Discovery of family of genes linked to the development of liver cancer

An interdisciplinary team of researchers at Stony Brook University Medical Center has identified a family of genes linked to the development of liver cancer.

Principal Investigator Wadie F. Bahou, M.D., Professor of Medicine and Genetics, and colleagues discovered in a mouse model that the loss of one specific gene (Iqgap2) in this family causes Hepatocellular carcinoma (HCC). They also found that when another member of the gene family (Iqgap1) is turned on, a more aggressive form of the disease occurs. Their findings are reported in the March issue of Molecular and Cellular Biology.

Dr. Bahou says that the findings regarding the two genes demonstrate that both genes could serve as a basis for developing important targets for early diagnosis and/or treatment of HCC. The disease accounts for more than 80 percent of all liver cancer in humans, which causes death in 500,000 to 1 million adults annually worldwide. Treatment for advanced HCC is often ineffective. A recently approved chemotherapy drug developed to treat metastatic liver cancer provides disease stabilization but not a cure.

“This is an exciting development in the field of cancer research, as there is a tremendous need for targeted therapies for liver cancer,” emphasizes Dr. Bahou. “The data resulting from our research provides important insights into genes that may predispose to HCC development,” he adds, further noting that the model is a valuable tool for testing therapeutic agents aimed at curing liver cancer.

Dr. Bahou explains that to date attempts to treat liver cancer have been difficult without appropriate animal models of disease. He says that the model generated by the Stony Brook team is the closest to human disease because: 1) The disease closely resembles human HCC microscopically; 2) does not require intervention from outside sources, such as chemically induced cancer models; 3) is associated with a reproducible and very high incidence of HCC, and 4) is strictly limited to HCC.

With expertise ranging from hematology/oncology, genetics, pharmacology and pathology, the team detailed their results in an article titled “Development of Hepatocellular Carcinoma in Iqgap2-Deficient Mice Is Iqgap1-dependent.” They collectively found that Iqgap1 and Iqgap2 have functionally divergent roles in hepatocellular carcinogenesis. When they removed the Iqgap2 gene using sophisticated genetic techniques, the mice developed HCC. This result confirmed that Iqgap2 has a fundamentally important protective role against the development of liver cancer.

When mice retained Iqgap1, the cousin gene of Iqgap2, the animals developed more advanced disease. Further experimentation showed that inactivation of Iqgap1 in the mouse liver limits the aggressiveness of HCC caused by Iqgap2 deficiency.

According to Dr. Bahou, the researchers are currently conducting similar genetic analyses in human liver cancer. Co-investigators of the mouse study include lead author Valentina A. Schmidt, Ph.D., Department of Medicine; Carmine S. Chiariello, Ph.D., Program in Genetics; Encarnación Capilla, Ph.D., Department of Pharmaological Sciences, and Frederick Miller, M.D., Department of Pathology. The research was supported by the National Institutes of Health.