Plasma Inflammatory Markers and Risk of Advanced Colorectal Adenoma in Women

Abstract

Evidence remains inconclusive about the association of systemic inflammatory markers with colorectal neoplasia. We investigated whether circulating inflammatory markers were associated with risk of advanced colorectal adenoma. We measured plasma macrophage inhibitory cytokine-1 (MIC-1), C-reactive protein (CRP), interleukin-6 (IL-6), and soluble tumor necrosis factor receptor 2 (sTNFR-2) in blood samples drawn from 32,826 women in 1989-1990 in the Nurses' Health Study. Through 2008, we documented 757 cases of advanced colorectal adenomas (≥1cm or any size with advanced histology); each case was matched by age and time of blood draw with one control randomly selected from participants who underwent lower endoscopy and did not have neoplasia. Plasma MIC-1 was associated with higher risk of advanced adenoma (Ptrend=0.04), with an odds ratio of 1.55 (95% CI, 1.03-2.32) comparing extreme quintiles of MIC-1 after adjusting for colorectal cancer-risk factors and other inflammatory markers. Among cases, MIC-1 level was positively associated with the number of adenomas (P<0.001) and gradually increased from adenomas located in the rectum, distal colon, and up to the proximal colon. There was a strong positive association between MIC-1 and risk of adenomas with multiplicity, ≥1cm size and location in the proximal colon (all Ptrend<0.05). CRP, IL-6 or sTNFR-2 was not associated with adenoma risk. In conclusion, plasma MIC-1 was associated with higher risk of colorectal adenoma, especially multiple, large and proximal adenomas. Our results provide further support for a role for MIC-1 in carcinogenesis and the potential for MIC-1 as an adjunctive biomarker for detection of advanced colorectal adenoma.

Circulating levels of C-reactive protein, interleukin-6 and tumor necrosis factor-α and risk of colorectal adenomas: a meta-analysis

“…However, the limited information precluded a more robust assessment of the above-mentioned findings. The pooled results on CRP and IL-6 and risk of colorectal adenomas are consistent with those from nested case-control studies [ 8 , 17 , 23 ] in which circulating levels measurement preceded colorectal adenomas incidence. No nested case-control study on circulating levels of TNF-α and colorectal adenomas was identified.…”

“…The departure from a linear relationship was not significant between CRP (P for nonlinearity =0.18), IL-6 (P for nonlinearity =0.35) and TNF-α (P for nonlinearity =0.87) and risk of colorectal adenoma, respectively. The risk of colorectal adenomas increased by 2% [1.02 (0.97-1.08)] for each 1 mg/L increment in circulation CRP levels (eight studies [ 8 , 10 , 17 , 20 , 22 – 25 ] including 4,981 cases), 9% [1.09 (0.91-1.31)] for each 1 ng/L increment in circulation IL-6 levels (five studies [ 8 , 13 , 15 , 20 , 25 ] including 1,763 cases), and 6% [1.06 (0.93-1.21)] for each 1 pg/mL increment in circulation TNF-α levels (four studies [ 12 – 13 , 18 , 25 ] including 1,452 cases), respectively.…”

“…C-reactive protein (CRP), one of the acute-phase proteins in inflammation, is produced in response to increased circulating IL-6 and TNF-α, etc. [ 5 ] Although results from experimental studies indicated that CRP, IL-6 and TNF-α may be involved in the development of colorectal neoplasia [ 5 – 6 ], published data on circulating CRP, IL-6 and TNF-α and the risk of colorectal adenomas are not conclusive [ 8 – 37 ], respectively. Considering no meta-analysis is available to systematically explore the above-mentioned associations, we conducted a meta-analysis of observational studies following the PRISMA statement ( Appendix 1 ) to assess the association between circulating levels of CRP, IL-6 and TNF-α and the risk of colorectal adenomas.…”

The MIC-1/GDF15-GFRAL Pathway in Energy Homeostasis: Implications for Obesity, Cachexia, and Other Associated Diseases

“…In humans, MIC-1/GDF15 serum levels rise when adenomatous polyps develop, rise further in proportion to the stage and extent of colon cancer, and predict the cancer outcome (Brown et al, 2003;Danta et al, 2017;Song et al, 2016;Chen et al, 2017;Mehta et al, 2015;Li et al, 2016) (Figure 3). Further, a coding region H6D polymorphism in mature MIC-1/GDF15 alters colorectal cancer behavior and risk (Brown et al, 2003;Wang et al, 2015a).…”

Markers of systemic inflammation and colorectal adenoma risk: Meta-analysis of observational studies

“…Grouping studies by fasting status and measurement method showed statistically significant results when considering studies that collected fasting blood samples (OR = 1.38, 95%CI: 1.02-1.88; I 2 = 32%, P heterogeneity = 0.21) and INA measurement (OR = 1.54, 95%CI: 1.06-2.23; I 2 = 29%, P heterogeneity = 0.24). Moreover, including one study[23] in which blood analyses were not uniformly conducted on fasting samples but risk estimates were adjusted for fasting/non-fasting, did not change markedly results (OR = 1.29, 95%CI: 1.01-1.64; I 2 = 25%, P heterogeneity = 0.25). No significant confounders were detected when grouping by gender, sample size, geographical location, and quality score.…”