title: 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.
authors.affiliation: 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).
authors.forename: Raaj S
authors.initials: RS
authors.lastname: Mehta
authors.forename: Mingyang
authors.initials: M
authors.lastname: Song
authors.forename: Navya
authors.initials: N
authors.lastname: Bezawada
authors.forename: Kana
authors.initials: K
authors.lastname: Wu
authors.forename: Xabier
authors.initials: X
authors.lastname: Garcia-Albeniz
authors.forename: Teppei
authors.initials: T
authors.lastname: Morikawa
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.forename: Edward L
authors.initials: EL
authors.lastname: Giovannucci
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
mesh_terms: D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D001241:Aspirin / Q000008:administration & dosage; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D055436:Growth Differentiation Factor 15 / Q000378:metabolism*; D006282:Health Personnel / Q000706:statistics & numerical data; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000150:complications; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D011795:Surveys and Questionnaires; D014481:United States
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D001241:Aspirin