Allelic imbalance of APAF-1 locus at 12q23 is related to progression of colorectal carcinoma.
APAF-1 gene, located at chromosome locus 12q23, is a key factor in the mitochondrial apoptotic pathway downstream 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.
Umetani
Naoyuki
N
Department of Molecular Oncology, John Wayne Cancer Institute, Saint Johns Health Science Center, Santa Monica, CA 90404, USA.
Fujimoto
Akihide
A
Takeuchi
Hiroya
H
Shinozaki
Masaru
M
Bilchik
Anton J
AJ
Hoon
Dave S B
DS
D000483:Alleles; D053477:Apoptotic Protease-Activating Factor 1; D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12; D015179:Colorectal Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D018450:Disease Progression; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D018895:Microsatellite Repeats / Q000235:genetics; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics
C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; D011506:Proteins; D012333:RNA, Messenger