In this prospective, sigmoidoscopy-based investigation of colorectal adenoma, circulating levels of CRP, a systemic marker of inflammation, were inversely associated with colorectal adenoma incidence. These data suggest that healthy individuals with elevated levels of CRP may be at lower risk of developing colorectal adenomas-a result that contrasts with findings from several studies of CRP and colorectal cancer incidence and with mechanistic studies of inflammation and colorectal tumorigenesis.
A number of epidemiologic studies have investigated the association of pre-diagnostic CRP concentrations and colorectal cancer risk and have yielded inconsistent results. However, a recent meta-analysis, which summarized data from eight independent prospective investigations, concluded that CRP was a weak, positive risk factor for colorectal cancer (summary relative risk per one unit change in natural log-transformed CRP, 1.12 (95% CI, 1.01-1.25) (24
). The inverse association between CRP levels and colorectal adenoma risk observed in the current investigation was surprising given our a priori
hypothesis that predicted a positive relationship, in keeping with the tumorigenic effects of inflammation in the colonic mucosa and the aforementioned findings from prospective studies of CRP levels and colorectal cancer risk. However, the results from the current study, though unexpected, are in fact somewhat concurrent with a previous investigation of CRP levels and incident colorectal adenoma development that was conducted within the CLUE II cohort (19
). In the CLUE II study, which evaluated pre-diagnostic CRP concentrations and incident adenoma risk among 135 colorectal adenoma cases and 269 matched controls, CRP levels were also inversely, albeit non-significantly, associated with colorectal adenoma risk. In that investigation, the inverse association between CRP levels and colorectal adenoma appeared to be stronger for proximal and tubular adenomas. For the latter, individuals in the highest quartile of CRP had a statistically significant 70% reduction in risk of developing a tubular adenoma than those in the lowest CRP quartile. While these findings are based on a relatively small number of cases, the consistency of the CLUE II data with the results of the current investigation are notable. In addition, our data are partially supported by the results of a recent case-control study conducted in Hawaii which reported that a polymorphism in the CRP
gene which is associated with higher circulating CRP levels, was inversely associated with colorectal adenoma prevalence(25
If the observed inverse association between CRP and colorectal adenoma development is indeed real, it may suggest that an elevated systemic inflammatory state is somehow protective in the early stages of colorectal tumorigenesis. This hypothesis stands in direct contrast to mechanistic and observational evidence which point towards tumorigenic effects of inflammation. However, there are data to demonstrate that neoplastic lesions can be targeted for removal by the immune system(26
). In colon cancer patients specifically, atopic dermatitis is accompanied by up-regulation of cytokines that stimulate T-cell infiltration against colon tumor cells(28
). Further, circulating levels of eosinophils and mast cells are associated with better prognosis(29
) and the type and density of T-cells adjacent to colon tumor cells was shown to be a better predictor of survival than traditional staging(30
). Therefore, it may be hypothesized that an individual with a heightened immune response may be at lower risk of developing early neoplastic lesions because they are targeted and removed more effectively than in an individual with a weaker response. This hypothesis is also supported by epidemiologic data which have revealed inverse associations between allergies and cancer risk(31
). Allergies are associated with enhanced immunosurveillance and the increased immunoglobulin E (IgE) levels which accompany an allergic response have been shown to decrease tumor development and increase survival time in murine models(32
). In a recent investigation nested within the Iowa Women's Health Study, a statistically significant reduced incidence of colorectal cancer was observed among allergy-sufferers compared to those with no reported allergies, suggesting that heightened immunosurveillance associated with allergic response may indeed be protective against colorectal tumorigenesis(35
). In addition, CRP itself may play a direct role in the elimination of neoplastic lesions through its function as an opsonin. CRP plays a key role in tissue repair and maintenance of tissue homeostasis - binding to damaged or apoptotic cells and targeting them for removal by immune cells(36
). Therefore, higher CRP levels may lead to more efficient elimination of pre-cancerous cells and reduced incidence of colorectal adenoma.
The findings of this study may, however, raise questions regarding the utility of CRP as a biomarker of colonic inflammation. CRP synthesis occurs in the liver in response to pro-inflammatory cytokines such as IL-6 and TNF-α which are released by phagocytes and adipocytes. CRP levels are routinely measured in clinical settings to evaluate a patient's overall inflammatory state and are considered a sensitive, yet non-specific, marker of chronic inflammation. However, CRP is also an acute phase protein and circulating levels of CRP can be influenced by a wide range of exogenous and endogenous factors and it is not known to what degree circulating CRP levels reflect low-grade inflammation in the colonic mucosa. A serologic biomarker that is specific to colonic inflammation has yet to be identified; however, a recent cross-sectional study of colorectal adenomas reported a significant positive relationship between circulating levels of IL-6 and TNF-α and colorectal adenoma prevalence, and a weaker, non-significant association for CRP(37
). Unfortunately, the current study lacks data on IL-6 and TNF- α levels but the assessment of these factors in relation to incident colorectal adenoma could prove highly informative. In addition, further work is required to ascertain the degree to which circulating CRP level is indicative of colonic inflammation, while future prospective studies of colorectal adenoma may wish to explore the additional inflammatory parameters and cytokines that have been mechanistically linked to colorectal tumorigenesis to more accurately evaluate the role of inflammation in the early stages of colorectal cancer.
Given that CRP levels can be influenced by a broad range of factors, it is also plausible that the current findings are the result of bias or confounding by unrecognized parameters. One possibility is that individuals with high levels of CRP may be more likely to be at higher risk for cardiovascular disease or other diseases associated with obesity and the metabolic syndrome, and they may have been using medications which are protective against colorectal adenomas, e.g. NSAIDs or statins. Indeed, in our study population, NSAID use was more common among those with the highest CRP levels; however, the inverse association between CRP levels and colorectal adenoma incidence did not differ according to use of NSAIDs. We note, however, that the NSAID data was only collected at the baseline sigmoidoscopy, and assessment of NSAIDs and other lifestyle factors at multiple time points may have allowed more accurate classification of habitual exposure. Further, data on other medications that may be relevant, such as statin use, were also not available, however, we feel it is unlikely that our findings were significantly influenced by statin use due to the relatively low prevalence of use at the time the baseline blood specimens were collected (38
). We also considered the fact that some individuals had very high levels of CRP (>10 mg/L)-indicative of acute inflammation at any site in the body, and speculated that these subjects might be driving the inverse association between CRP and colorectal adenoma. We, therefore, performed a sensitivity analysis whereby we evaluated the relation of CRP with colorectal adenoma following exclusion of all subjects with CRP >10 mg/L (N = 80), and found the results to be essentially unaltered. Similarly, we also analyzed the data using CRP cutpoints that have been proposed clinically for cardiovascular disease prevention (≥ 3mg/L compared to < 3mg/L), and likewise observed no overall change in the findings (data not shown).
Strengths of the study include a population of subjects with incident colorectal adenomas and matched controls that had undergone a flexible sigmoidoscopy and were known to be free of neoplasia in the left-sided colorectum at the baseline screen. A limitation is lack of data on polyp status in the right-sided colorectum as this was not evaluated during the screening procedure. The availability of serum from multiple time points in a sub-set of both the case and control groups enabled us to perform an assessment of the temporal reproducibility of CRP levels in both the cases and the controls. The relative stability of CRP levels over a five-year period in both the case and control groups suggests that a one-time measurement of CRP provides an accurate estimate of medium-term levels and that the development of colorectal adenoma is not associated with any significant changes in circulating CRP levels .
In summary, we found CRP levels to be inversely related to the development of colorectal adenoma-data that is not inconsistent with the majority of results from other studies of CRP and colorectal adenoma risk. This finding suggests that an elevated systemic inflammatory response (as evaluated by CRP levels) may be protective against the early stages of colorectal tumorigenesis, hypothetically through enhanced immunosurveillance.