title: Association Between Plasma Levels of Macrophage Inhibitory Cytokine-1 Before Diagnosis of Colorectal Cancer and Mortality.
abstract: OBJECTIVE
  Patients with colorectal cancer (CRC) have high circulating levels of macrophage inhibitory cytokine-1 (MIC1 or growth differentiation factor 15), a marker of inflammation that might be involved in carcinogenesis. We analyzed blood samples collected from individuals before they were diagnosed with CRC to determine whether levels of MIC1 were associated with mortality.
  
  
  METHODS
  We collected data on survival of 618 participants diagnosed with CRC who provided prediagnosis blood specimens in 1990 (Nurses' Health Study) and 1994 (Health Professionals' Follow-up Study) and were followed through 2010. Levels of MIC1 were measured by enzyme-linked immunosorbent assay and then were categorized into quartiles based on the known distribution of MIC1 levels among previously matched individuals without CRC (controls) within each cohort. We then examined the association of MIC1 levels with overall and CRC-specific mortality using Cox proportional hazards models, with adjustments for mortality-associated risk factors and other plasma markers of inflammation. We also assessed the relationship between levels of MIC1 and levels of prostaglandin-endoperoxide synthase 2 expression (PTGS2 or cyclooxygenase-2), measured in 245 tumor samples by immunohistochemistry.
  
  
  RESULTS
  Compared with participants in the lowest quartile for plasma level of MIC1, the multivariate hazard ratio for CRC-specific death for participants in the highest quartile of MIC1 level was 2.40 (95% confidence interval: 1.33-4.34; P for linear trend = .009). The association of MIC1 with survival varied with level of PTGS2 expression in tumor samples (Pinteraction = .04). For individuals with PTGS2-positive tumors, the hazard ratio for CRC-specific death among those with high levels of MIC1 (equal to or greater than the median) was 2.13 (95% confidence interval: 0.99-4.58) compared with participants with low levels of MIC1 (below the median). In individuals with PTGS2-negative CRC, a high level of MIC1 was not associated with an increased risk of CRC-specific death (multivariate hazard ratio = 0.61; 95% confidence interval: 0.13-2.93).
  
  
  CONCLUSIONS
  Based on an analysis of blood and colorectal tumor samples from 2 large studies, high plasma levels of MIC1 (growth differentiation factor 15) before diagnosis of CRC are associated with greater CRC-specific mortality, particularly in individuals with PTGS2-positive tumors.
authors.affiliation: Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Raaj S
authors.initials: RS
authors.lastname: Mehta
authors.affiliation: Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, Massachusetts; National Cancer Centre Singapore, Singapore.
authors.forename: Dawn Q
authors.initials: DQ
authors.lastname: Chong
authors.affiliation: Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, Massachusetts; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Mingyang
authors.initials: M
authors.lastname: Song
authors.affiliation: Harvard Medical School, Boston, Massachusetts; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Meyerhardt
authors.affiliation: Harvard Medical School, Boston, Massachusetts; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Kimmie
authors.initials: K
authors.lastname: Ng
authors.affiliation: Harvard Medical School, Boston, Massachusetts; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Reiko
authors.initials: R
authors.lastname: Nishihara
authors.affiliation: Harvard Medical School, Boston, Massachusetts; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Qian
authors.affiliation: Harvard Medical School, Boston, Massachusetts; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Teppei
authors.initials: T
authors.lastname: Morikawa
authors.affiliation: Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Kana
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Giovannucci
authors.affiliation: Harvard Medical School, Boston, Massachusetts; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.affiliation: Harvard Medical School, Boston, Massachusetts; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.affiliation: Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, Massachusetts; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Electronic address: achan@mgh.harvard.edu.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood*; D015179:Colorectal Neoplasms / Q000097:blood* / Q000175:diagnosis / Q000201:enzymology / Q000401:mortality*; D051546:Cyclooxygenase 2 / Q000032:analysis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D055436:Growth Differentiation Factor 15 / Q000097:blood*; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D018836:Inflammation Mediators; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human
keywords: Colon Cancer Risk Factor; Cyclooxygenase; GDF15; Immunity