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Alleles of APC modulate the frequency and classes of mutations that lead to colon polyps

Nature Genetics volume 20, pages 385–388 (1998)Cite this article

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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Figure 1: Loss of the mutant allele in an adenoma from an AAPC patient detected by DNA marker analysis and DNA sequencing.
Figure 2: IVSP analysis of segment 3 of APC exon 15 reveals mutations (bands indicated by dots) in the remaining 'normal' allele in three of four AAPC adenomas (P) and the single carcinoma (C) that had shown loss of the mutant allele by LOH studies.
Figure 3: Mutations in APC in adenomas and carcinomas from patients with AAPC.

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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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  1. Lisa N. Spirio

    Present address: The Whitehead Institute, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, Massachusetts, 02142, USA

Authors and Affiliations

  1. Huntsman Cancer Institute and Department of Oncological Sciences, University of Utah, Salt Lake City, 84112, Utah, USA

    Lisa N. Spirio, Jennifer Robertson, Margaret Robertson & Ray White.

  2. Department of Pathology, University of Utah, Salt Lake City, 84132, Utah, USA

    Wade Samowitz

  3. Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, 84132, Utah, USA

    Randall W. Burt

  4. Department of Human Genetics, University of Utah, Salt Lake City, 84112, Utah, USA

    Mark Leppert

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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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