Somatic alterations of the c-Ha-rus gene were examined in 21 Japanese patients with hepatocellular carcinoma. Restriction endonuclease analysis by double digestion with Map1 and HpuII revealed that DNAs from two of 21 hepatocellular carcinoma tissues were affected by nucleotide substitution at the twelfth amino acid codingsequence of the c-Ha-rus gene. DNAs from cirrhotic noncancerous liver tissue, but not leukocytes, of one of these patients possessed the mutation, whereas DNAs from noncirrhotic liver tissue and leukocytes of the other patient did not. In one of the nine patients harboring heterozygosity for c-Harus-related BumHI-fragments, the loss of one allele was demonstrated as a somatic change not only in DNA from the tumor tissue but also in DNA from the cirrhotic nontumorous tissue. In two of the 19 patients comparatively examined for digestion patterns of c-Harus locus with H' II and MspI, extensive methylation was observed as a somatic modification in both DNAs from the tumor and the cirrhotic nontumorous tissues. These results thus indicate that the genetic lesions affecting the c-Ha-rua gene do occur in human hepatocellular carcinoma and probably serve as one of the multiple steps in the process of hepatic carcinogenesis. (HEPATOLOGY 1991; 13:31-37.)
Hepatocellular carcinoma (HCC) is a common neoplasm in Japan and in other Asian and African countries. Epidemiological surveys have shown that persistent infection with HBV is closely linked to the occurrence of HCC (11, and molecular analyses have demonstrated that the HBV genome is integrated into chromosomes of HCC (2,3). However, since the integration of HBV DNA alone does not lead to the development of HCC (4,5) and not all HCCs are related to HBV infection, it has been hypothesized that functional changes of cellular genes also may have some significance for the progression of HCC (6).
Among several types of gene alterations that have been considered to play important roles in malignant