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. 2017 Feb 2:9:10.
doi: 10.1186/s13148-017-0316-8. eCollection 2017.

Immunomethylomic approach to explore the blood neutrophil lymphocyte ratio (NLR) in glioma survival

John K Wiencke #  1 , Devin C Koestler #  2 , Lucas A Salas  3 , Joseph L Wiemels  4 , Ritu P Roy  5   3 , Helen M Hansen  1 , Terri Rice  1 , Lucie S McCoy  1 , Paige M Bracci  4 , Annette M Molinaro  4 , Karl T Kelsey #  6 , Margaret R Wrensch #  1 , Brock C Christensen #  7
Affiliations

Immunomethylomic approach to explore the blood neutrophil lymphocyte ratio (NLR) in glioma survival

John K Wiencke et al. Clin Epigenetics. .

Abstract

Background: 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.

Results: 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 (adjusted R2 ≥ 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.

Conclusions: 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.

Keywords: DNA methylation; Glioma; Immunomethylomics; Neutrophil lymphocyte ratio; Systemic inflammation.

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Figures

Fig. 1
Fig. 1
a Comparison of the distributions of mdNLR among glioma cases and a non-cancer comparison group. b Boxplot comparing mdNLR of glioma patients by tumor grade. c Boxplot comparing mdNLR of glioma patients by tumor molecular subtype. d Kaplan-Meier survival curves stratified by mdNLR (<4 vs > = 4) e Kaplan-Meier survival curves stratified by histopathology (GBM vs non-GBM) and mdNLR (<4 vs > = 4)
Fig. 2
Fig. 2
Identification of myeloid and lymphoid specific CpG probes. Scatterplot depicting Illumina 450K methylation beta values among isolated lymphocyte subtypes (X-axis: T cells, B cell, NK cells) and myeloid subtypes (Y-axis; granulocytes, monocytes). The lower right quadrant identifies loci that are unmethylated in myeloid cells and densely methylated in lymphocytes
Fig. 3
Fig. 3
Correlation of myeloid locus with mdNLR
See this image and copyright information in PMC

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