Joint Detection of Associations between DNA Methylation and Gene Expression from Multiple Cancers

DNA methylation plays an important role in the development of various cancers mainly through the regulation on gene expression. Hence, the study on the relation between DNA methylation and gene expression is of particular interest to understand cancers. Recently, an increasing number of datasets are available from multiple cancers, which makes it possible to study both the similarity and difference of genomic alterations across multiple tumor types. However, most of the existing pan-cancer analysis methods perform simple aggregations, which may overlook the heterogeneity of the interactions. In this paper, we propose a novel method to jointly detect complex associations between DNA methylation and gene expression levels from multiple cancers. The main idea is to apply joint sparse canonical correlation analysis to detect a small set of methylated sites, which are associated with another set of genes either shared across cancers or specific to a particular group (group-specific) of cancers. These methylated sites and genes form a complex module with strong multivariate correlations. We further introduced a joint sparse precision matrix estimation method to identify driver methylation-gene pairs in the module. These pairs are characterized by significant partial correlations, which may imply high functional impacts and contribute to complementary information to the main step. We apply our method to The Cancer Genome Atlas(TCGA) datasets with 1166 samples from four cancers. The results reveal significant shared and groupspecific interactions between DNA methylation and gene expression levels. To promote reproducible research, the Matlab code is available at https://sites.google.com/site/jianfang86/jointTCGA.