Funded in partnership with WWE in honor of Connor’s Cure
Hepatoblastoma (HB) is the most common cancer of the liver in children. Although usually very curable, some HBs have less than 20% survival. About 80% of these have changes in a protein known as b-catenin. Many also show abnormal regulation of another protein called YAP. Together, these are the most common changes in HB. Mice develop HB if a mutant form of b-catenin, termed D(90) and a mutant form of YAP known as YAPS127Aare expressed together in the liver although neither one alone causes tumors. 5-10% of HBs also contain mutations in a third protein, NFE2L2, that normally prevents certain types of DNA damage. In initial studies, NFE2L2 mutants sped up tumor growth in response to D(90)+YAPS127A. Unexpectedly, NFE2L2 mutants caused tumors when present in livers with either D(90) or YAPS127A. Thus, any two combinations of these mutations cause cancer. This research will ask exactly how each pair of mutant proteins alters tumor growth. It will also identify the small number of common changes that underlie these tumors. This has previously been impossible because the differences between normal livers and tumors is so large. Identifying the genes shared by different mutant combinations should make this easier. Our proposal is innovative because it will find the most important changes that cause HB. It is translationally important because knowing these changed genes may uncover new ways to treat HB and other pediatric and adult cancers.