title: DNA Methylation-Derived Neutrophil-to-Lymphocyte Ratio: An Epigenetic Tool to Explore Cancer Inflammation and Outcomes.
abstract: Background:The peripheral blood neutrophil-to-lymphocyte ratio (NLR) is a cytologic marker of both inflammation and poor outcomes in patients with cancer. DNA methylation is a key element of the epigenetic program defining different leukocyte subtypes and may provide an alternative to cytology in assessing leukocyte profiles. Our aim was to create a bioinformatic tool to estimate NLR using DNA methylation, and to assess its diagnostic and prognostic performance in human populations.Methods:We developed a DNA methylation-derived NLR (mdNLR) index based on normal isolated leukocyte methylation libraries and established cell-mixture deconvolution algorithms. The method was applied to cancer case-control studies of the bladder, head and neck, ovary, and breast, as well as publicly available data on cancer-free subjects.Results:Across cancer studies, mdNLR scores were either elevated in cases relative to controls, or associated with increased hazard of death. High mdNLR values (>5) were strong indicators of poor survival. In addition, mdNLR scores were elevated in males, in nonHispanic white versus Hispanic ethnicity, and increased with age. We also observed a significant interaction between cigarette smoking history and mdNLR on cancer survival.Conclusions:These results mean that our current understanding of mature leukocyte methylomes is sufficient to allow researchers and clinicians to apply epigenetically based analyses of NLR in clinical and epidemiologic studies of cancer risk and survival.Impact:As cytologic measurements of NLR are not always possible (i.e., archival blood), mdNLR, which is computed from DNA methylation signatures alone, has the potential to expand the scope of epigenome-wide association studies.Cancer Epidemiol Biomarkers Prev; 26(3); 328-38. ©2016 AACR.
authors.affiliation: Department of Biostatistics, University of Kansas Medical Center, Kansas City, Kansas. dkoestler@kumc.edu.
authors.forename: Devin C
authors.initials: DC
authors.lastname: Koestler
authors.affiliation: Department of Biostatistics, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Joseph
authors.initials: J
authors.lastname: Usset
authors.affiliation: Department of Epidemiology, Geisel School of Medicine at Dartmouth College, Lebanon New Hampshire.|Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth College, New Hampshire.|Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth College, Lebanon New Hampshire.
authors.forename: Brock C
authors.initials: BC
authors.lastname: Christensen
authors.affiliation: Department of Epidemiology, Geisel School of Medicine at Dartmouth College, Lebanon New Hampshire.|Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth College, New Hampshire.|Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth College, Lebanon New Hampshire.
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Marsit
authors.affiliation: Department of Epidemiology, Geisel School of Medicine at Dartmouth College, Lebanon New Hampshire.|Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth College, Lebanon New Hampshire.
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Karagas
authors.affiliation: Department of Epidemiology, Brown University, Providence, Rhode Island.
authors.forename: Karl T
authors.initials: KT
authors.lastname: Kelsey
authors.affiliation: Department of Neurological Surgery, Helen Diller Family Cancer Center, University of California San Francisco, San Francisco, California.
authors.forename: John K
authors.initials: JK
authors.lastname: Wiencke
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood; D001943:Breast Neoplasms / Q000097:blood* / Q000235:genetics; D016022:Case-Control Studies; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006258:Head and Neck Neoplasms / Q000097:blood* / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000097:blood; D007962:Leukocytes; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D009504:Neutrophils; D010051:Ovarian Neoplasms / Q000097:blood* / Q000235:genetics; D016016:Proportional Hazards Models; D001749:Urinary Bladder Neoplasms / Q000097:blood* / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor