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. 1999 Feb;79(5-6):921–926. doi: 10.1038/sj.bjc.6690147

p53 mutations in human cutaneous melanoma correlate with sun exposure but are not always involved in melanomagenesis

S F Zerp 1, A van Elsas 1, L T C Peltenburg 1, P I Schrier 1
PMCID: PMC2362648  PMID: 10070891

Abstract

In melanoma, the relationship between sun exposure and the origin of mutations in either the N-ras oncogene or the p53 tumour-suppressor gene is not as clear as in other types of skin cancer. We have previously shown that mutations in the N-ras gene occur more frequently in melanomas originating from sun-exposed body sites, indicating that these mutations are UV induced. To investigate whether sun exposure also affects p53 in melanoma, we analysed 81 melanoma specimens for mutations in the p53 gene. The mutation frequency is higher than thus far reported: 17 specimens (21%) harbour one or more p53 mutations. Strikingly, 17 out of 22 mutations in p53 are of the C:G to T:A or CC:GG to TT:AA transitional type, strongly suggesting an aetiology involving UV exposure. Interestingly, the p53 mutation frequency in metastases was much lower than in primary tumours. In the case of metastases, a role for sun exposure was indicated by the finding that the mutations are present exclusively in skin metastases and not in internal metastases. Together with a relatively frequent occurrence of silent third-base pair mutations in primary melanomas, this indicates that the p53 mutations, at least in these tumours, have not contributed to melanomagenesis and may have originated after establishment of the primary tumour. 1999 Cancer Research Campaign

Keywords: p53, UV, mutations, sun exposure, melanoma

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Selected References

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  1. Akslen L. A., Monstad S. E., Larsen B., Straume O., Ogreid D. Frequent mutations of the p53 gene in cutaneous melanoma of the nodular type. Int J Cancer. 1998 Feb 20;79(1):91–95. doi: 10.1002/(sici)1097-0215(19980220)79:1<91::aid-ijc17>3.0.co;2-k. [DOI] [PubMed] [Google Scholar]
  2. Albino A. P., Vidal M. J., McNutt N. S., Shea C. R., Prieto V. G., Nanus D. M., Palmer J. M., Hayward N. K. Mutation and expression of the p53 gene in human malignant melanoma. Melanoma Res. 1994 Feb;4(1):35–45. doi: 10.1097/00008390-199402000-00006. [DOI] [PubMed] [Google Scholar]
  3. Brash D. E., Rudolph J. A., Simon J. A., Lin A., McKenna G. J., Baden H. P., Halperin A. J., Pontén J. A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10124–10128. doi: 10.1073/pnas.88.22.10124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Campbell C., Quinn A. G., Ro Y. S., Angus B., Rees J. L. p53 mutations are common and early events that precede tumor invasion in squamous cell neoplasia of the skin. J Invest Dermatol. 1993 Jun;100(6):746–748. doi: 10.1111/1523-1747.ep12475717. [DOI] [PubMed] [Google Scholar]
  5. Castresana J. S., Rubio M. P., Vázquez J. J., Idoate M., Sober A. J., Seizinger B. R., Barnhill R. L. Lack of allelic deletion and point mutation as mechanisms of p53 activation in human malignant melanoma. Int J Cancer. 1993 Oct 21;55(4):562–565. doi: 10.1002/ijc.2910550407. [DOI] [PubMed] [Google Scholar]
  6. Flørenes V. A., Oyjord T., Holm R., Skrede M., Børresen A. L., Nesland J. M., Fodstad O. TP53 allele loss, mutations and expression in malignant melanoma. Br J Cancer. 1994 Feb;69(2):253–259. doi: 10.1038/bjc.1994.48. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Greenblatt M. S., Bennett W. P., Hollstein M., Harris C. C. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994 Sep 15;54(18):4855–4878. [PubMed] [Google Scholar]
  8. Hainaut P., Soussi T., Shomer B., Hollstein M., Greenblatt M., Hovig E., Harris C. C., Montesano R. Database of p53 gene somatic mutations in human tumors and cell lines: updated compilation and future prospects. Nucleic Acids Res. 1997 Jan 1;25(1):151–157. doi: 10.1093/nar/25.1.151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hartmann A., Blaszyk H., Cunningham J. S., McGovern R. M., Schroeder J. S., Helander S. D., Pittelkow M. R., Sommer S. S., Kovach J. S. Overexpression and mutations of p53 in metastatic malignant melanomas. Int J Cancer. 1996 Jul 29;67(3):313–317. doi: 10.1002/(SICI)1097-0215(19960729)67:3<313::AID-IJC1>3.0.CO;2-U. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. Hollstein M., Shomer B., Greenblatt M., Soussi T., Hovig E., Montesano R., Harris C. C. Somatic point mutations in the p53 gene of human tumors and cell lines: updated compilation. Nucleic Acids Res. 1996 Jan 1;24(1):141–146. doi: 10.1093/nar/24.1.141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hsiao M. H., Yu A. L., Yeargin J., Ku D., Haas M. Nonhereditary p53 mutations in T-cell acute lymphoblastic leukemia are associated with the relapse phase. Blood. 1994 May 15;83(10):2922–2930. [PubMed] [Google Scholar]
  13. Kanjilal S., Pierceall W. E., Cummings K. K., Kripke M. L., Ananthaswamy H. N. High frequency of p53 mutations in ultraviolet radiation-induced murine skin tumors: evidence for strand bias and tumor heterogeneity. Cancer Res. 1993 Jul 1;53(13):2961–2964. [PubMed] [Google Scholar]
  14. Kress S., Sutter C., Strickland P. T., Mukhtar H., Schweizer J., Schwarz M. Carcinogen-specific mutational pattern in the p53 gene in ultraviolet B radiation-induced squamous cell carcinomas of mouse skin. Cancer Res. 1992 Nov 15;52(22):6400–6403. [PubMed] [Google Scholar]
  15. Lehman T. A., Bennett W. P., Metcalf R. A., Welsh J. A., Ecker J., Modali R. V., Ullrich S., Romano J. W., Appella E., Testa J. R. p53 mutations, ras mutations, and p53-heat shock 70 protein complexes in human lung carcinoma cell lines. Cancer Res. 1991 Aug 1;51(15):4090–4096. [PubMed] [Google Scholar]
  16. Lübbe J., Reichel M., Burg G., Kleihues P. Absence of p53 gene mutations in cutaneous melanoma. J Invest Dermatol. 1994 May;102(5):819–821. doi: 10.1111/1523-1747.ep12381544. [DOI] [PubMed] [Google Scholar]
  17. Molès J. P., Moyret C., Guillot B., Jeanteur P., Guilhou J. J., Theillet C., Basset-Sèguin N. p53 gene mutations in human epithelial skin cancers. Oncogene. 1993 Mar;8(3):583–588. [PubMed] [Google Scholar]
  18. Montano X., Shamsher M., Whitehead P., Dawson K., Newton J. Analysis of p53 in human cutaneous melanoma cell lines. Oncogene. 1994 May;9(5):1455–1459. [PubMed] [Google Scholar]
  19. Moshinsky D. J., Wogan G. N. UV-induced mutagenesis of human p53 in a vector replicated in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2266–2271. doi: 10.1073/pnas.94.6.2266. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Moyret C., Madsen M. W., Cooke J., Briand P., Theillet C. Gradual selection of a cellular clone presenting a mutation at codon 179 of the p53 gene during establishment of the immortalized human breast epithelial cell line HMT-3522. Exp Cell Res. 1994 Dec;215(2):380–385. doi: 10.1006/excr.1994.1355. [DOI] [PubMed] [Google Scholar]
  21. Murakami Y., Hayashi K., Sekiya T. Detection of aberrations of the p53 alleles and the gene transcript in human tumor cell lines by single-strand conformation polymorphism analysis. Cancer Res. 1991 Jul 1;51(13):3356–3361. [PubMed] [Google Scholar]
  22. Papp T., Jafari M., Schiffmann D. Lack of p53 mutations and loss of heterozygosity in non-cultured human melanocytic lesions. J Cancer Res Clin Oncol. 1996;122(9):541–548. doi: 10.1007/BF01213550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Rady P., Scinicariello F., Wagner R. F., Jr, Tyring S. K. p53 mutations in basal cell carcinomas. Cancer Res. 1992 Jul 1;52(13):3804–3806. [PubMed] [Google Scholar]
  24. Sparrow L. E., Soong R., Dawkins H. J., Iacopetta B. J., Heenan P. J. p53 gene mutation and expression in naevi and melanomas. Melanoma Res. 1995 Apr;5(2):93–100. doi: 10.1097/00008390-199504000-00004. [DOI] [PubMed] [Google Scholar]
  25. Volkenandt M., Schlegel U., Nanus D. M., Albino A. P. Mutational analysis of the human p53 gene in malignant melanoma. Pigment Cell Res. 1991 Feb;4(1):35–40. doi: 10.1111/j.1600-0749.1991.tb00311.x. [DOI] [PubMed] [Google Scholar]
  26. Weiss J., Schwechheimer K., Cavenee W. K., Herlyn M., Arden K. C. Mutation and expression of the p53 gene in malignant melanoma cell lines. Int J Cancer. 1993 Jun 19;54(4):693–699. doi: 10.1002/ijc.2910540427. [DOI] [PubMed] [Google Scholar]
  27. Ziegler A., Jonason A. S., Leffell D. J., Simon J. A., Sharma H. W., Kimmelman J., Remington L., Jacks T., Brash D. E. Sunburn and p53 in the onset of skin cancer. Nature. 1994 Dec 22;372(6508):773–776. doi: 10.1038/372773a0. [DOI] [PubMed] [Google Scholar]
  28. Ziegler A., Leffell D. J., Kunala S., Sharma H. W., Gailani M., Simon J. A., Halperin A. J., Baden H. P., Shapiro P. E., Bale A. E. Mutation hotspots due to sunlight in the p53 gene of nonmelanoma skin cancers. Proc Natl Acad Sci U S A. 1993 May 1;90(9):4216–4220. doi: 10.1073/pnas.90.9.4216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. van Elsas A., Zerp S. F., van der Flier S., Krüse K. M., Aarnoudse C., Hayward N. K., Ruiter D. J., Schrier P. I. Relevance of ultraviolet-induced N-ras oncogene point mutations in development of primary human cutaneous melanoma. Am J Pathol. 1996 Sep;149(3):883–893. [PMC free article] [PubMed] [Google Scholar]
  30. van Kranen H. J., de Gruijl F. R., de Vries A., Sontag Y., Wester P. W., Senden H. C., Rozemuller E., van Kreijl C. F. Frequent p53 alterations but low incidence of ras mutations in UV-B-induced skin tumors of hairless mice. Carcinogenesis. 1995 May;16(5):1141–1147. doi: 10.1093/carcin/16.5.1141. [DOI] [PubMed] [Google Scholar]

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