A distinct plasma lipid signature associated with poor prognosis in castration-resistant prostate cancer

Hui-Ming Lin, Kate L. Mahon, Jacquelyn M. Weir, Piyushkumar A Mundra, Calan Spielman, Karen Briscoe, Howard Gurney, Girish Mallesara, Gavin M Marx, Martin R Stockler, PRIMe Consortium, Robert G Parton, Andrew J. Hoy, Roger J. Daly, Peter J. Meikle, Lisa G Horvath

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Lipids are known to influence tumour growth, inflammation and chemoresistance. However, the association of circulating lipids with the clinical outcome of metastatic castration-resistant prostate cancer (CRPC) is unknown. We investigated associations between the plasma lipidome and clinical outcome in CRPC. Lipidomic profiling by liquid chromatography-tandem mass spectrometry was performed on plasma samples from a Phase 1 discovery cohort of 96 CRPC patients. Results were validated in an independent Phase 2 cohort of 63 CRPC patients. Unsupervised analysis of lipidomic profiles (323 lipid species) classified the Phase 1 cohort into two patient subgroups with significant survival differences (HR 2.31, 95% CI 1.44–3.68, p = 0.0005). The levels of 46 lipids were individually prognostic and were predominantly sphingolipids with higher levels associated with poor prognosis. A prognostic three-lipid signature was derived (ceramide d18:1/24:1, sphingomyelin d18:2/16:0, phosphatidylcholine 16:0/16:0) and was also associated with shorter survival in the Phase 2 cohort (HR 4.8, 95% CI 2.06–11.1, p = 0.0003). The signature was an independent prognostic factor when modelled with clinicopathological factors or metabolic characteristics. The association of plasma lipids with CRPC prognosis suggests a possible role of these lipids in disease progression. Further research is required to determine if therapeutic modulation of the levels of these lipids by targeting their metabolic pathways may improve patient outcome.

Original languageEnglish
Pages (from-to)2112-2120
Number of pages9
JournalInternational Journal of Cancer
Volume141
Issue number10
DOIs
Publication statusPublished - 15 Nov 2017

Keywords

  • biomarker
  • castration-resistant
  • lipids
  • prognosis
  • prostate cancer

Cite this

Lin, H-M., Mahon, K. L., Weir, J. M., Mundra, P. A., Spielman, C., Briscoe, K., ... Horvath, L. G. (2017). A distinct plasma lipid signature associated with poor prognosis in castration-resistant prostate cancer. International Journal of Cancer, 141(10), 2112-2120. https://doi.org/10.1002/ijc.30903
Lin, Hui-Ming ; Mahon, Kate L. ; Weir, Jacquelyn M. ; Mundra, Piyushkumar A ; Spielman, Calan ; Briscoe, Karen ; Gurney, Howard ; Mallesara, Girish ; Marx, Gavin M ; Stockler, Martin R ; PRIMe Consortium ; Parton, Robert G ; Hoy, Andrew J. ; Daly, Roger J. ; Meikle, Peter J. ; Horvath, Lisa G. / A distinct plasma lipid signature associated with poor prognosis in castration-resistant prostate cancer. In: International Journal of Cancer. 2017 ; Vol. 141, No. 10. pp. 2112-2120.
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abstract = "Lipids are known to influence tumour growth, inflammation and chemoresistance. However, the association of circulating lipids with the clinical outcome of metastatic castration-resistant prostate cancer (CRPC) is unknown. We investigated associations between the plasma lipidome and clinical outcome in CRPC. Lipidomic profiling by liquid chromatography-tandem mass spectrometry was performed on plasma samples from a Phase 1 discovery cohort of 96 CRPC patients. Results were validated in an independent Phase 2 cohort of 63 CRPC patients. Unsupervised analysis of lipidomic profiles (323 lipid species) classified the Phase 1 cohort into two patient subgroups with significant survival differences (HR 2.31, 95{\%} CI 1.44–3.68, p = 0.0005). The levels of 46 lipids were individually prognostic and were predominantly sphingolipids with higher levels associated with poor prognosis. A prognostic three-lipid signature was derived (ceramide d18:1/24:1, sphingomyelin d18:2/16:0, phosphatidylcholine 16:0/16:0) and was also associated with shorter survival in the Phase 2 cohort (HR 4.8, 95{\%} CI 2.06–11.1, p = 0.0003). The signature was an independent prognostic factor when modelled with clinicopathological factors or metabolic characteristics. The association of plasma lipids with CRPC prognosis suggests a possible role of these lipids in disease progression. Further research is required to determine if therapeutic modulation of the levels of these lipids by targeting their metabolic pathways may improve patient outcome.",
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author = "Hui-Ming Lin and Mahon, {Kate L.} and Weir, {Jacquelyn M.} and Mundra, {Piyushkumar A} and Calan Spielman and Karen Briscoe and Howard Gurney and Girish Mallesara and Marx, {Gavin M} and Stockler, {Martin R} and {PRIMe Consortium} and Parton, {Robert G} and Hoy, {Andrew J.} and Daly, {Roger J.} and Meikle, {Peter J.} and Horvath, {Lisa G}",
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Lin, H-M, Mahon, KL, Weir, JM, Mundra, PA, Spielman, C, Briscoe, K, Gurney, H, Mallesara, G, Marx, GM, Stockler, MR, PRIMe Consortium, Parton, RG, Hoy, AJ, Daly, RJ, Meikle, PJ & Horvath, LG 2017, 'A distinct plasma lipid signature associated with poor prognosis in castration-resistant prostate cancer' International Journal of Cancer, vol. 141, no. 10, pp. 2112-2120. https://doi.org/10.1002/ijc.30903

A distinct plasma lipid signature associated with poor prognosis in castration-resistant prostate cancer. / Lin, Hui-Ming; Mahon, Kate L.; Weir, Jacquelyn M.; Mundra, Piyushkumar A; Spielman, Calan; Briscoe, Karen; Gurney, Howard; Mallesara, Girish; Marx, Gavin M; Stockler, Martin R; PRIMe Consortium; Parton, Robert G; Hoy, Andrew J.; Daly, Roger J.; Meikle, Peter J.; Horvath, Lisa G.

In: International Journal of Cancer, Vol. 141, No. 10, 15.11.2017, p. 2112-2120.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - A distinct plasma lipid signature associated with poor prognosis in castration-resistant prostate cancer

AU - Lin, Hui-Ming

AU - Mahon, Kate L.

AU - Weir, Jacquelyn M.

AU - Mundra, Piyushkumar A

AU - Spielman, Calan

AU - Briscoe, Karen

AU - Gurney, Howard

AU - Mallesara, Girish

AU - Marx, Gavin M

AU - Stockler, Martin R

AU - PRIMe Consortium

AU - Parton, Robert G

AU - Hoy, Andrew J.

AU - Daly, Roger J.

AU - Meikle, Peter J.

AU - Horvath, Lisa G

PY - 2017/11/15

Y1 - 2017/11/15

N2 - Lipids are known to influence tumour growth, inflammation and chemoresistance. However, the association of circulating lipids with the clinical outcome of metastatic castration-resistant prostate cancer (CRPC) is unknown. We investigated associations between the plasma lipidome and clinical outcome in CRPC. Lipidomic profiling by liquid chromatography-tandem mass spectrometry was performed on plasma samples from a Phase 1 discovery cohort of 96 CRPC patients. Results were validated in an independent Phase 2 cohort of 63 CRPC patients. Unsupervised analysis of lipidomic profiles (323 lipid species) classified the Phase 1 cohort into two patient subgroups with significant survival differences (HR 2.31, 95% CI 1.44–3.68, p = 0.0005). The levels of 46 lipids were individually prognostic and were predominantly sphingolipids with higher levels associated with poor prognosis. A prognostic three-lipid signature was derived (ceramide d18:1/24:1, sphingomyelin d18:2/16:0, phosphatidylcholine 16:0/16:0) and was also associated with shorter survival in the Phase 2 cohort (HR 4.8, 95% CI 2.06–11.1, p = 0.0003). The signature was an independent prognostic factor when modelled with clinicopathological factors or metabolic characteristics. The association of plasma lipids with CRPC prognosis suggests a possible role of these lipids in disease progression. Further research is required to determine if therapeutic modulation of the levels of these lipids by targeting their metabolic pathways may improve patient outcome.

AB - Lipids are known to influence tumour growth, inflammation and chemoresistance. However, the association of circulating lipids with the clinical outcome of metastatic castration-resistant prostate cancer (CRPC) is unknown. We investigated associations between the plasma lipidome and clinical outcome in CRPC. Lipidomic profiling by liquid chromatography-tandem mass spectrometry was performed on plasma samples from a Phase 1 discovery cohort of 96 CRPC patients. Results were validated in an independent Phase 2 cohort of 63 CRPC patients. Unsupervised analysis of lipidomic profiles (323 lipid species) classified the Phase 1 cohort into two patient subgroups with significant survival differences (HR 2.31, 95% CI 1.44–3.68, p = 0.0005). The levels of 46 lipids were individually prognostic and were predominantly sphingolipids with higher levels associated with poor prognosis. A prognostic three-lipid signature was derived (ceramide d18:1/24:1, sphingomyelin d18:2/16:0, phosphatidylcholine 16:0/16:0) and was also associated with shorter survival in the Phase 2 cohort (HR 4.8, 95% CI 2.06–11.1, p = 0.0003). The signature was an independent prognostic factor when modelled with clinicopathological factors or metabolic characteristics. The association of plasma lipids with CRPC prognosis suggests a possible role of these lipids in disease progression. Further research is required to determine if therapeutic modulation of the levels of these lipids by targeting their metabolic pathways may improve patient outcome.

KW - biomarker

KW - castration-resistant

KW - lipids

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