Epigenetic inactivation of ID4 in colorectal carcinomas correlates with poor differentiation and unfavorable prognosis

Naoyuki Umetani, Hiroya Takeuchi, Akihide Fujimoto, Masaru Shinozaki, Anton J. Bilchik, Dave S.B. Hoon

Research output: Contribution to journalArticlepeer-review

101 Citations (Scopus)


Purpose: ID4 gene is a member of the inhibitor of DNA binding (ID) family proteins that inhibit DNA binding of basic helix-loop-helix transcription factors. The epigenetic inactivation of ID4 gene on colorectal cancer (CRC) development and its clinical significance was assessed. Experimental Design: In CRC cell lines, ID4 methylation status of the promoter region was assessed by methylation-specific PCR and bisulfite sequencing. The mRNA expression level was assessed by quantitative real-time reverse transcription-PCR. The methylation status of 9 normal epithelia, 13 adenomas, 92 primary CRCs, and 26 liver metastases was assessed by methylation-specific PCM. ID4 protein expression was assessed by immunohistochemistry analysis of tissue specimen. Results: CRC cell lines were shown to be hypermethylated, and mRNA expression was suppressed and could be restored by 5-aza-cytidine treatment. In clinical specimens from normal epithelia, adenomas, primary CRCs, and liver metastases, the frequency of ID4 hypermethylation was 0 of 9 (0%), 0 of 13 (0%), 49 of 92 (53%), and 19 of 26 (73%), respectively, with a significant elevation according to CRC pathological progression. Methylation status of primary CRCs significantly correlated with histopathological tumor grade (P = 0.028). Immunohistochemistry analysis showed ID4 expression of normal colon epithelia, adenomas, and unmethylated primary CRCs but not hypermethylated CRC specimens. Among 76 American Joint Committee on Cancer stage I to IV patients who had undergone curative surgical resection, overall survival was significantly poorer in patients with hypermethylated ID4 bearing tumors (P = 0.0066). Conclusions: ID4 gene is a potential tumor suppressor gene for which methylation status may play an important role in the CRC progression.

Original languageEnglish
Pages (from-to)7475-7483
Number of pages9
JournalClinical Cancer Research
Issue number22
Publication statusPublished - 2004 Dec 15

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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