A New Polygenic Model for Nonfamilial Colorectal Cancer Inheritance Based on the Genetic Architecture of the Azoxymethane-Induced Mouse Model

Abstract

The azoxymethane model of colorectal cancer (CRC) was used to gain insights into the genetic heterogeneity of nonfamilial CRC. We observed significant differences in susceptibility parameters across 40 mouse inbred strains, with 6 new and 18 of 24 previously identified mouse CRC modifier alleles detected using genome-wide association analysis. Tumor incidence varied in F1 as well as intercrosses and backcrosses between resistant and susceptible strains. Analysis of inheritance patterns indicates that resistance to CRC development is inherited as a dominant characteristic genome-wide, and that susceptibility appears to occur in individuals lacking a large-effect, or sufficient numbers of small-effect, polygenic resistance alleles. Our results suggest a new polygenic model for inheritance of nonfamilial CRC, and that genetic studies in humans aimed at identifying individuals with elevated susceptibility should be pursued through the lens of absence of dominant resistance alleles rather than for the presence of susceptibility alleles.

Keywords: cancer susceptibility; genetic architecture; heterogeneity; mouse models.

Figure 1

Variable response of mouse strains to azoxymethane. (A) Penetrance of colon tumors. (B) Average number of colon tumors in those mice with one or more tumor. (C) Average diameter of colon tumors in tumor bearing mice. Number of mice used from each strain and distributed by sex is noted. (B) and (C) are mean +/− SE.

Figure 2

Strains have characteristic responses to azoxymethane. (A) Location of tumors throughout the colon in those strains with at least one tumor-bearing mouse. (B) Penetrance of colon tumors separated by sex in tumor bearing strains.

Figure 3

Resistance to colon carcinogenesis is dominant. (A) Crosses analyzed between strains with penetrance of inbred strains used in the crosses. (B) Penetrance and multiplicity (average tumor number) in each cross showing the number of mice used for the analysis.

Figure 4

Haplotype association mapping of loci influencing colon carcinogenesis. (A) Distribution of statistical associations (y-axis) between colon tumor phenotypes and genomic region (x-axis). (B) Map of colon tumor modifier locations compared to previously mapped modifiers (green bars). Modifiers for categorical penetrance (red), original penetrance (blue) mean tumor size (purple), mean tumor multiplicity (yellow), and tumor load (green) are marked by squares.

Figure 5

Tree-based mapping of loci influencing colon carcinogenesis. (A) Genome-wide distribution of statistical associations. (B) Strains distributed on tree structure for modifier on Chr 4. (C) Strains distributed on tree structure for Chr 6.