Open AccessAberrant promoter methylation of PPP1R3C and EFHD1 in plasma of colorectal cancer patients
Author(s) -
Takane Kiyoko,
Midorikawa Yutaka,
Yagi Koichi,
Sakai Ayako,
Aburatani Hiroyuki,
Takayama Tadatoshi,
Kaneda Atsushi
Publication year - 2014
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.273
Subject(s) - colorectal cancer , methylation , promoter , cancer research , oncology , dna methylation , medicine , cancer , biology , genetics , gene , gene expression
Aberrant DNA methylation is a common epigenetic alteration involved in colorectal cancer ( CRC ). In our previous study, we performed methylated DNA immunoprecipitation‐on‐chip analysis combined with gene re‐expression analysis by 5‐aza‐2′‐deoxycytidine treatment, to identify methylation genes in CRC genome widely. Among these genes, 12 genes showed aberrant hypermethylation frequently in >75% of 149 CRC samples but did not in normal samples. In this study, we aim to find out any of these methylation genes to be utilized for CRC detection using plasma DNA samples. Primers for methylation‐specific PCR and pyrosequencing were designed for seven of the 12 genes. Among them, PPP 1R3C and EFHD 1 were rarely hypermethylated in peripheral blood cells, but frequently hypermethylated in 24 CRC tissue samples and their corresponding plasma samples. In plasma samples, PPP 1R3C was methylated in 81% (97/120) of CRC patients, but only in 19% (18/96) of noncancer patients ( P = 6 × 10 −20 , Fisher's exact test). In combined analysis with EFHD 1 , both genes were methylated in 53% (64/120) of CRC patients, but only in 4% (4/96) of noncancer patients ( P = 2 × 10 −16 ), giving high specificity of 96%. At least one of the two genes was methylated in 90% (108/120) of CRC patients, and 36% (35/96) of control patients, giving high sensitivity of 90%. Compared with low sensitivity of carcinoembryonic antigen (17% at stage I, 40% at stage II) and CA 19‐9 (0% at stage I, 13% at stage II) for early‐stage CRC s, sensitivity of aberrant methylation was significantly higher: PPP 1R3C methylation at 92% (11/12) for stage I and 77% (23/30) for stage II, and methylation of at least one gene at 100% (12/12) for stage I and 87% (26/30) for stage II. PPP 1R3C methylation or its combined use of EFHD 1 methylation was highly positive in CRC plasma samples, and they might be useful in detection of CRC , especially for early‐stage CRC s.