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.