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

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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.

In: Cells, Vol. 9, No. 6, 1362, 06.2020.

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@article{f6d830fba7914f4391a956e6d82f1bb7,
title = "Epigenetic Analysis of Circulating Tumor DNA in Localized and Metastatic Prostate Cancer: Evaluation of Clinical Biomarker Potential",
abstract = "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-na{\"i}ve mPCa patients who could benefit from intensified treatment.",
keywords = "biomarkers, circulating tumor DNA, DNA methylation, liquid biopsy, prostatic neoplasms",
author = "Bjerre, {Marianne Trier} and Maibritt N{\o}rgaard and Larsen, {Ole Halfdan} and Jensen, {Sarah {\O}strup} and Strand, {Siri H.} and Peter {\O}stergren and Mikkel Fode and Jacob Freds{\o}e and Ulh{\o}i, {Benedicte Parm} and Mortensen, {Martin M{\o}rck} and Jensen, {J{\o}rgen Bjerggaard} and Michael Borre and S{\o}rensen, {Karina D.}",
year = "2020",
month = jun,
doi = "10.3390/cells9061362",
language = "English",
volume = "9",
journal = "Cells",
issn = "2073-4409",
publisher = "MDPI AG",
number = "6",

}

RIS

TY - JOUR

T1 - Epigenetic Analysis of Circulating Tumor DNA in Localized and Metastatic Prostate Cancer

T2 - Evaluation of Clinical Biomarker Potential

AU - Bjerre, Marianne Trier

AU - Nørgaard, Maibritt

AU - Larsen, Ole Halfdan

AU - Jensen, Sarah Østrup

AU - Strand, Siri H.

AU - Østergren, Peter

AU - Fode, Mikkel

AU - Fredsøe, Jacob

AU - Ulhøi, Benedicte Parm

AU - Mortensen, Martin Mørck

AU - Jensen, Jørgen Bjerggaard

AU - Borre, Michael

AU - Sørensen, Karina D.

PY - 2020/6

Y1 - 2020/6

N2 - 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.

AB - 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.

KW - biomarkers

KW - circulating tumor DNA

KW - DNA methylation

KW - liquid biopsy

KW - prostatic neoplasms

UR - http://www.scopus.com/inward/record.url?scp=85085908873&partnerID=8YFLogxK

U2 - 10.3390/cells9061362

DO - 10.3390/cells9061362

M3 - Journal article

C2 - 32486483

AN - SCOPUS:85085908873

VL - 9

JO - Cells

JF - Cells

SN - 2073-4409

IS - 6

M1 - 1362

ER -