Genetic and epigenetic inactivation of TNFRSF10C in human prostate cancer.
BACKGROUND
TNFRSF10C, is located on 8p21.3, one of the most frequently deleted loci in the genome of prostate cancer (PCa). Hypermethylation of TNFRSF10C promoter CpG island (CGI) had been reported in many tumors including PCa. However, the interplay between somatic deletion and promoter hypermethylation of TNFRSF10C on PCa development has not been investigated.


METHODS
Methylation status of promoter CGI and deletion status of the TNFRSF10C locus was investigated by bisulfite sequencing and Affymetrix SNP array, respectively, in 59 pairs of PCa tumor and matched normal samples with three PCa cell lines. TNFRSF10C gene expression changes in relation to cancer-associated genetic/epigenetic changes in clinical specimens, and change of TNFRSF10C expression before and after 5-aza-2'-deoxycytidine treatment in the PC3 PCa cell line was assessed by real-time RT-PCR.


RESULTS
We found that TNFRSF10C promoter CGI was differentially methylated in 46 of 59 primary cancers (78.0%). Hemizygous deletion at TNFRSF10C was found in 44 of the 59 prostate tumors (74.5%). Interestingly, in 94.9% of the tumors (56 out of 59), TNFRSF10C was either hemizygously deleted or its promoter CGI hypermethylated. Deletion and/or methylation of the TNFRSF10C gene were correlated with decreased mRNA expression of the gene in clinical specimens. Demethylation of the TNFRSF10C promoter CGI was accompanied by transcriptional re-activation of TNFRSF10C in the PCa cell line PC3.


CONCLUSIONS
We found a notably high frequency of promoter CGI methylation and deletion of TNFRSF10C in PCa tissues. Our results indicated that inactivation of TNFRSF10C by chromosomal deletion and promoter methylation may play an important role in PCa development.
Cheng
Yu
Y
Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Kim
Jin Woo
JW
Liu
Wennuan
W
Dunn
Thomas A
TA
Luo
Jun
J
Loza
Matthew J
MJ
Kim
Seong-Tae
ST
Zheng
Siqun Lilly
SL
Xu
Jianfeng
J
Isaacs
William B
WB
Chang
Bao-Li
BL
D045744:Cell Line, Tumor; D002872:Chromosome Deletion; D018899:CpG Islands / Q000502:physiology; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000502:physiology*; D058851:GPI-Linked Proteins; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D011401:Promoter Regions, Genetic / Q000502:physiology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D053319:Tumor Necrosis Factor Decoy Receptors / Q000235:genetics
D058851:GPI-Linked Proteins; D053320:Receptors, Tumor Necrosis Factor, Member 10c; C108661:TNFRSF10C protein, human; D053319:Tumor Necrosis Factor Decoy Receptors