Raaj S Mehta1, Mingyang Song, Navya Bezawada, Kana Wu, Xabier Garcia-Albeniz, Teppei Morikawa, Charles S Fuchs, Shuji Ogino, Edward L Giovannucci, Andrew T Chan. 1. Affiliations of authors: Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (RSM, ATC); Gastrointestinal Research Group, Institute of Medical Sciences, Aberdeen University, Aberdeen, United Kingdom (NB); Department of Epidemiology (XG, SO, ELG) and Department of Nutrition (MS, KW, XG, ELG), Harvard School of Public Health, Boston, MA; Department of Pathology, University of Tokyo, Tokyo, Japan (TM); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, ATC) and Department of Pathology (SO), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (CSF, SO).
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.
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.
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