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p300 gene alterations in colorectal and gastric carcinomas
M Muraoka1, M Konishi, R Kikuchi-Yanoshita
1Department of Biochemistry, Tokyo Metropolitan Institute of Medical Science, Japan.
Abstract:
Colorectal tumors frequently have loss of heterozygosity on chromosome 22q, suggesting that inactivation of tumor suppressor gene(s) on 22q participates in the tumor development. Neurofibromatosis 2 (NF2) gene and E1A binding protein p300 gene, recently identified on 22q, are thought to be candidates for tumor suppressor genes. In this study, mutation of the NF2 gene in 59 colorectal carcinomas, and mutation of the p300 gene in 27 colorectal and two gastric carcinomas, were analysed using PCR-SSCP, RT-PCR-SSCP and direct sequencing methods. Missense mutations of p300 gene were detected in a colorectal carcinoma, and in a gastric carcinoma, though no mutation of NF2 gene was detected. Both p300 mutations were somatic and coupled to deletion of the second allele of the gene, which suggests inactivation of the p300 gene, in these carcinomas. The mutations are located within the Cys/His-rich regions, which are assumed to play important roles in the function of p300. These are the first cases in which p300 gene has been found to be altered in both alleles, suggesting that inactivation of the p300 gene may be involved in the development of carcinomas, and that this gene may be the target of loss of 22q in carcinomas of the digestive tract.
Insights
Tumor suppressor gene inactivation on chromosome 22q is implicated in colorectal cancer. This study found p300 gene mutations in colorectal and gastric carcinomas, suggesting its role in digestive tract cancer development.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Loss of heterozygosity on chromosome 22q is common in colorectal tumors.
- Candidate tumor suppressor genes on 22q include Neurofibromatosis 2 (NF2) and E1A binding protein p300.
- Inactivation of these genes may contribute to tumor development.
Purpose of the Study:
- To investigate mutations in the NF2 and p300 genes in colorectal and gastric carcinomas.
- To determine if p300 gene inactivation is associated with loss of heterozygosity on 22q in digestive tract cancers.
Main Methods:
- Polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and reverse transcription PCR-SSCP (RT-PCR-SSCP) were used to screen for mutations.
- Direct sequencing was employed to confirm detected mutations.
- Analysis included 59 colorectal carcinomas and two gastric carcinomas for p300 gene mutations.
Main Results:
- No mutations were detected in the NF2 gene in 59 colorectal carcinomas.
- Missense mutations in the p300 gene were identified in one colorectal and one gastric carcinoma.
- Both p300 mutations were somatic and associated with the deletion of the second allele, indicating gene inactivation.
Conclusions:
- Inactivation of the p300 gene, through mutation and loss of the second allele, may play a role in the development of digestive tract carcinomas.
- The p300 gene is a potential target of 22q loss in these cancers.
- These findings provide the first evidence of biallelic alteration of the p300 gene in carcinomas.