Genome-wide methylation analysis identifies involvement of TNF-α mediated cancer pathways in prostate cancer.
Altered signaling pathways resulting from aberrant changes in epigenetic parameters may play a pivotal role in carcinogenesis. To identify biological pathways likely to be affected by methylation-mediated alterations in gene expression in prostate cancer, we performed a genome-wide methylation analysis of 27,578 CpG sites, corresponding to 14,495 genes on a pooled sample of 12 pairs of prostate tumor and adjacent normal tissues. In all, 972 CpG sites were significantly hypermethylated while 209 sites were hypomethylated in prostate tumor tissue (FDR adjusted p-value<0.05; fold change≥2) corresponding to 1043 unique genes, which is consistent with genome-wide gene-specific hypermethylation patterns previously observed in multiple cancer models. Global hypomethylation in prostate tumor was also detected by measuring methylation changes in ALU repeat sequences. Pathway analysis of the genes with altered methylation patterns identifies the involvement of a cancer related network of genes whose activity may be heavily regulated by TNF-α in prostate tumorigenesis. Our results suggest that epigenetic dysregulation of cellular processes relevant to TNF-α-dependent apoptosis and electrophile detoxification may be intimately involved in prostate carcinogenesis. These findings may lend credence to the possibility of using tumor-specific alterations in methylation patterns as biomarkers in estimating prognosis and assessing treatment options for prostate cancer.
Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT, USA.
Sun Jung
SJ
Kim
William Kevin
WK
Kelly
Alan
A
Fu
Kenneth
K
Haines
Aaron
A
Hoffman
Tongzhang
T
Zheng
Yong
Y
Zhu
D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D008297:Male; D008957:Models, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D014409:Tumor Necrosis Factor-alpha