Epigenetic field defect discriminates normal tissues from healthy and tumor-bearing kidneys

Abstract

AbstractBackgroundThe detection of alterations in DNA methylation (DNAm) in normal human tissues may provide molecular insights for cancer development, the estimation of personal cancer risk, and a basis for early diagnosis of malignancies to reduce cancer lethality. Thus, whether DNAm allows discrimination between healthy normal and normal tumor-adjacent renal tissues is an important question.MethodsDNAm of loci in the LINE1 repetitive sequence andANKRD34B, NHLH2, TBR1, andZIC1was measured in a total of 493 tissue samples representing 342 normal autopsy and 151 histopathological normal tumor-adjacent renal tissues by pyro-sequencing a total of 22 CpG sites.ResultsUnsupervised k-means clustering demonstrated a significant imbalance of tissue samples in three stable tissue clusters. Random forest classification demonstrated discrimination of normal and normal tumor-adjacent renal tissues with a median area under the ROC curve of 0.81 (p=2.7×10−9, diagnostic odds ratio 10.4). Variable importance analysis revealed CpG sites in LINE1 andANKRD34Bas the most important model contributors.ConclusionsDNAm alterations in normal tissues allow detection of renal cancer with high diagnostic efficiency, defining a DNAm field effect in the kidney. The methylation signature may serve as a basis for an epigenetic DNAm clock permitting estimation of individual renal cancer risk.