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Epigenetic biomarkers of T-cells in human glioma
Authors:John K Wiencke  William P Accomando  Shichun Zheng  Joe Patoka  Xiaoqin Dou  Joanna J Phillips  George Hsuang  Brock C Christensen  E Andres Houseman  Devin C Koestler  Paige Bracci  Joseph L Wiemels  Margaret Wrensch  Heather H Nelson  Karl T Kelsey
Institution:1.Department of Neurological Surgery; University of California San Francisco; San Francisco, CA USA;2.Department of Pathology and Laboratory Medicine; Brown University; Providence, RI USA;3.Department of Epidemiology; Brown University; Providence, RI USA;4.Department of Epidemiology & Biostatistics; University of California San Francisco; San Francisco, CA USA;5.Department of Epidemiology; University of Minnesota; Minneapolis, MN USA
Abstract:Immune factors are thought to influence glioma risk and outcomes, but immune profiling studies to further our understanding of the immune response are limited by current immunodiagnostic methods. We developed a new assay to capture glioma immune biology based on quantitative methylation specific PCR (qMSP) of two T-cell genes (CD3Z: T-cells, and FOXP3: Tregs). Flow cytometry of T-cells correlated well with the CD3Z demethylation assay (r = 0.93; p < 2.2 × 10−16), demonstrating the validity of the assay. Furthermore, there was a high correlation between qMSP and immunohistochemistry (IHC) in quantifying tumor infiltrating T-cells (r = 0.85; p = 3.4 × 10−11). Applying our qMSP methods to archival whole blood from 65 glioblastoma multiforme (GBM) cases and 94 non-diseased controls, GBM cases had highly statistically significantly lower T-cells (p = 1.7 × 10−9) as well as Tregs (p = 5.2 × 10−11) and a modestly lower ratio of Tregs/T-cells (p = 0.024). Applying the methods to 120 excised glioma tumors, we observed that tumor infiltrating CD3+ T-cells were positively correlated with glioma tumor grade (p = 5.7 × 10−7), and that Tregs were enriched in tumors compared with peripheral blood indicating active chemoattraction of suppressive Tregs into the tumor compartment. Poorer patient survival was correlated with higher levels of tumor infiltrating T-cells (p = 0.01) and Tregs (p = 0.04). DNA methylation based immunodiagnostics represent a new generation of powerful laboratory tools offering many advantages over conventional methods that will facilitate large clinical epidemiologic studies and capitalize on stored archival blood and tissue banks.
Keywords:DNA methylation  glioma  Tregs  T-cells  biomarkers
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