A prospective study of macrophage inhibitory cytokine-1 (MIC-1/GDF15) and risk of colorectal cancer

Abstract

Background: Chronic inflammation plays a role in the development of colorectal cancer (CRC). The novel plasma inflammatory biomarker macrophage inhibitory cytokine-1 (MIC-1, GDF15) may have a direct mechanistic role in colorectal carcinogenesis.

Methods: We conducted a prospective, nested, case-control study of incident CRC among men and women who provided a prediagnostic blood specimen. We used an enzyme-linked immunosorbent assay to measure MIC-1 and examined associations between quintiles of MIC-1 and CRC using logistic regression adjusted for matching factors (age and date of blood draw), risk factors, and other plasma inflammatory markers. We also assessed the relationship between MIC-1 levels and prostaglandin-endoperoxide synthase 2 (PTGS2)/cyclooxygenase-2 (COX-2) enzyme status in tumors with available tissue for analysis. All statistical tests were two-sided.

Results: Compared with men and women within the lowest quintile of plasma MIC-1, the multivariable relative risk (RR) for CRC was 1.93 (95% confidence interval [CI] = 1.27 to 2.94) for the highest quintile (P linear trend = .004). In an exploratory analysis, we found that among individuals with high plasma MIC-1 levels (quintiles 2-5), compared with nonuse, regular use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with a lower risk of PTGS2-positive CRC (multivariable RR = 0.60; 95% confidence interval = 0.41 to 0.88) but not PTGS2-negative CRC (multivariable RR = 1.21; 95% CI = 0.71 to 2.07). In contrast, among individuals with low MIC-1 levels (quintile 1), aspirin and NSAID use was not associated with a lower risk of PTGS2-positive CRC (multivariable RR = 0.57; 95% CI = 0.21 to 1.54) or PTGS2-negative CRC (multivariable RR = 1.41; 95% CI = 0.47 to 4.23).

Conclusions: Our results support an association between higher levels of circulating MIC-1 (GDF15) and CRC. Aspirin/NSAID use appeared to lower risk of PTGS2-positive cancers, particularly among individuals with high levels of circulating MIC-1.

Figure 1.

Restricted cubic spline plot for macrophage inhibitory cytokine 1 (MIC-1) and risk of colorectal cancer. Relative risk (RR) of colorectal cancer is plotted accordingly to serum MIC-1 level (pg/mL). Hatched lines represent 95% confidence intervalss. Spline was adjusted for age at blood draw, date of blood draw, race, sex, body mass index, physical activity (metabolic equivalent task score hours per week), current or past smoking (yes or no), prior/current use of postmenopausal hormones (yes or no), prior history of screening (yes or no), previous occurrence of adenoma, colorectal cancer in parent or sibling, regular use of multivitamins, regular use of aspirin or nonsteroidal anti-inflammatory drugs (≥2 tablets per week), energy-adjusted intake (including supplements) of calcium and folate, servings of red meat as a main dish, and alcohol consumption. A test for overall significance of the curve was statistically significant (P = .02). The test for curvature (ie, nonlinear relation) was 0.12. Test for linear relation was 0.01. All P values listed here are two-sided. A smoothed histogram below the plot shows the distribution of MIC-1 among case patients and control subjects in both cohorts.