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Centre for Occupational and Environmental Health, School of Epidemiology and Health Sciences, University of Manchester, Manchester, M13 9PL,
*
Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, Manchester, M20 9BX and
Department of General Surgery, Wythenshawe Hospital, Manchester M23 9LT, England
3To whom correspondence should be addressed. E-mail: apovey{at}man.ac.uk.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONDNA alkylation damage and...DNA alkylation damage and...Association between DNA repair...LITERATURE CITED |
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AT transition mutations, which is consistent with the mutagenic properties of O6-MeG: such mutations are also commonly found in human colorectal cancers. O6-Alkylguanine adducts are removed by the DNA repair protein, O6-alkylguanine DNA-alkyltransferase (MGMT). MGMT overexpression in transgenic mice reduces the formation of K-ras GCAT mutations and tumors induced by methylating agents. Interindividual variations in human colon MGMT activity are large and large bowel tumors can occur in regions of low activity. Low MGMT activity in normal mucosa has been associated with the occurrence of K-ras GCAT mutations, whereas reduced MGMT expression and an increased frequency of K-ras GCAT mutations in colorectal cancers have been linked to MGMT promoter methylation. MGMT activity is also lower in adenomas than in adjacent normal tissue but only in those adenomas with this specific mutation. These results are entirely consistent with the hypothesis that GCAT mutations in the K-ras oncogene result from the formation and persistence of O6-alkylguanine lesions in colorectal DNA. Human exposure to endogenous or exogenous alkylating agents may thus be an environmental determinant of colorectal cancer risk.
KEY WORDS: • O6-methylguanine • O6-alkylguanine DNA-alkyltransferase • MGMT • K-ras • colorectal cancer
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONDNA alkylation damage and...DNA alkylation damage and...Association between DNA repair...LITERATURE CITED |
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,2
), dietary and environmental factors that are major determinants of sporadic cancer risk remain largely unidentified (3
). The identification of these etiological factors is important because this may lead to the development of new approaches to identify high-risk populations or to prevent this cancer.
The variety of molecular changes occurring in human colorectal tumors are not consistent with exposure to a single genotoxic agent but suggest that a number of different agents may increase colorectal cancer risk (4
,5
). Furthermore, as with most human tissues, colorectal DNA contains damage arising from exposure to a number of different genotoxic agents, including those known collectively as alkylating agents (6
–11
). The aim of this report was to discuss the role of DNA alkylation damage and the repair of such damage in the etiology of human colorectal cancer.
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DNA alkylation damage and DNA repair in human colorectal tissue |
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TOPABSTRACTINTRODUCTIONDNA alkylation damage and...DNA alkylation damage and...Association between DNA repair...LITERATURE CITED |
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–11
). The source of this exposure is unknown but can potentially occur through dietary, lifestyle and occupational exposures; from endogenous alkylating agents; and via in situ formation typically mediated by the bacterial or chemical nitrosation of amines (12
,13
). Although there are many potential methylating agents (14
), DNA alkylation can also arise through exposure to other alkylating agents [e.g., ethylating or carboxymethylating agents (15
,16
)] and potentially to agents that are as yet not chemically characterized. The relative importance of such exposures is currently unknown, but available evidence shows damage to DNA arising from methylating agents (9
–11
). Interindividual variation in O6-MeG levels is large, being at least 100-fold (9
,11
), and we reported some evidence suggesting that the highest O6-MeG levels occur in the regions of the large bowel where most tumors occur—that is, the sigmoid colon and rectum (11
).
O6-MeG is a known toxic, mutagenic and carcinogenic DNA base modification; in the absence of DNA repair, O6-MeG has been shown to induce GCAT transition mutations (17
). In DNA repair–deficient cell lines exposed to methylating agents, it has been calculated that one mutation results from every 8 O6-MeG adducts produced in the coding region of the hypoxanthine phosphoribosyltransferase gene (18
). Adduct levels observed in human colon cells correspond to 10s to 100s of adducts per cell (assuming that 1 µg of DNA contains 3124 pmol of nucleotides) but may, in certain cell populations, be much higher (19
,20
). Human DNA adduct levels may thus be sufficient to cause biological effects, particularly in cells that are DNA repair deficient.
Removal of O6-MeG by the DNA repair protein O6-alkylguanine DNA alkyltransferase (MGMT) is a stoichiometric process that results in the transfer of the methyl group from O6-MeG to a cysteine acceptor group (position 145) in the mammalian protein (18
,21
). This process inactivates the protein, which is subsequently degraded through ubiquitination pathways (22
). Continued protection of the DNA thus requires continuous de novo synthesis of active protein; overexpression of MGMT in cells and animals protects against toxicity, mutagenicity and carcinogenicity induced by alkylating agents (23
). If O6-MeG is not repaired before DNA replication, then O6-MeG-thymidine mispairs can be formed. These mispairs are recognized by the hMSH2-hMSH6 heterodimer of the mismatch repair system (24
). This results in the generation of an intermediate structure that, on a further round of DNA replication, results in a DNA double-strand break, triggering recombination and p53-mediated apoptotic cell death (25
). Mice lacking both MGMT and functional mismatch repair are thus more prone to develop cancer in response to alkylation damage than are MGMT-deficient but mismatch repair–proficient animals (26
).
Interindividual variations in functional colon MGMT activity can be large. In different studies, variations between 2- and 18-fold were reported in normal tissue and variations between 2- and 33-fold were reported in tumor tissue (27
). Although the complete absence of functional MGMT activity in human colorectal tissue was reported (28
,29
), this phenotype seems relatively rare, being present in <1% of normal tissue samples and 3% of tumor samples (27
).
Intraindividual variation in MGMT activity has been poorly characterized. We recently studied MGMT activity in multiple biopsy samples from the large bowel of patients with colorectal cancer (30
). In five patients, intraindividual variation was 1.1- to 2.5-fold, but in two patients, intraindividual variation was 12- and >24-fold: in the latter case there was no detectable activity in two normal mucosal biopsy samples. A consistent topographical pattern of MGMT activity in normal mucosa associated with colorectal cancers was found with tumors occurring in regions of low MGMT activity. There was a modest but significant fall in MGMT activity, unrelated to tumor subsite or stage, upstream of left-sided tumors with a mean gradient of 0.22 fmol/(µg DNA · cm) (95% confidence interval, 0.03–0.42; P = 0.02). Over a 10-cm length of tissue, this would correspond to a 10–80% drop in MGMT activity. The gradient in activity along the colon may reflect a number of different mechanisms, including longitudinal changes in gene expression (and hence be a susceptibility factor) or varying exposure to alkylating agents (and hence be an exposure marker).
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DNA alkylation damage and repair in dimethylhydrazine-induced colon cancer |
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TOPABSTRACTINTRODUCTIONDNA alkylation damage and...DNA alkylation damage and...Association between DNA repair...LITERATURE CITED |
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), a wide variation in tumor response in different rodent strains (32
–35
), the diet-induced modulation in tumor incidence (36
), a distribution of tumors similar to those within the human colon (37
,38
) and the similarity between animal and human pathology (39
). Implicit in such work is the assumption that DNA alkylation may also be important in human colon cancer formation.
DMH produces predominantly distal colon tumors but at widely varying rates depending on the strain of the animal (32
–34
,40
42
). After DMH administration, susceptible mouse strains can have higher amounts of DNA strand breaks and DNA adducts in colonic DNA than do nonsusceptible strains (43
,44
), but such observations are not consistently reported (45
,46
). DNA alkylation is also detected in tissues other than the colon (e.g., liver, kidney) and the specific induction of colon tumors has been ascribed to tissue-specific differences in the persistence of certain DNA adducts (45
,47
–49
). Other factors, such as whether damaged stem cells at positions 1 and 2 within the crypt that are selectively removed by apoptosis or undergo deleterious mutations, may also be important in DMH tumor induction (50
). Intracolonic differences in baseline proliferative parameters (crypt length, labeling index and proliferative zone) have also been reported and are associated with the tumor formation (51
,52
).
Treating female SWR mice with DMH (6.8 mg/kg intraperitoneal injection) once weekly for up to 20 wk generated the site-specific induction of colon tumors with 0%, 43% and 87% of animals having proximal, mid and distal colon tumors, respectively (53
). Separate groups of mice were killed up to 1 wk after the final DMH injection, and the large bowel was removed and divided into thirds (proximal, mid and distal colon) (54
). O6-MeG levels in colonic DNA, colonic MGMT activity and cell proliferative indexes in the colon were found to vary in a location-, dose- and time-dependent manner. O6-MeG levels were generally lowest in proximal colon DNA and highest in distal colon DNA and ranged from <0.1 to 16.6 fmol of O6-MeG/µg of DNA. Steady state O6-MeG levels were obtained at the highest cumulative dose (DMH at 136 mg/kg) with levels in the mid and distal colon DNA being 5 and 10 times those in proximal colon DNA. The cumulative sum of persistent O6-MeG was associated with tumor incidence in both the distal and mid colon: the distal colon was more susceptible in that similar levels of persistent O6-MeG adducts in the mid and distal colon were associated with higher tumor yield in the distal colon. Basal MGMT activity varied between 0.97 and 1.22 fmol/µg of DNA within the colon but was not associated with adduct levels, tumor induction or differences in tumor yield within the colon.
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Association between DNA repair and molecular changes in human colorectal tumors |
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TOPABSTRACTINTRODUCTIONDNA alkylation damage and...DNA alkylation damage and...Association between DNA repair...LITERATURE CITED |
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AT transition mutations in the K-ras oncogene (53
,55
). This mutation is consistent with the known mutagenic properties of O6-MeG; because overexpression of MGMT in the colon reduces the formation of DMH-induced K-ras mutations (56
), this suggests that the formation and persistence of O6-MeG are important etiological determinants of colon tumors in these models. Because GCAT transition mutations also account for the majority of the K-ras mutations seen within human colorectal cancers (5
), it is not unreasonable to suggest that the persistence of O6-MeG in human tissues plays an important role in cancer formation.
Although we found no association between the presence of O6-MeG in human colorectal tissues and the presence of K-ras GCAT gene mutations (57
), we did find that low MGMT activity in normal colon tissue was associated with K-ras GCAT transition mutations in colorectal tumors (58
). Further evidence of the importance of MGMT in influencing K-ras mutational activation has come from promoter methylation studies. Methylation of CpG islands within the promotor region of the MGMT gene has been associated with both reduced MGMT expression (59
) and an increased frequency of GCAT transition mutations in K-ras in colorectal cancers (60
,61
). More recently we reported that adenomas containing a K-ras GCAT mutation had lower MGMT levels (relative to adjacent normal tissue) than adenomas without this mutation (62
). Because MGMT removes O6-alkylguanine lesions from DNA, these observations strongly support the hypothesis that alkylating agents are involved in the etiology of at least a portion of colorectal cancers
Evidence from animal models and human studies increasingly implicates exposure to alkylating agents as a key event resulting in K-ras mutational activation of at least a subset of colorectal tumors. The role of alkylating agents in colorectal tumorigenesis is potentially larger than this because alkylating agent exposure has been linked to changes in other key targets such as mismatch repair genes (63
). Furthermore the recombinogenic effects of O6-MeG may make an important contribution to genetic instability and other steps associated with the multiple events involved in malignant transformation. The precise nature and origin of the alkylating agents are still uncertain; thus it will be difficult to identify not only individuals and populations at increased risk (through exposure or susceptibility) but also ways of reducing this risk. Further research is required to better characterize these agents so as to identify exposure sources and appropriate ways to reduce this exposure.
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FOOTNOTES |
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2 Supported by Cancer Research UK, the Christie Hospital Endowment Fund and the Association for International Cancer Research.
4 Present address: Division of Population Sciences, Fox Chase Cancer Center, Philadelphia, PA 19111.
5 Present address: Micromass UK Limited, Wythenshawe, Manchester, M23 9LZ.
6 Present address: Department of Environmental Health Sciences, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD 21205.
8 Abbreviations used: DMH, 1,2-dimethylhydrazine; MGMT, O6-alkylguanine DNA-alkyltransferase; O6-MeG, O6-methylguanine.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONDNA alkylation damage and...DNA alkylation damage and...Association between DNA repair...LITERATURE CITED |
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