Combined with the Data Integration Analysis for Biomarker discovery (DIABLO) framework for machine learning and multi-omic analysis, we revisited the TCGA DNA methylation and RNA-Seq datasets for breast, colorectal, lung, and prostate cancer, and identified differentially methylated genes within the NRF2-KEAP1/PI3K oncogenic pathway, which regulates the expression of cytoprotective genes, that serve as potential therapeutic targets to treat different cancers. This evidence concerns the gene PIK3CG and Familial prostate cancer.