Heterogeneous DNA methylation contributes to tumorigenesis through inducing the loss of coexpression connectivity in colorectal cancer.

Increasing evidence indicates the high heterogeneity of cancer cells. Recent studies have revealed distinct subtypes of DNA methylation in colorectal cancer (CRC); however, the mechanism of heterogeneous methylation remains poorly understood. Gene expression is a natural, intermediate quantitative trait that bridges genotypic and phenotypic features. In this work, we studied the role of heterogeneous DNA methylation in tumorigenesis via gene expression analyses. Specifically, we integrated methylation and expression data in normal and tumor tissues, and examined the perturbations in coexpression patterns. We found that the heterogeneity of methylation leads to significant loss of coexpression connectivity in CRC; this finding was validated in an independent cohort. Functional analyses showed that the lost coexpression partners participate in important cancer-related pathways/networks, such as ErbB and mitogen-activated protein kinase (MAPK) signaling pathways. Our analyses suggest that the loss of coexpression connectivity induced by methylation heterogeneity might play an important role in CRC. To our knowledge, this is the first study to interpret methylation heterogeneity in cancer from the perspective of coexpression perturbation. Our results provide new perspectives in tumor biology and may facilitate the identification of potential biomedical therapies for cancer treatment.