To date, the sensitivity of currently available biomarkers based on the methylation of gene promoters is suboptimal for detecting adenomas and earlystage colorectal cancer (CRC). We aimed to develop biomarkers with methylated DNA binding sites of the multifunctional transcriptional factor CTCF for early detection of CRC. Using combined analyses of genome-wide occupation and the methylation profile of CTCF-binding sites, we identified candidate CTCF-binding sites. Then, we applied methylation-sensitive high-resolution melting (MS-HRM) and mass spectrometry analysis to screen and validate these candidate sites in diverse sample sets. We identified a set of colorectal neoplasia-specific biomarkers with robust performance. The top five biomarkers were selected and recommended for early detection of colorectal neoplasia. All of the five novel biomarkers exhibited a more robust discriminatory performance than that by BMP3 and NDRG4, two currently acknowledged robust methylation biomarkers. When the five new biomarkers were considered as a marker panel and tumor-positive was defined as having two or more (of the five) positive biomarkers, the marker panel could achieve a sensitivity of 91.67% for adenomas, 97.44% for Stage I CRC, 94.06% for Stage II CRC, 93.62% for Stage III CRC, and 93.54% for total colorectal tumors with a specificity of 94.05%. To our knowledge, this is the first study for colorectal neoplasia-specific methylation biomarkers based on CTCF-binding sites. Using a similar strategy, CTCF-binding sites could be potentially developed into biomarkers for other tumors. In summary, this study opens a new area in developing biomarkers for tumor prevention and treatment.
[1]Kunming Med Univ, Affiliated Hosp 1, Dept Reprod & Genet, Kunming 650032, Yunnan, Peoples R China.
[2]Chinese Acad Sci, Kunming Inst Zool, Publ Tech Serv Ctr, Kunming 650032, Yunnan, Peoples R China.
[3]Chinese Acad Sci, Kunming Biol Divers Reg Ctr Large Apparat & Equip, Kunming 650032, Yunnan, Peoples R China.
[4]Kunming Med Univ, Affiliated Hosp 1, Yunnan Inst Digest Dis, Dept Gastrointestinal Surg, Kunming 650032, Yunnan, Peoples R China.
[5]Kunming Med Univ, Sch Stomatol, Kunming 650500, Yunnan, Peoples R China.
[6]Kunming Med Univ, Affiliated Hosp 1, Yunnan Inst Digest Dis, Dept Gastroenterol, Kunming 650032, Yunnan, Peoples R China.
[7]First Peoples Hosp Yunnan Prov, Kunming 650031, Yunnan, Peoples R China.
(8.0+极速模式)