TY - JOUR
T1 - Gene expression and epigenetic discovery screen reveal methylation of SFRP2 in prostate cancer
AU - Perry, Antoinette S.
AU - O'Hurley, Gillian
AU - Raheem, Omer A.
AU - Brennan, Kevin
AU - Wong, Simon
AU - O'Grady, Anthony
AU - Kennedy, Anne Marie
AU - Marignol, Laure
AU - Murphy, Therese M.
AU - Sullivan, Linda
AU - Barrett, Ciara
AU - Loftus, Barbara
AU - Thornhill, John
AU - Hewitt, Stephen M.
AU - Lawler, Mark
AU - Kay, Elaine
AU - Lynch, Thomas
AU - Hollywood, Donal
PY - 2013/4/15
Y1 - 2013/4/15
N2 - Aberrant activation of Wnts is common in human cancers, including prostate. Hypermethylation associated transcriptional silencing of Wnt antagonist genes SFRPs (Secreted Frizzled-Related Proteins) is a frequent oncogenic event. The significance of this is not known in prostate cancer. The objectives of our study were to (i) profile Wnt signaling related gene expression and (ii) investigate methylation of Wnt antagonist genes in prostate cancer. Using TaqMan Low Density Arrays, we identified 15 Wnt signaling related genes with significantly altered expression in prostate cancer; the majority of which were upregulated in tumors. Notably, histologically benign tissue from men with prostate cancer appeared more similar to tumor (r = 0.76) than to benign prostatic hyperplasia (BPH; r = 0.57, p < 0.001). Overall, the expression profile was highly similar between tumors of high (≥ 7) and low (≤ 6) Gleason scores. Pharmacological demethylation of PC-3 cells with 5-Aza-CdR reactivated 39 genes (≥ 2-fold); 40% of which inhibit Wnt signaling. Methylation frequencies in prostate cancer were 10% (2/20) (SFRP1), 64.86% (48/74) (SFRP2), 0% (0/20) (SFRP4) and 60% (12/20) (SFRP5). SFRP2 methylation was detected at significantly lower frequencies in high-grade prostatic intraepithelial neoplasia (HGPIN; 30%, (6/20), p = 0.0096), tumor adjacent benign areas (8.82%, (7/69), p < 0.0001) and BPH (11.43% (4/35), p < 0.0001). The quantitative level of SFRP2 methylation (normalized index of methylation) was also significantly higher in tumors (116) than in the other samples (HGPIN = 7.45, HB = 0.47, and BPH = 0.12). We show that SFRP2 hypermethylation is a common event in prostate cancer. SFRP2 methylation in combination with other epigenetic markers may be a useful biomarker of prostate cancer. What's new? Aberrant Wnt signaling is a characteristic of many cancers, but its causes are poorly understood. In a comprehensive gene expression and DNA methylation study, the authors identify a set of Wnt-related genes that are dysregulated in prostate cancer. They further demonstrate frequent hypermethylation of the SFRP family of Wnt antagonist genes, especially SFRP2, in tumors and pre-invasive lesions. These results bring new insight into the causes of dysregulated Wnt signaling and point toSFRP2 methylation as a novel biomarker in prostate cancer.
AB - Aberrant activation of Wnts is common in human cancers, including prostate. Hypermethylation associated transcriptional silencing of Wnt antagonist genes SFRPs (Secreted Frizzled-Related Proteins) is a frequent oncogenic event. The significance of this is not known in prostate cancer. The objectives of our study were to (i) profile Wnt signaling related gene expression and (ii) investigate methylation of Wnt antagonist genes in prostate cancer. Using TaqMan Low Density Arrays, we identified 15 Wnt signaling related genes with significantly altered expression in prostate cancer; the majority of which were upregulated in tumors. Notably, histologically benign tissue from men with prostate cancer appeared more similar to tumor (r = 0.76) than to benign prostatic hyperplasia (BPH; r = 0.57, p < 0.001). Overall, the expression profile was highly similar between tumors of high (≥ 7) and low (≤ 6) Gleason scores. Pharmacological demethylation of PC-3 cells with 5-Aza-CdR reactivated 39 genes (≥ 2-fold); 40% of which inhibit Wnt signaling. Methylation frequencies in prostate cancer were 10% (2/20) (SFRP1), 64.86% (48/74) (SFRP2), 0% (0/20) (SFRP4) and 60% (12/20) (SFRP5). SFRP2 methylation was detected at significantly lower frequencies in high-grade prostatic intraepithelial neoplasia (HGPIN; 30%, (6/20), p = 0.0096), tumor adjacent benign areas (8.82%, (7/69), p < 0.0001) and BPH (11.43% (4/35), p < 0.0001). The quantitative level of SFRP2 methylation (normalized index of methylation) was also significantly higher in tumors (116) than in the other samples (HGPIN = 7.45, HB = 0.47, and BPH = 0.12). We show that SFRP2 hypermethylation is a common event in prostate cancer. SFRP2 methylation in combination with other epigenetic markers may be a useful biomarker of prostate cancer. What's new? Aberrant Wnt signaling is a characteristic of many cancers, but its causes are poorly understood. In a comprehensive gene expression and DNA methylation study, the authors identify a set of Wnt-related genes that are dysregulated in prostate cancer. They further demonstrate frequent hypermethylation of the SFRP family of Wnt antagonist genes, especially SFRP2, in tumors and pre-invasive lesions. These results bring new insight into the causes of dysregulated Wnt signaling and point toSFRP2 methylation as a novel biomarker in prostate cancer.
KW - SFRP2
KW - Wnt signaling
KW - hypermethylation
KW - prostate cancer
UR - http://www.scopus.com/inward/record.url?scp=84873993636&partnerID=8YFLogxK
U2 - 10.1002/ijc.27798
DO - 10.1002/ijc.27798
M3 - Article
C2 - 22915211
AN - SCOPUS:84873993636
SN - 0020-7136
VL - 132
SP - 1771
EP - 1780
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 8
ER -