Identification of human cancer-related genes by naturally occurring Hepatitis B Virus DNA tagging

Proviral tagging has been used in animals as a powerful tool for cancer gen etics. We show that a similar approach is possible in patients with hepatoc ellular carcinoma (HCC) infected by Hepatitis B Virus (HBV), a human parare trovirus which may act by insertional mutagenesis. In this work, the HBV ge nome is used as a probe to identify cancer-related genes. By using HBV-Alu- PCR, we obtained 21 HBV/cellular DNA junctions from 18 different patients. In six of 21, we found the HBV DNA integrated into a cellular gene: (1) Sar co/Endoplasmic Reticulum Calcium ATPase1 Gene; (2) Thyroid Hormone Receptor Associated Protein 150 alpha Gene; (3) Human Telomerase Reverse Transcript ase Gene; (4) Minichromosome Maintenance Protein (MCM)-Related Gene; (5) FR 7, a new gene expressed in human liver and cancer tissues; and (6) Nuclear Matrix Protein p84 Gene. Seven junctions contained unique cellular sequence s. In the remaining eight, the HBV DNA was next to repetitive sequences, fi ve of them of LINE1 type. The cellular genes targeted by HBV are key regula tors of cell proliferation and viability. Our results show that studies on HBV-related HCCs allow to identify cellular genes involved in cancer. We th erefore propose this approach as a valuable tool for functional cancer geno mic studies in humans.