p53 Suppressor Gene Mutations in Ovarian Cancer
Keywords:
p53 mutation in ovarian cancer, p53 overexpression, DNA sequence, ovarian cancer, p53 suppressor geneAbstract
PRECIS: Mutations of p53 gene have been discovered in a wide variety of human cancers. We studied the mutation of p53 gene in 40 consecutive ovarian cancers and found p53 proteins overexpression by Western Transfer Method to be at the rate of 95 per cent (38/40), while the presence of p53 mutation by DNA Sequencing was at the rate of 78 per cent (31/40). DNA Sequencing should be done in all cases without exception to be able to capture all mutations.
Mutations of p53 suppressor gene have been discovered in a wide variety of human cancer ranging from most common, such as basal cell cancers to the least common, such as soft tissue sarcoma. It is believed that the accumulation of mutations, exogenous or endogenous in the genome of cells can lead to deregulation of cell growth and finally development of cancer.
We studied the p53 mutations in 40 consecutive ovarian cancers by using Immunoblotting (Western Transfer Method) to detect mutant p53 protein in ovarian cancer cells and DNA sequencing technique to identify mutation in p53 gene.
It was discovered that overexpression of p53 protein was at the rate of 38/40 = 95 per cent and the presence of mutations in p53 gene was 31/40 = 78 per cent. Even though the correlation between p53 overexpression and presence of mutation was not perfect, the data clearly showed that the p53 mutation was found in most ovarian cancer and perhaps represented somatic mutation leading to this cancer. A total of 41 mutations and one deletion were discovered in 31 cases, more than were of Transition mutation type and less than were of Transversion type of mutations.
p53 Mutation was detected in ovarian cancer from early to late stage. It is thought perhaps that p53 mutation should be viewed as initial step of carcinogenesis rather than late event. One half of the p53 mutations may arise from spontaneous mutation, yet the other one half may arise from interaction of carcinogens with DNA.
References
2. Findlay CA, Hinds PW, Levine AJ. The p53 protooncogene can act as a suppressor Of transformation. Cell 1989; 57:1083-93.
3. Lane DP, p53, guardian of the genome. Nature 1992;358:15-6.
4. Vogelstein B, Kinzler KW. p53 Function and dysfunction. Cell 1992;70:523-6.
5. Lane DP, Crawford LV. T-Antigen is bound to a host protein in SV40 transformed cells. Nature 1979:278:261-3.
6. Bishop JM. Molecular themes in oncogenesis. Cell 1991;64:235-48.
7. Weinberg RA. Tumor suppressor gene. Science 1991; 64:1138-46.
8. Harris CC. Molecular epidemiology of basal cell carcinoma. J Natl Cancer Inst 1996;88:315-7.
9. Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 Mutations in human cancers. Science 1991;253:49-53.
10. Nigro JM, Baker SI, Preisinger AC, et al. Mutations in the p53 gene occur in diverse human tumor types. Nature 1989;342:705-8.
11. Prosser J, Thompson AM, Cranston G, Evans HJ. Evidence that p53 behaves as a tumor suppressor in sporadic breast tumors. Oncogene 1990; 5:1573-9.
12. Mazars R, Spinardi L, Bencheikh M, Simony-Lafontaine J, Jeanteur P, Theillet C. p53 mutations occur in aggressive breast cancer. Cancer Res 1992; 52:3918-23.
13. Takahashi T, Nau MM, Chiba I, et al. p53:A frequent target for genetic abnormalities in lung cancer. Science 1989;246:491-4.
14. Sidransky D, Mikkelsen T, Schwechheimer K, Rosenblum ML, Cavanee W, Vogelstein B. Clonal expansion of p53 mutant cells is associated with brain tumor progression. Nature 1992; 355:846-7.
15. Caron de Fromentel C, Soussi T. p53 tumor suppressor gene: A model for investigating human mutagenesis. Genes Chrom & Cancer 1992; 4:1-15.
16. Hsu IC, Metcalf RA, Sun T, Welsh JA, Wang NJ, Harris CC. Mutational hotspot in the p53 gene in human hepatocellular carcinomas. Nature 1991; 350:427-8.
17. Bressac BKM, Wands J, Ozturk M. Selective G to T mutations of p53 gene in hepatocellular carcinoma from Southern Africa. Nature 1991; 350:429-31.
18. Bartek J, Bartkova J, Vojtesek B, et al. Aberrant expression of the p53 oncoprotein is a common feature of a wide spectrum of human malignancies. Oncogene 1991;6:1699-703.
19. Marks JR, Davidoff AM, Kerns BJ, et al. Overexpression and mutation of p53 in epithelial ovarian cancer. Cancer Res 1991;51:2979-84.
20. Okamoto A, Sameshima Y, Yokoyama S, et al. Frequent allelic losses and mutations of the p53 gene in human ovarian cancer. Cancer Res 1951;51:5171-6.
21. Mazars R, Pujol P, Maudelonde T, Jeanteur P, Theillet C. p53 Mutations in Ovarian Cancer: A late event? Oncogene 1991;6:1685-90.
22. Kohler MF, Marks JR, Wiseman RW, et al. Spectrum of mutation and frequency of allelic deletion of the p53 gene in ovarian cancer. J Natl Cancer Inst 1993; 85:1513-9.
23. Kohler MF, Kerns BJ, Humphrey PA, Marks JR, Bast RC, Berchuck A. Mutation and overexpression of p53 in early stage epithelial ovarian cancer. Obstet Gynecol 1993;81:643-8.
24. Milner BJ, Allan LA, Eceles DM, et al. p53 mutation is a common genetic event in ovarian carcinoma. Cancer Res 1993;53:23128-32.
25. Teneriello MG, Ebina M, Linnoila RI, et al. p53 and ki-ras gene mutations in epithelial ovarian neoplasms. Cancer Res 1993;53:3103-8.
26. Sheridan E, Silcocks P, Smith J, Hancock BW, Goyns MH. p53 mutation in a series of epithelial ovarian cancers from the U.K, and its prognostic significance. Eur J Cancer 1993; 30A:1701-4.
27. Kim JW, Cho YH, Kwon DJ, et al. Aberrations of the p53 tumor suppressor gene in human epithelial ovarian carcinoma. Gynecol Oncol 1995;57:199-204.
28. Kupryjanczyk J, Thor AD, Beauchamp R, et al. p53 gene mutations and protein accumulation in human ovarian cancer. Proc Natl Acad Sci USA 1993; 90:4961-5.
29. Ausubel FM, Brent R, Kingston RE, et al. Short protocols in molecular biology. John Wiley and Sons: 1992; 10.5-10.25.
30. Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970;227:680-5.
31. Sambrook J, Fritsch EF, Maniatis T. Molecular cloning: a laboratory manual. Cold Spring Laboratory, Cold Spring Harbor 1989.
32. Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain terminating inhibitors. Proc Natl Acad Sci 1977;74:5463-33. FIGO Cancer Committee: Staging announcement. Gynecol Oncol 1986;25:383.
34. Orita M, Iwahana H, Kanazawa H, Hayashi K, Sekiya T.7. Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc Natl Acad Sci 1989;86:2766-70.
35. Moll UM, Riou G, Levine AJ. Two distinct mechanisms alter p53 in breast cancer: mutation and nuclear exclusion. Proc Natl Acad Sci 1992; 89:7262-6.
36. Louis DM, VonDeimling A, Chung RY. Comparative study of p53 gene and protein alterations in human astrocytic tumors. J Neuropath Exp Neurol 1993;52:31-8.
37. Sjogren S, Inganas M, Norberg T, et al. The p53 gene in breast cancer: prognostic value of complementary DNA sequencing versus immunohistochemistry. J Natl Cancer Inst 1996;88:173-82.
38. Hinds Pw, Findlay CA, Levine AJ. Mutation is required to activate the p53 gene for cooperation with the ras oncogence and transformation. J Virol 1989;63:739-46.
39. Wertheim I, Muto MG, Welch WR, Bell DA, Berkowitz RS, Mok SC. p53 gene mutation in human borderline epithelial ovarian tumors. J Natl Cancer Inst 1994;86:1549-51.
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