Higher Macrophage Inhibitory Cytokine-1 Levels Associated With Increased Risk of Colorectal Cancer
It is known that chronic inflammation plays a role in the development of colorectal cancer. In a study reported in the Journal of the National Cancer Institute, Mehta et al evaluated the association of the novel plasma inflammatory biomarker macrophage inhibitory cytokine-1 (MIC-1; growth differentiation factor 15, GDF15) with risk for colorectal cancer. They found that elevated circulating MIC-1 levels were associated with increased risk and that aspirin and nonsteroidal anti-inflammatory drug (NSAID) use was associated with lower risk of prostaglandin-endoperoxide synthase 2 (PTGS2)-positive cancers, particularly in subjects with higher MIC-1 levels.
Study Details
A prospective, nested case-control study was performed in men from the Health Professionals Follow-up Study (274 cases, 531 controls) and women from the Nurses’ Health Study (344 cases, 419 controls) who had prediagnostic blood specimens. Enzyme-linked immunosorbent assay was used to measure MIC-1, and associations between MIC-1 quintile and development of colorectal cancer were examined using logistic regression analysis adjusting for the matching factors of age at and date of blood draw and other factors.
Multivariate model 1 adjusted for race, sex, body mass index, physical activity, current or past smoking, prior/current use of postmenopausal hormones, prior history of screening, previous occurrence of adenoma, colorectal cancer in parent or sibling, regular use of multivitamins, regular use of aspirin or NSAIDs, energy-adjusted intake of calcium and folate, servings of red meat as a main dish, and alcohol consumption. In addition to these factors, multivariate model 2 adjusted for plasma inflammatory markers C-reactive protein, soluble tumor necrosis factor receptor 2, interleukin 6, and total adiponectin as continuous measures.
Since one proposed inflammatory pathway in colorectal cancer involves overexpression of PTGS2 (COX-2), the association of MIC-1 and colorectal cancer was also examined according to intratumor PTGS2 status in an exploratory analysis.
MIC-1 Levels Associated With Risk
There was significantly increased risk of colorectal cancer across MIC-1 quintiles for all patients and men for age-adjusted relative risk (RR; P = .005, P = .001 for trend), relative risk in multivariate model 1 (P = .007, P = .003 for trend), and relative risk in multivariate model 2 (P = .004, P = .0006 for trend). Although the trends were not significant for women (P = .46, .46, and .66 for trends), there was no evidence of significant interaction by sex (P = .13 for heterogeneity).
Among all subjects, compared with the lowest quintile (quintile 1), relative risks were significant for the age-adjusted model and both multivariate models in quintiles 3, 4, and 5, whereas relative risks were significant among men in quintiles 4 and 5 and among women in quintile 3. Among all subjects, relative risks on multivariate model 2 were 1.36 (95% confidence interval [CI] = 0.95–1.95) for quintile 2, 1.68 (95% CI = 1.16–2.43) for quintile 3, 1.88 (95% CI = 1.27–2.77) for quintile 4, and 1.93 (95% CI = 1.27–2.94) for quintile 5 vs quintile 1.
Effect of PTGS2 Status
In the exploratory analysis of effect of PTGS2 status, among subjects with higher plasma MIC-1 levels (quintiles 2–5), regular use of aspirin and NSAIDs (≥ 2 tablets per week) vs nonuse was associated with a significantly lower risk of PTGS2-positive colorectal cancer (multivariable RR = 0.60, 95% CI = 0.41–0.88) but not PTGS2-negative colorectal cancer (RR = 1.21, 95% CI = 0.71– 2.07). Among subjects with low MIC-1 levels (quintile 1), aspirin and NSAID use was not associated with a lower risk of either PTGS2-positive colorectal cancer (RR = 0.57, 95% CI = 0.21–1.54) or PTGS2-negative colorectal cancer (RR = 1.41, 95% CI = 0.47–4.23).
The investigators concluded, “Our results support an association between higher levels of circulating MIC-1 (GDF15) and [colorectal cancer]. Aspirin/NSAID use appeared to lower risk of PTGS2-positive cancers, particularly among individuals with high levels of circulating MIC-1.”
Andrew Chan, MD, MPH, of Massachusetts General Hospital, is the corresponding author for the Journal of the National Cancer Institute article.
The study was supported by grants from the National Institutes of Health. Dr. Chan previously served as a consultant for Bayer Healthcare, Millennium Pharmaceuticals, Pfizer Inc, and Pozen Inc, none of whom funded the current study.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
