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. 1996 Oct;39(4):569–573. doi: 10.1136/gut.39.4.569

Post-irradiation somatic mutation and clonal stabilisation time in the human colon.

F Campbell 1, G T Williams 1, M A Appleton 1, M F Dixon 1, M Harris 1, E D Williams 1
PMCID: PMC1383271  PMID: 8944567

Abstract

BACKGROUND: Colorectal crypts are clonal units in which somatic mutation of marker genes in stem cells leads to crypt restricted phenotypic conversion initially involving part of the crypt, later the whole crypt. Studies in mice show that the time taken for the great majority of mutated crypts to be completely converted, the clonal stabilisation time, is four weeks in the colon and 21 weeks in the ileum. Differences in the clonal stabilisation time between tissues and species are thought to reflect differences in stem cell organisation and crypt kinetics. AIM: To study the clonal stabilisation time in the human colorectum. METHODS: Stem cell mutation can lead to crypt restricted loss of O-acetylation of sialomucins in subjects heterozygous for O-acetyltransferase gene activity. mPAS histochemistry was used to visualise and quantify crypts partially or wholly involved by the mutant phenotype in 21 informative cases who had undergone colectomy up to 34 years after radiotherapy. RESULTS: Radiotherapy was followed by a considerable increase in the discordant crypt frequency that remained significantly increased for many years. The proportion of discordant crypts showing partial involvement was initially high but fell to normal levels about 12 months after irradiation. CONCLUSIONS: Crypts wholly involved by a mutant phenotype are stable and persistent while partially involved crypts are transient. The clonal stabilisation time is approximately one year in the human colon compared with four weeks in the mouse. The most likely reason for this is a difference in the number of stem cells in a crypt stem cell niche, although differences in stem cell cycle time and crypt fission may also contribute. These findings are of relevance to colorectal gene therapy and carcinogenesis in stem cell systems.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Campbell F., Appleton M. A., Fuller C. E., Greeff M. P., Hallgrimsson J., Katoh R., Ng O. L., Satir A., Williams G. T., Williams E. D. Racial variation in the O-acetylation phenotype of human colonic mucosa. J Pathol. 1994 Nov;174(3):169–174. doi: 10.1002/path.1711740305. [DOI] [PubMed] [Google Scholar]
  2. Campbell F., Fuller C. E., Williams G. T., Williams E. D. Human colonic stem cell mutation frequency with and without irradiation. J Pathol. 1994 Nov;174(3):175–182. doi: 10.1002/path.1711740306. [DOI] [PubMed] [Google Scholar]
  3. Fuller C. E., Davies R. P., Williams G. T., Williams E. D. Crypt restricted heterogeneity of goblet cell mucus glycoprotein in histologically normal human colonic mucosa: a potential marker of somatic mutation. Br J Cancer. 1990 Mar;61(3):382–384. doi: 10.1038/bjc.1990.83. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Griffiths D. F., Davies S. J., Williams D., Williams G. T., Williams E. D. Demonstration of somatic mutation and colonic crypt clonality by X-linked enzyme histochemistry. Nature. 1988 Jun 2;333(6172):461–463. doi: 10.1038/333461a0. [DOI] [PubMed] [Google Scholar]
  5. Jass J. R. Colonic O-acetylation phenotype and somatic mutation. J Pathol. 1995 Jul;176(3):322–323. [PubMed] [Google Scholar]
  6. Kronenberg A. Radiation-induced genomic instability. Int J Radiat Biol. 1994 Nov;66(5):603–609. doi: 10.1080/09553009414551691. [DOI] [PubMed] [Google Scholar]
  7. Loeffler M., Birke A., Winton D., Potten C. Somatic mutation, monoclonality and stochastic models of stem cell organization in the intestinal crypt. J Theor Biol. 1993 Feb 21;160(4):471–491. doi: 10.1006/jtbi.1993.1031. [DOI] [PubMed] [Google Scholar]
  8. Pandha H. S., Lemoine N. R. Gene therapy in gastroenterology. Gut. 1996 Feb;38(2):161–165. doi: 10.1136/gut.38.2.161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Park H. S., Goodlad R. A., Wright N. A. Crypt fission in the small intestine and colon. A mechanism for the emergence of G6PD locus-mutated crypts after treatment with mutagens. Am J Pathol. 1995 Nov;147(5):1416–1427. [PMC free article] [PubMed] [Google Scholar]
  10. Potten C. S., Loeffler M. Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. Development. 1990 Dec;110(4):1001–1020. doi: 10.1242/dev.110.4.1001. [DOI] [PubMed] [Google Scholar]
  11. Williams E. D., Lowes A. P., Williams D., Williams G. T. A stem cell niche theory of intestinal crypt maintenance based on a study of somatic mutation in colonic mucosa. Am J Pathol. 1992 Oct;141(4):773–776. [PMC free article] [PubMed] [Google Scholar]
  12. Winton D. J., Blount M. A., Ponder B. A. A clonal marker induced by mutation in mouse intestinal epithelium. Nature. 1988 Jun 2;333(6172):463–466. doi: 10.1038/333463a0. [DOI] [PubMed] [Google Scholar]
  13. Winton D. J., Ponder B. A. Stem-cell organization in mouse small intestine. Proc Biol Sci. 1990 Jul 23;241(1300):13–18. doi: 10.1098/rspb.1990.0059. [DOI] [PubMed] [Google Scholar]

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