Aberrant DOCK2, GRASP, HIF3A and PKFP Hypermethylation has Potential as a Prognostic Biomarker for Prostate Cancer

Marianne T. Bjerre; Siri H. Strand; Maibritt Nørgaard; Helle Kristensen; Anne Ki Rasmussen; Martin Mørck Mortensen; Jacob Fredsøe; Peter Mouritzen; Benedicte Ulhøi; Torben Ørntoft; Michael Borre; Karina D. Sørensen

doi:10.3390/ijms20051173

Aberrant DOCK2, GRASP, HIF3A and PKFP Hypermethylation has Potential as a Prognostic Biomarker for Prostate Cancer

Marianne T. Bjerre, Siri H. Strand, Maibritt Nørgaard, Helle Kristensen, Anne Ki Rasmussen, Martin Mørck Mortensen, Jacob Fredsøe, Peter Mouritzen, Benedicte Ulhøi, Torben Ørntoft, Michael Borre, Karina D. Sørensen

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

Prostate cancer (PCa) is a clinically heterogeneous disease and currently, accurate diagnostic and prognostic molecular biomarkers are lacking. This study aimed to identify novel DNA hypermethylation markers for PCa with future potential for blood-based testing. Accordingly, to search for genes specifically hypermethylated in PCa tissue samples and not in blood cells or other cancer tissue types, we performed a systematic analysis of genome-wide DNA methylation data (Infinium 450K array) available in the Marmal-aid database for 4072 malignant/normal tissue samples of various types. We identified eight top candidate markers (cg12799885, DOCK2, FBXO30, GRASP, HIF3A, MOB3B, PFKP, and TPM4) that were specifically hypermethylated in PCa tissue samples and hypomethylated in other benign and malignant tissue types, including in peripheral blood cells. Potential as diagnostic and prognostic biomarkers was further assessed by the quantitative methylation specific PCR (qMSP) analysis of 37 nonmalignant and 197 PCa tissue samples from an independent population. Here, all eight hypermethylated candidates showed high sensitivity (75⁻94%) and specificity (84⁻100%) for PCa. Furthermore, DOCK2, GRASP, HIF3A and PKFP hypermethylation was significantly associated with biochemical recurrence (BCR) after radical prostatectomy (RP; 197 patients), independent of the routine clinicopathological variables. DOCK2 is the most promising single candidate marker (hazard ratio (HR) (95% confidence interval (CI)): 1.96 (1.24⁻3.10), adjusted p = 0.016; multivariate cox regression). Further validation studies are warranted and should investigate the potential value of these hypermethylation candidate markers for blood-based testing also.

Original language	English
Article number	1173
Journal	International Journal of Molecular Sciences
Volume	20
Issue	5
ISSN	1661-6596
DOIs	https://doi.org/10.3390/ijms20051173
Publication status	Published - Mar 2019

Keywords

biomarker
diagnosis
DNA methylation
epigenetics
prognosis
prostate cancer

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Bjerre, M. T., Strand, S. H., Nørgaard, M., Kristensen, H., Rasmussen, A. K., Mortensen, M. M., Fredsøe, J., Mouritzen, P., Ulhøi, B., Ørntoft, T., Borre, M., & Sørensen, K. D. (2019). Aberrant DOCK2, GRASP, HIF3A and PKFP Hypermethylation has Potential as a Prognostic Biomarker for Prostate Cancer. International Journal of Molecular Sciences , 20(5), Article 1173. https://doi.org/10.3390/ijms20051173

@article{3fa4441587ae4937b2f720178c3e06a3,

title = "Aberrant DOCK2, GRASP, HIF3A and PKFP Hypermethylation has Potential as a Prognostic Biomarker for Prostate Cancer",

abstract = "Prostate cancer (PCa) is a clinically heterogeneous disease and currently, accurate diagnostic and prognostic molecular biomarkers are lacking. This study aimed to identify novel DNA hypermethylation markers for PCa with future potential for blood-based testing. Accordingly, to search for genes specifically hypermethylated in PCa tissue samples and not in blood cells or other cancer tissue types, we performed a systematic analysis of genome-wide DNA methylation data (Infinium 450K array) available in the Marmal-aid database for 4072 malignant/normal tissue samples of various types. We identified eight top candidate markers (cg12799885, DOCK2, FBXO30, GRASP, HIF3A, MOB3B, PFKP, and TPM4) that were specifically hypermethylated in PCa tissue samples and hypomethylated in other benign and malignant tissue types, including in peripheral blood cells. Potential as diagnostic and prognostic biomarkers was further assessed by the quantitative methylation specific PCR (qMSP) analysis of 37 nonmalignant and 197 PCa tissue samples from an independent population. Here, all eight hypermethylated candidates showed high sensitivity (75⁻94%) and specificity (84⁻100%) for PCa. Furthermore, DOCK2, GRASP, HIF3A and PKFP hypermethylation was significantly associated with biochemical recurrence (BCR) after radical prostatectomy (RP; 197 patients), independent of the routine clinicopathological variables. DOCK2 is the most promising single candidate marker (hazard ratio (HR) (95% confidence interval (CI)): 1.96 (1.24⁻3.10), adjusted p = 0.016; multivariate cox regression). Further validation studies are warranted and should investigate the potential value of these hypermethylation candidate markers for blood-based testing also.",

keywords = "biomarker, diagnosis, DNA methylation, epigenetics, prognosis, prostate cancer",

author = "Bjerre, {Marianne T.} and Strand, {Siri H.} and Maibritt N{\o}rgaard and Helle Kristensen and Rasmussen, {Anne Ki} and Mortensen, {Martin M{\o}rck} and Jacob Freds{\o}e and Peter Mouritzen and Benedicte Ulh{\o}i and Torben {\O}rntoft and Michael Borre and S{\o}rensen, {Karina D.}",

year = "2019",

month = mar,

doi = "10.3390/ijms20051173",

language = "English",

volume = "20",

journal = "International Journal of Molecular Sciences ",

issn = "1661-6596",

publisher = "MDPI AG",

number = "5",

}

Bjerre, MT, Strand, SH, Nørgaard, M, Kristensen, H, Rasmussen, AK, Mortensen, MM, Fredsøe, J, Mouritzen, P, Ulhøi, B, Ørntoft, T , Borre, M & Sørensen, KD 2019, 'Aberrant DOCK2, GRASP, HIF3A and PKFP Hypermethylation has Potential as a Prognostic Biomarker for Prostate Cancer', International Journal of Molecular Sciences , vol. 20, no. 5, 1173. https://doi.org/10.3390/ijms20051173

Aberrant DOCK2, GRASP, HIF3A and PKFP Hypermethylation has Potential as a Prognostic Biomarker for Prostate Cancer. / Bjerre, Marianne T.; Strand, Siri H.; Nørgaard, Maibritt et al.
In: International Journal of Molecular Sciences , Vol. 20, No. 5, 1173, 03.2019.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Aberrant DOCK2, GRASP, HIF3A and PKFP Hypermethylation has Potential as a Prognostic Biomarker for Prostate Cancer

AU - Bjerre, Marianne T.

AU - Strand, Siri H.

AU - Nørgaard, Maibritt

AU - Kristensen, Helle

AU - Rasmussen, Anne Ki

AU - Mortensen, Martin Mørck

AU - Fredsøe, Jacob

AU - Mouritzen, Peter

AU - Ulhøi, Benedicte

AU - Ørntoft, Torben

AU - Borre, Michael

AU - Sørensen, Karina D.

PY - 2019/3

Y1 - 2019/3

N2 - Prostate cancer (PCa) is a clinically heterogeneous disease and currently, accurate diagnostic and prognostic molecular biomarkers are lacking. This study aimed to identify novel DNA hypermethylation markers for PCa with future potential for blood-based testing. Accordingly, to search for genes specifically hypermethylated in PCa tissue samples and not in blood cells or other cancer tissue types, we performed a systematic analysis of genome-wide DNA methylation data (Infinium 450K array) available in the Marmal-aid database for 4072 malignant/normal tissue samples of various types. We identified eight top candidate markers (cg12799885, DOCK2, FBXO30, GRASP, HIF3A, MOB3B, PFKP, and TPM4) that were specifically hypermethylated in PCa tissue samples and hypomethylated in other benign and malignant tissue types, including in peripheral blood cells. Potential as diagnostic and prognostic biomarkers was further assessed by the quantitative methylation specific PCR (qMSP) analysis of 37 nonmalignant and 197 PCa tissue samples from an independent population. Here, all eight hypermethylated candidates showed high sensitivity (75⁻94%) and specificity (84⁻100%) for PCa. Furthermore, DOCK2, GRASP, HIF3A and PKFP hypermethylation was significantly associated with biochemical recurrence (BCR) after radical prostatectomy (RP; 197 patients), independent of the routine clinicopathological variables. DOCK2 is the most promising single candidate marker (hazard ratio (HR) (95% confidence interval (CI)): 1.96 (1.24⁻3.10), adjusted p = 0.016; multivariate cox regression). Further validation studies are warranted and should investigate the potential value of these hypermethylation candidate markers for blood-based testing also.

AB - Prostate cancer (PCa) is a clinically heterogeneous disease and currently, accurate diagnostic and prognostic molecular biomarkers are lacking. This study aimed to identify novel DNA hypermethylation markers for PCa with future potential for blood-based testing. Accordingly, to search for genes specifically hypermethylated in PCa tissue samples and not in blood cells or other cancer tissue types, we performed a systematic analysis of genome-wide DNA methylation data (Infinium 450K array) available in the Marmal-aid database for 4072 malignant/normal tissue samples of various types. We identified eight top candidate markers (cg12799885, DOCK2, FBXO30, GRASP, HIF3A, MOB3B, PFKP, and TPM4) that were specifically hypermethylated in PCa tissue samples and hypomethylated in other benign and malignant tissue types, including in peripheral blood cells. Potential as diagnostic and prognostic biomarkers was further assessed by the quantitative methylation specific PCR (qMSP) analysis of 37 nonmalignant and 197 PCa tissue samples from an independent population. Here, all eight hypermethylated candidates showed high sensitivity (75⁻94%) and specificity (84⁻100%) for PCa. Furthermore, DOCK2, GRASP, HIF3A and PKFP hypermethylation was significantly associated with biochemical recurrence (BCR) after radical prostatectomy (RP; 197 patients), independent of the routine clinicopathological variables. DOCK2 is the most promising single candidate marker (hazard ratio (HR) (95% confidence interval (CI)): 1.96 (1.24⁻3.10), adjusted p = 0.016; multivariate cox regression). Further validation studies are warranted and should investigate the potential value of these hypermethylation candidate markers for blood-based testing also.

KW - biomarker

KW - diagnosis

KW - DNA methylation

KW - epigenetics

KW - prognosis

KW - prostate cancer

UR - http://www.scopus.com/inward/record.url?scp=85062889461&partnerID=8YFLogxK

U2 - 10.3390/ijms20051173

DO - 10.3390/ijms20051173

M3 - Journal article

C2 - 30866497

AN - SCOPUS:85062889461

SN - 1661-6596

VL - 20

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

IS - 5

M1 - 1173

ER -

Aberrant DOCK2, GRASP, HIF3A and PKFP Hypermethylation has Potential as a Prognostic Biomarker for Prostate Cancer

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