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Int. J. Cancer: 85, 68–72 (2000)
r 2000 Wiley-Liss, Inc.
Publication of the International Union Against Cancer
Publication de l’Union Internationale Contre le Cancer
DETERMINANTS OF O 6-ALKYLGUANINE-DNA ALKYLTRANSFERASE ACTIVITY
IN NORMAL AND TUMOUR TISSUE FROM HUMAN COLON AND RECTUM
A.C. POVEY1,2*, C.N. HALL3, D.P. COOPER1, P.J. O’CONNOR1 and G.P. MARGISON1
1Cancer Research Campaign, Section of Genome Damage and Repair, Paterson Institute for Cancer Research, Manchester, UK
2School of Epidemiology and Health Sciences, Medical School, University of Manchester, Manchester, UK
3Department of Surgery, Wythenshawe Hospital, Wythenshawe, Manchester, UK
O6-Alkylguanine-DNA-alkyltransferase (ATase) is an important modulator of alkylating agent–induced toxicity and carcinogenicity, but those factors which influence the expression
of this repair protein in human tissues are poorly characterised. In this study, we have determined ATase levels in
macroscopically normal and tumour tissues from 76 individuals with benign or malignant colorectal disease. All tissue
samples had detectable ATase activity, with values ranging
from 35 to 451 fmol/mg protein. ATase activity in normal
rectal tissue was significantly higher than that in normal
tissue from the sigmoid colon (148 ⴞ 76 vs. 100 ⴞ 40 fmol/mg
protein, p ⴝ 0.01), whereas ATase levels within different
regions of the colon (proximal vs. sigmoid colon) were similar.
In normal tissue, inter-individual variation in ATase activity
was 4-fold in the colon and 6-fold in the rectum, whereas in
tumour tissue the corresponding figures were approx. 13.0and 7-fold, respectively. There was no detectable difference in
normal tissue ATase activity between individuals with benign
or malignant disease of the colon. Normal and tumour tissue
ATase activities were strongly correlated in the sigmoid
colon (r ⴝ 0.80) and rectum (r ⴝ 0.59) but not the caecum
(r ⴝ ⴚ0.03). In a multivariate analysis, ATase activity in
normal colon tissue increased with age (p ⴝ 0.01) and current
smoking (p ⴝ 0.06), whereas tumour ATase activity increased only with use of anti-histamines (p ⴝ 0.05). In rectal
tumour tissue, activity decreased with age (p ⴝ 0.05) and use
of anti-muscarinic medications (p ⴝ 0.01): in normal rectal
tissue, no modulating factors were identified. Int. J. Cancer
85:68–72, 2000.
r 2000 Wiley-Liss, Inc.
The presence of O 6-alkylguanine in DNA can have a number of
deleterious cellular effects as this adduct is one of the principal
cytotoxic, mutagenic and carcinogenic lesions induced by exposure
to alkylating agents. By repairing O 6-alkylguanine in DNA,
O 6-alkylguanine-DNA-alkyltransferase (ATase, also known as
MGMT and AGT) provides protection against these effects. The
alkyl group from the O 6 position is transferred to a cysteine in the
protein in a process that regenerates the guanine base but inactivates the repair protein (Pegg et al., 1995). The cellular capacity for
repairing O 6-alkylguanine lesions is thus dependent on the number
of ATase molecules present within cells. Depletion of cellular
ATase levels will render cells more susceptible to alkylating agents,
whereas increased ATase expression will increase resistance. ATase
expression in human tumour and normal cells is thus an important
determinant of the effectiveness and toxicity of alkylating agent–
induced chemotherapy, and in modulating the effects of the
unavoidable exposure to methylating agents, ATase expression in
normal cells may influence susceptibility to alkylating agent–
induced carcinogenesis.
ATase is generally expressed constitutively in normal cells, but a
small number of individuals have no detectable expression of
ATase in either normal or tumour cells (e.g., Gerson et al., 1995;
White et al., 1997). The absence of ATase expression in these
individuals arises from a lack of gene transcription, probably as a
result of methylation of CpG islands within the promoter region of
the ATase gene (Qian and Brent, 1997). Factors which affect ATase
expression are poorly characterised, but tissue and cellular heterogeneities in ATase expression indicate the presence of tissue- and
cell-specific enhancers or inhibitors. DNA strand breaks can act as
inducing signals, and ionising radiation can induce ATase expres-
sion in murine tissues and cell lines; this induction is dependent on
wild-type p53 (Rafferty et al., 1996). ATase expression is also
increased in both human and rodent tissues and cells by DNAdamaging agents such as cigarette smoke (Drin et al., 1994). ATase
expression in the rat liver is reduced following a single ethanol
dose, but after chronic administration ATase expression increases
(data not shown). In humans, ATase RNA expression is similar in
the liver of alcoholics and non-alcoholics with chronic hepatitis or
cirrhosis (Miyakawa et al., 1996). ATase activity can also be
inhibited by the use of alkylating agents and pseudo-substrates
(e.g., Pegg et al., 1995). Polymorphisms within the ATase gene
have been reported, but whether they are associated with changes
in expression or altered substrate specificity remains to be determined (Otsuka et al., 1996).
As with other human tissues, ATase expression in normal and
tumour tissue from the colon is highly variable. Expression in
normal colon tissue has been reported to vary up to 18-fold (Gerson
et al., 1992; Zaidi et al., 1996) and in tumour tissue by 25-fold
(Zaidi et al., 1996). There is increasing evidence that such
variations in ATase expression within the colon may be important
in determining cancer susceptibility. The RER phenotype, present
in approx. 10% of sporadic colorectal tumours, is induced in vitro
by continuous exposure to methylating agents in the presence of
low ATase expression (Karran and Bignami, 1994). Colorectal
DNA contains O 6-methylguanine, clearly indicating that colorectal
tissue is exposed to methylating agents (Jackson et al., 1996). We
have also observed that individuals with low ATase activity in
normal colorectal tissue were more likely to have a K-ras GC =
AT transition mutation than individuals with high ATase activity
(Jackson et al., 1997). It thus becomes increasingly important to
characterise those factors (whether genetic or environmental)
which may influence ATase expression within the large bowel. In
this population, we have examined whether ATase activity is
associated with any demographic variable or exposure to cigarette
smoke, alcohol, or medications.
MATERIAL AND METHODS
The study population consisted of 34 men and 42 women with a
median age of 72 years: 22 were current smokers and 48 current
drinkers. Of these 76 people, 14 had benign colon disease and 62
tumours of the colon or rectum. Paired tumour and macroscopically
normal tissue, sufficient for ATase analysis, was obtained from 55
individuals. Tissue samples were obtained at surgery, snap-frozen
and then stored at ⫺70°C until processed. Between 1 and 10 mg
Grant sponsor: Cancer Research Campaign.
D.P. Cooper’s current address is: Micromass UK Ltd., Floats Road,
Wythenshawe, Manchester, M23 9LZ, UK.
*Correspondence to: School of Epidemiology and Health Sciences,
Medical School, University of Manchester, Oxford Rd., Manchester, M13
9PT, UK. Fax: ⫹44 161 275 5595. E-mail: [email protected]
Received 11 May 1999; Revised 19 July 1999
O 6-ALKYLGUANINE-DNA ALKYLTRANSFERASE IN COLORECTAL CANCER
69
TABLE I – ATase LEVELS IN TUMOUR AND MACROSCOPICALLY NORMAL TISSUE FROM PATIENTS WITH DISEASES OF
THE COLON AND RECTUM
Normal tissue
Sample set
Colon disease
Benign
Malignant
Colorectal tumours
Proximal colon3
Sigmoid colon
Rectum
Tumour tissue
Mean ⫾ SD
(n)1
Range
Mean ⫾ SD
(n)1
Range
98 ⫾ 35 (14)
107 ⫾ 44 (36)
53–162
52–201
—
146 ⫾ 104 (34)2
—
35–451
118 ⫾ 47 (15)
100 ⫾ 40 (21)
148 ⫾ 76 (26)5
52–201
56–194
57–342
150 ⫾ 90 (14)
144 ⫾ 115 (20)4
170 ⫾ 90 (21)
41–320
35–451
48–348
1Results expressed in fmol/mg protein (n ⫽ number of samples).–2Activity significantly higher than in
normal tissue ( p ⫽ 0.03 using t-test for paired samples).–3Includes individuals with tumours of the hepatic
flexure or transverse colon or caecum.–4Activity significantly higher than in normal tissue ( p ⫽ 0.04 using
t-test for paired samples).–5Activity significantly higher than in normal tissue from the sigmoid colon
( p ⫽ 0.01) using Mann-Whitney U-test.
FIGURE 1 – Relationship between ATase activity in paired normal and tumour tissue from individuals with tumours of the proximal colon (a),
sigmoid colon (b) and rectum (c). Proximal colon includes tumours of the caecum, transverse colon and hepatic flexure.
tissue were analysed for ATase activity using calf thymus DNA
methylated in vitro with N-nitroso-N-( 3H)-methylurea (approx. 20
Ci/mmol) as the substrate. Details of the assay procedure are
described in full elsewhere (Watson and Margison, 1999). Associations were evaluated between ATase activity in either normal or
tumour tissue and exposure variables (age, sex, tissue site, smoking, alcohol consumption and medication). Cigarette smoking and
alcohol consumption were examined both as dichotomous (current
vs. never/ex) and as polychotomous variables (non-smokers/exsmokers, 1 to 19 and ⱖ20 cigarettes per day, and non-drinkers,
⬍10 units/week, ⬎10 units/week). Univariate analysis was carried
out using parametric techniques. Linear regression analysis was
then performed using variables identified in the initial univariate
analysis (at a significance level of p ⬍ 0.1), adjusted for age and
gender.
RESULTS
ATase activity was detected in all colorectal normal and tumour
tissue samples analysed, with levels ranging from 35 to 451
fmol/mg protein (Table I). In normal tissues, ATase activity varied
by about 4-fold in the colon and 6-fold in the rectum, whereas in
tumour tissue the corresponding figures were 13- and 7-fold,
respectively. Differences in mean ATase activity within the large
bowel were also observed in individuals with colorectal tumours
(Table I). In particular, ATase activity in normal rectal tissue (but
not tumour tissue) was significantly higher than that in normal
tissue from the sigmoid colon (148 ⫾ 76 vs. 100 ⫾ 40 fmol/mg
protein, p ⫽ 0.01), whereas ATase levels within different regions of
the colon (proximal vs. sigmoid colon) were similar. There was no
detectable difference in normal tissue ATase activity between
individuals with benign or malignant colon disease (Table I).
In the sigmoid colon but not the proximal colon or rectum,
tumour ATase activity was significantly higher than normal tissue
activity (144 ⫾ 115 vs. 100 ⫾ 40 fmol/mg protein, p ⫽ 0.04).
There was no association between ATase levels in normal and
tumour tissue from the same individual when the samples were
located in the proximal colon (Fig. 1a), but there was a strong
positive association in the sigmoid colon (r ⫽ 0.80, Fig. 1b) and
rectum (r ⫽ 0.59, Fig. 1c).
ATase levels in both normal and tumour tissue were slightly
higher in men (between 1.2- and 1.4-fold) than in women, but these
differences were not significant (data not shown). ATase activity in
normal colon tissue increased significantly with age (Fig. 2a): a
small but statistically significant positive association between
ATase activity and age was detected in men ( p ⫽ 0.029) but not in
women ( p ⫽ 0.19). Activity in colon tumour tissue varied little
with age (Fig. 2b), whereas ATase activity in both normal and
tumour tissue from the rectum decreased with age but not
significantly (Fig. 2c,d).
ATase activity in normal and tumour tissue from individuals with
colon disease or rectal tumours was similar in drinkers and
non-drinkers: in addition, ATase activity was not related to the
70
POVEY ET AL.
FIGURE 2 – Relationship between ATase activity and age in samples
from (a) normal colon tissue, (b) tumour tissue from the colon, (c)
normal rectal tissue and (d) tumour tissue from the rectum.
amount of alcohol consumed (data not shown). In the colon, ATase
activity was higher in smokers than in non/ex-smokers in both
normal [mean ⫾ SD 119 ⫾ 49 (n ⫽ 14) vs. 99 ⫾ 37 (n ⫽ 36)
fmol/mg protein, p ⫽ 0.12] and tumour tissue [210 ⫾ 173 (n ⫽ 8)
vs. 127 ⫾ 65 (n ⫽ 26) fmol/mg protein, p ⫽ 0.04]. However, there
did not appear to be a dose-response relationship between the
extent of smoking and ATase activity (Fig. 3a): highest ATase levels
were obtained in individuals who smoked 1 to 19 cigarettes per day.
In the rectum, there were no significant differences in the level of
ATase activity between smokers and non/ex-smokers in either
normal [150 ⫾ 68 (n ⫽ 8) vs. 147 ⫾ 81 (n ⫽ 18) fmol/mg protein,
p ⫽ 0.93] or tumour [200 ⫾ 78 (n ⫽ 8) vs. 151 ⫾ 94 (n ⫽ 13)
fmol/mg protein, p ⫽ 0.24] tissue, and increasing consumption of
cigarettes also did not alter ATase activity significantly (Fig. 3b).
The association between ATase activity and the use of medications was then examined. Evidence that medications influenced
ATase activity was found only for anti-histamines, anti-muscarinics
and benzodiazepines (Table II). ATase activity in normal and
tumour colon tissue (but not rectal tissue) was higher in individuals
receiving anti-histamine medication, but these results were of
borderline significance. In normal colon tissue, ATase activity was
137 ⫾ 40 (n ⫽ 5) in users vs. 101 ⫾ 40 fmol/mg protein (n ⫽ 35)
in non-users ( p ⫽ 0.07); in tumour tissue from the colon, the
corresponding figures were 220 ⫾ 67 (n ⫽ 5) vs. 134 ⫾ 108
(n ⫽ 23, p ⫽ 0.09). Individuals using anti-muscarinic medication
had significantly lower ATase activity in tumour tissue from the
rectum, 143 ⫾ 91 (n ⫽ 14) in users vs. 223 ⫾ 61 fmol/mg protein
in non-users (n ⫽ 7, p ⫽ 0.05), but there were no detectable effects
in normal tissue from the rectum or normal and tumour tissue from
the colon. ATase activity in normal colon tissue was lower in
individuals receiving benzodiazepines [89 ⫾ 37 (n ⫽ 13) vs.
111 ⫾ 41 (n ⫽ 39), p ⫽ 0.08], but no effects were observed in
colon tumour tissue or normal and tumour tissue from the rectum.
FIGURE 3 – Effect of cigarette smoking in ATase activity in normal
and tumour tissue from (a) colon and (b) rectum. In the colon, ATase
activity in smokers who smoked ⬍20 cigarettes per day was significantly higher than that in non-smokers in both normal ( p ⫽ 0.03) and
tumour ( p ⫽ 0.006) tissue. No significant difference in activity was
observed between non-smokers and smokers who smoked ⱖ20 cigarettes per day ( p ⬎ 0.38) and between smokers who smoked ⬍20 or
ⱖ20 cigarettes per day ( p ⬎ 0.2) in either normal or tumour tissue. In
the rectum, there was no association between ATase activity and the
numbers of cigarettes smoked.
In a multivariate analysis, ATase activity was associated with age
and current smoking in normal colon tissue but only with use of
anti-histamine medication in tumour tissue (Table III). In the
rectum, tumour ATase activity was associated with both age and use
O 6-ALKYLGUANINE-DNA ALKYLTRANSFERASE IN COLORECTAL CANCER
71
TABLE II – ATase ACTIVITY IN COLON AND TUMOUR TISSUE AS A FUNCTION OF MEDICATION
ATase activity (fmol/mg protein)1
Medication
Colon tissue
Anti-histamine
Use
Non-use
Anti-muscarinic
Use
Non-use
Benzodiazepines
Use
Non-use
Rectal tissue
Normal
Tumour
Normal
Tumour
137 ⫾ 40 (5)
101 ⫾ 40 (45)
220 ⫾ 67 (5)
134 ⫾ 108 (23)
163 ⫾ 84 (5)
145 ⫾ 76 (21)
195 ⫾ 106 (4)
164 ⫾ 88 (7)
101 ⫾ 41 (29)
111 ⫾ 41 (21)
126 ⫾ 95 (17)
169 ⫾ 112 (17)
146 ⫾ 88 (18)
153 ⫾ 43 (8)
143 ⫾ 91 (14)
223 ⫾ 61 (7)2
89 ⫾ 37 (13)
111 ⫾ 41 (39)
156 ⫾ 145 (8)
143 ⫾ 91 (26)
150 ⫾ 68 (13)
147 ⫾ 86 (13)
187 ⫾ 96 (11)
151 ⫾ 82 (10)
1Results are expressed as mean ⫾ SD (n).–2Activity significantly higher in non-users than users of the
medication ( p ⫽ 0.05).
TABLE III – REGRESSION ANALYSIS FOR THE EFFECT OF AGE, GENDER, CURRENT SMOKING AND USE OF MEDICATIONS ON ATase
ACTIVITY IN COLORECTAL TISSUES
Site
Normal tissue
Variable
b (95% CI)
Colon
Age1
Rectum
Current smoker
—3
0.79 (0.19, 1.39)
24.1 (⫺1.3, 49.7)
—
Tumour tissue
p
0.01
0.06
—
Variable
Use of
anti-histamines2
Age4
Use of anti-muscarinics
b (95% CI)
95.2 (0.4 to 190.8)
⫺2.6 (⫺5.1 to ⫺0.02)
⫺99.6 (⫺26.8 to ⫺172.5)
p
0.05
0.05
0.01
Variables excluded from the models: 1gender ( p ⫽ 0.22), use of benzodiazepines ( p ⫽ 0.19) and use of anti-histamines ( p ⫽ 0.11); 2age
( p ⫽ 0.46), gender ( p ⫽ 0.27) and current smoking ( p ⫽ 0.17); 3age ( p ⫽ 0.54) and gender ( p ⫽ 0.55); 4gender ( p ⫽ 0.38).
of anti-muscarinic medication, but there was no detectable association between normal tissue activity and any study variable (Table III).
We have reported that ATase activity in normal colorectal tissue
was lower in individuals with a K-ras GC = AT transition mutation
in the colorectal tumour than in individuals with other mutations or
no mutation (Jackson et al., 1997), suggesting that high levels of
ATase activity provide protection against the formation of an
alkylating agent–induced K-ras GC = AT transition mutation. As
there is a difference between ATase levels in the colon and rectum,
we re-analysed the earlier mutation data for each tissue site (i.e.,
colon and rectum). In the colon, 6 of 17 individuals with normal
tissue ATase activity below the median value (93.5 fmol/mg
protein) had this GC = AT transition mutation compared to 1 of 19
individuals whose ATase activity was above the median ( p ⫽ 0.04,
Fisher’s exact test). In the rectum (median normal ATase activity ⫽ 128 fmol/mg protein), 6 of 13 individuals with ATase activity
below the median had the mutation compared to 2 of 12 whose
ATase activity was greater than the median, a difference that did not
reach statistical significance ( p ⫽ 0.20, Fisher’s exact test).
DISCUSSION
Studies in different populations have reported that mean ATase
activities in normal colon tissue range from approx. 100 to 200
fmol/mg protein (this study; Myrnes et al., 1983, 1984; Gerson et
al., 1986; Souliotis et al., 1992; White et al., 1997), whereas in
tumour tissues, activity has ranged from approx. 145 to 990
fmol/mg protein (this study; Myrnes et al., 1983, 1984; Gerson et
al., 1995; White et al., 1997). Inter-individual variations in activity
from both normal and tumour tissue from the colon are large, being
between 2- and 18-fold and 2- and 33-fold, respectively (Myrnes et
al., 1983, 1984; Grafstrom et al., 1984; Gerson et al., 1986, 1992,
1995; Redmond et al., 1991; Chen et al., 1992; Souliotis et al.,
1992; Zaidi et al., 1996; White et al., 1997); inter-individual
variations in tumour activities were greater than those observed in
normal tissue in all but one study (Souliotis et al., 1992). Two
studies have also reported the absence of detectable ATase activity
in a small number of individual normal and tumorous colon tissue
specimens (Gerson et al., 1995; White et al., 1997). In contrast with
other tissues, this phenotype is relatively rare, being present in
⬍1% of normal ATase tissue samples (2/352) and 3% of tumour
samples (7/286), but this difference in frequency was not significant ( p ⫽ 0.09, Fisher’s exact test) (Myrnes et al., 1983, 1984;
Grafstrom et al., 1984; Gerson et al., 1986, 1992, 1995; Redmond
et al., 1991; Chen et al., 1992; Souliotis et al., 1992; Zaidi et al.,
1996; White et al., 1997). The causes of the variation in activity of
normal tissues and the larger variation in tumour tissues remains to
be determined, but it is likely to reflect the fact that tumour samples
are more heterogenous and contain different cells with varying
ATase levels (e.g., Zaidi et al., 1996). It has also been reported in
one study (Gerson et al., 1995) but not confirmed (Gerson et al.,
1992) that ATase activity decreases along with advanced stages of
disease.
Previous studies have indicated that ATase activity does not vary
within the human large bowel (Redmond et al., 1991; Gerson et al.,
1995), and we also observed no significant variation in ATase
activity within the mouse colon (data not shown). Our own
re-analysis of the data of Redmond et al. (1991), however, suggests
that ATase activity in normal caecal tissue (2.6 ⫾ 0.6 fmol/µg) was
significantly lower than that in normal tissue from either the
sigmoid colon (4.9 ⫾ 0.8 fmol/µg, p ⫽ 0.03, Mann-Whitney Utest) or rectum (4.8 ⫾ 1.3 fmol/µg, p ⫽ 0.01, Mann-Whitney
U-test). In this study, we found that ATase activity in normal rectal
tissue was much higher than that in the sigmoid colon, but there
were no differences between the sigmoid colon and the proximal
colon (i.e., caecum, transverse colon and hepatic flexure). Comparison of ATase activity at different locations is generally carried out
using tissue samples obtained from different individuals, and the
pronounced inter-individual variation observed in ATase activity
may obscure these differences. For example, differences between
normal and tumour ATase activities in the colon are generally
detected only in studies using paired normal and tumour tissue
from the same individual (this study; Redmond et al., 1991) rather
than non-paired samples [i.e., from different individuals (Gerson et
al., 1992; Zaidi et al., 1996)]. Differences in ATase activity within
the colon may thus be detected only with multiple sampling from
the same individual.
72
POVEY ET AL.
In the present study, we found that different factors affected
ATase expression in normal and tumour tissue and in tissue from
the colon and rectum. In normal colon tissue, ATase activity was
positively associated with age and, to a lesser extent, current
smoking (Table III), but no study variable was associated with
ATase activity in normal rectal tissue. Previous reports found no
association between age and ATase activity in either the lung (Drin
et al., 1994) or the colon, though the location of the tissue samples
within the colon was not stated (Gerson et al., 1995; White et al.,
1997). Cigarette smoking was also associated with a 1.4-fold
increase in ATase expression in peripheral lung and in ex-smokers,
was shown to decrease with time since that person had stopped
smoking (Drin et al., 1994).
Tumour ATase activity, but not normal tissue activity, was
modified by the use of anti-histamines and anti-muscarinic medication in the colon and rectum, respectively. Although this association
may reflect differences in disease between users and non-users of
the medications or other confounding factors, it is also possible that
it represents a direct effect of the medications concerned. If the
latter is true, then it may be possible to identify other agents that
may selectively modify ATase activity in normal and tumour tissue
(i.e., increased activity in normal tissue but decreased activity in
tumour tissue), which would be of value in chemotherapy employing relevant alkylating agents. In addition, it may be possible to
identify those individuals whose tumours may respond to alkylating agent chemotherapy by measuring ATase activity within a
biopsy of normal colon tissue as there is a strong correlation
between normal and tumour tissue ATase activity in the sigmoid
colon and rectum. As the assay is relatively simple and results can
be obtained within a few hours, this may also be of therapeutic
value.
Whether the phenotypic variation in ATase activity in normal
human tissue results in increased susceptibility to alkylating
agent–induced cancer remains to be determined. We have found
that ATase activity in normal colorectal tissue was lower in
individuals with a K-ras GC = AT transition mutation in the
colorectal tumour than in individuals with other mutations or no
mutation, suggesting that high levels of ATase activity provide
protection against the formation of an alkylating agent–induced
K-ras GC = AT transition mutation (Jackson et al., 1997).
Re-analysis of these data suggests that the effect may be confined to
the colon, and further work in other populations is required to
confirm this hypothesis. It is also of interest both for cancer
treatment and chemoprevention to further establish whether medications and dietary components can modulate ATase and other
DNA repair enzyme levels (e.g., mismatch repair enzymes).
ACKNOWLEDGEMENTS
We thank Mr J. Davis for technical support and Dr J. So for
advice in classifying the medications.
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