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Published on: October 6, 2014
Somatic genetic events linked to the Apc locus in intestinal adenomas of the Min mouse
1McArdle Laboratory for Cancer Research and Laboratory of Genetics, University of Wisconsin Medical School, Madison 53706, USA.
Abstract:
We have found previously that all spontaneous intestinal adenomas from Apc+/ApcMin mice lose the wild type Apc marker on two genetic backgrounds. On the (AKR x B6)F1 background, this event involves loss of the entire homolog of mouse chromosome 18 carrying Apc+. This chromosome carries both the Mcc and Dcc genes, which are homologs of genes that have been implicated in human colorectal cancer. To determine whether the loss of alleles of Mcc and/or Dcc is necessary for the formation of intestinal adenomas, subchromosomal somatic events were induced by gamma-irradiation. The observed spectrum of intrachromosomal somatic genetic losses rules out a requirement for loss of heterozygosity at either locus during adenoma formation. Subchromosomal allelic losses linked to Apc+ occur spontaneously on other genetic backgrounds. In the majority of these events, the Apc+ allele itself was somatically lost, as judged by the wild type marker at the Min site. However, on the [M. musculus castaneous (CAST) x B6-Min]F1 and (129/Sv x B6-Min)F1 backgrounds, spontaneous adenomas were observed in which the wild type marker at the Min site was retained. Further analysis will be required to determine whether these exceptions involve intra-Apc mutations. If not, then these events would illustrate routes to intestinal neoplasia that do not require complete inactivation of wild type Apc function.
Insights
Researchers investigated intestinal adenoma formation in mice, finding that while loss of the Apc gene is common, alternative pathways to neoplasia exist. These alternative routes may not require complete inactivation of Apc function, offering new insights into colorectal cancer development.
Area of Science:
- Genetics
- Cancer Biology
- Mouse Models
Background:
- Spontaneous intestinal adenomas in Apc+/ApcMin mice typically involve loss of the wild-type Apc allele.
- Chromosome 18 homologs, Mcc and Dcc, implicated in human colorectal cancer, are located on the chromosome carrying Apc+.
- Understanding the genetic events leading to adenoma formation is crucial for cancer research.
Purpose of the Study:
- To determine if loss of Mcc and/or Dcc alleles is necessary for intestinal adenoma formation.
- To investigate the role of subchromosomal somatic events in adenoma development.
- To explore alternative genetic pathways in intestinal neoplasia.
Main Methods:
- Induction of subchromosomal somatic events via gamma-irradiation in mouse models.
- Analysis of allelic losses on mouse chromosome 18.
- Genotyping to assess the status of Apc, Mcc, and Dcc alleles in spontaneous adenomas.
Main Results:
- Loss of heterozygosity at Mcc and Dcc loci is not required for adenoma formation.
- Spontaneous subchromosomal allelic losses linked to Apc+ occur on different genetic backgrounds.
- A subset of spontaneous adenomas retained the wild-type Apc marker, suggesting alternative oncogenic pathways.
Conclusions:
- The study rules out a requirement for Mcc or Dcc loss of heterozygosity in intestinal adenoma formation.
- Alternative genetic mechanisms, potentially independent of complete Apc inactivation, can drive intestinal neoplasia.
- Further research is needed to elucidate the intra-Apc mutations or other pathways involved in these exceptional cases.
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