title: Epigenetic markers of prostate cancer in plasma circulating DNA.
abstract: Epigenetic differences are a common feature of many diseases, including cancer, and disease-associated changes have even been detected in bodily fluids. DNA modification studies in circulating DNA (cirDNA) may lead to the development of specific non-invasive biomarkers. To test this hypothesis, we investigated cirDNA modifications in prostate cancer patients with locally confined disease (n = 19), in patients with benign prostate hyperplasias (n = 20) and in men without any known prostate disease (n = 20). This initial discovery screen identified 39 disease-associated changes in cirDNA modification, and seven of these were validated using the sodium bisulfite-based mapping of modified cytosines in both the discovery cohort and an independent 38-patient validation cohort. In particular, we showed that the DNA modification of regions adjacent to the gene encoding ring finger protein 219 distinguished prostate cancer from benign hyperplasias with good sensitivity (61%) and specificity (71%). We also showed that repetitive sequences detected in this study were meaningful, as they indicated a highly statistically significant loss of DNA at the pericentromeric region of chromosome 10 in prostate cancer patients (p = 1.8 × 10(-6)). Based on these strong univariate results, we applied machine-learning techniques to develop a multi-locus biomarker that correctly distinguished prostate cancer samples from unaffected controls with 72% accuracy. Lastly, we used systems biology techniques to integrate our data with publicly available DNA modification and transcriptomic data from primary prostate tumors, thereby prioritizing genes for further studies. These data suggest that cirDNA epigenomics are promising source for non-invasive biomarkers.
authors.affiliation: The Krembil Family Epigenetics Laboratory, Centre for Addiction and Mental Health, Toronto, ON, Canada M5T 1R8.
authors.forename: Rene
authors.initials: R
authors.lastname: Cortese
authors.forename: Andrew
authors.initials: A
authors.lastname: Kwan
authors.forename: Emilie
authors.initials: E
authors.lastname: Lalonde
authors.forename: Olga
authors.initials: O
authors.lastname: Bryzgunova
authors.forename: Anna
authors.initials: A
authors.lastname: Bondar
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.forename: Juozas
authors.initials: J
authors.lastname: Gordevicius
authors.forename: Mina
authors.initials: M
authors.lastname: Park
authors.forename: Gabriel
authors.initials: G
authors.lastname: Oh
authors.forename: Zachary
authors.initials: Z
authors.lastname: Kaminsky
authors.forename: Justina
authors.initials: J
authors.lastname: Tverkuviene
authors.forename: Arvydas
authors.initials: A
authors.lastname: Laurinavicius
authors.forename: Feliksas
authors.initials: F
authors.lastname: Jankevicius
authors.forename: Dorota H S
authors.initials: DH
authors.lastname: Sendorek
authors.forename: Syed
authors.initials: S
authors.lastname: Haider
authors.forename: Sun-Chong
authors.initials: SC
authors.lastname: Wang
authors.forename: Sonata
authors.initials: S
authors.lastname: Jarmalaite
authors.forename: Pavel
authors.initials: P
authors.lastname: Laktionov
authors.forename: Paul C
authors.initials: PC
authors.lastname: Boutros
authors.forename: Arturas
authors.initials: A
authors.lastname: Petronis
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics*; D016022:Case-Control Studies; D002503:Centromere; D002879:Chromosomes, Human, Pair 10; D003596:Cytosine / Q000737:chemistry; D019175:DNA Methylation; D004270:DNA, Circular / Q000097:blood*; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D046228:Microarray Analysis / Q000379:methods; D008875:Middle Aged; D011470:Prostatic Hyperplasia / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid; D012680:Sensitivity and Specificity
chemical_list: D014408:Biomarkers, Tumor; D004270:DNA, Circular; D003596:Cytosine