Koestler Devin C, Usset Joseph, Christensen Brock C, Marsit Carmen J, Karagas Margaret R, Kelsey Karl T, Wiencke John K
Department of Biostatistics, University of Kansas Medical Center, Kansas City, Kansas.
Department of Epidemiology, Geisel School of Medicine at Dartmouth College, Lebanon New Hampshire.
Cancer Epidemiol Biomarkers Prev. 2017 Mar;26(3):328-338. doi: 10.1158/1055-9965.EPI-16-0461. Epub 2016 Dec 13.
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. 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. 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. 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. 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. .
外周血中性粒细胞与淋巴细胞比值（NLR）是癌症患者炎症和不良预后的细胞学标志物。DNA甲基化是定义不同白细胞亚型的表观遗传程序的关键要素，可能为评估白细胞谱提供一种替代细胞学的方法。我们的目的是创建一种生物信息学工具，利用DNA甲基化来估计NLR，并评估其在人群中的诊断和预后性能。我们基于正常分离的白细胞甲基化文库开发了一种DNA甲基化衍生的NLR（mdNLR）指数，并建立了细胞混合去卷积算法。该方法应用于膀胱癌、头颈癌、卵巢癌和乳腺癌的病例对照研究，以及无癌受试者的公开可用数据。在各项癌症研究中，mdNLR评分在病例组相对于对照组中要么升高，要么与死亡风险增加相关。高mdNLR值（>5）是生存不良的有力指标。此外，mdNLR评分在男性、非西班牙裔白人相对于西班牙裔种族中升高，并随年龄增加而增加。我们还观察到吸烟史与mdNLR在癌症生存方面存在显著交互作用。这些结果意味着我们目前对成熟白细胞甲基化组的理解足以让研究人员和临床医生在癌症风险和生存的临床和流行病学研究中应用基于表观遗传学的NLR分析。由于并非总是能够进行NLR的细胞学测量（即存档血液），仅根据DNA甲基化特征计算得出的mdNLR有可能扩大全表观基因组关联研究的范围。
