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

K. L. Mahon, W. Qu, J. Devaney, C. Paul, L. Castillo, R. J. Wykes, M. D. Chatfield, M. J. Boyer, M. R. Stockler, G. Marx, H. Gurney, G. Mallesara, P. L. Molloy, L. G. Horvath, S. J. Clark

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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.

Original languageEnglish
Pages (from-to)1802-1809
Number of pages8
JournalBritish Journal of Cancer
Volume111
Issue number9
DOIs
Publication statusPublished - 2014

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Glutathione Transferase
Genetic Markers
Epigenomics
Prostatic Neoplasms
Drug Therapy
DNA
Survival
CpG Islands
Methylation
Polymerase Chain Reaction

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Mahon, K. L. ; Qu, W. ; Devaney, J. ; Paul, C. ; Castillo, L. ; Wykes, R. J. ; Chatfield, M. D. ; Boyer, M. J. ; Stockler, M. R. ; Marx, G. ; Gurney, H. ; Mallesara, G. ; Molloy, P. L. ; Horvath, L. G. ; Clark, S. J. / 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. In: British Journal of Cancer. 2014 ; Vol. 111, No. 9. pp. 1802-1809.
@article{32c55552dcce47739018050dcefdfbbb,
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.",
author = "Mahon, {K. L.} and W. Qu and J. Devaney and C. Paul and L. Castillo and Wykes, {R. J.} and Chatfield, {M. D.} and Boyer, {M. J.} and Stockler, {M. R.} and G. Marx and H. Gurney and G. Mallesara and Molloy, {P. L.} and Horvath, {L. G.} and Clark, {S. J.}",
year = "2014",
doi = "10.1038/bjc.2014.463",
language = "English",
volume = "111",
pages = "1802--1809",
journal = "British Journal of Cancer",
issn = "0007-0920",
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Mahon, KL, Qu, W, Devaney, J, Paul, C, Castillo, L, Wykes, RJ, Chatfield, MD, Boyer, MJ, Stockler, MR, Marx, G, Gurney, H, Mallesara, G, Molloy, PL, Horvath, LG & Clark, SJ 2014, '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', British Journal of Cancer, vol. 111, no. 9, pp. 1802-1809. https://doi.org/10.1038/bjc.2014.463

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. / Mahon, K. L.; Qu, W.; Devaney, J.; Paul, C.; Castillo, L.; Wykes, R. J.; Chatfield, M. D.; Boyer, M. J.; Stockler, M. R.; Marx, G.; Gurney, H.; Mallesara, G.; Molloy, P. L.; Horvath, L. G.; Clark, S. J.

In: British Journal of Cancer, Vol. 111, No. 9, 2014, p. 1802-1809.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - 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

AU - Mahon, K. L.

AU - Qu, W.

AU - Devaney, J.

AU - Paul, C.

AU - Castillo, L.

AU - Wykes, R. J.

AU - Chatfield, M. D.

AU - Boyer, M. J.

AU - Stockler, M. R.

AU - Marx, G.

AU - Gurney, H.

AU - Mallesara, G.

AU - Molloy, P. L.

AU - Horvath, L. G.

AU - Clark, S. J.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

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DO - 10.1038/bjc.2014.463

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SP - 1802

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