title: Methylated Glutathione S-transferase 1 (mGSTP1) is a potential plasma free DNA epigenetic marker of prognosis and response to chemotherapy in castrate-resistant prostate cancer.
abstract: BACKGROUND
  Glutathione S-transferase 1 (GSTP1) inactivation is associated with CpG island promoter hypermethylation in the majority of prostate cancers (PCs). This study assessed whether the level of circulating methylated GSTP1 (mGSTP1) in plasma DNA is associated with chemotherapy response and overall survival (OS).
  
  
  METHODS
  Plasma samples were collected prospectively from a Phase I exploratory cohort of 75 men with castrate-resistant PC (CRPC) and a Phase II independent validation cohort (n=51). mGSTP1 levels in free DNA were measured using a sensitive methylation-specific PCR assay.
  
  
  RESULTS
  The Phase I cohort identified that detectable baseline mGSTP1 DNA was associated with poorer OS (HR, 4.2 95% CI 2.1-8.2; P<0.0001). A decrease in mGSTP1 DNA levels after cycle 1 was associated with a PSA response (P=0.008). In the Phase II cohort, baseline mGSTP1 DNA was a stronger predictor of OS than PSA change after 3 months (P=0.02). Undetectable plasma mGSTP1 after one cycle of chemotherapy was associated with PSA response (P=0.007).
  
  
  CONCLUSIONS
  We identified plasma mGSTP1 DNA as a potential prognostic marker in men with CRPC as well as a potential surrogate therapeutic efficacy marker for chemotherapy and corroborated these findings in an independent Phase II cohort. Prospective Phase III assessment of mGSTP1 levels in plasma DNA is now warranted.
authors.affiliation: 1] Chris O'Brien Lifehouse, Missenden Rd, Camperdown, New South Wales, 2050, Australia [2] Cancer Research Division, Garvan Institute of Medical Research/The Kinghorn Cancer Centre, Darlinghurst, New South Wales, 2010, Australia [3] Sydney Medical School, University of Sydney, Camperdown, New South Wales, 2050, Australia.
authors.forename: K L
authors.initials: KL
authors.lastname: Mahon
authors.affiliation: Cancer Research Division, Garvan Institute of Medical Research/The Kinghorn Cancer Centre, Darlinghurst, New South Wales, 2010, Australia.
authors.forename: W
authors.initials: W
authors.lastname: Qu
authors.affiliation: Cancer Research Division, Garvan Institute of Medical Research/The Kinghorn Cancer Centre, Darlinghurst, New South Wales, 2010, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Devaney
authors.affiliation: Cancer Research Division, Garvan Institute of Medical Research/The Kinghorn Cancer Centre, Darlinghurst, New South Wales, 2010, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Paul
authors.affiliation: Cancer Research Division, Garvan Institute of Medical Research/The Kinghorn Cancer Centre, Darlinghurst, New South Wales, 2010, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Castillo
authors.affiliation: Royal Prince Alfred Hospital, Missenden Rd, Camperdown, New South Wales, 2050, Australia.
authors.forename: R J
authors.initials: RJ
authors.lastname: Wykes
authors.affiliation: Menzies School of Health Research, Darwin, Northern Territory, Australia.
authors.forename: M D
authors.initials: MD
authors.lastname: Chatfield
authors.affiliation: 1] Chris O'Brien Lifehouse, Missenden Rd, Camperdown, New South Wales, 2050, Australia [2] Sydney Medical School, University of Sydney, Camperdown, New South Wales, 2050, Australia [3] Royal Prince Alfred Hospital, Missenden Rd, Camperdown, New South Wales, 2050, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: Boyer
authors.affiliation: 1] Chris O'Brien Lifehouse, Missenden Rd, Camperdown, New South Wales, 2050, Australia [2] Sydney Medical School, University of Sydney, Camperdown, New South Wales, 2050, Australia [3] NHMRC Clinical Trials Centre, University of Sydney, New South Wales, 2050, Australia.
authors.forename: M R
authors.initials: MR
authors.lastname: Stockler
authors.affiliation: 1] Sydney Medical School, University of Sydney, Camperdown, New South Wales, 2050, Australia [2] Northern Haematology and Oncology Group, SAN Clinic, Wahroonga, New South Wales, 2076, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Marx
authors.affiliation: 1] Sydney Medical School, University of Sydney, Camperdown, New South Wales, 2050, Australia [2] Westmead Hospital, Sydney, New South Wales, Australia.
authors.forename: H
authors.initials: H
authors.lastname: Gurney
authors.affiliation: Calvary Mater Newcastle, New South Wales, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Mallesara
authors.affiliation: CSIRO Animal, Food and Health Sciences, North Ryde, New South Wales, 2113, Australia.
authors.forename: P L
authors.initials: PL
authors.lastname: Molloy
authors.affiliation: 1] Chris O'Brien Lifehouse, Missenden Rd, Camperdown, New South Wales, 2050, Australia [2] Cancer Research Division, Garvan Institute of Medical Research/The Kinghorn Cancer Centre, Darlinghurst, New South Wales, 2010, Australia [3] Sydney Medical School, University of Sydney, Camperdown, New South Wales, 2050, Australia [4] Royal Prince Alfred Hospital, Missenden Rd, Camperdown, New South Wales, 2050, Australia.
authors.forename: L G
authors.initials: LG
authors.lastname: Horvath
authors.affiliation: 1] Cancer Research Division, Garvan Institute of Medical Research/The Kinghorn Cancer Centre, Darlinghurst, New South Wales, 2010, Australia [2] St Vincent's Clinical School, University of NSW, Sydney, 2010, New South Wales, Australia.
authors.forename: S J
authors.initials: SJ
authors.lastname: Clark
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics*; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics*; D057890:Epigenomics; D005500:Follow-Up Studies; D051549:Glutathione S-Transferase pi / Q000097:blood / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009360:Neoplastic Cells, Circulating / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011446:Prospective Studies; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D015996:Survival Rate; D054928:Validation Studies as Topic
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi