Accounting for differential variability in detecting differentially methylated regions.

DNA methylation plays an essential role in cancer. Differential variability (DV) in cancer was recently observed that contributes to cancer heterogeneity and has been shown to be crucial in detecting epigenetic field defects, DNA methylation alterations happening early in carcinogenesis. As neighboring CpG sites are highly correlated, here, we present a new method to detect differentially methylated regions (DMRs) that uses combined signals from differential methylation and DV between sample groups. We demonstrated in simulation studies the superior performance of the new method than existing methods that use only one type of signals when true DMRs have both. Applications to DNA methylation data of breast invasive carcinoma (BRCA) and kidney renal clear cell carcinoma (KIRC) from The Cancer Genome Atlas (TCGA) and BRCA from Gene Expression Omnibus (GEO) suggest that the new method identified additional cancer-related DMRs that were missed by methods using one type of signals. Replication analyses using two independent BRCA data sets suggest that DMRs detected based on DV are reproducible. Only the new method identified epigenetic field defects when comparing normal tissues adjacent to tumors and normal tissues from age-matched cancer-free women from the GEO BRCA data and confirmed their enrichment in the progression to breast cancer.