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Loss of heterozygosity involves multiple tumor suppressor genes in human esophageal cancers
Y Huang1, R F Boynton, P L Blount
1Department of Microbiology and Immunology, University of Maryland, Baltimore 21201.
Abstract:
Loss of heterozygosity occurring on various chromosomes has been described in the majority of human tumors. The targets of frequent or consistent subchromosomal deletions are believed to be tumor suppressor genes. We examined 72 esophageal tumors (46 squamous cell carcinomas and 26 adenocarcinomas) for loss of heterozygosity at the p53, Rb, APC, MCC, and DCC loci. Inclusion of these tumor suppressor genes in the allelic deletions was directly ascertained by performing polymerase chain reaction at polymorphic sites within the genes. Loss of heterozygosity occurred in 55% of informative cases at p53, in 48% of informative cases at Rb, in 66% at APC, in 63% at MCC, and in 24% at DCC. Ninety-three % of tumors informative at all loci (fully informative) lost heterozygosity of at least one locus. A high percentage of fully informative tumors (71%) also lost heterozygosity at more than one locus. There were no significant differences among histological types in the prevalence of loss of heterozygosity at any locus. There were correlations of losses involving MCC versus DCC, Rb, and p53. These data suggest that (a) allelic deletions including these tumor suppressor genes are important in the formation and/or progression of most esophageal cancers; (b) allelic deletions involving MCC may not occur independently of deletions involving other tumor suppressor genes; and (c) the accumulation of multiple allelic deletions involving specific tumor suppressor genes may be important in most esophageal tumorigenesis or tumor evolution.
Insights
Loss of heterozygosity in tumor suppressor genes like p53 and APC is common in esophageal cancers. Multiple genetic deletions frequently occur, suggesting their critical role in tumor development and progression.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Loss of heterozygosity (LOH) on various chromosomes is observed in most human tumors.
- Tumor suppressor genes are frequently targeted by subchromosomal deletions.
- Esophageal cancer encompasses squamous cell carcinomas and adenocarcinomas, with distinct genetic alterations potentially driving tumorigenesis.
Purpose of the Study:
- To investigate the frequency and patterns of LOH at specific tumor suppressor gene loci in esophageal tumors.
- To determine the involvement of p53, Rb, APC, MCC, and DCC genes in allelic deletions within esophageal cancer.
- To explore correlations between LOH at different tumor suppressor gene loci and their implications in esophageal tumorigenesis.
Main Methods:
- Analysis of 72 esophageal tumors (46 squamous cell carcinomas, 26 adenocarcinomas).
- Assessment of LOH at p53, Rb, APC, MCC, and DCC loci using polymerase chain reaction (PCR) at polymorphic sites.
- Categorization of tumors based on informative status for each locus and overall (fully informative).
Main Results:
- High frequencies of LOH were observed across multiple tumor suppressor gene loci: p53 (55%), Rb (48%), APC (66%), MCC (63%), and DCC (24%).
- 93% of fully informative tumors exhibited LOH at at least one locus, with 71% showing LOH at multiple loci.
- No significant differences in LOH prevalence were found between squamous cell carcinomas and adenocarcinomas.
- Correlations were identified between LOH at MCC and deletions involving DCC, Rb, and p53.
Conclusions:
- Allelic deletions of these tumor suppressor genes are crucial in the development and progression of most esophageal cancers.
- LOH at the MCC locus appears to be associated with deletions at other tumor suppressor gene loci, suggesting coordinated genetic events.
- The accumulation of multiple allelic deletions involving specific tumor suppressor genes is likely important in the tumorigenesis and evolution of esophageal cancers.