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Cancer Med. 2014 Oct;3(5):1235-45. doi: 10.1002/cam4.273. Epub 2014 May 24.

Aberrant promoter methylation of PPP1R3C and EFHD1 in plasma of colorectal cancer patients.

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Department of Digestive Surgery and Pathology, Nihon University School of Medicine, Tokyo, Japan; Department of Molecular Oncology, Graduate school of Medicine, Chiba University, Chiba, Japan.


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, PPP1R3C and EFHD1 were rarely hypermethylated in peripheral blood cells, but frequently hypermethylated in 24 CRC tissue samples and their corresponding plasma samples. In plasma samples, PPP1R3C 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 EFHD1, 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 CA19-9 (0% at stage I, 13% at stage II) for early-stage CRCs, sensitivity of aberrant methylation was significantly higher: PPP1R3C 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. PPP1R3C methylation or its combined use of EFHD1 methylation was highly positive in CRC plasma samples, and they might be useful in detection of CRC, especially for early-stage CRCs.


Biomarker; DNA methylation; cancer detection; colorectal cancer; plasma DNA

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