Abstract
The telomere reverse transcriptase promoter (TERTp) is frequently mutated in malignant gliomas, particularly glioblastomas (GBM, 85%), and is involved in maintaining telomere length. TERTp mutations are prognostic for patient survival. Given the evolving use of Infinium DNA methylation arrays in assaying biomarkers in glioma, we aimed to develop an accurate predictor of TERTp mutations in gliomas using this platform. We analyzed TCGA lower grade glioma (LGG) and GBM available with both TERTp sequencing and Infinium 450k data. Samples were split into training and testing set to determine predictor accuracy. Probes with potential quality issues were excluded and probe selection performed using an elastic net algorithm. Probes were selected across the genome, not limited to the TERTp locus. A logistic regression model with binomial distribution was built using the final optimized model, constructed based on 1000 CpG probes, all distinct from TERTp. Prediction accuracy was 100% (179/179, AUC=1) in the training set and 97.5% (116/119) in the test set. Comparison of the normalized frequency of selected probes by chromosome revealed enrichment for chromosomes 20 (0.4987%) and 18 (0.4859%). The majority of probes enriched in CpG islands (53.6%), followed by open sea (22.9%), shore (17.4%), and shelf (6.1%). Relative to known genes, probe enrichment occurred predominantly near transcriptional start sites (within 200–1500 bp, 31.0%), followed by gene bodies (26.3%) and intergenic regions (18.3%). Quite unexpectedly, probes within the predictor do not map near TERT or other telomere maintenance factors nor fell within known methylation signatures, such as G-CIMP, suggesting that TERTp mutation is associated with novel epigenetic changes. Moreover, this biomarker permits rapid and cost effective detection of TERTp mutation using the widely used Infinium platform.from Cancer via ola Kala on Inoreader http://ift.tt/2zmEv5Q
via IFTTT
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου