusively cancer-negative biopsies). Hypermethylation was detectable for all genes in malignant needle biopsy samples (AUC: 0.80 to 0.98), confirming previous findings in prostatectomy specimens. Furthermore, we identified a four-gene methylation signature (AOX1xGSTP1xHAPLN3xSLC18A2) that distinguished histologically non-malignant biopsies from patients with vs. without PC in other biopsies (AUC = 0.65; sensitivity = 30.8%; specificity = 100%). This signature was validated in an independent patient set (59 PC, 36 adjacent non-malignant, and 9 normal prostate tissue samples) analysed on Illumina 450 K methylation arrays (AUC = 0.70; sensitivity = 40.6%; specificity = 100%). Our results suggest that a novel four-gene signature may be used to increase sensitivity for PC diagnosis through detection of epigenetic field effects in histologically non-malignant prostate tissue samples.
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Mia
authors.initials: M
authors.lastname: Møller
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Siri Hundtofte
authors.initials: SH
authors.lastname: Strand
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.|Keck School of Medicine of University of Southern California, Los Angeles, California, USA.
authors.forename: Kamilla
authors.initials: K
authors.lastname: Mundbjerg
authors.affiliation: Keck School of Medicine of University of Southern California, Los Angeles, California, USA.
authors.forename: Gangning
authors.initials: G
authors.lastname: Liang
authors.affiliation: Keck School of Medicine of University of Southern California, Los Angeles, California, USA.
authors.forename: Inderbir
authors.initials: I
authors.lastname: Gill
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Christa
authors.initials: C
authors.lastname: Haldrup
authors.affiliation: Department of Urology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Borre
authors.affiliation: Department of Pathology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Høyer
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Torben Falck
authors.initials: TF
authors.lastname: Ørntoft
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Karina Dalsgaard
authors.initials: KD
authors.lastname: Sørensen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D001707:Biopsy, Needle; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods; D018740:Genetic Heterogeneity; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D011467:Prostate / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000601:surgery; D012372:ROC Curve; D015203:Reproducibility of Results
chemical_list: D014408:Biomarkers, Tumor