Allelic imbalance of APAF-1 locus at 12q23 is related to progression of colorectal carcinoma

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

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28 Citations (Scopus)

Abstract

APAF-1 gene, located at chromosome locus 12q23, is a key factor in the mitochondrial apoptotic pathway down-stream of p53, and is a potential tumor suppressor gene. We hypothesized that APAF-1 gene dysfunction due to allelic imbalance (AI) contributes to the development and progression of colorectal carcinoma (CRC). AI at APAF-1 locus and microsatellite instability (MIN) in CRCs and adenomas were assessed by multiple microsatellite markers. The frequency of AI significantly increased with tumor progression; 0 of 33 (0%) adenomas, 14 of 49 (29%) primary CRCs, and 18 of 34 (53%) liver metastases had AI. A total of 12 metastases were matched with corresponding primary CRCs; in 11 of 12 (92%) pairs, the metastasis had same AI status as the corresponding primary tumor. APAF-1 mRNA transcription level was significantly decreased with AI in liver metastases (P=0.009). Promoter hypermethylation was found in three of 35 (9%) primary CRCs and one of 15 (7%) liver metastases by methylation-specific PCR but was not correlated with AI. MIN was observed in 11 of 49 (23%) primary CRCs and was a favorable prognostic factor. Our results suggest that APAF-1 gene haploinsufficiency caused by AI increases with tumor progression, and relates to hepatic metastasis.

Original languageEnglish
Pages (from-to)8292-8300
Number of pages9
JournalOncogene
Volume23
Issue number50
DOIs
Publication statusPublished - 2004 Oct 28

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Keywords

  • APAF-1
  • Allelic imbalance
  • Apoptosis
  • Chromosome 12q23
  • Colorectal carcinoma

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Umetani, N., Fujimoto, A., Takeuchi, H., Shinozaki, M., Bilchik, A. J., & Hoon, D. S. B. (2004). Allelic imbalance of APAF-1 locus at 12q23 is related to progression of colorectal carcinoma. Oncogene, 23(50), 8292-8300. https://doi.org/10.1038/sj.onc.1208022