Epigenetic inactivation of SFRP genes and TP53 alteration act jointly as markers of invasive bladder cancer.
In the United States each year, almost 13,000 deaths are attributable to bladder cancer, with the majority of these deaths related to higher stage, muscle-invasive solid tumors. Epigenetic silencing of the secreted frizzled receptor proteins (SFRP), antagonists of the WNT pathway, leads to constitutive WNT signaling, altering cell morphology and motility. Identifying alterations in this pathway in bladder cancer may prove useful for defining the invasive phenotype and provide targets for guiding therapy. Using a population-based study of bladder cancer (n = 355), we examined epigenetic alterations, specifically gene promoter hypermethylation, of four SFRP genes in addition to immunohistochemical staining of TP53, which has been previously shown to be a predictor of invasive disease. We observed a significant linear trend (P < 0.0004) in the magnitude of the risk of invasive disease with the number of SFRP genes methylated. Both TP53 alteration and SFRP gene methylation showed significant independent associations with invasive bladder cancer. Strikingly, in examining the joint effect of these alterations, we observed a >30-fold risk of invasive disease for patients with both altered SFRP gene methylation and intense TP53 staining (odds ratio, 32.1; P < 10(-13)). Overall patient survival was significantly poorer in patients with any SFRP genes methylated (P < 0.0003) and in proportional hazards modeling, patients with methylation of any SFRP gene had significantly poorer overall survival (hazard ratio, 1.78; P < 0.02) controlled for TP53 staining intensity and other survival-associated factors. Classifying tumors based on SFRP methylation status and TP53 protein staining intensity may be a clinically powerful predictor of invasive, deadly disease.
Marsit
Carmen J
CJ
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Karagas
Margaret R
MR
Andrew
Angeline
A
Liu
Mei
M
Danaee
Hadi
H
Schned
Alan R
AR
Nelson
Heather H
HH
Kelsey
Karl T
KT
D000328:Adult; D000368:Aged; D019175:DNA Methylation; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology; D000099274:Frizzled-Related Proteins; D000094742:Secreted Frizzled-Related Proteins
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D000099274:Frizzled-Related Proteins; C109618:SFRP2 protein, human; D000094742:Secreted Frizzled-Related Proteins; C118723:SFRP4 protein, human