Abstract
Most inherited mutant alleles of the adenomatosis polyposis coli gene ( APC ) cause the appearance of large numbers of colon polyps 1, 2, 3, 4 , the familial polyposis syndrome. (These mutant alleles are designated APC P alleles.) A subset of APC mutations, the attenuated or APC AP alleles, predispose to only a few colon polyps 5 . This leads to the hypothesis that if mutation of the inherited normal allele is rate limiting in polyp development, the increased number of polyps associated with the APC P allele indicates that the frequency of mutations that can lead to polyp formation is higher among APC P carriers than among APC AP carriers. We have previously suggested that the APC protein might modulate the frequency of mutations, such as loss of heterozygosity 6 (LOH), necessary for colon polyp formation 5 . We thus reasoned that tumours from patients who carry an APC AP allele might show a reduced frequency of LOH compared with tumours from patients who carry an APC P allele. Loss of AAPC mutant alleles is designated as LOH AP . Screening of tumours from APC AP carriers revealed a reduction of LOH compared with that of an unselected group of polyposis patients 7 . In fact, no loss of the inherited APC N allele was observed, although sequencing showed that the inherited APC N allele had frequently undergone point mutations and small deletions in the tumours. A low frequency loss of the inherited APC AP allele was seen. These findings support the suggestion that the APC AP allele has residual gene activity and that this activity modulates the spectrum and frequency of mutations that lead to adenoma formation.
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References
Groden, J. et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66, 589– 600 (1991).
Joslyn, G. et al. Identification of deletion mutations and three new genes at the familial polyposis locus. Cell 66, 601– 613 (1991).
Kinzler, K.W. et al. Identification of FAP locus genes from chromosome 5q21. Science 253, 661–665 ( 1991).
Nishisho, I. et al. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253, 665– 668 (1991).
Spirio, L. et al. Alleles of the APC gene: an attenuated form of familial polyposis. Cell 75, 951–957 (1993).
Cavenee, W. et al. Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 305, 779– 784 (1983).
Miyaki, M. et al. Characteristics of somatic mutations of the adenomatous polyposis gene in colorectal tumors. Cancer Res. 54, 3011–3020 (1994).
Spirio, L., Nelson, L., Joslyn, G., Leppert, M. & White, R. A CA repeat 30-70 KB downstream from the adenomatous polyposis coli (APC) gene. Nucleic Acids Res. 19, 6348 (1991).
Utah-Marker-Development-Group et al. A collection of ordered tetra-nucleotide repeat markers from the human genome. Am. J. Hum. Genet. 57, 619–628 (1995).
Powell, S. et al. Molecular diagnosis of familial adenomatous polyposis. N. Engl. J. Med. 329, 1982–1987 (1993).
Miyoshi, Y. et al. Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Hum. Mol. Genet. 1, 229–233 (1992).
Samowitz, W., Thliveris, A., Spirio, L. & White, R. Alternatively spliced adenomatous polyposis coli (APC) gene transcripts that delete exons mutated in attenuated APC. Cancer Res. 55, 3732–3734 (1995).
Varesco, L. et al. Mutation in a splice-donor site of the APC gene in a family with polyposis and late age of colonic cancer death. Hum. Genet. 93, 281–286 ( 1994).
van der Luijt, R. et al. APC mutation in the alternatively spliced region of exon 9 associated with late onset familial adenomatous polyposis. Hum. Genet. 96, 705–710 ( 1995).
Samowitz, W., Slattery, M. & Kerber, R. Microsatellite instability in human colonic cancer is not a useful clinical indicator of familial colorectal cancer. Gastroenterology 109, 1765–1771 (1995).
Laken, S.J. et al. Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC. Nature Genet. 17, 79– 83 (1997).
Narayan, S. & Jaiswal, A. Activation of adenomatous polyposis coli (APC) gene expression by the DNA-alkylating agent N-methyl-N'nitro-Nnitrosoguanidine requires p53. J. Biol. Chem. 272, 30619– 30622 (1997).
Wright, D. & Manos, M. Sample preparation from paraffin-embedded tissues. in PCR Protocols: A Guide to Methods and Applications (eds Innis, M., Gelfand, D., Sninsky, J. & White, T.) 153– 158 (Academic Press, San Diego, 1990).
Spirio, L. et al. Three secretory phospholipase A2 genes that map to human chromosome 1P35-36 are not mutated in individuals with attenuated APC. Cancer Res. 56, 955–958 ( 1996).
Acknowledgements
The authors thank R. Foltz and J. Logan for editorial assistance and D. Lim for constructing the figures. We also thank the Huntsman Cancer Institute at the University of Utah for support of this project. L.N.S. was funded by the Department of Energy's Oak Ridge Institute for Science and Education as an Alexander Hollaender Postdoctoral Fellow.
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Spirio, L., Samowitz, W., Robertson, J. et al. Alleles of APC modulate the frequency and classes of mutations that lead to colon polyps. Nat Genet 20, 385–388 (1998). https://doi.org/10.1038/3865
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DOI: https://doi.org/10.1038/3865
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