Abstract
Forty-two patients with hepatocellular carcinoma (HCC) were resected and their tumours were analysed for p53 mutations by GC-clamped denaturing gradient gel electrophoresis (DGGE), single-strand conformation polymorphism (SSCP) and gene sequencing. All the exons have been analysed in this study. Eight of 12 HCCs with cirrhosis due to viral hepatitis and the two patients with sarcomatoid changes displayed p53 mutations. In contrast, no mutation was observed in the fibrolamellar variant (n = 9), non-cirrhotics (n = 13) and alcoholic cirrhosis (n = 6). The mutations observed were in exons 5-8. Two mutations were observed in codons 136 and 213 as well as a T insertion between residues 156 and 157 (exon 5) and these are reported for the first time in HCC. Likewise, the silent mutation polymorphism in codon 213 was noticed in 3 of the 42 patients. Survival analysis of these patients after surgery showed the mean and median survival in patients with wild-type p53 to be 60 and 43 months respectively. In the group with p53 mutations, the mean and median survival was 15 and 12 months. The difference was statistically significant (P= 0.003).
Full text
PDF






Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Abadie V., Lyonnet S., Maurin N., Berthelon M., Caillaud C., Giraud F., Mattei J. F., Rey J., Rey F., Munnich A. CpG dinucleotides are mutation hot spots in phenylketonuria. Genomics. 1989 Nov;5(4):936–939. doi: 10.1016/0888-7543(89)90137-7. [DOI] [PubMed] [Google Scholar]
- Adelman R., Saul R. L., Ames B. N. Oxidative damage to DNA: relation to species metabolic rate and life span. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2706–2708. doi: 10.1073/pnas.85.8.2706. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Beck J. S., Kwitek A. E., Cogen P. H., Metzger A. K., Duyk G. M., Sheffield V. C. A denaturing gradient gel electrophoresis assay for sensitive detection of p53 mutations. Hum Genet. 1993 Mar;91(1):25–30. doi: 10.1007/BF00230217. [DOI] [PubMed] [Google Scholar]
- Bressac B., Kew M., Wands J., Ozturk M. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature. 1991 Apr 4;350(6317):429–431. doi: 10.1038/350429a0. [DOI] [PubMed] [Google Scholar]
- Buetow K. H., Sheffield V. C., Zhu M., Zhou T., Shen F. M., Hino O., Smith M., McMahon B. J., Lanier A. P., London W. T. Low frequency of p53 mutations observed in a diverse collection of primary hepatocellular carcinomas. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9622–9626. doi: 10.1073/pnas.89.20.9622. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cho Y., Gorina S., Jeffrey P. D., Pavletich N. P. Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science. 1994 Jul 15;265(5170):346–355. doi: 10.1126/science.8023157. [DOI] [PubMed] [Google Scholar]
- D'Agostini F., Fronza G., Campomenosi P., Izzotti A., Petrilli G. L., Abbondandolo A., De Flora S. Cancer biomarkers in human atherosclerotic lesions: no evidence of p53 involvement. Cancer Epidemiol Biomarkers Prev. 1995 Mar;4(2):111–115. [PubMed] [Google Scholar]
- Ding S. F., Delhanty J. D., Bowles L., Dooley J. S., Wood C. B., Habib N. A. Infrequent chromosome allele loss in fibrolamellar carcinoma. Br J Cancer. 1993 Feb;67(2):244–246. doi: 10.1038/bjc.1993.47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ding S. F., Habib N. A., Dooley J., Wood C., Bowles L., Delhanty J. D. Loss of constitutional heterozygosity on chromosome 5q in hepatocellular carcinoma without cirrhosis. Br J Cancer. 1991 Dec;64(6):1083–1087. doi: 10.1038/bjc.1991.468. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Feitelson M. A., Duan L. X. Hepatitis B virus X antigen in the pathogenesis of chronic infections and the development of hepatocellular carcinoma. Am J Pathol. 1997 Apr;150(4):1141–1157. [PMC free article] [PubMed] [Google Scholar]
- Feitelson M. A., Zhu M., Duan L. X., London W. T. Hepatitis B x antigen and p53 are associated in vitro and in liver tissues from patients with primary hepatocellular carcinoma. Oncogene. 1993 May;8(5):1109–1117. [PubMed] [Google Scholar]
- Habib N. A., Ding S. F., el-Masry R., Mitry R. R., Honda K., Michail N. E., Dalla Serra G., Izzi G., Greco L., Bassyouni M. Preliminary report: the short-term effects of direct p53 DNA injection in primary hepatocellular carcinomas. Cancer Detect Prev. 1996;20(2):103–107. [PubMed] [Google Scholar]
- Hayashi H., Sugio K., Matsumata T., Adachi E., Takenaka K., Sugimachi K. The clinical significance of p53 gene mutation in hepatocellular carcinomas from Japan. Hepatology. 1995 Dec;22(6):1702–1707. [PubMed] [Google Scholar]
- Hino O., Shows T. B., Rogler C. E. Hepatitis B virus integration site in hepatocellular carcinoma at chromosome 17;18 translocation. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8338–8342. doi: 10.1073/pnas.83.21.8338. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hollstein M., Rice K., Greenblatt M. S., Soussi T., Fuchs R., Sørlie T., Hovig E., Smith-Sørensen B., Montesano R., Harris C. C. Database of p53 gene somatic mutations in human tumors and cell lines. Nucleic Acids Res. 1994 Sep;22(17):3551–3555. [PMC free article] [PubMed] [Google Scholar]
- Hosono S., Lee C. S., Chou M. J., Yang C. S., Shih C. H. Molecular analysis of the p53 alleles in primary hepatocellular carcinomas and cell lines. Oncogene. 1991 Feb;6(2):237–243. [PubMed] [Google Scholar]
- Hsu I. C., Metcalf R. A., Sun T., Welsh J. A., Wang N. J., Harris C. C. Mutational hotspot in the p53 gene in human hepatocellular carcinomas. Nature. 1991 Apr 4;350(6317):427–428. doi: 10.1038/350427a0. [DOI] [PubMed] [Google Scholar]
- Kakizoe S., Kojiro M., Nakashima T. Hepatocellular carcinoma with sarcomatous change. Clinicopathologic and immunohistochemical studies of 14 autopsy cases. Cancer. 1987 Jan 15;59(2):310–316. doi: 10.1002/1097-0142(19870115)59:2<310::aid-cncr2820590224>3.0.co;2-s. [DOI] [PubMed] [Google Scholar]
- Lamb P., Crawford L. Characterization of the human p53 gene. Mol Cell Biol. 1986 May;6(5):1379–1385. doi: 10.1128/mcb.6.5.1379. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nigro J. M., Baker S. J., Preisinger A. C., Jessup J. M., Hostetter R., Cleary K., Bigner S. H., Davidson N., Baylin S., Devilee P. Mutations in the p53 gene occur in diverse human tumour types. Nature. 1989 Dec 7;342(6250):705–708. doi: 10.1038/342705a0. [DOI] [PubMed] [Google Scholar]
- Nishida N., Fukuda Y., Kokuryu H., Toguchida J., Yandell D. W., Ikenega M., Imura H., Ishizaki K. Role and mutational heterogeneity of the p53 gene in hepatocellular carcinoma. Cancer Res. 1993 Jan 15;53(2):368–372. [PubMed] [Google Scholar]
- Nose H., Imazeki F., Ohto M., Omata M. p53 gene mutations and 17p allelic deletions in hepatocellular carcinoma from Japan. Cancer. 1993 Jul 15;72(2):355–360. doi: 10.1002/1097-0142(19930715)72:2<355::aid-cncr2820720208>3.0.co;2-w. [DOI] [PubMed] [Google Scholar]
- Robinson W. S. Molecular events in the pathogenesis of hepadnavirus-associated hepatocellular carcinoma. Annu Rev Med. 1994;45:297–323. doi: 10.1146/annurev.med.45.1.297. [DOI] [PubMed] [Google Scholar]
- Serra A., Gaidano G. L., Revello D., Guerrasio A., Ballerini P., Dalla Favera R., Saglio G. A new TaqI polymorphism in the p53 gene. Nucleic Acids Res. 1992 Feb 25;20(4):928–928. doi: 10.1093/nar/20.4.928. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shieh Y. S., Nguyen C., Vocal M. V., Chu H. W. Tumor-suppressor p53 gene in hepatitis C and B virus-associated human hepatocellular carcinoma. Int J Cancer. 1993 Jun 19;54(4):558–562. doi: 10.1002/ijc.2910540407. [DOI] [PubMed] [Google Scholar]
- Slagle B. L., Zhou Y. Z., Butel J. S. 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 carcinomas. Cancer Res. 1991 Jan 1;51(1):49–54. [PubMed] [Google Scholar]
- Teramoto T., Satonaka K., Kitazawa S., Fujimori T., Hayashi K., Maeda S. p53 gene abnormalities are closely related to hepatoviral infections and occur at a late stage of hepatocarcinogenesis. Cancer Res. 1994 Jan 1;54(1):231–235. [PubMed] [Google Scholar]
- Thukral S. K., Blain G. C., Chang K. K., Fields S. Distinct residues of human p53 implicated in binding to DNA, simian virus 40 large T antigen, 53BP1, and 53BP2. Mol Cell Biol. 1994 Dec;14(12):8315–8321. doi: 10.1128/mcb.14.12.8315. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vecchio F. M., Fabiano A., Ghirlanda G., Manna R., Massi G. Fibrolamellar carcinoma of the liver: the malignant counterpart of focal nodular hyperplasia with oncocytic change. Am J Clin Pathol. 1984 Apr;81(4):521–526. doi: 10.1093/ajcp/81.4.521. [DOI] [PubMed] [Google Scholar]
- Weghorst C. M., Buzard G. S., Calvert R. J., Hulla J. E., Rice J. M. Cloning and sequence of a processed p53 pseudogene from rat: a potential source of false 'mutations' in PCR fragments of tumor DNA. Gene. 1995 Dec 12;166(2):317–322. doi: 10.1016/0378-1119(95)00629-x. [DOI] [PubMed] [Google Scholar]