Although the putative effects of FAT4 mutations in HCC has not been reported, our findings that the missense mutations of FAT4 on c.G2530A and c.A14804C were located within an extracellular cadherin repeat and the cytoplasmic region respectively, implicated that FAT4 may act as a tumor suppressor gene regulating cell contact and signal transduction, thus, the somatic inactivation of FAT4 may be a key tumorigenic event in HCC. This evidence concerns the gene FAT4 and hepatocellular carcinoma.