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Updated: May 25, 2026
Real-time Imaging of Myeloid Cells Dynamics in ApcMin/+ Intestinal Tumors by Spinning Disk Confocal Microscopy
Published on: October 6, 2014
Monoallelic silencing and haploinsufficiency in early murine intestinal neoplasms
James M Amos-Landgraf1, Amy A Irving, Cory Hartman
1McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Madison, WI 53706, USA.
Abstract:
Studies of tumors from human familial adenomatous polyposis, sporadic colon cancer, and mouse and rat models of intestinal cancer indicate that the majority of early adenomas develop through loss of normal function of the Adenomatous polyposis coli (APC) gene. In murine models of familial adenomatous polyposis, specifically the multiple intestinal neoplasia mouse (Min) and the polyposis in the rat colon (Pirc) rat, most adenomas have lost their WT copy of the Apc gene through loss of heterozygosity by homologous somatic recombination. We report that large colonic adenomas in the Pirc rat have no detectable copy number losses or gains in genomic material and that most tumors lose heterozygosity only on the short arm of chromosome 18. Examination of early mouse and rat tumors indicates that a substantial subset of tumors shows maintenance of heterozygosity of Apc in genomic DNA, apparently violating Knudson's two-hit hypothesis. Sequencing of the Apc gene in a sampling of rat tumors failed to find secondary mutations in the majority of tumors that maintained heterozygosity of Apc in genomic DNA. Using quantitative allele-specific assays of Apc cDNA, we discovered two neoplastic pathways. One class of tumors maintains heterozygosity of Apc(Min/+) or Apc(Pirc/+) RNA expression and may involve haploinsufficiency for Apc function. Another class of tumors exhibits highly biased monoallelic expression of the mutant Apc allele, providing evidence for a stochastic or random process of monoallelic epigenetic silencing of the tumor suppressor gene Apc.
Insights
Most intestinal tumors arise from the loss of the Adenomatous polyposis coli (APC) gene. Some tumors maintain APC gene copies but show altered expression, suggesting new cancer development pathways beyond the traditional two-hit hypothesis.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- The Adenomatous polyposis coli (APC) gene is crucial for intestinal tumor suppression.
- Loss of APC function is a common event in the development of colon cancer and familial adenomatous polyposis.
- Murine models like Min mice and Pirc rats are used to study intestinal neoplasia.
Purpose of the Study:
- To investigate the mechanisms of APC gene inactivation in intestinal tumors.
- To explore alternative pathways in tumor development beyond the established two-hit hypothesis.
- To analyze APC gene and RNA expression in early and late-stage tumors.
Main Methods:
- Analysis of genomic DNA for copy number changes and loss of heterozygosity (LOH) in Pirc rat tumors.
- Sequencing of the APC gene in tumors with maintained heterozygosity.
- Quantitative allele-specific assays of APC cDNA to assess gene expression.
- Examination of tumors from mouse and rat models of intestinal cancer.
Main Results:
- Large colonic adenomas in Pirc rats showed no genomic copy number alterations but LOH on chromosome 18.
- A subset of early tumors maintained APC heterozygosity, challenging Knudson's two-hit hypothesis.
- Secondary APC mutations were not found in most tumors with maintained heterozygosity.
- Two distinct neoplastic pathways were identified: one involving APC haploinsufficiency and another with biased monoallelic expression of the mutant APC allele.
Conclusions:
- Intestinal tumor development can occur through mechanisms other than complete APC gene inactivation.
- Haploinsufficiency or epigenetic silencing of APC may contribute to tumor formation.
- These findings reveal novel pathways in colorectal cancer pathogenesis, expanding our understanding of tumor suppressor gene function.
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