CDO1 promoter methylation is associated with gene silencing and is a prognostic biomarker for biochemical recurrence-free survival in prostate cancer patients.
Molecular biomarkers may facilitate the distinction between aggressive and clinically insignificant prostate cancer (PCa), thereby potentially aiding individualized treatment. We analyzed cysteine dioxygenase 1 (CDO1) promoter methylation and mRNA expression in order to evaluate its potential as prognostic biomarker. CDO1 methylation and mRNA expression were determined in cell lines and formalin-fixed paraffin-embedded prostatectomy specimens from a first cohort of 300 PCa patients using methylation-specific qPCR and qRT-PCR. Univariate and multivariate Cox proportional hazards and Kaplan-Meier analyses were performed to evaluate biochemical recurrence (BCR)-free survival. Results were confirmed in an independent second cohort comprising 498 PCa cases. Methylation and mRNA expression data from the second cohort were generated by The Cancer Genome Atlas (TCGA) Research Network by means of Infinium HumanMethylation450 BeadChip and RNASeq. CDO1 was hypermethylated in PCa compared to normal adjacent tissues and benign prostatic hyperplasia (P < 0.001) and was associated with reduced gene expression (ρ = -0.91, P = 0.005). Using two different methodologies for methylation quantification, high CDO1 methylation as continuous variable was associated with BCR in univariate analysis (first cohort: HR = 1.02, P = 0.002, 95% CI [1.01-1.03]; second cohort: HR = 1.02, P = 0.032, 95% CI [1.00-1.03]) but failed to reach statistical significance in multivariate analysis. CDO1 promoter methylation is involved in gene regulation and is a potential prognostic biomarker for BCR-free survival in PCa patients following radical prostatectomy. Further studies are needed to validate CDO1 methylation assays and to evaluate the clinical utility of CDO1 methylation for the management of PCa.
a University Hospital Bonn, Institute of Pathology , Bonn , Germany.
Sebastian
S
Meller
a University Hospital Bonn, Institute of Pathology , Bonn , Germany.
Lisa
L
Zipfel
a University Hospital Bonn, Institute of Pathology , Bonn , Germany.
Heidrun
H
Gevensleben
b Department of Otolaryngology , Head and Neck Surgery, University Hospital Bonn , Bonn , Germany.
Jörn
J
Dietrich
c Department of Urology , University Hospital Bonn , Bonn , Germany.
Jörg
J
Ellinger
d Institute of Dermatopathology , Bonn , Germany.
Michael
M
Majores
c Department of Urology , University Hospital Bonn , Bonn , Germany.
Johannes
J
Stein
e Department of Pathology and Laboratory Medicine , New York Weill Cornell Medicine of Cornell University , NY , USA.|f Englander Institute for Precision Medicine, Weill Cornell Medicine of Cornell University New York , NY , USA.
Verena
V
Sailer
a University Hospital Bonn, Institute of Pathology , Bonn , Germany.
Maria
M
Jung
a University Hospital Bonn, Institute of Pathology , Bonn , Germany.
Glen
G
Kristiansen
a University Hospital Bonn, Institute of Pathology , Bonn , Germany.|b Department of Otolaryngology , Head and Neck Surgery, University Hospital Bonn , Bonn , Germany.
Dimo
D
Dietrich
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics*; D050558:Cysteine Dioxygenase / Q000096:biosynthesis / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D018572:Disease-Free Survival; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery
D014408:Biomarkers, Tumor; C579734:CDO1 protein, human; D050558:Cysteine Dioxygenase
Biomarker; CDO1; DNA methylation; cysteine dioxygenase 1; prognosis; prostate cancer
Am J Surg Pathol. 2016 Feb;40(2):244-52
26492179
Nature. 2009 Feb 12;457(7231):910-4
19212411
PLoS One. 2011;6(8):e22486
21853037
Virchows Arch. 2014 Oct;465(4):419-27
25172328
Nat Rev Cancer. 2014 Nov;14(11):709-21
25342630
BMC Bioinformatics. 2011 Aug 04;12:323
21816040
Mol Cancer. 2009 Aug 28;8:68
19715609
PLoS One. 2012;7(9):e44951
23028699
BMC Genomics. 2015 Aug 26;16:636
26306699
Clin Cancer Res. 2014 Apr 15;20(8):2169-81
24737792
PLoS One. 2014 Dec 03;9(12):e113546
25469504
BMC Cancer. 2010 Jun 01;10:247
20515469
Am J Physiol Endocrinol Metab. 2007 Jul;293(1):E62-9
17327371
Clin Cancer Res. 2015 Aug 1;21(15):3492-500
25904753
Histopathology. 2012 Jan;60(1):125-41
22212082
J Urol. 2009 Apr;181(4):1678-85
19233404
Cancer Discov. 2012 Nov;2(11):1024-35
22930729
N Engl J Med. 2015 Aug 20;373(8):737-46
26244877
Int J Mol Sci. 2014 Sep 18;15(9):16544-76
25238417
Toxicol Sci. 2015 May;145(1):59-67
25634538
Biochem J. 2003 Oct 15;375(Pt 2):441-7
12871209
PLoS One. 2016 Jan 19;11(1):e0144862
26785325
Amino Acids. 2009 May;37(1):55-63
19011731
Oncogene. 2008 Jan 31;27(6):831-8
17637738
Free Radic Biol Med. 1999 Nov;27(9-10):922-35
10569625
J Clin Oncol. 2013 Sep 10;31(26):3250-8
23918943
J Biol Chem. 2006 Jun 9;281(23):15774-9
16611641
Br J Cancer. 2015 Jan 6;112(1):140-8
25422912
FEMS Microbiol Lett. 2003 Sep 26;226(2):195-202
14553911
Crit Rev Clin Lab Sci. 2014 Aug;51(4):173-99
24878394
Oncotarget. 2016 Jan 12;7(2):1421-38
26623558
Int J Cancer. 2013 Jan 15;132(2):308-14
22700458
Exp Cell Res. 2015 Mar 1;332(1):47-59
25576381
J Urol. 2010 Jul;184(1):149-56
20478579
PLoS One. 2014 Apr 03;9(4):e93933
24699908
Curr Drug Targets. 2015;16(1):13-9
25585126
Chem Commun (Camb). 2007 Aug 28;(32):3338-49
18019494
Clin Cancer Res. 2016 Apr 15;22(8):1969-77
26573597
CA Cancer J Clin. 2016 Jan-Feb;66(1):7-30
26742998
Oncol Rep. 2008 Dec;20(6):1561-7
19020742
J Cell Biochem. 2005 Nov 1;96(4):810-20
16149076
Epigenetics. 2012 Nov;7(11):1249-57
22983262
Clin Cancer Res. 2013 Jun 15;19(12):3201-11
23630167