Reduced MGMT activity in human colorectal adenomas is associated with K-ras GC->AT transition mutations in a population exposed to methylating agents.

2.50
Hdl Handle:
http://hdl.handle.net/10541/78138
Title:
Reduced MGMT activity in human colorectal adenomas is associated with K-ras GC->AT transition mutations in a population exposed to methylating agents.
Authors:
Lees, Nicholas P; Harrison, Kathryn L; Hall, C Nicholas; Margison, Geoffrey P; Povey, Andrew C
Abstract:
There is increasing evidence to suggest that O(6)-alkyl guanine DNA-alkyltransferase (MGMT) activity provides protection against alkylating agent induced formation of GC-->AT transition mutations in the K-ras oncogene of colorectal tumours. As this mutagenic event occurs during the growth of adenomas, both biomarkers of exposure (N7-methylguanine levels in DNA) and susceptibility (MGMT activity) were measured in biopsy samples obtained from normal and adenomatous tissue from 34 patients with large adenomas (>10 mm in size). There was no correlation between MGMT activity in the adenoma and in matched normal tissue. However, MGMT activity was significantly lower in adenoma tissue than in adjacent normal mucosa (5.18 versus 7.05 fmol/microg DNA, P = 0.01), particularly in men and those whose age was greater than the median. Upon stratification by K-ras mutational status, MGMT activity was lower in adenomas bearing a K-ras GC-->AT transition mutation (mean 4.21 fmol/microg DNA) than in adjacent normal tissue (mean 7.7 fmol/microg DNA; P < 0.004). In contrast, there was no significant difference in MGMT activity in adenomas lacking a K-ras GC-->AT transition mutation and adjacent normal mucosa. N7-methylguanine levels however did not vary with age, gender, K-ras mutational status or MGMT activity. These results are consistent with the acquisition of K-ras GC-->AT transition mutations in adenomas with low MGMT activity as a result of unavoidable exposure to methylating agents.
Affiliation:
Department of Gastrointestinal Surgery, Wythenshawe Hospital, Southmoor Road, Wythenshawe, Manchester M23 9LT, UK.
Citation:
Reduced MGMT activity in human colorectal adenomas is associated with K-ras GC->AT transition mutations in a population exposed to methylating agents. 2004, 25 (7):1243-7 Carcinogenesis
Journal:
Carcinogenesis
Issue Date:
Jul-2004
URI:
http://hdl.handle.net/10541/78138
DOI:
10.1093/carcin/bgh111
PubMed ID:
14963016
Type:
Article
Language:
en
ISSN:
0143-3334
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorLees, Nicholas P-
dc.contributor.authorHarrison, Kathryn L-
dc.contributor.authorHall, C Nicholas-
dc.contributor.authorMargison, Geoffrey P-
dc.contributor.authorPovey, Andrew C-
dc.date.accessioned2009-08-21T10:35:49Z-
dc.date.available2009-08-21T10:35:49Z-
dc.date.issued2004-07-
dc.identifier.citationReduced MGMT activity in human colorectal adenomas is associated with K-ras GC->AT transition mutations in a population exposed to methylating agents. 2004, 25 (7):1243-7 Carcinogenesisen
dc.identifier.issn0143-3334-
dc.identifier.pmid14963016-
dc.identifier.doi10.1093/carcin/bgh111-
dc.identifier.urihttp://hdl.handle.net/10541/78138-
dc.description.abstractThere is increasing evidence to suggest that O(6)-alkyl guanine DNA-alkyltransferase (MGMT) activity provides protection against alkylating agent induced formation of GC-->AT transition mutations in the K-ras oncogene of colorectal tumours. As this mutagenic event occurs during the growth of adenomas, both biomarkers of exposure (N7-methylguanine levels in DNA) and susceptibility (MGMT activity) were measured in biopsy samples obtained from normal and adenomatous tissue from 34 patients with large adenomas (>10 mm in size). There was no correlation between MGMT activity in the adenoma and in matched normal tissue. However, MGMT activity was significantly lower in adenoma tissue than in adjacent normal mucosa (5.18 versus 7.05 fmol/microg DNA, P = 0.01), particularly in men and those whose age was greater than the median. Upon stratification by K-ras mutational status, MGMT activity was lower in adenomas bearing a K-ras GC-->AT transition mutation (mean 4.21 fmol/microg DNA) than in adjacent normal tissue (mean 7.7 fmol/microg DNA; P < 0.004). In contrast, there was no significant difference in MGMT activity in adenomas lacking a K-ras GC-->AT transition mutation and adjacent normal mucosa. N7-methylguanine levels however did not vary with age, gender, K-ras mutational status or MGMT activity. These results are consistent with the acquisition of K-ras GC-->AT transition mutations in adenomas with low MGMT activity as a result of unavoidable exposure to methylating agents.en
dc.language.isoenen
dc.subjectColorectal Canceren
dc.subject.meshAdenoma-
dc.subject.meshAlkyl and Aryl Transferases-
dc.subject.meshColorectal Neoplasms-
dc.subject.meshDNA Methylation-
dc.subject.meshGenes, ras-
dc.subject.meshGuanine-
dc.subject.meshHumans-
dc.subject.meshMutation-
dc.titleReduced MGMT activity in human colorectal adenomas is associated with K-ras GC->AT transition mutations in a population exposed to methylating agents.en
dc.typeArticleen
dc.contributor.departmentDepartment of Gastrointestinal Surgery, Wythenshawe Hospital, Southmoor Road, Wythenshawe, Manchester M23 9LT, UK.en
dc.identifier.journalCarcinogenesisen

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