Abstract
Background
C-reactive protein (CRP) has been associated with cancer risk in some prospective studies. However, the associations have not been entirely consistent and have not been evaluated in Chinese females. We conducted a large population-based cohort study to investigate whether elevated levels of CRP at baseline are associated with an increased risk of cancer among Chinese females.
Methods
A total of 19,437 women from the Chinese Kailuan Female Cohort were enrolled in the study in July 2006. Levels of high-sensitivity CRP (hsCRP) were tested at baseline for all subjects. Multivariable Cox proportional hazards regression models were used to evaluate the association between levels of hsCRP and risk of all cancers, including breast cancer, lung cancer, colorectal cancer, and other cancers.
Results
By December 31, 2011, a total of 322 incident cancer cases accrued. Compared with women with lower hsCRP levels (<1 mg/L), women with higher hsCRP (>3 mg/L) had a significantly increased risk of all incident cancers [HR, 1.62; 95% confidence intervals (CI), 1.23–2.14; Ptrend = 0.001] and breast cancer (HR, 1.74; 95% CI, 1.01–2.97; Ptrend = 0.047). The significant association between hsCRP levels and breast cancer risk was apparent among younger women (<50 years; HR, 2.76; 95% CI, 1.18–6.48).
Conclusion
Elevated levels of hsCRP at baseline may be associated with an increased risk of cancer, especially breast cancer, and particularly in younger Chinese women.
Impact
Our findings provide additional evidence for a role of inflammation in carcinogenesis and suggest that CRP may be a potentially useful biomarker of cancer risk in this population.
Introduction
A relationship between inflammation and cancer risk has long been suspected, as Virchow observed leucocytes in neoplastic tissues and hypothesized that the origin of cancer was related to chronic inflammation (1). Subsequent epidemiologic studies have found that several chronic inflammatory processes are associated with specific cancers, such as certain inflammatory bowel diseases with colorectal cancer, chronic bronchitis with lung cancer, and chronic viral infections with multiple cancer types (2). In recent years, there has been increasing molecular and epidemiologic evidence that inflammation plays an important role in the pathogenesis of many cancers (3).
C-reactive protein (CRP) is a general marker of inflammation and as such is the most widely used biomarker of inflammation. Levels of CRP are naturally very low in healthy individuals and are produced in the liver in response to cytokines, such as IL6, IL1, and TNFα, after an inflammatory stimulus (4). The use of CRP in epidemiologic studies has several advantages over other inflammatory cytokines in measuring chronic inflammation including the availability of reliable assays and temporal stability (5, 6).
Several studies have been performed to evaluate the relationship between levels of CRP and risk of chronic noninfectious diseases, including cancer (7–10); however, the findings have been inconsistent. Therefore, in this study, we performed a large population-based cohort study in Chinese women to evaluate whether elevated levels of high-sensitivity CRP (hsCRP) at baseline are associated with an increased risk of cancer.
Materials and Methods
Study design and population
The data were obtained from a health examination of employees of the Kailuan Company in the city of Tangshan in Northern China. Tangshan is situated about 90 miles southeast of Beijing and represents the overall Chinese population from a socioeconomic perspective. In addition to coal products, the Kailuan Company also manages machine building, construction installation, electric power, coking, new building materials, chemical production, bauxite, transportation, and trading. Eleven hospitals are affiliated with the Kailuan Company (9). From July 2006 to October 2007, a total of 20,400 current and retired female employees of the Kailuan Company (73.9% of eligible individuals) underwent a physical examination for the first time at the eleven hospitals and all expenses were paid by the Kailuan Company.
Among these subjects, we excluded participants with a diagnosis of any prevalent cancer (n = 147) at baseline and any woman who was pregnant or lactating (n = 296). In addition, we excluded participants who did not provide blood samples at baseline (n = 520). Thus, a total of 19,437 participants were included in the present analysis. Standardized questionnaires were administered face-to-face by trained research doctors. Information obtained from this questionnaire included assessments of demographics, socioeconomics, diet, lifestyle, medical history, family medical history, alcohol use, smoking habits, and physical activity. The study was performed according to the guidelines of the Helsinki Declaration, and was approved by the Ethics Committee of the hospital. Written informed consent was obtained from all the participants. At the time of the health examination, height and weight were measured for all women while they were wearing scrubs to standardize the measurements. Body mass index (BMI) was calculated as body weight (kg) divided by the square of height (m2). All individuals also completed a breast and gynecologic examination, a breast ultrasound examination, and a chest X-ray.
Clinical measurements
Blood samples were obtained from the antecubital vein and transfused into vacutainers containing EDTA in the morning after an overnight fasting period. Tubes were centrifuged at 3,000 × g for 10 minutes at room temperature. After separation, plasma samples were frozen as rapidly as possible to −80ºC for storage until laboratory determinations were performed. The levels of hsCRP were measured using a commercial, high-sensitivity nephelometry assay (Cias Latex CRP-H, Kanto Chemical Co. Inc), with a lower limit of detection of 0.1 mg/L. In-house intra- and inter-assay CVs for hsCRP were 6.53% and 4.78%, respectively. High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol, and triglycerides were measured by an enzymatic method (Mind Bioengineering Co. Ltd; inter-assay CV: 10%). All the blood variables were measured using an autoanalyzer (Hitachi 747; Hitachi) at the central laboratory of the Kailuan hospital (Tangshan, China).
Follow-up and cancer ascertainment
We followed participants beginning at the baseline examination and ending at occurrence of cancer, death, or December 31, 2011, whichever event came first. During the study period, all the participants were followed up through face-to-face interviews or through examination of death certificates. All cancer events were coded using the ICD-10 system to indicate cancer type. Participants were followed up by face-to-face interviews at every 2-year routine medical examination until December 31, 2011, or to cancer or death. The follow-ups were performed by trained physicians. The outcome information was further confirmed by checking discharge summaries from the 11 affiliated hospitals where participants were treated and diagnosed, as well as by evaluating medical records from medical insurance to double-check diagnoses that may have been missed. For the 1,757 participants without face-to-face follow-up, the outcome information was obtained directly by checking death certificates from the provincial vital statistics offices, discharge summaries, and medical records.
Statistical analysis
We divided baseline hsCRP levels into three categories, based on a previously described approach (10): low (<1 mg/L), average (1–3 mg/L), and high (>3 mg/L). Cox proportional hazards regression models adjusted for suspected confounders were used to calculate HRs and 95% confidence intervals (CI) for baseline hsCRP levels and incident cancer, with adjustments for age, smoking (ever/never), alcohol consumption (ever/never), BMI, diabetes, and physical activity. We evaluated overall cancer as well as the most common cancers in the cohort that had adequate case numbers, including breast, lung, and colorectal cancer. In models evaluating breast cancer, we further adjusted for marital status. The Cochran–Armitage test was used for trends in the association between increasing hsCRP levels and cancer risk. As a sensitivity analysis, we further excluded 805 participants with hsCRP levels greater than 10 mg/L, which potentially indicated an acute inflammatory response. A two-sided P value less than 0.05 was considered statistically significant. Statistical analyses were performed using SAS software, version 9.2.
Results
Baseline characteristics of participants
Selected baseline characteristics of participants in the Kailuan Female Cohort are listed in Table 1. The mean age of women was 49 years and most women did not smoke or drink alcohol at baseline. Baseline characteristics of the participants according to plasma levels of hsCRP at study entry are listed in Table 2. The hsCRP levels were higher in older women (≥50), and among those who smoked, had diabetes, and who were overweight or obese (BMI > 23.9 kg/m2), compared with younger women (<50) and those without these characteristics or conditions (P < 0.05; Table 2).
Table 1.
Baseline characteristics of participants in the Kailuan Female Cohort (n = 19,437)
| Characteristic | n (%) |
|---|---|
| Age, y | |
| Mean | 49.2 |
| SD | 11.3 |
| <50 | 10,130 (52.1) |
| ≥50 | 9,307 (47.9) |
| Smoking | |
| Never | 18,549 (95.4) |
| Ever | 447 (2.3) |
| Diabetes | |
| No | 17,402 (89.5) |
| Yes | 1,623 (8.4) |
| Marital status | |
| Single | 1,136 (5.8) |
| Married | 17,853 (91.6) |
| BMI, kg/m2 | |
| <23.9 | 8,682 (44.7) |
| 24–27.9 | 7,038 (36.2) |
| ≥28 | 3,500 (18.0) |
| Physical activitya | |
| <3 times/wk | 16,367 (84.2) |
| >3 times/wk | 2,590 (13.3) |
| Drinking | |
| Never | 17,707 (91.1) |
| Ever | 1,289 (6.6) |
| hsCRP (mg/L) | |
| Mean | 2.4 |
| SD | 5.0 |
| <1 | 10,351 (53.3) |
| 1–3 | 4,984 (25.6) |
| 3–10 | 3,297 (17.0) |
| >10 | 805 (4.1) |
Physical activity time longer than 30 minutes.
Table 2.
Baseline characteristics of participants in the Kailuan Female Cohort 2006 to 2007 examination according to plasma levels of hsCRP
| Characteristic | hsCRP (mg/L)
|
|||
|---|---|---|---|---|
| <1
|
1–3
|
>3
|
P | |
| n (%) | n (%) | n (%) | ||
| Female | 10,351 (53.25) | 4,984 (25.64) | 4,102 (21.10) | |
| Age | ||||
| <50 | 6,337 (62.56) | 2,213 (21.85) | 1,580 (15.60) | <0.0001 |
| ≥50 | 4,014 (43.13) | 2,771 (29.77) | 2,522 (27.10) | |
| Smoking | ||||
| No | 10,142 (54.68) | 4,818 (25.97) | 3,589 (19.35) | <0.0001 |
| Yes | 191 (42.73) | 139 (31.10) | 117 (26.17) | |
| Diabetes | ||||
| No | 9,782 (56.21) | 4,432 (25.47) | 3,188 (18.32) | <0.0001 |
| Yes | 545 (33.58) | 521 (32.10) | 557 (34.32) | |
| Marital status | ||||
| Single | 606 (53.35) | 274 (24.12) | 256 (22.54) | 0.022 |
| Married | 9,726 (54.48) | 4,676 (26.19) | 3,451 (19.33) | |
| BMI, kg/m2 | ||||
| <23.9 | 5,651 (65.08) | 1,720 (19.81) | 1,312 (15.11) | <0.0001 |
| 24–27.9 | 3,410 (48.45) | 2,023 (28.74) | 1,605 (22.80) | |
| ≥28 | 1,173 (33.51) | 1,171 (33.46) | 1,156 (33.03) | <0.0001 |
| Physical activitya | ||||
| No | 468 (53.00) | 218 (24.69) | 197 (22.31) | <0.0001 |
| <3 times/wk | 8,606 (55.58) | 3,880 (25.06) | 2,998 (19.36) | |
| >3 times/wk | 1,252 (48.34) | 854 (32.97) | 484 (18.69) | |
| Drinking | ||||
| No | 9,620 (54.33) | 4,609 (26.03) | 3,478 (19.64) | 0.285 |
| Yes | 713 (55.31) | 346 (26.84) | 230 (17.84) | |
Physical activity time longer than 30 minutes.
Cancer characteristics of Kailuan Female Cohort are listed in Table 3. During a mean follow-up time of 58.6 ± 5.9 months, a total of 322 incident cancers occurred, with the most common being breast cancer (n = 87, 27%), lung cancer (n = 38, 11.8%), and colorectal cancer (n = 31, 9.6%).
Table 3.
Cancer characteristics of Kailuan Female Cohort through December 31, 2011
| Cancer type | n (%) |
|---|---|
| All | 322 (100) |
| Breast cancer | 87 (27.0) |
| Lung cancer | 38 (11.8) |
| Colorectal cancer | 31 (9.6) |
| Other cancer | 166 (51.6) |
| Corpora uteri | 27 (8.3) |
| Brain and central nervous system | 21 (6.5) |
| Thyroid | 19 (5.9) |
| Liver and gallbladder | 18 (5.6) |
| Ovary | 14 (4.3) |
| Cervix | 12 (3.7) |
| Stomach | 11 (3.4) |
| Urinary system | 10 (3.1) |
| Pancreas | 6 (1.9) |
| Leukemia and malignant lymphoma | 6 (1.9) |
| Others | 22 (6.8) |
All cancers
Of the 322 incident cancers through December 31, 2011, 128 had low (<1 mg/L) hsCRP levels (39.8%), 87 had average (1–3 mg/L) hsCRP levels (27.0%), and 107 had high (>3 mg/L) hsCRP levels (33.2%). Individuals with high hsCRP levels at baseline had an increased risk of cancer overall relative to individuals with low hsCRP levels (HR, 1.62; 95% CI, 1.23–2.14) and increasing levels of hsCRP were associated with an increased risk of all cancers (Ptrend = 0.001), after adjustment for age, smoking, alcohol consumption, BMI, diabetes, and physical activity (Table 4).
Table 4.
Association between hsCRP levels at baseline and risk of cancer
| Cancer type | Patients (n %) | hsCRP (mg/L), HR (95% CI)
|
Ptrend | ||
|---|---|---|---|---|---|
| <1 | 1–3 | >3 | |||
| Any cancera | 322 (1.66) | 1 | 1.14 (0.86–1.52) | 1.62 (1.23–2.14) | 0.001 |
| Breast cancerb | 87 (0.45) | 1 | 1.25 (0.73–2.15) | 1.74 (1.01–2.97) | 0.047 |
| Lung cancera | 38 (0.20) | 1 | 1.00 (0.45–2.25) | 1.33 (0.60–2.96) | 0.525 |
| Colorectal cancera | 31 (0.16) | 1 | 1.07 (0.45–2.57) | 0.87 (0.32–2.36) | 0.880 |
| Other cancersa | 166 (0.85) | 1 | 1.13 (0.76–1.69) | 1.80 (1.23–2.64) | 0.004 |
Adjusted for age, smoking, drinking, BMI, diabetes, and physical activity.
Adjusted for age, smoking, drinking, BMI, diabetes, physical activity, and marital status.
Breast cancer
A total of 87 incident breast cancers occurred during the period of follow-up. Multivariate adjusted HRs for incident breast cancer showed an increased risk for women in the high hsCRP group compared with women with low levels of hsCRP (HR, 1.74; 95% CI, 1.01–2.97), and increasing levels of hsCRP were associated with an increased risk of breast cancer (Ptrend = 0.047, after adjustment for age, smoking, alcohol consumption, BMI, diabetes, physical activity, and marital status; Table 4). After results were stratified by age, the significant association between high levels of hsCRP and the risk of breast cancer was found among the younger women (<50 years; HR, 2.76; 95% CI, 1.18–6.48), but not among women ≥50 years old (HR, 1.34; 95% CI, 0.68–2.64; Table 5). However, there was no significant interaction between age and the level of hsCRP on the incidence of breast cancer (Pinteraction = 0.354).
Table 5.
Association between hsCRP levels at baseline and risk of breast cancer, stratified by age
| n | Patients | Adjusted HRa (95% CI) | |
|---|---|---|---|
| Age < 50 | |||
| hsCRP (mg/L) | |||
| <1 | 6,337 | 15 | 1.00 |
| 1–3 | 2,213 | 6 | 1.23 (0.47–3.23) |
| >3 | 1,580 | 9 | 2.76 (1.18–6.48) |
| Age ≥ 50 | |||
| hsCRP (mg/L) | |||
| <1 | 4,014 | 19 | 1.00 |
| 1–3 | 2,771 | 18 | 1.18 (0.61–2.28) |
| >3 | 2,522 | 20 | 1.34 (0.68–2.64) |
Adjusted for smoking, drinking, BMI, diabetes, physical activity, and marital status.
Lung cancer
A total of 38 incident lung cancers occurred during the period of follow-up. Levels of hsCRP were not significantly associated with risk of incident lung cancer. The HR was 1.33 (95% CI, 0.60–2.96) for the effect of hsCRP levels on lung cancer risk comparing women with high hsCRP levels to women with low hsCRP levels, adjusted for age, smoking, alcohol consumption, BMI, diabetes, and physical activity (Table 4). Furthermore, no significant trend with increasing hsCRP levels was observed for risk of lung cancer (Ptrend = 0.525).
Colorectal cancer
A total of 31 incident colorectal cancers occurred during the period of follow-up.
Levels of hsCRP were not significantly associated with risk of incident colorectal cancer. The HR was 0.87 (95% CI, 0.32–2.36) for the effect of hsCRP levels on colorectal cancer risk comparing women with high hsCRP levels with women with low hsCRP levels, adjusted for age, smoking, alcohol consumption, BMI, diabetes, and physical activity, and no significant trend was observed (Ptrend = 0.880; Table 4).
Other cancers
Of the 322 incident cancers, 166 (~52%) were other types aside from those analyzed separately above (Table 3). Women with high levels of hsCRP had a significantly increased risk of these other cancer types compared with women with low hsCRP levels (HR, 1.80; 95% CI, 1.23–2.64; Ptrend = 0.004; Table 4), adjusted for age, smoking, alcohol consumption, BMI, diabetes, and physical activity. A significant trend was observed for risk of other cancers in relation to increasing levels of hsCRP (Ptrend = 0.004; Table 4).
Sensitivity analyses
After excluding individuals with hsCRP levels greater than 10 mg/L (n = 805), which may be indicative of an acute inflammatory response, we found that compared with women with lower hsCRP levels (<1 mg/L), women with higher hsCRP levels (>3 mg/L) still had a significantly increased risk of all incident cancers (HR, 1.60; 95% CI, 1.19–2.16) and breast cancer (HR, 1.89; 95% CI, 1.08–3.32). The risk of all incident cancers (Ptrend = 0.003) and breast cancer (Ptrend = 0.029) was increased in a dose-dependent manner with increasing hsCRP levels (Table 6).
Table 6.
Association between hsCRP levels at baseline and risk of cancer (excluding hsCRP > 10 mg/L data)
| Cancer type | Patients (n %) | hsCRP (mg/L), HR (95% CI)
|
Ptrend | ||
|---|---|---|---|---|---|
| <1 | 1–3 | >3 | |||
| Any cancera | 295 | 1 | 1.16 (0.88–1.54) | 1.60 (1.19–2.16) | 0.003 |
| Breast cancerb | 80 | 1 | 1.29 (0.75–2.21) | 1.89 (1.08–3.32) | 0.029 |
| Lung cancera | 34 | 1 | 0.99 (0.44–2.90) | 1.20 (0.50–2.90) | 0.732 |
| Colorectal cancera | 26 | 1 | 1.18 (0.49–2.84) | 0.60 (0.17–2.16) | 0.579 |
| Other cancersa | 155 | 1 | 1.14 (0.76–1.70) | 1.77 (1.17–2.66) | 0.009 |
Adjusted for age, smoking, drinking, BMI, diabetes, and physical activity.
Adjusted for age, smoking, drinking, BMI, diabetes, physical activity, and marital status.
Discussion
In this large population-based prospective cohort study of over 19,000 participants, we found that increasing levels of hsCRP were associated with an increased risk of all cancers and breast cancer specifically, but no associations were observed with lung cancer or colorectal cancer. The incidence rate of overall cancer among females in our cohort adjusted to the Segi world standard population was 189 cases per 100,000, which is slightly higher than the overall cancer rate for females in the general population of China in 2009 (166 cases per 100,000). Furthermore, the incidence rate of breast cancer among females in our cohort was approximately 48 cases/100,000, a rate slightly higher than urban China as a whole in 2009 (~34 cases/100,000). The incidence rates of both cancer overall and breast cancer specifically among women in our cohort are lower compared with women in Western Europe and the United States (~297 cases/100,000 for overall cancer and ~93 cases/100,000 for breast cancer; ref. 11), where most previous studies of CRP and cancer risk have been conducted.
Although the exact molecular and cellular mechanisms underlying the association between inflammation and cancer risk remain unresolved, several possible mechanisms by which chronic inflammation and CRP in particular may promote cancer development have been hypothesized. In particular, inflammatory cells secrete cytokines, such as IL6, IL1, and TNFα, into the blood that can induce CRP secretion from hepatocytes after an inflammatory stimulus (4). CRP may have proinflammatory effects by itself and also may activate the NF-κβ pathway to induce carcinogenesis (12). Inflammation-induced damage leading to oxidation of DNA and important proteins could initiate carcinogenesis (13). Furthermore, inflammation may promote tumor progression through facilitating chronic activation of humoral immunity, infiltration of Th2 cells, vascular permeability, and angiogenesis (14, 15). Some epidemiologic evidence has supported these hypotheses; for example, prospective data have indicated that the regular use of aspirin, ibuprofen, or other NSAIDs may have a significant chemopreventive effect against the development of breast cancer (16).
Several previous prospective studies have evaluated the relationship between levels of CRP and risk of cancer (10), and results have been generally inconsistent, which may be due to different characteristics of the participants and/or different enrollment criteria as well as differences in CRP measurement methods. The Rotterdam Study (17), a population-based prospective cohort study, included a total of 4,209 female participants from the suburbs of Rotterdam in the Netherlands. Plasma levels of CRP were determined with a high-sensitivity assay in these women between 1989 and 1993, and baseline hsCRP levels were divided into the same three groups as in our study [i.e., low (<1 mg/L), average (1–3 mg/L), or high (>3 mg/L)]. The results from this study are consistent with our findings in that higher baseline hsCRP levels were significantly associated with all cancers (HR, 1.4; 95% CI, 1.1–1.7 based on 706 cases) as well as breast cancer (HR, 1.6; 95% CI, 1.1–2.4 based on 184 cases). Results from other prospective reports, including the Atherosclerosis Risk in Communities prospective cohort study (18) and the Multiethnic Cohort Study (19), also are consistent with our findings in showing an elevated association with breast cancer in particular based on 176 and 706 cases, respectively.
Conversely, a large population-based cohort study, which included 27,919 healthy American women ages 45 years and older (20), found no association between higher plasma levels of CRP at baseline and breast cancer (892 cases) after adjustment for other risk factors such as age, BMI, and family history of breast cancer. Similarly, reports from two prospective cohort studies (10, 21) that included Danish (164 breast cancer cases) and American participants (41 breast cancer cases) and two recently published nested case–control studies (3, 22) that included 218 and 302 breast cancer cases either did not find an association between baseline CRP levels with risk of breast cancer or noted weak associations. The inconsistent findings for breast cancer between studies may be due to several potential reasons. First, we note that the two previous American studies did not measure CRP with a high-sensitivity assay and the age at entry of the participants was older than in our study. Second, the prospective Danish study only included 5,369 female participants, and the median age and racial make-up are different than in our study.
Our study found no evidence for an association between baseline hsCRP levels and risk of either lung or colorectal cancer. In support of these findings, the British Women’s Heart and Health Study (BWHHS; ref. 23), which is a prospective cohort study of 4,286 women ages 60 to 79 years, also did not find positive results for these two cancers although the number of lung and colorectal cancer cases in the BWHHS and in our study was relatively small (i.e., <40). Nevertheless, a large population-based prospective cohort study (24) that included 27,913 female participants, and that had 169 cases of colorectal cancer during the follow-up period, also found no significant association between baseline CRP levels and colorectal cancer. Conversely, Prizment and colleagues (25) found a significant positive association between CRP and colorectal cancer (308 cases) in a cohort study including 13,414 individuals. And, more recently, Shiels and colleagues (26) observed a strong association between CRP and lung cancer (526 cases) risk in a nested case–control study of participants in the prospective Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Further large prospective studies are needed to evaluate these associations.
Although the breadth of evidence from studies of CRP and cancer risk generally support the hypothesis that chronic inflammation is a major driver of carcinogenesis, several factors could potentially explain the inconsistent associations observed for specific tumor types. In our study, although CRP was significantly associated with overall cancer and breast cancer specifically, we observed no association for either lung or CRC, both of which have established associations with factors that contribute to chronic inflammation (27, 28). First, we note that our cohort is relatively young both in terms of the age of the women and the number of years of follow-up that have accrued to date, and consequently the number of lung cancer and CRC cases was relatively small. Although the strongest associations with breast cancer were observed in younger women in our study, the case numbers for other tumor sites did not allow for stratified analyses by age. Considering that the incidence of lung cancer and CRC sharply increases with age and the average age at onset is slightly higher as compared with breast cancer, and the fact that breast cancer occurs at a generally younger age in Asian women with the highest rates apparent in those 45 to 50 years old (29), it is possible that the dynamics of our cohort are not yet conducive to detecting a significantly increased risk of CRC and lung cancer. This may particularly be the case if elevated levels of CRP, and the underlying processes contributing to these higher levels, have induction periods for carcinogenesis that vary by tumor type. Ongoing follow-up of our cohort will enable an evaluation of these hypotheses as well as associations with other specific cancer types. It will also allow for the determination of whether the observed associations persist with an increasing number of years between blood collection and cancer diagnosis.
There are several strengths and limitations that should be noted when interpreting the results of our study. The major limitations of our study include the single measurement of hsCRP at baseline. As with most biomarkers, including those associated with inflammatory status, it is likely that there is some degree of variability in marker levels over the length of the follow-up period in a prospective study. Some previous evidence has suggested that CRP levels are relatively stable over short periods of time and have little or no diurnal variation (30, 31). The stability over longer periods of time that would be applicable to most cohorts is not as certain, and as such, there is a possibility of nondifferential misclassification if CRP levels fluctuate during the follow-up period. For example, a recent study in the Chinese general population reported significant increases in hsCRP concentrations in men and women over a 2-year follow-up period (32). CRP levels are influenced by a variety of factors, including age and smoking (33), that vary over the course of a study and in different study populations. Only about 2.3% of the women in our cohort reported smoking. Another limitation is the relatively short follow-up time (~58 months), which precluded an evaluation of other cancer types due to small case numbers. The most important strength of our study is that it was a large population-based prospective cohort study, which minimizes the possibility that the associations observed in our study are due to early disease effects compared with retrospective studies; though as noted, future analyses will be needed to rule out this possibility. Additional strengths of our study included a high participation (73.9%) and follow-up rate (100%) among a population that is very generalizable to the overall Chinese population with respect to socioeconomic characteristics, collection of blood samples on a high percentage of subjects (97.5%), and the use of a highly sensitive assay with good QC characteristics to measure CRP.
In conclusion, our study suggested that elevated levels of hsCRP are associated with increased risk of all cancers and breast cancer, but are not associated with risk of lung cancer or colorectal cancer. Future research within our cohort will focus on follow-up studies of the cohort and other laboratory-based experimental studies; for example, the evaluation of other immune markers and genetic factors, to further explore the molecular mechanisms between hsCRP, other biomarkers, and risk of incident cancer.
Acknowledgments
The authors thank Liying Cao and Dongsheng Sun for participating in the study.
Grant Support
This work was partly supported by the National Cancer Institute (grant no. CA104786; to T. Zheng), Fogarty training grants from the NIH (grant nos. D43TW 008323 and D43TW 007864-01; to T. Zheng), the National Natural Science Fund from the National Natural Science Foundation of China (grant no. 81172757; to N. Li), the Beijing Natural Science Foundation (grant 7123225; to N. Li), and Beijing Nova Program grant xx2012067 (grant no. xx2012067; to N. Li and M. Dai).
Footnotes
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Disclaimer
The authors assume full responsibility for analyses and interpretation of these data.
Authors’ Contributions
Conception and design: S. Wu, M. Dai, J. He
Development of methodology: S. Wu
Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): G. Wang, S. Chang, K. Su, S. Wu, Y. Zou
Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): G. Wang, N. Li, L. Guo, J. Ren, S. Chen, T. Zheng
Writing, review, and/or revision of the manuscript: G. Wang, N. Li, B.A. Bassig, T. Zheng, J. He
Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): K. Su, F. Li, M. Dai, T. Zheng
Study supervision: J. He
Other (training the scientists who conducted the study, including training in methodology, principles, and practices of epidemiology and biostatistics): T. Zheng
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