Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1991 Nov 15;88(22):10124–10128. doi: 10.1073/pnas.88.22.10124

A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma.

D E Brash 1, J A Rudolph 1, J A Simon 1, A Lin 1, G J McKenna 1, H P Baden 1, A J Halperin 1, J Pontén 1
PMCID: PMC52880  PMID: 1946433

Abstract

Sunlight is a carcinogen to which everyone is exposed. Its UV component is the major epidemiologic risk factor for squamous cell carcinoma of the skin. Of the multiple steps in tumor progression, those that are sunlight-related would be revealed if they contained mutations specific to UV. In a series of New England and Swedish patients, we find that 14/24 (58%) of invasive squamous cell carcinomas of the skin contain mutations in the p53 tumor suppressor gene, each altering the amino acid sequence. Involvement of UV light in these p53 mutations is indicated by the presence in three of the tumors of a CC----TT double-base change, which is only known to be induced by UV. UV is also implicated by a UV-like occurrence of mutations exclusively at dipyrimidine sites, including a high frequency of C----T substitutions. p53 mutations in internal malignancies do not show these UV-specific mutations. The dipyrimidine specificity also implicates dipyrimidine photoproducts containing cytosine as oncogenic photoproducts. We believe these results identify a carcinogen-related step in a gene involved in the subsequent human cancer.

Full text

PDF
10124

Images in this article

10125Image
on p.10125
10125Image
on p.10125
10125Image
on p.10125
10125Image
on p.10125

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ananthaswamy H. N., Pierceall W. E. Molecular mechanisms of ultraviolet radiation carcinogenesis. Photochem Photobiol. 1990 Dec;52(6):1119–1136. doi: 10.1111/j.1751-1097.1990.tb08452.x. [DOI] [PubMed] [Google Scholar]
  2. Armstrong J. D., Kunz B. A. Site and strand specificity of UVB mutagenesis in the SUP4-o gene of yeast. Proc Natl Acad Sci U S A. 1990 Nov;87(22):9005–9009. doi: 10.1073/pnas.87.22.9005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barbacid M. ras genes. Annu Rev Biochem. 1987;56:779–827. doi: 10.1146/annurev.bi.56.070187.004023. [DOI] [PubMed] [Google Scholar]
  4. Boring C. C., Squires T. S., Tong T. Cancer statistics, 1991. CA Cancer J Clin. 1991 Jan-Feb;41(1):19–36. doi: 10.3322/canjclin.41.1.19. [DOI] [PubMed] [Google Scholar]
  5. Brash D. E., Seetharam S., Kraemer K. H., Seidman M. M., Bredberg A. Photoproduct frequency is not the major determinant of UV base substitution hot spots or cold spots in human cells. Proc Natl Acad Sci U S A. 1987 Jun;84(11):3782–3786. doi: 10.1073/pnas.84.11.3782. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cheng J., Haas M. Frequent mutations in the p53 tumor suppressor gene in human leukemia T-cell lines. Mol Cell Biol. 1990 Oct;10(10):5502–5509. doi: 10.1128/mcb.10.10.5502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chiba I., Takahashi T., Nau M. M., D'Amico D., Curiel D. T., Mitsudomi T., Buchhagen D. L., Carbone D., Piantadosi S., Koga H. Mutations in the p53 gene are frequent in primary, resected non-small cell lung cancer. Lung Cancer Study Group. Oncogene. 1990 Oct;5(10):1603–1610. [PubMed] [Google Scholar]
  8. Dotto G. P., O'Connell J., Patskan G., Conti C., Ariza A., Slaga T. J. Malignant progression of papilloma-derived keratinocytes: differential effects of the ras, neu, and p53 oncogenes. Mol Carcinog. 1988;1(3):171–179. doi: 10.1002/mc.2940010305. [DOI] [PubMed] [Google Scholar]
  9. Drobetsky E. A., Grosovsky A. J., Glickman B. W. The specificity of UV-induced mutations at an endogenous locus in mammalian cells. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9103–9107. doi: 10.1073/pnas.84.24.9103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fearon E. R., Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990 Jun 1;61(5):759–767. doi: 10.1016/0092-8674(90)90186-i. [DOI] [PubMed] [Google Scholar]
  11. Foti A., Bar-Eli M., Ahuja H. G., Cline M. J. A splicing mutation accounts for the lack of p53 gene expression in a CML blast crisis cell line: a novel mechanism of p53 gene inactivation. Br J Haematol. 1990 Sep;76(1):143–145. doi: 10.1111/j.1365-2141.1990.tb07849.x. [DOI] [PubMed] [Google Scholar]
  12. Freeman S. E., Hacham H., Gange R. W., Maytum D. J., Sutherland J. C., Sutherland B. M. Wavelength dependence of pyrimidine dimer formation in DNA of human skin irradiated in situ with ultraviolet light. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5605–5609. doi: 10.1073/pnas.86.14.5605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Glass A. G., Hoover R. N. The emerging epidemic of melanoma and squamous cell skin cancer. JAMA. 1989 Oct 20;262(15):2097–2100. [PubMed] [Google Scholar]
  14. Glickman B. W., Schaaper R. M., Haseltine W. A., Dunn R. L., Brash D. E. The C-C (6-4) UV photoproduct is mutagenic in Escherichia coli. Proc Natl Acad Sci U S A. 1986 Sep;83(18):6945–6949. doi: 10.1073/pnas.83.18.6945. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hollstein M. C., Metcalf R. A., Welsh J. A., Montesano R., Harris C. C. Frequent mutation of the p53 gene in human esophageal cancer. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9958–9961. doi: 10.1073/pnas.87.24.9958. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hollstein M., Sidransky D., Vogelstein B., Harris C. C. p53 mutations in human cancers. Science. 1991 Jul 5;253(5015):49–53. doi: 10.1126/science.1905840. [DOI] [PubMed] [Google Scholar]
  17. Horsfall M. J., Gordon A. J., Burns P. A., Zielenska M., van der Vliet G. M., Glickman B. W. Mutational specificity of alkylating agents and the influence of DNA repair. Environ Mol Mutagen. 1990;15(2):107–122. doi: 10.1002/em.2850150208. [DOI] [PubMed] [Google Scholar]
  18. Hsia H. C., Lebkowski J. S., Leong P. M., Calos M. P., Miller J. H. Comparison of ultraviolet irradiation-induced mutagenesis of the lacI gene in Escherichia coli and in human 293 cells. J Mol Biol. 1989 Jan 5;205(1):103–113. doi: 10.1016/0022-2836(89)90368-9. [DOI] [PubMed] [Google Scholar]
  19. Keyse S. M., Amaudruz F., Tyrrell R. M. Determination of the spectrum of mutations induced by defined-wavelength solar UVB (313-nm) radiation in mammalian cells by use of a shuttle vector. Mol Cell Biol. 1988 Dec;8(12):5425–5431. doi: 10.1128/mcb.8.12.5425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lavigueur A., Maltby V., Mock D., Rossant J., Pawson T., Bernstein A. High incidence of lung, bone, and lymphoid tumors in transgenic mice overexpressing mutant alleles of the p53 oncogene. Mol Cell Biol. 1989 Sep;9(9):3982–3991. doi: 10.1128/mcb.9.9.3982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lee G. S., Savage E. A., Ritzel R. G., von Borstel R. C. The base-alteration spectrum of spontaneous and ultraviolet radiation-induced forward mutations in the URA3 locus of Saccharomyces cerevisiae. Mol Gen Genet. 1988 Nov;214(3):396–404. doi: 10.1007/BF00330472. [DOI] [PubMed] [Google Scholar]
  22. Levine A. J., Momand J. Tumor suppressor genes: the p53 and retinoblastoma sensitivity genes and gene products. Biochim Biophys Acta. 1990 Jun 1;1032(1):119–136. doi: 10.1016/0304-419x(90)90015-s. [DOI] [PubMed] [Google Scholar]
  23. Ley R. D., Applegate L. A., Padilla R. S., Stuart T. D. Ultraviolet radiation--induced malignant melanoma in Monodelphis domestica. Photochem Photobiol. 1989 Jul;50(1):1–5. doi: 10.1111/j.1751-1097.1989.tb04123.x. [DOI] [PubMed] [Google Scholar]
  24. Liber H. L., Benforado K., Crosby R. M., Simpson D., Skopek T. R. Formaldehyde-induced and spontaneous alterations in human hprt DNA sequence and mRNA expression. Mutat Res. 1989 May;226(1):31–37. doi: 10.1016/0165-7992(89)90089-4. [DOI] [PubMed] [Google Scholar]
  25. Loeb L. A., Preston B. D. Mutagenesis by apurinic/apyrimidinic sites. Annu Rev Genet. 1986;20:201–230. doi: 10.1146/annurev.ge.20.120186.001221. [DOI] [PubMed] [Google Scholar]
  26. Maher V. M., Dorney D. J., Mendrala A. L., Konze-Thomas B., McCormick J. J. DNA excision-repair processes in human cells can eliminate the cytotoxic and mutagenic consequences of ultraviolet irradiation. Mutat Res. 1979 Sep;62(2):311–323. doi: 10.1016/0027-5107(79)90087-3. [DOI] [PubMed] [Google Scholar]
  27. Marks R., Jolley D., Lectsas S., Foley P. The role of childhood exposure to sunlight in the development of solar keratoses and non-melanocytic skin cancer. Med J Aust. 1990 Jan 15;152(2):62–66. doi: 10.5694/j.1326-5377.1990.tb124456.x. [DOI] [PubMed] [Google Scholar]
  28. McGregor W. G., Chen R. H., Lukash L., Maher V. M., McCormick J. J. Cell cycle-dependent strand bias for UV-induced mutations in the transcribed strand of excision repair-proficient human fibroblasts but not in repair-deficient cells. Mol Cell Biol. 1991 Apr;11(4):1927–1934. doi: 10.1128/mcb.11.4.1927. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Miller J. H. Mutagenic specificity of ultraviolet light. J Mol Biol. 1985 Mar 5;182(1):45–65. doi: 10.1016/0022-2836(85)90026-9. [DOI] [PubMed] [Google Scholar]
  30. Miller J. H. Mutational specificity in bacteria. Annu Rev Genet. 1983;17:215–238. doi: 10.1146/annurev.ge.17.120183.001243. [DOI] [PubMed] [Google Scholar]
  31. Mitchell D. L., Nairn R. S. The biology of the (6-4) photoproduct. Photochem Photobiol. 1989 Jun;49(6):805–819. doi: 10.1111/j.1751-1097.1989.tb05578.x. [DOI] [PubMed] [Google Scholar]
  32. Moraes E. C., Keyse S. M., Tyrrell R. M. Mutagenesis by hydrogen peroxide treatment of mammalian cells: a molecular analysis. Carcinogenesis. 1990 Feb;11(2):283–293. doi: 10.1093/carcin/11.2.283. [DOI] [PubMed] [Google Scholar]
  33. Münger K., Phelps W. C., Bubb V., Howley P. M., Schlegel R. The E6 and E7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes. J Virol. 1989 Oct;63(10):4417–4421. doi: 10.1128/jvi.63.10.4417-4421.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Recio L., Cochrane J., Simpson D., Skopek T. R., O'Neill J. P., Nicklas J. A., Albertini R. J. DNA sequence analysis of in vivo hprt mutation in human T lymphocytes. Mutagenesis. 1990 Sep;5(5):505–510. doi: 10.1093/mutage/5.5.505. [DOI] [PubMed] [Google Scholar]
  35. Rideout W. M., 3rd, Coetzee G. A., Olumi A. F., Jones P. A. 5-Methylcytosine as an endogenous mutagen in the human LDL receptor and p53 genes. Science. 1990 Sep 14;249(4974):1288–1290. doi: 10.1126/science.1697983. [DOI] [PubMed] [Google Scholar]
  36. Romano J. W., Ehrhart J. C., Duthu A., Kim C. M., Appella E., May P. Identification and characterization of a p53 gene mutation in a human osteosarcoma cell line. Oncogene. 1989 Dec;4(12):1483–1488. [PubMed] [Google Scholar]
  37. Sameshima Y., Akiyama T., Mori N., Mizoguchi H., Toyoshima K., Sugimura T., Terada M., Yokota J. Point mutation of the p53 gene resulting in splicing inhibition in small cell lung carcinoma. Biochem Biophys Res Commun. 1990 Dec 14;173(2):697–703. doi: 10.1016/s0006-291x(05)80091-9. [DOI] [PubMed] [Google Scholar]
  38. Seidman M. M., Bredberg A., Seetharam S., Kraemer K. H. Multiple point mutations in a shuttle vector propagated in human cells: evidence for an error-prone DNA polymerase activity. Proc Natl Acad Sci U S A. 1987 Jul;84(14):4944–4948. doi: 10.1073/pnas.84.14.4944. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Setlow R. B. The wavelengths in sunlight effective in producing skin cancer: a theoretical analysis. Proc Natl Acad Sci U S A. 1974 Sep;71(9):3363–3366. doi: 10.1073/pnas.71.9.3363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Setlow R. B., Woodhead A. D., Grist E. Animal model for ultraviolet radiation-induced melanoma: platyfish-swordtail hybrid. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8922–8926. doi: 10.1073/pnas.86.22.8922. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Shaulsky G., Goldfinger N., Ben-Ze'ev A., Rotter V. Nuclear accumulation of p53 protein is mediated by several nuclear localization signals and plays a role in tumorigenesis. Mol Cell Biol. 1990 Dec;10(12):6565–6577. doi: 10.1128/mcb.10.12.6565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Stratton M. R., Moss S., Warren W., Patterson H., Clark J., Fisher C., Fletcher C. D., Ball A., Thomas M., Gusterson B. A. Mutation of the p53 gene in human soft tissue sarcomas: association with abnormalities of the RB1 gene. Oncogene. 1990 Sep;5(9):1297–1301. [PubMed] [Google Scholar]
  43. Vrieling H., Van Rooijen M. L., Groen N. A., Zdzienicka M. Z., Simons J. W., Lohman P. H., van Zeeland A. A. DNA strand specificity for UV-induced mutations in mammalian cells. Mol Cell Biol. 1989 Mar;9(3):1277–1283. doi: 10.1128/mcb.9.3.1277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. de Boer J. G., Glickman B. W. Sequence specificity of mutation induced by the anti-tumor drug cisplatin in the CHO aprt gene. Carcinogenesis. 1989 Aug;10(8):1363–1367. doi: 10.1093/carcin/10.8.1363. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES