title: Identifying aggressive prostate cancer foci using a DNA methylation classifier.
abstract: Slow-growing prostate cancer (PC) can be aggressive in a subset of cases. Therefore, prognostic tools to guide clinical decision-making and avoid overtreatment of indolent PC and undertreatment of aggressive disease are urgently needed. PC has a propensity to be multifocal with several different cancerous foci per gland.
  
  
  
  Here, we have taken advantage of the multifocal propensity of PC and categorized aggressiveness of individual PC foci based on DNA methylation patterns in primary PC foci and matched lymph node metastases. In a set of 14 patients, we demonstrate that over half of the cases have multiple epigenetically distinct subclones and determine the primary subclone from which the metastatic lesion(s) originated. Furthermore, we develop an aggressiveness classifier consisting of 25 DNA methylation probes to determine aggressive and non-aggressive subclones. Upon validation of the classifier in an independent cohort, the predicted aggressive tumors are significantly associated with the presence of lymph node metastases and invasive tumor stages.
  
  
  
  Overall, this study provides molecular-based support for determining PC aggressiveness with the potential to impact clinical decision-making, such as targeted biopsy approaches for early diagnosis and active surveillance, in addition to focal therapy.
authors.affiliation: USC Institute of Urology and the Catherine & Joseph Aresty Department of Urology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA.
authors.forename: Kamilla
authors.initials: K
authors.lastname: Mundbjerg
authors.affiliation: USC Institute of Urology and the Catherine & Joseph Aresty Department of Urology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA.
authors.forename: Sameer
authors.initials: S
authors.lastname: Chopra
authors.affiliation: USC Institute of Urology and the Catherine & Joseph Aresty Department of Urology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA.
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Alemozaffar
authors.affiliation: USC Institute of Urology and the Catherine & Joseph Aresty Department of Urology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Duymich
authors.affiliation: USC Institute of Urology and the Catherine & Joseph Aresty Department of Urology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA.
authors.forename: Ranjani
authors.initials: R
authors.lastname: Lakshminarasimhan
authors.affiliation: Department of Pathology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Nichols
authors.affiliation: Department of Pathology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA.
authors.forename: Manju
authors.initials: M
authors.lastname: Aron
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA.
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Siegmund
authors.affiliation: USC Institute of Urology and the Catherine & Joseph Aresty Department of Urology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ukimura
authors.affiliation: USC Institute of Urology and the Catherine & Joseph Aresty Department of Urology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA.
authors.forename: Monish
authors.initials: M
authors.lastname: Aron
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA.
authors.forename: Mariana
authors.initials: M
authors.lastname: Stern
authors.affiliation: Department of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA.
authors.forename: Parkash
authors.initials: P
authors.lastname: Gill
authors.affiliation: Department of Translational Genomics, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Carpten
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, 8200, Aarhus N, Denmark.
authors.forename: Torben F
authors.initials: TF
authors.lastname: Ørntoft
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, 8200, Aarhus N, Denmark.
authors.forename: Karina D
authors.initials: KD
authors.lastname: Sørensen
authors.affiliation: Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weisenberger
authors.affiliation: USC Institute of Urology and the Catherine & Joseph Aresty Department of Urology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA.|Van Andel Research Institute, Grand Rapids, MI, 49503, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Jones
authors.affiliation: Department of Radiology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA.
authors.forename: Vinay
authors.initials: V
authors.lastname: Duddalwar
authors.affiliation: USC Institute of Urology and the Catherine & Joseph Aresty Department of Urology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA. igill@med.usc.edu.
authors.forename: Inderbir
authors.initials: I
authors.lastname: Gill
authors.affiliation: USC Institute of Urology and the Catherine & Joseph Aresty Department of Urology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA. gliang@usc.edu.
authors.forename: Gangning
authors.identifier: 0000-0001-8664-922X
authors.initials: G
authors.lastname: Liang
mesh_terms: D014408:Biomarkers, Tumor; D001706:Biopsy; D016000:Cluster Analysis; D019175:DNA Methylation; D018450:Disease Progression; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods*; D020869:Gene Expression Profiling; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000601:surgery; D040641:Quantitative Trait Loci; D015203:Reproducibility of Results; D059467:Transcriptome; D047368:Tumor Burden
chemical_list: D014408:Biomarkers, Tumor
keywords: Aggressiveness; DNA methylation; Multifocal; Prostate cancer