Genetic mapping of Mom5 , a novel modifier of Apc Min -induced intestinal tumorigenesis

Abstract

The initial purpose of this study was to assess the role of estrogen receptor beta (ERbeta) in intestinal tumorigenesis by examining the effects of an ERbeta knockout (ERbeta(-/-)) on Apc(Min) mice. In order to accomplish this goal on a uniform genetic background, we were required to backcross the ERbeta knockout from the 129P2 genetic background to the B6 genetic background for 10 generations. Midway through this process, we performed a test cross in which mice from the N(5) backcross generation of the ERbeta knockout strain were intercrossed with Apc(Min/+) mice to obtain Apc(Min/+) ERbeta(+/+), Apc(Min/+) ERbeta(+/-) and Apc(Min/+) ERbeta(-/-) mice. Intestinal tumorigenesis in the N(5)F(2) mice was evaluated at 14 weeks of age. The analysis of the impact of ERbeta in the N(5) cross was complicated by segregating 129P2-derived alleles that affected tumor number and were unlinked to ERbeta. Genetic linkage analysis of this cross permitted the localization of a single genetic modifier of tumor number in Apc(Min/+) mice. This locus, Modifier of Min 5 (Mom5), maps to proximal mouse chromosome 5; the 129P2 allele of this locus is associated with a 50% reduction in mean intestinal tumor number. Through in silico analysis and confirmatory sequencing, we have identified the Rad50-interacting protein-1 gene as a strong candidate for Mom5.

Genetic control of susceptibility to carcinogen-induced colorectal cancer in mice: TheCcs3andCcs5loci regulate different aspects of tumorigenesis

“…27,28 Breeding of penetrant C57Bl/6J-derived Apc Min mutation onto different genetic backgrounds (A/J, AKR/J, BTBr, 129P2/OlaHsd) identified modifier loci Mom1-Mom13. [29][30][31][32][33][34][35][36] Human chromosomal regions (Chr. 1p35-36) showing conserved synteny with mouse Mom1 and Mom4 have been associated with familial and sporadic cases of CRC.…”

Human Cancer Xenografts in Outbred Nude Mice Can Be Confounded by Polymorphisms in a Modifier of Tumorigenesis

“…Many of these polymorphisms were found in the promoter region of Pla2g2a; however, some were also found in other coding and noncoding regions of the gene. The long-lived Apc Min mouse did not have alterations in other described genetic "modifiers of Min" (Mom2, Mom5, and Mom7) as determined by direct sequencing of PCR amplified genomic DNA (Baran et al 2007;Kwong et al 2007;Oikarinen et al 2009). …”

“…For analysis of Mom2, Mom5, and Mom7, sequence variation-specific primers spanning published sequences were used to amplify DNA by PCR (Table 1) (Baran et al 2007;Kwong et al 2007;Oikarinen et al 2009). This examination did not lead to identification of a candidate modifier.…”

“…In addition, 18 genetic modifiers were found to contribute to these wide variations in intestinal tumor number (Kwong and Dove 2009;Zeineldin and Neufeld 2013a,b). For some of these modifiers, specific sequence variants have been defined (Kwong et al 2007;McCart et al 2008;Oikarinen et al 2009;Crist et al 2011;Nnadi et al 2012).…”

Identification ofMom12andMom13, two novel modifier loci ofApcMin-mediated intestinal tumorigenesis

“…21,24 Six Mom loci have been described, with genes identified for two of the loci. 22,23,[25][26][27][28] By combining both forward and reverse genetics approaches, the Apc Min model has been an important tool for identifying and analyzing genes relevant to human colorectal cancer.…”