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Genetic Changes and Histopathological Types in Colorectal Tumors from Patients with Familial Adenomatous Polyposis¹

Department of Biochemistry, The Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome [M. M., M. S., M. O., K. T., R. K.], Department of Pathology, The Tokyo Metropolitan Komagome Hospital, 3-18-22 Honkomagome [A. Y., Y. M., M. K.], and Departments of Surgery [T. Iw.] and Cytogenetics, Medical Research Institute [T. Ik., A. T.], Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113; Department of Biochemistry, Cancer Institute, Kamiikebukuro, Toshima-ku, Tokyo 170 [Y. N.), Japan; Howard Hughes Medical Institute and Department of Human Genetics, University of Utah Health Science Center, Salt Lake City, Utah 84132 [R. W.]; and Department of Surgery, Hyogo College of Medicine, Mukogawa-cho, Nishinomiya 663, Japan [Y. M., J. U.]

Loss of heterozygosity (LOH) and K-ras mutation were analyzed in 111 colorectal polyps and 26 invasive carcinomas from 40 patients with familial adenomatous polyposis of distinct histopathological types.

LOH, being <2% in moderate adenomas, was detected on chromosome 5q (20%) in severe adenomas, on 5q (26%) and 17p (38%) in intramucosal carcinomas, and on 5q (52%), 17p (56%), 18 (46%), and 22q (33%) in invasive carcinomas. LOH on chromosome 5q occurred most frequently in the region close to the APC gene both in adenomas and carcinomas, and a loss of the normal allele of the APC gene was demonstrated in 3 cases. K-ras mutation markedly increased in the step of development from moderate (11%) to severe (36%) adenomas.

These results suggest the following mechanisms for the development of colon tumors in patients with familial adenomatous polyposis: (a) the heterozygous mutant/wild-type condition at the APC gene causes formation of mild or moderate adenoma; (b) the loss of the normal allele in the APC gene leads to a change from moderate to severe adenoma; (c) LOH on chromosome 17p contributes to the conversion of adenoma to intramucosal carcinoma; (d) LOH on other chromosomes, such as 18 and 22q, are involved in the progression of intramucosal carcinoma to invasive carcinoma; and (e) K-ras mutation may also affect the development of moderate to severe adenoma.

¹ This work was supported in part by Grants-in-Aid for Cancer Research from the Ministry of Education, Science and Culture of Japan, and from the Ministry of Health and Welfare of Japan.

² To whom requests for reprints should be addressed.

Received 5/21/90. Accepted 7/20/90.

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