Associations of circulating C-reactive protein and interleukin-6 with cancer risk: Findings from two prospective cohorts and a meta-analysis

Department of Social Medicine, University of Bristol, Canynge Hall, Whiteladies Road, Bristol, BS8 2PR, UK.
Cancer Causes and Control (Impact Factor: 2.74). 09/2008; 20(1):15-26. DOI: 10.1007/s10552-008-9212-z
Source: PubMed


We investigated the associations of circulating C-reactive protein (CRP) and interleukin-6 (IL-6) with cancer risk.
We examined the associations of CRP and IL-6 with incident cancer in two prospective cohorts, the British Women's Heart and Health Study (4,286 women aged 60-80) and the Caerphilly Cohort (2,398 men aged 45-59) using Cox regression and pooled our findings with previous prospective studies' in fixed and random effects meta-analyses.
CRP and IL-6 were associated with some incident cancers in our cohorts, but the numbers of cancer cases were small. In our meta-analyses elevated CRP was associated with an increased overall risk of cancer (random effects estimate (RE): 1.10, 95% CI: 1.02, 1.18) and lung cancer (RE: 1.32, 95% CI: 1.08, 1.61). Its associations with colorectal (RE: 1.09, 95% CI: 0.98, 1.21) and breast cancer risks (RE: 1.10, 95% CI: 0.97, 1.26) were weaker. CRP appeared unrelated to prostate cancer risk (RE: 1.00 0.88, 1.13). IL-6 was associated with increased lung and breast cancer risks and decreased prostate cancer risk, and was unrelated to colorectal cancer risk.
Our findings suggest an etiological role for CRP and IL-6 in some cancers. Further large prospective and genetic studies would help to better understand this role.

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    • "Activation of innate immunity promotes various inflammatory reactions and triggers the release of inflammatory cytokines as well as other inflammatory mediators, such as tumor necrosis factor alpha (TNFα), interleukin-1 beta (IL1β) and interleukin-6 (IL-6) [7]. Elevated circulating levels of inflammatory biomarkers, i.e., IL6, TNFα, C-reactive protein (CRP), have been associated with a greater risk for several types of cancer and cancer prognosis, including breast [8,9]. Several studies have also identified inflammation and immune-related signatures as being important for disease prognosis for triple negative breast cancer, the aggressive breast cancer subtype often observed in young AA women [10]. "
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    ABSTRACT: African American (AA) women are more likely than European American (EA) women to be diagnosed with early, aggressive breast cancer. Possible differences in innate immune pathways (e.g., inflammatory responses) have received little attention as potential mechanisms underlying this disparity. We evaluated distributions of selected genetic variants in innate immune pathways in AA and EA women, and examined their associations with breast cancer risk within the Women's Circle of Health Study (WCHS). In stage I of the study (864 AA and 650 EA women) we found that genotype frequencies for 35 of 42 tested SNPs (18 candidate genes) differed between AAs and EAs (corroborated by ancestry informative markers). Among premenopausal AA women, comparing variant allele carriers to non-carriers, reduced breast cancer risk was associated with CXCL5-rs425535 (OR=0.61, P=0.02), while among EA women, there were associations with TNFA-rs1799724 (OR =2.31, P =0.002) and CRP-rs1205 (OR=0.54, P=0.01). For postmenopausal women, IL1B-rs1143627 (OR=1.80, P=0.02) and IL1B-rs16944 (OR=1.85, P =0.02) were associated with risk among EA women, with significant associations for TNFA-rs1799724 limited to estrogen receptor (ER) positive cancers (OR=2.0, P =0.001). However, none of the SNPs retained significance after Bonferroni adjustment for multiple testing at the level of P0.0012 (0.05/42) except for TNFA-rs1799724 in ER positive cancers. In a stage II validation (1,365 AA and 1,307 EA women), we extended evaluations for four SNPs (CCL2-rs4586, CRP-rs1205, CXCL5-rs425535, and IL1RN-rs4251961), which yielded similar results. In summary, distributions of variants in genes involved in innate immune pathways were found to differ between AA and EA populations, and showed differential associations with breast cancer according to menopausal or ER status. These results suggest that immune adaptations suited to ancestral environments may differentially influence breast cancer risk among EA and AA women.
    PLoS ONE 08/2013; 8(8):e72619. DOI:10.1371/journal.pone.0072619 · 3.23 Impact Factor
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    • "Our results are supported by the findings of several large prospective studies that did not find any significant association between baseline circulating CRP (Ito et al, 2005; Zhang et al, 2005; Siemes et al, 2006; Trichopoulos et al, 2006; Allin et al, 2009; Heikkila et al, 2009; Chan et al, 2011), IL-6 (Il'yasova et al, 2005; Heikkila et al, 2009; Chan et al, 2011; Ho et al, 2012) or TNF-α (Il'yasova et al, 2005; Ho et al, 2012) levels and risk of CRC. In addition, a recent study that used instrumental variable analysis (Mendelian randomisation) also did not observe an association between either plasma CRP or genetically determined CRP levels and risk of CRC (Allin et al, 2010). "
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    ABSTRACT: Background: Chronic inflammation may mediate risk of colorectal cancer (CRC); however, the association between circulating inflammatory markers and risk of CRC has been inconsistent. Methods: We prospectively evaluated the association of plasma C-reactive protein (CRP), interleukin-6 (IL-6), and the soluble tumour necrosis factor receptor 2 (sTNFR-2) with incident CRC among 274 cases and 532 matched controls nested in the Health Professionals Follow-up Study. Results: Multivariate relative risk (RR) of CRC comparing the extreme quartiles of plasma IL-6 was 1.54 (95% confidence interval (CI), 0.99–2.40; Ptrend=0.02). However, after excluding cases diagnosed within 2 years of blood draw, this association was not statistically significant (RR=1.26, 95% CI, 0.78–2.05; Ptrend=0.21). In analyses restricted to cases diagnosed at least 2 years after blood draw, the association of IL-6 with CRC appeared to differ by body mass index such that the significantly positive association was only present among lean individuals (Pinteraction=0.03). We did not observe any significant association between CRP or sTNFR-2 and CRC. Conclusion: Plasma inflammatory markers are not generally associated with risk of CRC among men. However, the possibility that plasma IL-6 is associated with increased risk of CRC among lean men requires further investigation.
    British Journal of Cancer 04/2013; 108(9). DOI:10.1038/bjc.2013.172 · 4.84 Impact Factor
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    • "The three studies that have investigated the association between circulating CRP and risk of colorectal cancer in women only [47–49] did not observe positive associations, suggesting that inconsistency in studies published so far may be related to sex differences. Three studies that have investigated circulating IL-6 in relation to colorectal cancer risk observed no association [48, 50], and two studies on TNF-alpha and colorectal cancer risk did not observe an association [50, 51••]. In a case-cohort study within the Women’s Health Initiative published during the past year, high levels of IL-6 were positively associated with risk of colorectal cancer, but the effect was likely to be mediated by insulin [51••]. "
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    ABSTRACT: Obesity and related metabolic alterations have been implicated to play a role in colorectal cancer risk. The metabolic syndrome, as assessed according to current international definitions by the key components, abdominal obesity, dyslipidemia, elevated blood pressure, and abnormal glucose metabolism, is associated with colorectal cancer. Recent studies suggest that abdominal obesity and abnormal glucose metabolism may primarily account for this association. Visceral adipose tissue is physiologically more active than subcutaneous adipose tissue and generates hormones and cytokines with inflammatory, metabolic, and direct carcinogenic potential, which may directly or indirectly increase colorectal cancer risk. Current evidence suggests that obesity acts as a risk factor for colorectal cancer by several mechanisms, including chronic low-grade inflammation, hyperinsulinemia, as well as alterations in insulin-like growth factor and adipokine concentrations. Metabolic biomarkers reflecting these processes may not only provide clues for etiological understanding of colorectal carcinogenesis but also might be an alternative way to define an "obesity phenotype" that is relevant for colorectal cancer development.
    03/2013; 2(1):1-9. DOI:10.1007/s13668-012-0036-9
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