Human colonic stem cell mutation frequency with and without irradiation

Campbell, Fiona; Ce, Fuller; Williams, Gwyn T.; Ed, Williams

doi:10.1002/path.1711740306

Cited by 32 publications

(32 citation statements)

References 8 publications

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“…The fact that the colonic mutation frequency in the young (<49 years) group of HNPCC patients was lower than in age-matched Crohn's disease patients suggests that it may represent the 'normal' cumulative mutation frequency at this age. While it is possible that the sporadic CRC group contains unrecognised HNPCC cases, we believe that this is unlikely to have had a major influence on the findings because the age distribution and frequency of somatic mutation in our patients with right-sided CRC were not significantly different from a previously reported group of rectal cancer patients (Campbell et al, 1994b).…”

Section: Methodscontrasting

confidence: 66%

“…Since HNPCC patients showed a much wider age range than the other two groups, they have also been divided into those aged <49 years and those >50 years. This is particularly important for the comparison of wholly mutated crypt frequencies because they result from fixed stem cell mutations and reflect the lifetime accumulated mutational load (Campbell et al, 1994b).…”

Section: Methodsmentioning

confidence: 99%

“…This technique, which is a modification of the periodic-acid Schiff procedure, allows non-O-acetylated sialomucins to be distinguished from O-acetylated sialomucins (Veh et al, 1992 (Fuller et al, 1990;Campbell et al, 1994b (Campbell et al, 1994b). We have therefore quantified the frequency of discordant crypts in microscopically normal colon from patients with HNPCC, and compared this with their frequency in uninvolved colon from patients with either Crohn's disease (for younger HNPCC patients) or sporadic right-sided CRC (for older HNPCC patients).…”

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confidence: 99%

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Normal colonic mucosa in hereditary non-polyposis colorectal cancer shows no generalised increase in somatic mutation

Williams

Geraghty²,

Campbell³

et al. 1995

Br J Cancer

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S_mmimary Hereditary non-polyposis colorectal cancer (HNPCC) has recently been linked to germline defects of DNA repair genes. Colorectal tumours in HNPCC frequently show DNA microsatellite instability, but it is not certain whether this mutator phenotype occurs throughout the morphologically normal colonic mucosa. We have previously used the mPAS histochemical technique in human colorectal mucosa to identify a polymorphism for O-acetyltransferase activity that shows monogenic inheritance and to show that cryptrestricted loss of O-acetyltransferase activity in heterozygotes is due to somatic mutation. We have now used this histochemical technique to measure the somatic mutation frequency in the uninvolved colon of 12 heterozygous patients with HNPCC, 15 with ileocaecal Crohn's disease and 16 with sporadic colorectal cancer (CRC). HNPCC patients showed a significant increase in mutation frequency with age (Mann-Whitney U. P=0.02). In HNPCC patients aged <49 years the mean stem cell mutation frequency was significantly lower than in the slightly younger group of patients with Crohn's disease (0.8 ± 0.9 x 10-' vs 3.5 ± 3.3 x 10-4, P<0.01), probably reflecting an increased mutation rate relating to chronic mucosal damage in Crohn's disease. Although not statistically significant, the stem cell mutation frequency was slightly less in HNPCC patients >50 years than in sporadic CRC cases (4.9 ± 3.4 x 10-4vs 5.9 ± 3.6 x 10-4, P>0.5 al., 1993).The APC gene is thought to act as a tumour-suppressor gene and, although the function of its product is not established, there is evidence to suggest that it is involved in cell adhesion (Su et al., 1993). The four putative HNPCC genes so far identified, on the other hand, appear to be involved in DNA repair. Colorectal adenomas and carcinomas, and extracolonic carcinomas, of HNPCC patients show a high frequency of DNA microsatellite instability (Aaltonen et al., 1994), and human homologues of the prokaryotic DNA mismatch repair genes mutS and mutL map to the regions of chromosomes 2, 3 and 7 that have been shown by linkage studies to bear the HNPCC loci. Moreover, germline mutations of these repair genes occur in affected patients (Fishel et al., 1993;Leach et al., 1993;Bronner et al., 1994;Nicolaides et al., 1994). HNPCC patients might therefore be expected to show an increased frequency of somatic mutation in a wide range of other genes. Loss of heterozygosity for chromosomes 2 or 3 is not common in HNPCC tumours Lindblom et al., 1993) and it is not certain whether the gene is acting dominantly, conferring increased mutation in the normal colon as well as in tumours, or whether its action is confined to tumours. Evidence suggesting-the latter is derived from the fact that a lymphoblastoid cell line from an HNPCC-affected individual was proficient in mismatch repair and that normal tissue (of unspecified type) from HNPCC patients was not found to show microsatellite instability . However, the possibility that the inherited DNA defect is confined to tissues with an increased inci...

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Section: Methodscontrasting

confidence: 66%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Normal colonic mucosa in hereditary non-polyposis colorectal cancer shows no generalised increase in somatic mutation

Williams

Geraghty²,

Campbell³

et al. 1995

Br J Cancer

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confidence: 99%

“…In fact, radiotherapy of heterozygotes induces a considerable increase in the mPAS-positive crypt frequency, which subsequently remains significantly elevated for 2-34 years, indicating that crypts with a mutant phenotype are stable. (11,12) Recently, we demonstrated that the number of wholly mPASpositive (stem cell mutated) crypts and clusters of two or more mPAS-positive crypts in foci significantly increases with the duration of ulcerative colitis in heterozygote individuals, pointing to a possible role in the chronic inflammationcarcinoma sequence. (13) Using the same staining approach in the present study, we assessed mutated crypts in non-cancerous mucosa of patients with sporadic colorectal cancers and mucosa of diverticulosis patients without colorectal cancers to ascertain whether they might similarly accumulate with age without the background of ulcerative colitis.…”

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confidence: 99%

Significant increase of colonic mutated crypts correlates with age in sporadic cancer and diverticulosis cases, with higher frequency in the left‐ than right‐side colorectum

Okayasu¹,

Hana

Tsuruta

et al. 2006

Cancer Science

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Mild periodic acid-Schiff (mPAS) staining can discriminate non-Oacetylated (mPAS-positive) from O-acetylated (mPAS-negative) epithelial sialoglycoproteins in human colonic mucosa, allowing the three haplotypes expressed from a single polymorphic autosomal gene (oat) to be distinguished. In heterozygotes, we previously demonstrated wholly mPAS-positive (stem cell mutated ) crypts and clusters of two or more mPAS-positive crypts to be significantly increased with duration of ulcerative colitis. To establish whether such an increase in the number of mutated crypts with age also occurs in normal individuals or in cases with diverticulosis, the O-acetylation phenotype in the non-cancerous colonic mucosa of 47 sporadic colorectal cancer patients who were heterozygotes for oat was tested with mild-PAS staining. PAS-positive crypts were assessed histologically in relation to age and compared between the left (sigmoid colon and rectum) and right (cecum and ascending colon) sides of the colorectum. I t is widely accepted that the likelihood of developing sporadic colorectal carcinoma increases with age.(1-3) Colorectal tumorigenesis is a multistage process, (4) with increased colonic mucosal cell proliferation believed to be important for initiation and subsequent growth, (5,6) acting together with the cumulative effects of protracted exposure to cancer-causing agents. Recently, it was demonstrated that mPAS staining can discriminate non-O-acetylated (mPAS-positive) from O-acetylated (mPASnegative) epithelial sialoglycoproteins. . In fact, the frequency distribution of these three phenotypes in different racial groups, including Japanese and British people, is consistent with that predicted by the Hardy-Weinberg law. (8) This suggests that they result from expression of a single polymorphic autosomal gene (oat) encoding the O-acetyl transferase active in generating colonic sialomucins. Further, the three phenotypes are similar to those seen in C57BL/6 J × SWR F1 mice, where the Dlb-1 gene determines another intestinal mucus glycoprotein phenotype that can be visualized by virtue of Dolichos biflorus agglutinin binding. (9) In this mouse model, discordant crypts are produced in heterozygotes by mutation. The altered crypts seen in humans using the mPAS technique are also similar in morphology to carcinogen-induced crypts with changes in glucose-6-phosphate dehydrogenase expression in the mouse colon, indicating a role for somatic mutations. (10) It is conceivable that somatic mutations of the high acetylator allele in colonic crypt stem cells in heterozygous subjects followed by crypt colonization by mutant progeny leads to conversion of the crypt phenotype from mPAS negative to mPAS positive. In fact, radiotherapy of heterozygotes induces a considerable increase in the mPAS-positive crypt frequency, which subsequently remains significantly elevated for 2-34 years, indicating that crypts with a mutant phenotype are stable. (11,12) Recently, we demonstrated that the number of wholly mPASpositive (stem cell mutated) crypts a...

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Clonal overexpression of metallothionein is induced by somatic mutation in morphologically normal colonic mucosa

et al. 1998

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Human colonic stem cell mutation frequency with and without irradiation

Cited by 32 publications

References 8 publications

Normal colonic mucosa in hereditary non-polyposis colorectal cancer shows no generalised increase in somatic mutation

Normal colonic mucosa in hereditary non-polyposis colorectal cancer shows no generalised increase in somatic mutation

Significant increase of colonic mutated crypts correlates with age in sporadic cancer and diverticulosis cases, with higher frequency in the left‐ than right‐side colorectum

Clonal overexpression of metallothionein is induced by somatic mutation in morphologically normal colonic mucosa

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