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

Br J Cancer. 2014 Oct 28;111(9):1802-9. doi: 10.1038/bjc.2014.463. Epub 2014 Aug 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biomarkers, Tumor / blood
  • Biomarkers, Tumor / genetics*
  • Clinical Trials, Phase I as Topic
  • Clinical Trials, Phase II as Topic
  • CpG Islands
  • DNA Methylation*
  • DNA, Neoplasm / blood
  • DNA, Neoplasm / genetics*
  • Epigenomics*
  • Follow-Up Studies
  • Glutathione S-Transferase pi / blood
  • Glutathione S-Transferase pi / genetics*
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Neoplastic Cells, Circulating / drug effects
  • Neoplastic Cells, Circulating / metabolism
  • Neoplastic Cells, Circulating / pathology
  • Polymerase Chain Reaction
  • Prognosis
  • Promoter Regions, Genetic / genetics
  • Prospective Studies
  • Prostatic Neoplasms, Castration-Resistant / blood
  • Prostatic Neoplasms, Castration-Resistant / drug therapy
  • Prostatic Neoplasms, Castration-Resistant / genetics*
  • Prostatic Neoplasms, Castration-Resistant / mortality
  • Survival Rate
  • Validation Studies as Topic

Substances

  • Biomarkers, Tumor
  • DNA, Neoplasm
  • GSTP1 protein, human
  • Glutathione S-Transferase pi