title: Circulating Inflammation Markers, Risk of Lung Cancer, and Utility for Risk Stratification.
abstract: BACKGROUND
  We conducted two independent nested case-control studies to identify circulating inflammation markers reproducibly associated with lung cancer risk and to investigate the utility of replicated markers for lung cancer risk stratification.
  
  
  METHODS
  Nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, the previously published discovery study included 526 lung cancer patients and 592 control subjects and the replication study included 526 lung cancer case patients and 625 control subjects. Control subjects were matched by sex, age, smoking, study visit, and years of blood draw and exit. Serum levels of 51 inflammation markers were measured. Odds ratios (ORs) were estimated with conditional logistic regression. All statistical tests were two-sided.
  
  
  RESULTS
  Of 11 markers identified in the discovery study, C-reactive protein (CRP) (odds ratio [OR] [highest vs. lowest category] = 1.77, 95% confidence interval [CI] = 1.23 to 2.54), serum amyloid A (SAA) (OR = 1.88, 95% CI = 1.28 to 2.76), soluble tumor necrosis factor receptor-2 (sTNFRII) (OR = 1.70, 95% CI = 1.18 to 2.45), and monokine induced by gamma interferon (CXCL9/MIG) (OR = 2.09, 95% CI = 1.41 to 3.00) were associated with lung cancer risk in the replication study (P trend < .01). In pooled analyses, CRP, SAA, and CXCL9/MIG remained associated with lung cancer more than six years before diagnosis (P trend < .05). The incorporation of an inflammation score combining these four markers did not improve the sensitivity (77.6% vs 75.8%, P = .33) or specificity (56.1% vs 56.1%, P = .98) of risk-based lung cancer models.
  
  
  CONCLUSIONS
  Circulating levels of CRP, SAA, sTNFRII, and CXCL9/MIG were reproducibly associated with lung cancer risk in two independent studies within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, underscoring an etiologic role for inflammation in lung carcinogenesis, though replication is needed in other populations. Markers did not improve lung cancer risk stratification beyond standard demographic and behavioral characteristics.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD (MSS, HAK, AH, RMP, EAE, NEC, AKC); HPV Immunology Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD (MW, TJK, LAP). shielsms@mail.nih.gov.
authors.forename: Meredith S
authors.initials: MS
authors.lastname: Shiels
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD (MSS, HAK, AH, RMP, EAE, NEC, AKC); HPV Immunology Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD (MW, TJK, LAP).
authors.forename: Hormuzd A
authors.initials: HA
authors.lastname: Katki
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD (MSS, HAK, AH, RMP, EAE, NEC, AKC); HPV Immunology Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD (MW, TJK, LAP).
authors.forename: Allan
authors.initials: A
authors.lastname: Hildesheim
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD (MSS, HAK, AH, RMP, EAE, NEC, AKC); HPV Immunology Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD (MW, TJK, LAP).
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Pfeiffer
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD (MSS, HAK, AH, RMP, EAE, NEC, AKC); HPV Immunology Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD (MW, TJK, LAP).
authors.forename: Eric A
authors.initials: EA
authors.lastname: Engels
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD (MSS, HAK, AH, RMP, EAE, NEC, AKC); HPV Immunology Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD (MW, TJK, LAP).
authors.forename: Marcus
authors.initials: M
authors.lastname: Williams
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD (MSS, HAK, AH, RMP, EAE, NEC, AKC); HPV Immunology Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD (MW, TJK, LAP).
authors.forename: Troy J
authors.initials: TJ
authors.lastname: Kemp
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD (MSS, HAK, AH, RMP, EAE, NEC, AKC); HPV Immunology Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD (MW, TJK, LAP).
authors.forename: Neil E
authors.initials: NE
authors.lastname: Caporaso
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD (MSS, HAK, AH, RMP, EAE, NEC, AKC); HPV Immunology Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD (MW, TJK, LAP).
authors.forename: Ligia A
authors.initials: LA
authors.lastname: Pinto
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD (MSS, HAK, AH, RMP, EAE, NEC, AKC); HPV Immunology Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD (MW, TJK, LAP).
authors.forename: Anil K
authors.initials: AK
authors.lastname: Chaturvedi
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D014408:Biomarkers, Tumor / Q000097:blood*; D002097:C-Reactive Protein / Q000378:metabolism*; D016022:Case-Control Studies; D054370:Chemokine CXCL9 / Q000097:blood*; D055088:Early Detection of Cancer; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood*; D016015:Logistic Models; D008175:Lung Neoplasms / Q000097:blood* / Q000453:epidemiology*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood*; D015203:Reproducibility of Results; D018570:Risk Assessment; D012307:Risk Factors; D012680:Sensitivity and Specificity; D000685:Serum Amyloid A Protein / Q000378:metabolism*; D012907:Smoking / Q000009:adverse effects / Q000453:epidemiology; D014481:United States / Q000453:epidemiology
chemical_list: D015415:Biomarkers; D014408:Biomarkers, Tumor; C080810:CXCL9 protein, human; D054370:Chemokine CXCL9; D047889:Receptors, Tumor Necrosis Factor, Type II; D000685:Serum Amyloid A Protein; D002097:C-Reactive Protein