POLYMORPHISMS OF THE E2F-1 BINDING ELEMENT AND METHODS OF DETERMINING CANCER SUSCEPTIBILITY

摘要

Up-regulated ZNFN3A1, a histone methyltransferase, is a critical promoter of cell growth in a great majority of the human colorectal, liver, and breast cancers. Herein, transcriptional regulatory regions in the 5' flanking region of ZNFN3A1 that contains four E2F-1 binding motifs and one Nrf1 binding motif are identified. In particular, experimental data disclosed herein suggest that E2F-1 induces of ZNFN3A1 expression by transcriptional activation through a binding to the promoter region. In addition, a significant association between a variable number tandem repeat (VNTR) polymorphism of a CCGCC unit in the regulatory region of the ZNFN3A1 gene and an increased risk of colorectal cancer ( Chi-square=17.86, p=3.8 x 10^-5, odds ratio=2.20), hepatocellular carcinoma ( Chi-square=25.39, p=4.7 x 10^-7, odds ratio=2.74) and also breast cancer ( Chi-square=38.91, p=3.4 x 10^-9, odds ratio=3.79) was discovered. This tandem-repeated sequence was shown to be a binding-site for the transcriptional factor E2F-1 and the common VNTR polymorphism in ZNFN3A1 is shown herein to be a susceptibility factor for certain types of human cancer.