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Epigenetic Analysis of Circulating Tumor DNA in Localized and Metastatic Prostate Cancer: Evaluation of Clinical Biomarker Potential

Novel and minimally-invasive prostate cancer (PCa)-specific biomarkers are needed to improve diagnosis and risk stratification. Here, we investigated the biomarker potential in localized and de novo metastatic PCa (mPCa) of methylated circulating tumor DNA (ctDNA) in plasma. Using the Marmal-aid dat...

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Autores principales: Bjerre, Marianne Trier, Nørgaard, Maibritt, Larsen, Ole Halfdan, Jensen, Sarah Østrup, Strand, Siri H., Østergren, Peter, Fode, Mikkel, Fredsøe, Jacob, Ulhøi, Benedicte Parm, Mortensen, Martin Mørck, Jensen, Jørgen Bjerggaard, Borre, Michael, Sørensen, Karina D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349912/
https://www.ncbi.nlm.nih.gov/pubmed/32486483
http://dx.doi.org/10.3390/cells9061362
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author Bjerre, Marianne Trier
Nørgaard, Maibritt
Larsen, Ole Halfdan
Jensen, Sarah Østrup
Strand, Siri H.
Østergren, Peter
Fode, Mikkel
Fredsøe, Jacob
Ulhøi, Benedicte Parm
Mortensen, Martin Mørck
Jensen, Jørgen Bjerggaard
Borre, Michael
Sørensen, Karina D.
author_facet Bjerre, Marianne Trier
Nørgaard, Maibritt
Larsen, Ole Halfdan
Jensen, Sarah Østrup
Strand, Siri H.
Østergren, Peter
Fode, Mikkel
Fredsøe, Jacob
Ulhøi, Benedicte Parm
Mortensen, Martin Mørck
Jensen, Jørgen Bjerggaard
Borre, Michael
Sørensen, Karina D.
author_sort Bjerre, Marianne Trier
collection PubMed
description Novel and minimally-invasive prostate cancer (PCa)-specific biomarkers are needed to improve diagnosis and risk stratification. Here, we investigated the biomarker potential in localized and de novo metastatic PCa (mPCa) of methylated circulating tumor DNA (ctDNA) in plasma. Using the Marmal-aid database and in-house datasets, we identified three top candidates specifically hypermethylated in PCa tissue: DOCK2, HAPLN3, and FBXO30 (specificity/sensitivity: 80%–100%/75–94%). These candidates were further analyzed in plasma samples from 36 healthy controls, 61 benign prostatic hyperplasia (BPH), 102 localized PCa, and 65 de novo mPCa patients using methylation-specific droplet digital PCR. Methylated ctDNA for DOCK2/HAPLN3/FBXO30 was generally not detected in healthy controls, BPH patients, nor in patients with localized PCa despite a positive signal in 98%–100% of matched radical prostatectomy tissue samples. However, ctDNA methylation of DOCK2, HAPLN3, and/or FBXO30 was detected in 61.5% (40/65) of de novo mPCa patients and markedly increased in high- compared to low-volume mPCa (89.3% (25/28) vs. 32.1% (10/31), p < 0.001). Moreover, detection of methylated ctDNA was associated with significantly shorter time to progression to metastatic castration resistant PCa, independent of tumor-volume. These results indicate that methylated ctDNA (DOCK2/HAPLN3/FBXO30) may be potentially useful for identification of hormone-naïve mPCa patients who could benefit from intensified treatment.
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spelling pubmed-73499122020-07-15 Epigenetic Analysis of Circulating Tumor DNA in Localized and Metastatic Prostate Cancer: Evaluation of Clinical Biomarker Potential Bjerre, Marianne Trier Nørgaard, Maibritt Larsen, Ole Halfdan Jensen, Sarah Østrup Strand, Siri H. Østergren, Peter Fode, Mikkel Fredsøe, Jacob Ulhøi, Benedicte Parm Mortensen, Martin Mørck Jensen, Jørgen Bjerggaard Borre, Michael Sørensen, Karina D. Cells Article Novel and minimally-invasive prostate cancer (PCa)-specific biomarkers are needed to improve diagnosis and risk stratification. Here, we investigated the biomarker potential in localized and de novo metastatic PCa (mPCa) of methylated circulating tumor DNA (ctDNA) in plasma. Using the Marmal-aid database and in-house datasets, we identified three top candidates specifically hypermethylated in PCa tissue: DOCK2, HAPLN3, and FBXO30 (specificity/sensitivity: 80%–100%/75–94%). These candidates were further analyzed in plasma samples from 36 healthy controls, 61 benign prostatic hyperplasia (BPH), 102 localized PCa, and 65 de novo mPCa patients using methylation-specific droplet digital PCR. Methylated ctDNA for DOCK2/HAPLN3/FBXO30 was generally not detected in healthy controls, BPH patients, nor in patients with localized PCa despite a positive signal in 98%–100% of matched radical prostatectomy tissue samples. However, ctDNA methylation of DOCK2, HAPLN3, and/or FBXO30 was detected in 61.5% (40/65) of de novo mPCa patients and markedly increased in high- compared to low-volume mPCa (89.3% (25/28) vs. 32.1% (10/31), p < 0.001). Moreover, detection of methylated ctDNA was associated with significantly shorter time to progression to metastatic castration resistant PCa, independent of tumor-volume. These results indicate that methylated ctDNA (DOCK2/HAPLN3/FBXO30) may be potentially useful for identification of hormone-naïve mPCa patients who could benefit from intensified treatment. MDPI 2020-05-31 /pmc/articles/PMC7349912/ /pubmed/32486483 http://dx.doi.org/10.3390/cells9061362 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bjerre, Marianne Trier
Nørgaard, Maibritt
Larsen, Ole Halfdan
Jensen, Sarah Østrup
Strand, Siri H.
Østergren, Peter
Fode, Mikkel
Fredsøe, Jacob
Ulhøi, Benedicte Parm
Mortensen, Martin Mørck
Jensen, Jørgen Bjerggaard
Borre, Michael
Sørensen, Karina D.
Epigenetic Analysis of Circulating Tumor DNA in Localized and Metastatic Prostate Cancer: Evaluation of Clinical Biomarker Potential
title Epigenetic Analysis of Circulating Tumor DNA in Localized and Metastatic Prostate Cancer: Evaluation of Clinical Biomarker Potential
title_full Epigenetic Analysis of Circulating Tumor DNA in Localized and Metastatic Prostate Cancer: Evaluation of Clinical Biomarker Potential
title_fullStr Epigenetic Analysis of Circulating Tumor DNA in Localized and Metastatic Prostate Cancer: Evaluation of Clinical Biomarker Potential
title_full_unstemmed Epigenetic Analysis of Circulating Tumor DNA in Localized and Metastatic Prostate Cancer: Evaluation of Clinical Biomarker Potential
title_short Epigenetic Analysis of Circulating Tumor DNA in Localized and Metastatic Prostate Cancer: Evaluation of Clinical Biomarker Potential
title_sort epigenetic analysis of circulating tumor dna in localized and metastatic prostate cancer: evaluation of clinical biomarker potential
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349912/
https://www.ncbi.nlm.nih.gov/pubmed/32486483
http://dx.doi.org/10.3390/cells9061362
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