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[Cancer Research 62, 5413-5417, October 1, 2002]
© 2002 American Association for Cancer Research

Advances in Brief

The CAST/Ei Strain Confers Significant Protection against ApcMin Intestinal Polyps, Independent of the Resistant Modifier of Min 1 (Mom1R) Locus1

Revati Koratkar, Ed Pequignot, Walter W. Hauck and Linda D. Siracusa2

Department of Microbiology and Immunology, Kimmel Cancer Center, Jefferson Medical College, Philadelphia, Pennsylvania 19107 [R. K., L. D. S.], and Biostatistics Section, Department of Medicine, Jefferson Medical College, Philadelphia, Pennsylvania 19107 [E. P., W. W. H.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 
Intestinal adenoma development in ApcMin mice is influenced by genetic background. We generated a congenic line between the CAST and B6 inbred strains to study the effects of a resistant CAST background in the absence of a major modifier locus, Modifier of Min 1 (Mom1R). Progeny from a CAST.B6 Mom1R/S x B6 ApcMin/+ intercross were 110 or 200 days of age and screened for intestinal polyps. There was a significant decrease (P < 0.0001) in polyp multiplicity and size in CASTB6F1 Mom1R/S, ApcMin/+ and CASTB6F1 Mom1S/S, ApcMin/+ progeny compared with B6 Mom1S/S, ApcMin/+ controls. A complete absence of colon polyps was observed in all mice heterozygous for the CAST background. These results demonstrate that the CAST strain carries dominant modifier loci, in addition to Mom1R, that dramatically reduce polyp burden in the small intestine and eliminate polyp burden in the colon of ApcMin mice.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results and Discussion
 REFERENCES
 
The Min3 mouse was discovered during N-ethyl-N-nitrosourea mutagenesis experiments (1) . Min mice spontaneously develop multiple polyps along their intestinal tract. The Min phenotype is a result of a dominant mutation at codon 850 in exon 15 of the mouse Apc gene (2) . Germ-line mutations in the APC gene are seen in >95% of patients with familial adenomatous polyposis, whereas nearly 80% of sporadic colorectal tumors show either loss of heterozygosity or somatic mutations in APC (3 , 4) . Loss of APC function appears to be an early event in colorectal cancer (5 , 6) .

Polyp multiplicity in Min mice is greatly influenced by genetic background. C57BL/6J (B6) mice heterozygous for the ApcMin mutation were initially reported to develop an average of 29 polyps (counting one-third of the small intestine) and rarely survived beyond 150 days of age (1) . Hybrid F1 offspring generated from B6 ApcMin/+ mice crossed to either AKR/J (AKR), MA/MyJ (MA), or Mus musculus castaneus (CAST) mice showed a significant decrease in polyp number, suggesting that these inbred strains carry modifier genes that affect polyp multiplicity in ApcMin mice (7) . A modifier locus, called Mom1, was subsequently localized to distal mouse chromosome 4 by quantitative trait loci analysis (8) . The location of Mom1 was further refined to a 4-cM interval using congenic strains (9) . This region is syntenic with human chromosome 1p35–p36 (Chromosome Committee Reports, MGD, MGI, The Jackson Laboratory, Bar Harbor, ME),4 which is deleted in various human cancers and may contain a modifier of familial adenomatous polyposis (10 , 11) .

The gene encoding secretory type II nonpancreatic phospholipase A2 (Pla2g2a) is responsible for most of the Mom1 phenotype (12 , 13) . The B6, A/J, BTBR, C58/J, P/J, and 129/Sv inbred strains carry a spontaneous mutation in the Pla2g2a gene that results in a nonfunctional protein, whereas the AKR, BALB/c, CAST, CBA, C3H/HeJ, MA, and SWR/J inbred strains are wild type at the Pla2g2a locus (9 , 12 , 14) . Among the inbred strains which were tested, B6, BTBR, and 129/Sv are susceptible for polyp formation in the presence of the ApcMin mutation, whereas the AKR, BALB/c, CAST, MA, and SWR/J are resistant to polyp formation, indicating a 100% concordance between Pla2g2a genotype and Mom1 phenotype (9) . Recently, a second gene at the Mom1 locus (distal to Pla2g2a) has been implicated in influencing polyp phenotype in the medial small intestine of the AKR strain (15) . Overall, the Mom1 locus is estimated to account for ~40% of the genetic variance in intestinal polyp multiplicity in ApcMin mice (15) .

Among the various strains we analyzed for polyp multiplicity, F1 offspring from a CAST x B6 ApcMin/+ intercross had an average of 11 polyps, whereas B6 ApcMin/+ mice had an average of 60 polyps. The 82% decrease in polyp number is well below the ~40% decrease expected from a single Mom1R allele. Therefore, the CAST strain must have other modifier genes that reduce polyp number. However, the effects of other modifier loci would be difficult to detect and quantitate in the presence of one copy of the Mom1R locus. Therefore, we chose a strategy that would eliminate the contribution of the Mom1R locus from the otherwise highly resistant CAST background. We generated a congenic line with the recipient CAST strain, receiving a donor B6 Mom1S region. The CAST strain was selected not only because of the low polyp numbers observed in the CASTB6F1 hybrids, but also because CAST mice have diverged from common laboratory strains by 1–2 million years (16) . The unique collection of alleles present in the CAST strain would facilitate the localization and identification of novel modifier genes of the ApcMin phenotype.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results and Discussion
 REFERENCES
 
Mice.
CAST/Ei (CAST), C57BL/6J (B6), and B6 ApcMin/+ mice were originally purchased from The Jackson Laboratory (Bar Harbor, ME) and propagated at the Thomas Jefferson University American Association of Laboratory Animal Care accredited Facility. The CAST.B6 Mom1R/S congenic line was generated at the Thomas Jefferson University Animal Facility. Mice were fed laboratory autoclavable rodent diet 5010 (PMI Nutrition International, Inc., Brentwood, MO). All cages, food, bedding, and water were autoclaved before use.

Generation of CAST.B6 Mom1R/S Congenic Mice.
B6 female mice were mated with CAST male mice to obtain B6CASTF1 hybrids. B6CASTF1 hybrids were backcrossed to CAST mice, and N2 offspring were genotyped to select pups that carried one copy of the B6 Pla2g2a null allele, along with flanking loci (D4Mit203– D4Mit127). To ensure the integrity of the B6 Mom1S region during transfer onto the CAST background, we analyzed nine markers spanning the entire Mom1 region. Continued backcrossing of offspring to CAST mice, along with genotyping of pups at each subsequent backcross generation, systematically eliminated the remainder of the unlinked B6 genome, while retaining the region flanking the B6 Pla2g2a null allele (Fig. 1A)Citation . To eliminate residual heterozygosity at loci other than the Mom1 locus, we scanned the genomes of backcross progeny with 70 SSLP markers (Whitehead Institute for Biomedical Research, Center for Genome Research, Cambridge, MA).5 To ensure that the sex chromosomes were of CAST origin, congenic females were crossed to CAST males. Male congenic offspring were then selected and crossed to CAST females for two generations.



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  		Fig. 1. Representation of the congenic CAST.B6 Mom1S chromosome 4. A, markers used to analyze the Mom1 region. The circle at the top represents the centromere. The markers are listed by their D4Mit#, along with the distance in cM from the centromere (MGD, MGI, The Jackson Laboratory, Bar Harbor, ME).4 Filled boxes, B6 alleles; unfilled boxes, CAST alleles. The dotted line represents regions where breakpoints have occurred between the donor B6 segment and the recipient CAST chromosome. B, cross showing inheritance of the congenic chromosome. A circle represents the centromere; filled bars, B6 chromosome; open bars, CAST chromosome. Female CAST.B6 Mom1R/S mice at the N5-N6 backcross generation were mated to B6 ApcMin/+ males. CASTB6F1 ApcMin/+ offspring were grouped into two classes, depending on allelic inheritance at the Mom1 locus (Mom1R/S and Mom1S/S).

 
Genotyping the Mom1 Locus (SSLP Markers and the Pla2g2a Gene) and the ApcMin mutation.
Genomic DNAs were isolated from tail biopsies for use in PCR analysis of the Pla2g2a locus and the ApcMin mutation (17) . SSLP markers were selected based on map position and polymorphisms between the B6 and CAST strains (MGD, MGI, The Jackson Laboratory, Bar Harbor, ME).4 SSLP primer pairs were purchased from Research Genetics (Huntsville, AL). The selected markers were analyzed by standard PCR conditions, electrophoresed on 3% agarose gels in 1x TBE (0.09 M Tris-borate, 0.002 M EDTA, pH 8.0), and visualized by staining with ethidium bromide (18) .

Scoring for Polyps Along the Small Intestine and Colon.
ApcMin progeny generated from the cross between CAST.B6 Mom1R/S females and B6 ApcMin/+ males were either 100–120 or 185–215 days of age. B6 ApcMin/+ mice were used as controls. Tumors were counted from the entire small intestine and colon (17) . The number and size of polyps were measured using a Nikon SMZ-U dissecting microscope (x15 eyepiece magnification) with a #KR-617 reticle (base power x2.3 magnification).

Statistical Analysis.
Statistical analysis for polyp number (summed across location for each mouse) was performed using Poisson regression with litter nested within cage as clusters and exchangeable correlation structure; gender was included as a covariate. Polyp size (diameter in mm) was analyzed using mixed effects ANOVA. Genotype, days, gender, location, and genotype/days interaction were fixed effects. Cage and litter nested within cage were random effects with variance components covariance structure, and location was a random effect with unstructured covariance structure. Residuals were visually examined for validity of distributional assumptions. Ps were adjusted for multiple comparisons using the stepdown Bonferroni method of Holm (19) . Colon polyp incidence was analyzed by Fisher’s exact test. Analysis was performed using SAS version 8.02.


   Results and Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
REFERENCES
 
To confirm the relationship between the inheritance of the Pla2g2a gene and the Mom1 phenotype, a series of intercrosses between B6 ApcMin/+ and several inbred strains were established. Among the various strains tested, F1 hybrid offspring from a cross between CAST x B6 ApcMin/+ mice exhibited the lowest number of polyps (mean, 10.5 ± 4.5 SD) compared with B6 ApcMin/+ mice (mean, 59.9 ± 25.5 SD) along their entire small intestine at ~150 days of age.

We generated a congenic line between the CAST and B6 inbred strains to study the effects of a resistant CAST background in the absence of the resistant modifier (Mom1R) allele. An 18-cM region of mouse chromosome 4 (from the proximal marker D4Mit203 to the distal marker D4Mit127) that contains the susceptible Mom1S allele was transferred from the donor B6 strain onto the recipient CAST strain by sequential backcrosses (Fig. 1A)Citation . Although the Mom1 region had been refined to a 4-cM interval (9) , we chose to transfer a larger region of chromosome 4 to ensure that the entire CAST resistant Mom1R region was replaced by the B6-susceptible Mom1S region (15) .

Congenic CAST.B6 Mom1R/S females were mated to B6 Mom1S/S, ApcMin/+ males (Fig. 1B)Citation . ApcMin/+ F1 hybrid offspring fall into two classes (Mom1R/S and Mom1S/S), because the congenic line was heterozygous at the Mom1 locus when placed in mating. The ApcMin/+ F1 hybrid progeny were 100–120 days of age (indicated as 110 days) or 185–215 days of age (indicated as 200 days) before scoring for polyps along the entire intestinal tract. Fig. 2Citation shows a graphical representation of polyp distribution in CASTB6F1 Mom1R/S, ApcMin/+ and Mom1S/S, ApcMin/+ offspring as well as B6 Mom1S/S, ApcMin/+ control mice. A comparison of CASTB6F1 Mom1R/S, ApcMin/+ and CASTB6F1 Mom1S/S, ApcMin/+ offspring will indicate the influence of one CAST-resistant Mom1R allele on polyp number. A comparison of B6 Mom1S/S, ApcMin/+ and CASTB6F1 Mom1S/S, ApcMin/+ offspring, both homozygous susceptible at the Mom1S/S locus, will establish the influence of the CAST background (minus the Mom1R allele) on Apc-induced intestinal polyp formation.



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  		Fig. 2. Polyp multiplicity of F1 offspring generated from CAST.B6 Mom1R/S females mated to B6 ApcMin/+ males. ApcMin progeny were either 100–120 or 185–215 (listed at the top) days of age after birth and then analyzed for polyp multiplicity in the entire small intestine and colon. Black columns, male progeny; white columns, female progeny. The number of mice is shown on the Y axis, and the number of polyps is shown on the X axis. A–D, CASTB6F1 Mom1R/S, ApcMin/+ progeny. E–H, CASTB6F1 Mom1S/S, ApcMin/+ progeny. I–L, B6 Mom1S/S, ApcMin/+ progeny.

 
Table 1ACitation shows that there is a significant reduction (P < 0.0001) in average polyp number in CASTB6F1 ApcMin/+ offspring that carry one resistant Mom1R allele (derived from the CAST genome) and one susceptible Mom1S allele (derived from the B6 genome) compared with mice that carry two susceptible Mom1S alleles. This difference is evident at both 110 days of age (2.8 versus 8.2 average polyp number) and 200 days of age (6.8 versus 15.2 average polyp number). The data show that one copy of the Mom1R allele results in a 55–66% reduction in average polyp number in the small intestine. These findings constitute formal proof that the CAST genome contains a resistant Mom1R locus.


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  		Table 1 Pairwise comparisons of average small intestinal polyp multiplicity in ApcMin/+ F1 offspring from congenic CAST.B6 Mom1R/S females mated to B6 ApcMin/+ males

ApcMin/+ F1 offspring were grouped into two classes depending on allelic inheritance at the Mom1 locus (Mom1R/S or Mom1S/S). B6 Mom1S/S, ApcMin/+ mice served as controls. Polyps were counted at 100–120 (indicated as 110) and 185–215 (indicated as 200) days of age. Polyp numbers obtained in each group are represented as mean ± SD. The number in parentheses represents the number of mice in each group. Statistical analysis was performed using Poission regression.

 
Another important finding from this data (Table 1A)Citation is that there were significant increases (P < 0.0001) in average polyp number between 110 and 200 days of age for both classes of CASTB6F1 offspring. The CASTB6F1 Mom1R/S, ApcMin/+ offspring had an average of 2.8 polyps at 110 days of age and an average of 6.8 polyps at 200 days of age. The CASTB6F1 Mom1S/S, ApcMin/+ offspring had an average of 8.2 polyps at 110 days of age and an average of 15.2 polyps at 200 days of age. However, B6 Mom1S/S, ApcMin/+ mice do not show significant differences (P = 0.59) in average polyp number at 110 and 200 days of age (56.1 and 63.0, respectively; Table 1BCitation ). This lack of statistical significance in polyp numbers between B6 Mom1S/S, ApcMin/+ mice at 110 and at 200 days may be because the majority of polyps on the B6 background arise early in life (by 100 days of age; Refs. 7 , 20 , 21 ). Polyp initiation may be slower in the CAST strain than the B6 strain, and therefore we observed statistical significance in polyp number at 110 and 200 days of age. These results suggest that the timing of polyp initiation is different between the B6 and CAST strains.

Table 1BCitation shows highly significant (P < 0.0001) differences in average polyp numbers between CASTB6F1 Mom1S/S, ApcMin/+ and B6 Mom1S/S, ApcMin/+ mice. CASTB6F1 Mom1S/S, ApcMin/+ offspring have an average of 6-fold fewer polyps than B6 Mom1S/S, ApcMin/+ mice (8.2 and 56.1, respectively) at 110 days of age. Similarly, CASTB6F1 Mom1S/S, ApcMin/+ offspring have an average of 4-fold fewer polyps than B6 Mom1S/S, ApcMin/+ mice (15.2 and 63.0, respectively) at 200 days of age. These data clearly demonstrate that the CAST strain harbors one or more modifier genes that can effectively suppress polyp formation in the small intestine, even in the absence of a resistant Mom1R allele.

We also analyzed a subset of the mice (from Table 1Citation ) to evaluate the effects of the CAST strain background on polyp size in ApcMin mice (Table 2)Citation . When comparing CASTB6F1 Mom1R/S, ApcMin/+ to CASTB6F1 Mom1S/S, ApcMin/+ offspring, polyp sizes did not vary between these mice at either 110 days (P = 1.00) or 200 days (P = 0.74) of age (Table 2A)Citation . These data suggest that the Mom1R allele does not have a detectable effect on polyp size in CASTB6F1 offspring. A comparison of CASTB6F1 Mom1S/S, ApcMin/+ to B6 Mom1S/S, ApcMin/+ mice (0.64 mm versus 1.17 mm at 110 days; 1.00 mm versus 2.06 mm at 200 days) showed a ~2-fold difference in polyp size at both time points (Table 2B)Citation . The results demonstrate a significant difference (P < 0.02) in average polyp size between CASTB6F1 Mom1S/S, ApcMin/+ and B6 Mom1S/S, ApcMin/+ mice. Overall, the average size of polyps in both the CASTB6F1 Mom1R/S, ApcMin/+ and CASTB6F1 Mom1S/S, ApcMin/+ mice was approximately half that observed in the B6 Mom1S/S, ApcMin/+ mice (0.73–0.64 mm versus 1.17 mm at 110 days; 0.86–1.00 mm versus 2.06 mm at 200 days of age). The observed differences indicate that the CAST background has potent effects on polyp size compared with the B6 strain. These data also show that effects of the CAST background on polyp size are not dependent on the presence of a resistant Mom1R allele. These results suggest that on the susceptible B6 background, there is no significant difference in polyp number in B6 ApcMin/+ mice counted at 110 days or at 200 days, whereas there is a highly significant (P < 0.0001) increase in polyp size. In contrast, on the resistant CAST background, there is a significant (P < 0.0001) increase in polyp number between CASTB6F1 offspring counted at 110 or 200 days, whereas there is no significant difference in polyp size. If polyps are arising later in CASTB6F1 mice than in B6 mice (Table 1)Citation , then average polyp size might be expected to be smaller in CASTB6F1 mice. Alternatively, if the growth rate of polyps is slower in CASTB6F1 mice than in B6 mice, then we might not be able to visually detect most polyps until the CASTB6F1 mice are older. Thus, the mechanism by which the CAST background causes significant decreases in polyp number and polyp size may involve differences in the timing of polyp initiation and/or an inherent difference in growth rate. Further experimentation is needed to distinguish between these possibilities.


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  		Table 2 Pairwise comparisons of average small intestinal polyp size in ApcMin/+ F1 offspring from congenic CAST.B6 Mom1R/S females mated to B6 ApcMin/+ males

ApcMin/+ F1 offspring were grouped into two classes depending on allelic inheritance at the Mom1 locus (Mom1R/S or Mom1S/S). B6 Mom1S/S, ApcMin/+ mice served as controls. Polyps along the entire small intestine were counted and measured (total of ~3000 polyps) at 100–120 (indicated as 110) and 185–215 (indicated as 200) days of age. Mean polyp size obtained in each group is represented in diameter ± SE (mm). The number in parentheses represents the number of mice in each group. These mice were a subset of mice from Table 1Citation . Statistical analysis was performed using the mixed effects analysis of variance.

 
Surprisingly, there were no colon polyps (even at 215 days) in any of the CASTB6F1 ApcMin/+ offspring (Fig. 2, C, D, G, and H)Citation . The comparisons of CASTB6F1 Mom1S/S, ApcMin/+ to B6 Mom1S/S, ApcMin/+ mice revealed highly significant differences (P < 0.002) in colon polyp incidence at both 110 days of age (0 of 12 versus 11 of 20) and 200 days of age (0 of 13 versus 19 of 28; Table 3Citation ). The data clearly demonstrate that the CAST genome contains highly potent dominant and/or semidominant modifiers of colon tumorigenesis, and that a resistant Mom1R allele is not required for complete polyp suppression in the large intestine.


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  		Table 3 Pairwise comparisons of colon polyp incidence in CASTB6F1 Mom1S/S, ApcMin/+ and B6 Mom1S/S, ApcMin/+ micea

 
Previous studies have shown that genes such as Pla2g2a, Egfr (epidermal growth factor receptor), Dnmt1 (DNA methyltransferase), and Mmp7 (matrix metalloproteinase Matrilysin) can influence polyp number and polyp size in ApcMin mice (15 , 21, 22, 23, 24, 25) . Because the CASTB6F1 Mom1S/S, ApcMin/+ and the B6 Mom1S/S, ApcMin/+ mice are homozygous for the null Pla2g2a allele, differences in the Dnmt1, Egfr and/or Mmp7 genes may be governing differences in polyp number and polyp size. Alternatively, other as yet unidentified modifier genes that influence polyp number and/or polyp size may be responsible for these dramatic differences.

Thus, the CAST strain, because of its divergent evolution, should contain unique alleles of many genes, providing a rich genetic reservoir for identification of new modifier genes. Therefore, quantitative trait loci analysis between the congenic CAST.B6 Mom1S/S line and B6 ApcMin/+ mice should reveal chromosomal regions that contain modifier genes that can either compensate for the loss of the resistant Mom1 region or affect different pathways that modify ApcMin-induced intestinal neoplasia. The ultimate identification and characterization of modifier genes will encourage the development of studies to decipher mechanisms that can alter pathways that influence the penetrance of tumor suppressor genes.


   ACKNOWLEDGMENTS
 
We thank Dr. Arthur M. Buchberg, Dr. Karen Silverman, and Peter Wermuth for critical suggestions. We thank David Green, Joseph Zeskand, Ben McEntee, and Denise Ancharski for excellent technical assistance.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Research supported in part by National Cancer Institute Grants (to L. D. S.). R. K. was supported by NIH Training Grant T32-CA09678. Back

2 To whom requests for reprints should be addressed, at Kimmel Cancer Center, Jefferson Medical College, 233 South 10th Street, Philadelphia, PA 19107. Phone: (215) 503-4536; Fax: (215) 923-4153; E-mail: siracusa{at}mail.jci.tju.edu Back

3 The abbreviations used are: Min, multiple intestinal neoplasia; Apc, adenomatous polyposis coli; Mom1, Modifier of Min 1; MGD, Mouse Genome Database; MGI, Mouse Genome Informatics; SSLP, simple sequence length polymorphism. Back

4 URL: http://www.informatics.jax.org/ccr 2000. Back

5 URL: http://www-genome.wi.mit.edu/. Back

Received 7/ 1/02. Accepted 8/19/02.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
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A. A. Baran, K. A. Silverman, J. Zeskand, R. Koratkar, A. Palmer, K. McCullen, W. J. Curran Jr, T. B. Edmonston, L. D. Siracusa, and A. M. Buchberg
The modifier of Min 2 (Mom2) locus: Embryonic lethality of a mutation in the Atp5a1 gene suggests a novel mechanism of polyp suppression
Genome Res., May 1, 2007; 17(5): 566 - 576.
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