Integrative analysis identifies potential DNA methylation biomarkers for pan-cancer diagnosis and prognosis

Epigenetics. 2019 Jan;14(1):67-80. doi: 10.1080/15592294.2019.1568178. Epub 2019 Jan 29.


DNA methylation status is closely associated with diverse diseases, and is generally more stable than gene expression, thus abnormal DNA methylation could be important biomarkers for tumor diagnosis, treatment and prognosis. However, the signatures regarding DNA methylation changes for pan-cancer diagnosis and prognosis are less explored. Here we systematically analyzed the genome-wide DNA methylation patterns in diverse TCGA cancers with machine learning. We identified seven CpG sites that could effectively discriminate tumor samples from adjacent normal tissue samples for 12 main cancers of TCGA (1216 samples, AUC > 0.99). Those seven potential diagnostic biomarkers were further validated in the other 9 different TCGA cancers and 4 independent datasets (AUC > 0.92). Three out of the seven CpG sites were correlated with cell division, DNA replication and cell cycle. We also identified 12 CpG sites that can effectively distinguish 26 different cancers (7605 samples), and the result was repeatable in independent datasets as well as two disparate tumors with metastases (micro-average AUC > 0.89). Furthermore, a series of potential signatures that could significantly predict the prognosis of tumor patients for 7 different cancer were identified via survival analysis (p-value < 1e-4). Collectively, DNA methylation patterns vary greatly between tumor and adjacent normal tissues, as well as among different types of cancers. Our identified signatures may aid the decision of clinical diagnosis and prognosis for pan-cancer and the potential cancer-specific biomarkers could be used to predict the primary site of metastatic breast and prostate cancers.

Keywords: DNA methylation; cancer diagnosis; machine learning; pan-cancer; prognosis; survival analysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / genetics*
  • CpG Islands
  • DNA Methylation*
  • Humans
  • Machine Learning
  • Neoplasms / genetics*
  • Neoplasms / pathology
  • Survival Analysis


  • Biomarkers, Tumor

Grant support

This work was supported by the National High Technology Research and Development Program of China (2015AA020108), National Key Research and Development Program of China (2016YFC0902100), National Science Foundation of China (31671377, 31771460, 91629103) and Shanghai 111 Project (B14019).