The role of mutant Apc in the development of dysplasia and cancer in the mouse model of dextran sulfate sodium-induced colitis

Background & Aims: Differences in genetic background may play a role in the development of ulcerative colitis (UC)-related neoplasia. Loss of heterozy gosity (LOH) of APC has been reported in human UC-associated neoplasia. To investigate the role of genetic differences in UC-associated neoplasia, we compared differences in dextran sodium sulfate (DSS) colitis-associated neo plasia between wild-type C57BL/6J mice (WT-DSS) and C57BL/6J mice with a ge rmline mutation in Apc (Min-DSS). Methods: DSS colitis was induced in femal e wildtype and Min mice. Age- and sex-matched non-DSS-treated Mins were als o studied. Animals were sacrificed after 1 and 2 cycles of DSS. The cecums and large intestines were studied for numbers of dysplasias/cancers. Dyspla sias were studied for LOH of Apc. Results: No WT-DSS, 100% of Min-DSS, and 50% of non-DSS-treated Mins had dysplasia. The mean numbers of lesions per mouse were 0 (WT-DSS), 15.6 and 29.3 (1 and 2 cycles Min-DSS, respectively) , 1.2 and 1.9 (age-matched control Min, 1 and 2 cycle equivalents, respecti vely; P < 0.0002, Min-DSS vs. WT-DSS and non-DSS-treated Min; P = 0.03, Min -DSS 2 cycle vs. Min-DSS 1 cycle). Cancers were seen in 0%, 22%, and 40% of non-DSS Min, Min-DSS-1 cycle, and Min-DSS-2 cycle animals, respectively. L OH of Apc was observed in 90.6% of dysplasias and 6% of nondysplastic mucos a. Conclusions: A germline mutation in Apc contributes significantly to the development of colitis-associated neoplasia. Colitis markedly accelerates the development of dysplasia and cancer in the Min mouse. Dysplasia in Min- DSS occurs through LOH of Apc.