Context Inflammation may play a role in the pathogenesis of colorectal cancer;
however, epidemiological evidence supporting this hypothesis in average-risk
persons is sparse.
Objective To determine the risk of incident colon and rectal cancer associated
with elevated baseline plasma concentrations of C-reactive protein (CRP).
Design, Setting, and Participants Prospective, nested case-control study of a cohort of 22 887 adults
(>18 years and Washington County, Maryland, residents) enrolled between May
and October 1989 and followed up through December 2000. A total of 172 colorectal
cancer cases were identified through linkage with the Washington County and
Maryland State Cancer registries. Up to 2 controls (n = 342) were selected
from the cohort for each case and matched by age, sex, race, and date of blood
draw.
Main Outcome Measure Odds ratio (OR) of incident colon and rectal cancer.
Results Plasma CRP concentrations were higher among all colorectal cases combined
than controls (median CRP, 2.44 vs 1.94 mg/L; P =
.01). The highest concentration was found in persons who subsequently developed
colon cancer vs matched controls (median CRP, 2.69 vs 1.97 mg/L; P<.001). Among rectal cancer cases, CRP concentrations were not
significantly different from controls (median CRP, 1.79 vs 1.81 mg/L; P = .32). The risk of colon cancer was higher in persons
in the highest vs lowest quartile of CRP (OR, 2.55; 95% confidence interval
[CI], 1.34-4.88; P for trend = .002). In nonsmokers,
the corresponding association was stronger (OR, 3.51; 95% CI, 1.64-7.51; P for trend<.001). A 1-SD increase in log CRP (1.02
mg/L) was associated with an increased risk of colon cancer after adjusting
for potential confounders and excluding cases occurring within 2 years of
baseline (OR, 1.35; 95% CI, 1.05-1.74) or excluding those with late-stage
colon cancer at the time of diagnosis (OR, 1.38; 95% CI, 0.99-1.91).
Conclusions Plasma CRP concentrations are elevated among persons who subsequently
develop colon cancer. These data support the hypothesis that inflammation
is a risk factor for the development of colon cancer in average-risk individuals.
Inflammation has been hypothesized to increase the risk of cancer.1 Although there is growing evidence from laboratory
studies supporting the role of inflammation in the pathogenesis of colorectal
cancer, data from epidemiologic studies are sparse. However, inflammation
could be particularly important in the pathogenesis of colorectal cancers.
Chronic inflammatory bowel diseases, such as ulcerative colitis, have been
associated with increased risk of colon cancer.2 Moreover,
several studies3-8 have
shown a reduced risk of colon cancer with use of aspirin or other anti-inflammatory
agents.
C-reactive protein (CRP) is an acute-phase protein produced primarily
in the liver in response to stimulation by interleukin 6 (IL-6). In recent
years, elevated levels of CRP have been shown to reliably predict cardiovascular
events in several populations.9 Both CRP and
IL-6 have been shown to be associated with total and noncardiovascular mortality
as well.10,11 These findings are
consistent with those from studies12-14 that
demonstrate an increased risk of mortality from cancer using other markers
of inflammation and raise the possibility that inflammation could play a role
in the development of cancer. Therefore, elevated circulating markers of inflammation,
in particular CRP, could help identify persons at risk for developing colorectal
cancer. To examine this hypothesis, we determined the risk of colon and rectal
cancer associated with elevated CRP levels in a prospective, nested case-control
study.
Colorectal cancer cases and controls were identified among members of
the CLUE II cohort, a prospective study established in May 1989 and named
for its campaign slogan, "Give Us A Clue to Cancer and Heart Disease." The
cohort consisted of 32 897 individuals, among whom 22 887 were Washington
County, Maryland, residents older than 18 years who formed the analytic cohort
for this study. Participants provided a blood sample and completed a brief
questionnaire at baseline, after providing written informed consent. Loss
to follow-up was less than 5% among cohort members who were 45 years or older
at baseline, the age range of most cases at baseline and the pool of cohort
members eligible to be selected as age-matched controls. Enrollment took place
from May to October 1989. Individuals are still under active follow-up. For
the purpose of case-control selection from this cohort, the final date of
case diagnosis was December 2000 (maximum of 11 years of follow-up). To ensure
equal follow-up time between cases and controls, the matched control was selected
to have a date of blood draw (enrollment date) within 2 weeks of the case,
and the matched control had to still be alive and free of a cancer diagnosis
at the date of the case's colorectal cancer diagnosis. The institutional review
board at the Johns Hopkins Bloomberg School of Public Health approved the
study.
Selection of Colorectal Cancer Cases and Controls
Cases were identified through linkage with the Washington County Cancer
Registry and, since 1992, with the Maryland State Cancer Registry. A total
of 172 men and women who did not have a prior cancer diagnosis (except possibly
for nonmelanoma skin cancer or cervix in situ) were diagnosed as having colon
or rectal cancer following the date of blood draw through December 2000. Of
these, 131 individuals had cancer of the colon (International
Classification of Diseases, Ninth Revision [ICD-9] code 153) and 41
had cancer of the rectum (ICD-9 code 154). Ninety-eight
percent of the cases were confirmed by review of pathology report. Information
on stage of diagnosis was available for 130 (99 colon, 31 rectal) of the 172
cases.
For each case, up to 2 controls were selected from among CLUE II participants
who did not have a diagnosis of cancer through December 2000 and who were
not known to be deceased at the time the case was diagnosed (n = 342). Controls
were matched to each case on age (plus or minus 1 year), sex, race, date of
blood draw (plus or minus 2 weeks), and time since last meal (0-1, 2-3, 4-5,
6-7, and ≥8 hours).
The Maryland Cancer Registry is certified by the North American Association
of Central Cancer Registries as being more than 95%
complete (http://www.naaccr.org/index.asp?Col_SectionKey=12&Col_ContentID=55). Compared with the Maryland Cancer Registry, the Washington County
Cancer Registry captured 98% of the colorectal cancer cases diagnosed in Washington
County residents in 1998.
Smoking history and self-reported weight and height were recorded for
each participant at baseline. Medication use was assessed at baseline. Hormone
use in women was defined as self-report of oral contraceptives or any other
estrogen or progesterone use, including hormone therapy, within the last 48
hours. Use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) within
the last 48 hours was determined by self-report. Follow-up questionnaires
were mailed in 1996 and 2000, which ascertained whether participants had a
history of inflammatory bowel disease before 1989 or had a family history
(parent or sibling) of colon or rectal cancer. Diabetes was defined as taking
any diabetic medication at baseline or having a hemoglobin A1C of
6.1% or higher.
C-reactive protein concentrations were measured in duplicate among cases
and controls from plasma stored at −70°C since baseline examination
using a high-sensitivity assay (Dade Behring, Newark, Del).15 Twenty-seven
quality control samples (equal to 5% of total sample) aliquotted from pooled
plasma were arranged in triplets among the cases and controls. Each case and
its controls (the triplets) were run adjacently. The laboratory was blind
to case-control and quality control sample status. The mean intrapair coefficient
of variation among quality control samples was 3.3%. Hemoglobin A1C levels
were determined by turbidimetric immunoinhibition in red blood cells (Hitachi
911 analyzer, Boehringer Mannheim, Indianapolis, Ind).
Matched sets that contained the case and at least 1 control with a CRP
measurement were used in the main analysis. Of 173 original cases and matched
controls (n = 346), 1 case and 2 controls had less than the detectable limit
of CRP (0.02 mg/L) and were excluded from the analysis, as were the corresponding
controls for the excluded case. Analyses that imputed the values to one half
the detection limit did not appreciably change our findings; therefore, these
cases and controls were excluded. Because CRP values are right-skewed, the
Wilcoxon signed rank test was used to determine differences in the distribution
of baseline CRP between cases and controls. Results were replicated using
log-transformed CRP and paired t tests. Matched odds
ratios (ORs) for colorectal cancer, calculated as an estimate of the relative
risk, and corresponding 95% confidence intervals (CIs) were estimated using
conditional logistic regression. Quartile cut points for CRP were based on
the distribution of concentration among controls. Tests for trend were conducted
by entering a single ordinal variable using the median of each category. Additional
analyses were conducted according to cancer site (ie, colon vs rectal). Smoking
status was not associated with outcomes in this sample, and log CRP levels
were similar among never and former smokers after adjusting for body mass
index (BMI, calculated as weight in kilograms divided by the square of height
in meters; P = .15). However, CRP levels remained
significantly higher among smokers compared with former and never smokers
in this and other studies16; therefore, we
report results separately for nonsmokers. In subsidiary analyses using all
controls, the continuous association with colon cancer associated with a 1-SD
increase in log CRP (1.02 mg/L) was determined using multivariate logistic
regression adjusting for potential confounders (age, sex, smoking status,
BMI, and use of hormones, aspirin, and NSAIDs), after excluding cases that
occurred within 2 and 5 years of blood draw and stage III or IV cancers at
the time of diagnosis (to reduce the effect of subclinical disease), and stratified
by sex, overweight status, and use of aspirin or other NSAIDs. Overweight
was defined as having a BMI of 25 or higher. Associations remained unchanged
after computing new CRP quartile cut points based on nonsmokers only. All
analyses were performed using STATA version 7.0 statistical software (STATA
Corp, College Station, Tex). Reported P values are
for 2-sided statistical tests, and P<.05 was considered
statistically significant.
Table 1 shows baseline characteristics
of cases and controls. Because of matching, cases and controls were of similar
age, race, and sex. Equal proportions of cases and controls were current smokers
at baseline. Small differences in BMI (P = .15),
hormone use in women (P = .17), and use of aspirin
(P = .17) and NSAIDs (P =
.13) were not statistically significant.
Among controls, BMI was significantly greater for persons in the highest
quartile of CRP compared with persons in the lowest quartile (mean [SD], 27.8
[4.8] vs 24.3 [3.2]; P for trend <.001; Table 2). No statistically significant
differences were observed for other covariates.
Table 3 shows baseline geometric
mean and median concentrations of CRP in cases and controls. Baseline geometric
mean and median concentrations of CRP were higher among persons who subsequently
developed colorectal cancer than among those who remained free of disease
(P = .01). This association was present for colon
cancer but not rectal cancer. Among persons who subsequently developed colon
cancer, median CRP concentrations were 2.69 vs 1.97 mg/L for matched controls
(P<.001). In contrast, CRP concentrations were
not significantly different between cases of rectal cancer and controls (1.79
vs 1.81 mg/L, P = .32). Among nonsmokers, median
CRP levels were higher among colorectal cancer cases compared with matched
controls (2.44 vs 1.85 mg/L, respectively; P = .002)
and among colon cancer cases compared with matched controls (2.67 vs 1.84
mg/L, respectively; P<.001). Only 21 cases and
41 controls were smokers at baseline. No association was found between CRP
levels and risk of cancer among smokers.
The odds of developing colorectal cancer increased with higher concentrations
of CRP, such that persons in the highest quartile of CRP had a 2-fold increased
risk of colorectal cancer compared with persons in the lowest quartile (OR,
2.00; 95% CI, 1.16-3.46; P for trend = .008) (Table 4). This increase in risk was primarily
observed among those who developed colon cancer (highest vs lowest quartile,
OR, 2.55; 95% CI, 1.34-4.88; P for trend = .002).
The risk of colorectal cancer associated with higher concentrations
of CRP was greater among nonsmokers (highest vs lowest quartile, OR, 2.52;
95% CI, 1.36-4.70; P for trend = .004). Nonsmokers
in the highest quartile of CRP had more than a 3-fold increased risk of developing
colon cancer compared with those in the lowest quartile (OR, 3.51; 95% CI,
1.64-7.51; P for trend<.001). No association was
found between CRP and risk of rectal cancer in nonsmokers (P for trend = .63, data not shown).
Additional analyses were conducted to determine the association between
CRP and subsequent risk of colon cancer among selected subgroups and to determine
the potential influence of undiagnosed colorectal cancer at baseline. In general,
associations were similar across subgroups (Table 5). To reduce associations due to occult disease at baseline,
we conducted analyses limited to early-stage disease and after excluding cases
that occurred within 2 and 5 years of follow-up. Among cases in which the
initial stage of tumor was stage I or II (n = 51), the adjusted OR of developing
colon cancer associated with a 1-SD increase in log CRP was 1.38 (95% CI,
0.99-1.91). Among nonsmokers, the corresponding OR was 1.51 (95% CI, 1.07-2.14).
After excluding cases of colon cancer that occurred within 2 years of follow-up,
the adjusted OR of colon cancer associated with a 1-SD increase in log CRP
was 1.35 (95% CI, 1.05-1.74) among all participants and 1.57 (95% CI, 1.20-2.07)
among nonsmokers. C-reactive protein remained significantly associated with
a higher risk of colon cancer in nonsmokers after excluding cases that occurred
within 5 years of follow-up (OR, 1.52; 95% CI, 1.08-2.13). In addition, there
was no correlation among colon cancer cases between time to diagnosis and
CRP level (Spearman r = 0.04), indicating that cases
that occurred early did not have appreciably higher levels of CRP at baseline
than cases that occurred later.
Consistent with the hypothesis that inflammation increases the risk
of colorectal cancer, use of either aspirin or NSAIDs within the last 48 hours
was associated with a reduced risk of colorectal cancer (OR, 0.63; 95% CI,
0.41-0.97). Nonsignificant decreases in risk were present for both colon cancer
(OR, 0.67; 95% CI, 0.41-1.09) and rectal cancer (OR, 0.53; 95% CI, 0.22-1.31).
Of the 337 respondents to the 1996 and 2000 follow-up questionnaires in the
current study, 5 (2 cases, 3 controls) had a history of inflammatory bowel
disease before 1989, and 23 (10 cases, 13 controls) had a positive family
history of colon or rectal cancer in a parent or sibling. All results were
unchanged when we repeated analyses after excluding persons with a baseline
history of inflammatory bowel disease or a positive family history of colorectal
cancer.
Finally, to determine whether the association between CRP and colon
cancer risk was independent of diabetes, we limited the analysis to persons
without diabetes. After adjusting for all covariates, a 1-SD increase in log
CRP was still associated with a significantly increased risk of colon cancer
(OR, 1.35; 95% CI, 1.03-1.75). Among nonsmokers, the association was stronger
(OR, 1.47; 95% CI, 1.09-1.96). These results suggest that the association
between colon cancer and inflammation is independent of diabetes.
These prospective findings demonstrate that prediagnostic concentrations
of CRP are strongly associated with the subsequent development of colon cancer.
This association was slightly stronger in nonsmokers and remained significant
after excluding higher-stage tumors at diagnosis and cases that occurred within
5 years of follow-up, thus reducing the likelihood that our results could
reflect the presence of subclinical disease at the time of blood collection.
Results were similar in men and women and remained significant when limiting
analyses to persons without diabetes.
These findings are consistent with several lines of evidence that suggest
that the risk of colon cancer in particular is increased with inflammation.
Individuals with chronic inflammatory bowel disease, particularly ulcerative
colitis, are at substantially higher risk of developing colorectal cancer
than nonaffected persons and the risk increases with duration of disease.17 In laboratory studies, inflammation has been shown
to promote the conversion of colonic adenoma cells to adenocarcinoma cells.18 Moreover, IL-6, a pleiotropic cytokine that is a
potent stimulator of CRP, has been shown to stimulate the growth of primary
and metastatic colon cancer cell lines.19 Observational
studies12-14 have
shown that modest elevations in inflammatory markers, including total white
blood cell count and fibrinogen, are associated with an increased risk of
cancer mortality in persons free of cancer at baseline. Finally, clinical
trials have demonstrated that anti-inflammatory agents can reduce the risk
of developing colon adenomatous polyps.3-5,8 The
lack of an association with rectal cancer could reflect insufficient power
to detect associations within this small subset of participants who developed
rectal cancer or an alternative biological pathway. Additional studies are
needed to clarify this issue.
Despite evidence that inflammation could play a role in the pathogenesis
of colon cancer among persons without a history of inflammatory bowel disease,
data from epidemiologic studies are sparse. We know of only 1 other prospective
study20 that has examined the risk of incident
colon cancer associated with higher concentrations of CRP. Although the association
was not statistically significant, that study was aimed at risk of any cancer,
had few colon cancer cases (n = 44), and had limited follow-up time (58 months).
A study conducted in CLUE I (started in 1974 and also conducted among residents
of Washington County, Maryland) found that lower concentrations of serum albumin
were associated with an increased risk of incident colon cancer.21 Because
serum albumin is reduced in the presence of inflammation, an inverse association
between serum albumin levels and risk of colon cancer supports our hypothesis
that inflammation increases the risk of colon cancer.
Several factors should be considered in the interpretation of our findings.
A major strength of the current study is that it is a prospective study, and
thus, we can more confidently infer a temporal association between inflammation
and the occurrence of colon cancer. In addition, most cases (98%) were histologically
confirmed, thus reducing the likelihood of misclassification. One potential
limitation is that CRP was measured at one point in time. However, unaccounted
intraindividual variation would tend to attenuate the association and thus
cannot account for our results. Finally, CRP is a nonspecific marker of inflammation,
and additional studies of specific cytokines or factors that regulate acute-phase
response are necessary to elucidate the mechanisms by which inflammation increases
the risk of colon cancer.
Although confirmation of these results is clearly warranted, this finding,
if true, could have implications for prevention strategies. Several studies
have demonstrated that CRP levels can be reduced with smoking cessation22 and weight loss.23,24 In
addition, several trials have demonstrated a reduced risk of polyps and colon
cancer from use of aspirin and NSAIDs.3-8 Consistent
with these findings, in the present study we found a reduced risk of colorectal
cancer with use of these agents, but the results of tests for interaction
between use of anti-inflammatory agents and CRP were not statistically significant
(data not shown). However, data on use of anti-inflammatory agents were limited
to use within the last 48 hours. Additional studies are needed to clarify
whether use of anti-inflammatory agents modifies the association between CRP
and colon cancer risk. Finally, the cut points for CRP associated with moderate
(1-3 mg/L) and high (>3 mg/L) risk of cardiovascular disease are in the same
range associated with increased colon cancer risk in the present study.25
In summary, this study demonstrates that elevated concentrations of
CRP are strongly associated with the development of colon cancer in individuals
believed to be free of this disease at baseline. This finding is consistent
with literature that supports the role of chronic inflammation in the pathogenesis
of colon cancer. Additional studies are needed to confirm these findings and
to determine the implications on screening and prevention of colon cancer.
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