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Hepatitis B Virus Integration Event in Human Chromosome 17p near the p53 Gene Identifies the Region of the Chromosome Commonly Deleted in Virus-positive Hepatocellular Carcinomas¹

Division of Molecular Virology, Baylor College of Medicine, Houston, Texas 77030 [B. L. S., J. S. B.], and Shanghai Institute of Biochemistry, Academia Sinica, Shanghai, [Y-Z. Z.] China

The development of hepatocellular carcinoma (HCC) presumably occurs in multiple steps and is influenced by numerous factors. Hepatitis B virus (HBV) is strongly associated with the development of HCC in people chronically infected with the virus, but the mechanism of viral involvement remains unclear. One possibility is that the gross chromosomal alterations frequently observed in HCC DNA at the site of HBV integration may alter the expression of important nearby cellular genes. We previously reported the cloning and characterization of a HBV insert from a Chinese HCC. The viral insert mapped to chromosome 17p11.2-12, and cellular sequences were duplicated at the site of viral integration. In the present study a DNA probe derived from cellular DNA sequences adjacent to the previously characterized HBV insert was used to analyze a set of 19 matched normal liver and HBV-positive hepatoma samples obtained from the same region of China, near Shanghai. Tumor-specific DNA changes were detected in two additional HCCs, suggesting that the small region of chromosome 17p defined by the flanking cell DNA probe is commonly altered in hepatomas. Restriction fragment length polymorphism studies demonstrated that the loss of one copy of portions of chromosome 17 occurred in 10 (53%) of the 19 patients. The loss of one allele of the p53 gene (located on chromosome 17p13) occurred in at least 6 (60%) of the 10 patients who were heterozygous at the p53 locus. As the p53 gene is known to possess tumor suppressor activity, the functional loss of this gene may be a significant step in the development of a subset of HCCs. High levels of allele loss also were detected for chromosomes 8q (4 of 9; 44%) and 16p (5 of 6; 83%) and may indicate the presence of additional cellular genes whose functional loss is important in the development of HCCs.

¹ This work was supported by Research Grant CA25215 from the National Cancer Institute and by The Joseph L. Melnick Professorship of Virology.

² To whom requests for reprints should be addressed, at Division of Molecular Virology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030.

Received 9/17/90. Accepted 9/28/90.