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Somatic Mutational Mechanisms Involved in Intestinal Tumor Formation in Min Mice¹

McArdle Laboratory for Cancer Research [A. R. S., C. L., A. R. M., L. J. M., W. F. D.], Laboratory of Genetics [A. R. S., C. L., W. F. D.], and Department of Pathology and Laboratory of Medicine [L. J. M.], University of Wisconsin Medical School, Madison, Wisconsin 53706

We have demonstrated previously that intestinal tumor formation in B6 Min/+ mice is always accompanied by loss of the wild-type adenomatous polyoposis coli (Apc) allele and that intestinal tumor multiplicity in B6 Min/+ mice can be significantly increased by treatment with a single dose of N-ethyl-N-nitrosourea (ENU). Here, we show that some tumors from ENU-treated Min/+ mice can form without complete elimination of Apc⁺. At least 25% of these tumors acquired somatic Apc truncation mutations. Interestingly, some ENU-induced tumors demonstrated loss of the Apc⁺ allelic marker examined by the quantitative PCR assay used here. Using two methods of mutation detection, we identified no Apc mutations in at least 12% of the tumors from ENU-treated B6 Min/+ mice. Finally, no H- or K-ras-activating mutations were detected in intestinal tumors from either untreated or ENU-treated Min/+ mice. The majority of somatic human APC mutations in intestinal tumors lead to APC truncation. Our results demonstrate that somatic Apc truncation mutations also frequently occur in ENU-induced intestinal tumors in Min mice.

¹ This work was supported by Grant CA50585 and Core Grant CA07175 from the National Cancer Institute.

² Present address: Bock Laboratories, University of Wisconsin, Madison, WI 53706.

³ Present address: Department of Human Oncology, University of Wisconsin Comprehensive Cancer Center, Madison, WI 53792.

⁴ To whom requests for reprints should be addressed, at McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, 1400 University Avenue, Madison, WI 53706.

Received 10/ 4/96. Accepted 3/24/97.

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