Further detailed analysis of Estrogen-mediated S-phase pathway elements revealed several key downstream signaling genes that are upregulated in association with promoter DNA hypomethylation in RB tumors, including CCNA1 and CCNA2 for Cyclin A, CCNE1 and CCNE2 for Cyclin E, as well as E2F1, E2F2, and CDC2 (Fig. 4D). This evidence concerns the gene CCNE1 and retinoblastoma.