Immunomethylomic approach to explore the blood neutrophil lymphocyte ratio (NLR) in glioma survival.
Differentially methylated regions (DMRs) within DNA isolated from whole blood can be used to estimate the proportions of circulating leukocyte subtypes. We use the term "immunomethylomics" to describe the application of these immune lineage DMRs to studying leukocyte profiles. Here, we applied this approach to peripheral blood DNA from 72 glioma patients with molecularly defined brain tumors, representing common patient groups with defined characteristic survival times and risk factors. We first estimated the proportions of leukocyte subtypes in samples using deconvolution algorithms with reference DMR libraries from isolated leukocyte populations and Illumina 450K DNA methylation data. Then, we calculated the neutrophil to lymphocyte ratio (NLR) using methylation-derived cell composition estimates (mdNLR). The NLR is considered an indicator of immunosuppressive cells in cancer patients.



Elevated mdNLR scores were observed in glioma patients compared to mdNLR values of published controls. Significantly decreased survival times were associated with mdNLR ≥ 4.0 in Cox proportional hazards models adjusted for age, gender, tumor grade, and molecular subtype (HR 2.02, 95% CI, 1.11-3.69). We also identified five myeloid-related CpGs that were highly correlated with the mdNLR (adjustedR2≥ 0.80). Each of the five myeloid CpG loci was associated with survival when adjusted for the above covariates and offer a simplified approach for utilizing fresh or archived peripheral blood samples for interrogating a very small number of methylation markers to estimate myeloid immune influences in glioma survival.



The mdNLR (based on DNA methylation) is a novel candidate methylation biomarker that represents immunosuppressive myeloid cells within the blood of glioma patients with potential application in clinical trials and future epidemiologic studies of glioma risk and survival.
Department of Neurological Surgery, University of California San Francisco, 1450 3rd Street, San Francisco, CA 94158-0520 USA.
John K
JK
Wiencke
Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS 66160 USA.
Devin C
DC
Koestler
Computational Biology Core, University of California San Francisco, San Francisco, CA 94158 USA.
Lucas A
LA
Salas
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA 94158 USA.
Joseph L
JL
Wiemels
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158 USA.|Computational Biology Core, University of California San Francisco, San Francisco, CA 94158 USA.
Ritu P
RP
Roy
Department of Neurological Surgery, University of California San Francisco, 1450 3rd Street, San Francisco, CA 94158-0520 USA.
Helen M
HM
Hansen
Department of Neurological Surgery, University of California San Francisco, 1450 3rd Street, San Francisco, CA 94158-0520 USA.
Terri
T
Rice
Department of Neurological Surgery, University of California San Francisco, 1450 3rd Street, San Francisco, CA 94158-0520 USA.
Lucie S
LS
McCoy
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA 94158 USA.
Paige M
PM
Bracci
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA 94158 USA.
Annette M
AM
Molinaro
Department of Epidemiology, Department of Pathology and Laboratory Medicine, Brown University, Providence, RI 02912 USA.
Karl T
KT
Kelsey
Department of Neurological Surgery, University of California San Francisco, 1450 3rd Street, San Francisco, CA 94158-0520 USA.
Margaret R
MR
Wrensch
Departments of Epidemiology, Pharmacology & Toxicology, and Community and Family Medicine, Geisel School of Medicine at Dartmouth College, Lebanon, NH 03756 USA.
Brock C
BC
Christensen
D000328:Adult; D000465:Algorithms; D001932:Brain Neoplasms / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005910:Glioma / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007958:Leukocyte Count; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D016019:Survival Analysis
DNA methylation; Glioma; Immunomethylomics; Neutrophil lymphocyte ratio; Systemic inflammation