Monoallelic silencing and haploinsufficiency in early murine intestinal neoplasms

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.epigenetics | genomic stability | loss of imprinting | X-inactivation

How many molecular subtypes? Implications of the unique tumor principle in personalized medicine

“…However, this dichotomy is often too simplistic. Evidence supports a ‘continuum model’ for oncogene and tumor-suppressor gene function [22,52], which certainly appears to be more natural and plausible than ‘a black-and-white model’ or ‘all-or-none model’. In addition, accumulating evidence suggests that different mutations in the same gene can have different biological effects [53–56], which adds to the continuum model of mutation effects.…”

Mechanisms that drive inflammatory tumor microenvironment, tumor heterogeneity, and metastatic progression

“…Studies suggest a strong correlation between colon cancer progression and tumor-associated inflammation [11, 89]. In mouse models, mono-allelic deletion of Apc in intestinal epithelial cells ( Apc +/Δ ) results in tumor development upon inactivation of the wt Apc allele due to a loss of heterozygocity (LOH) [90–92]. When Apc +/Δ mice are crossed with transgenic mice expressing constitutively active IKKβ in intestinal epithelial cells (IECs), the compound mice exhibit more β-catenin positive (+) early lesions and small intestinal and colonic tumors relative to the parental Apc +/Δ line [93].…”

The utility of Apc-mutant rats in modeling human colon cancer

“…Thus, one can identify loss of heterozygosity at DNA loci throughout the tumor genome, thereby revealing genetic changes that drive tumor development. Furthermore, by genotyping polymorphic markers in both genomic DNA and cDNA from heterozygous F 1 Pirc rats, some tumors have been shown to involve loss of the wild-type allele at the Apc locus, whereas others involved only loss of expression of the wild-type Apc allele ( Amos-Landgraf et al, 2012 ). This latter case could reflect stochastic epigenetic silencing at the Apc locus ( Amos-Landgraf et al, 2012 ).…”