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.

Clustering of colon, lung, and other cancer susceptibility genes with protein tyrosine phosphatases and protein kinases in multiple short genomic regions

“…12 of the 15 mouse colon cancer susceptibility loci (Scc -Susceptibility to colon cancer) and 22 lung cancer susceptibility loci (mostly used symbols Sluc -Susceptibility to lung cancer or Pas -Pulmonary adenoma susceptibility) were frequently linked pair-wise together 5 , forming 19 clusters (14 of them shorter than 2.5 cM) that included also 10 pre-GWAS human and 3 rat 6 colon cancer susceptibility loci. 3 This clustering was obvious in spite of different species, different tumor induction protocols, different strains 3.5,7 , and use of different carcinogens: 1,2 dimethylhydrazine (DMH), or azoxymethane (AOM) 5,7,8 for colon cancers and N-ethyl-Nnitroso-urea (ENU), or ethyl-carbamate (urethane) 5,9 for lung cancers. b. GWAS data confirmed the intra-and inter-species co-localization of colon and lung cancer susceptibility loci…”

“…32 of the 41 clusters (78%) contained loci from at least two species (Table 1). Tests of colon tumor susceptibility in additional mouse strains and different mouse subspecies mapped 3 additional susceptibility loci into the clusters listed in Table 1: Scc22 - cluster 9, Scc25 - cluster 16, and Scc27 - cluster 38 7 .…”

Epithelial-specific ERBB3 deletion results in a genetic background-dependent increase in intestinal and colon polyps that is mediated by EGFR

“…A working stock of 1.25 mg/ml AOM was made by diluting individual 250 ul aliquots into 10 ml of saline (0.9% NaCl). Three-month-old mice were injected intraperitoneal (IP) 10 mg AOM per kg body weight once a week for 4 weeks as described [ 48 , 49 ]. Age-matched controls were injected with saline.…”

Mapping of novel loci involved in lung and colon tumor susceptibility by the use of genetically selected mouse strains

“…The mixture of strains of different origins ensured a wide genetic variability in this population, thus bringing the model closer to the heterogeneity found in human populations. In addition, the progenitor strains have divergent sensitivities to colon and lung tumorigenesis reviewed in [ 2 , 3 ] and thus genetic components related to organ-specific carcinogenesis were present in the background of the foundation population. Dimethylhydrazine (DMH) and its metabolite Azoximethane (AOM) are pro-carcinogens with tropism to colon and induce the appearance of tumors molecularly similar to non-familial colon cancers in humans.…”