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. 1997;75(8):1125–1130. doi: 10.1038/bjc.1997.194

K-ras and p53 mutations are an independent unfavourable prognostic indicator in patients with non-small-cell lung cancer.

Y Fukuyama 1, T Mitsudomi 1, K Sugio 1, T Ishida 1, K Akazawa 1, K Sugimachi 1
PMCID: PMC2222780  PMID: 9099959

Abstract

We examined 159 consecutive cases of non-small-cell lung cancer (NSCLC) for a mutation at codon 12 of the K-ras gene and for a mutation of the p53 gene occurring in exons 5-8. Eleven (6.9%) had mutations of the K-ras (ras+) and 57 (35.8%) had mutations of the p53 (p53+). There were 95 cases (59.7%) with ras- p53-, seven cases (4.4%) with ras+/p53-, 53 cases (33.3%) with ras-/p53+ and four cases (2.5%) with ras+/p53+. The ras+ group had a worse prognosis than the ras group in all cases and in 107 early-stage cases (stage I-II, P<0.05). The p53+ group had a worse prognosis in 107 early-stage cases (P<0.01), but there was no statistically significant difference when 52 advanced-stage cases (stage III-IV) or all patients were considered. Both ras and p53 mutations were unfavourable prognostic factors in 94 cases with adenocarcinoma, but there was no statistical significance in 57 cases with squamous cell carcinoma. According to Cox's model, the pathological stage, ras mutation and p53 mutation were found to be independent prognostic factors. Our results suggest that ras and p53 mutations were independent unfavourable prognostic markers especially in the early stage of NSCLC or in adenocarcinoma.

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Selected References

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  1. Bos J. L. ras oncogenes in human cancer: a review. Cancer Res. 1989 Sep 1;49(17):4682–4689. [PubMed] [Google Scholar]
  2. Børresen A. L., Andersen T. I., Eyfjörd J. E., Cornelis R. S., Thorlacius S., Borg A., Johansson U., Theillet C., Scherneck S., Hartman S. TP53 mutations and breast cancer prognosis: particularly poor survival rates for cases with mutations in the zinc-binding domains. Genes Chromosomes Cancer. 1995 Sep;14(1):71–75. doi: 10.1002/gcc.2870140113. [DOI] [PubMed] [Google Scholar]
  3. Eliyahu D., Raz A., Gruss P., Givol D., Oren M. Participation of p53 cellular tumour antigen in transformation of normal embryonic cells. Nature. 1984 Dec 13;312(5995):646–649. doi: 10.1038/312646a0. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Hinds P. W., Finlay C. A., Quartin R. S., Baker S. J., Fearon E. R., Vogelstein B., Levine A. J. Mutant p53 DNA clones from human colon carcinomas cooperate with ras in transforming primary rat cells: a comparison of the "hot spot" mutant phenotypes. Cell Growth Differ. 1990 Dec;1(12):571–580. [PubMed] [Google Scholar]
  6. Horio Y., Takahashi T., Kuroishi T., Hibi K., Suyama M., Niimi T., Shimokata K., Yamakawa K., Nakamura Y., Ueda R. Prognostic significance of p53 mutations and 3p deletions in primary resected non-small cell lung cancer. Cancer Res. 1993 Jan 1;53(1):1–4. [PubMed] [Google Scholar]
  7. Hunter T. Cooperation between oncogenes. Cell. 1991 Jan 25;64(2):249–270. doi: 10.1016/0092-8674(91)90637-e. [DOI] [PubMed] [Google Scholar]
  8. Iggo R., Gatter K., Bartek J., Lane D., Harris A. L. Increased expression of mutant forms of p53 oncogene in primary lung cancer. Lancet. 1990 Mar 24;335(8691):675–679. doi: 10.1016/0140-6736(90)90801-b. [DOI] [PubMed] [Google Scholar]
  9. Kern J. A., Slebos R. J., Top B., Rodenhuis S., Lager D., Robinson R. A., Weiner D., Schwartz D. A. C-erbB-2 expression and codon 12 K-ras mutations both predict shortened survival for patients with pulmonary adenocarcinomas. J Clin Invest. 1994 Feb;93(2):516–520. doi: 10.1172/JCI117001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kishimoto Y., Murakami Y., Shiraishi M., Hayashi K., Sekiya T. Aberrations of the p53 tumor suppressor gene in human non-small cell carcinomas of the lung. Cancer Res. 1992 Sep 1;52(17):4799–4804. [PubMed] [Google Scholar]
  11. Land H., Parada L. F., Weinberg R. A. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature. 1983 Aug 18;304(5927):596–602. doi: 10.1038/304596a0. [DOI] [PubMed] [Google Scholar]
  12. Lee J. S., Yoon A., Kalapurakal S. K., Ro J. Y., Lee J. J., Tu N., Hittelman W. N., Hong W. K. Expression of p53 oncoprotein in non-small-cell lung cancer: a favorable prognostic factor. J Clin Oncol. 1995 Aug;13(8):1893–1903. doi: 10.1200/JCO.1995.13.8.1893. [DOI] [PubMed] [Google Scholar]
  13. Levine A. J., Momand J., Finlay C. A. The p53 tumour suppressor gene. Nature. 1991 Jun 6;351(6326):453–456. doi: 10.1038/351453a0. [DOI] [PubMed] [Google Scholar]
  14. McLaren R., Kuzu I., Dunnill M., Harris A., Lane D., Gatter K. C. The relationship of p53 immunostaining to survival in carcinoma of the lung. Br J Cancer. 1992 Oct;66(4):735–738. doi: 10.1038/bjc.1992.348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Miller C. W., Simon K., Aslo A., Kok K., Yokota J., Buys C. H., Terada M., Koeffler H. P. p53 mutations in human lung tumors. Cancer Res. 1992 Apr 1;52(7):1695–1698. [PubMed] [Google Scholar]
  16. Minna J. D. The molecular biology of lung cancer pathogenesis. Chest. 1993 Apr;103(4 Suppl):449S–456S. doi: 10.1378/chest.103.4_supplement.449s. [DOI] [PubMed] [Google Scholar]
  17. Mitsudomi T., Oyama T., Kusano T., Osaki T., Nakanishi R., Shirakusa T. Mutations of the p53 gene as a predictor of poor prognosis in patients with non-small-cell lung cancer. J Natl Cancer Inst. 1993 Dec 15;85(24):2018–2023. doi: 10.1093/jnci/85.24.2018. [DOI] [PubMed] [Google Scholar]
  18. Mitsudomi T., Oyama T., Nishida K., Ogami A., Osaki T., Nakanishi R., Sugio K., Yasumoto K., Sugimachi K. p53 nuclear immunostaining and gene mutations in non-small-cell lung cancer and their effects on patient survival. Ann Oncol. 1995;6 (Suppl 3):S9–13. doi: 10.1093/annonc/6.suppl_3.s9. [DOI] [PubMed] [Google Scholar]
  19. Mitsudomi T., Steinberg S. M., Nau M. M., Carbone D., D'Amico D., Bodner S., Oie H. K., Linnoila R. I., Mulshine J. L., Minna J. D. p53 gene mutations in non-small-cell lung cancer cell lines and their correlation with the presence of ras mutations and clinical features. Oncogene. 1992 Jan;7(1):171–180. [PubMed] [Google Scholar]
  20. Mitsudomi T., Viallet J., Mulshine J. L., Linnoila R. I., Minna J. D., Gazdar A. F. Mutations of ras genes distinguish a subset of non-small-cell lung cancer cell lines from small-cell lung cancer cell lines. Oncogene. 1991 Aug;6(8):1353–1362. [PubMed] [Google Scholar]
  21. Nishio M., Koshikawa T., Kuroishi T., Suyama M., Uchida K., Takagi Y., Washimi O., Sugiura T., Ariyoshi Y., Takahashi T. Prognostic significance of abnormal p53 accumulation in primary, resected non-small-cell lung cancers. J Clin Oncol. 1996 Feb;14(2):497–502. doi: 10.1200/JCO.1996.14.2.497. [DOI] [PubMed] [Google Scholar]
  22. Orita M., Iwahana H., Kanazawa H., Hayashi K., Sekiya T. Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2766–2770. doi: 10.1073/pnas.86.8.2766. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Parada L. F., Land H., Weinberg R. A., Wolf D., Rotter V. Cooperation between gene encoding p53 tumour antigen and ras in cellular transformation. Nature. 1984 Dec 13;312(5995):649–651. doi: 10.1038/312649a0. [DOI] [PubMed] [Google Scholar]
  24. Passlick B., Izbicki J. R., Häussinger K., Thetter O., Pantel K. Immunohistochemical detection of P53 protein is not associated with a poor prognosis in non-small-cell lung cancer. J Thorac Cardiovasc Surg. 1995 Jun;109(6):1205–1211. doi: 10.1016/S0022-5223(95)70204-0. [DOI] [PubMed] [Google Scholar]
  25. Peto R., Pike M. C., Armitage P., Breslow N. E., Cox D. R., Howard S. V., Mantel N., McPherson K., Peto J., Smith P. G. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. analysis and examples. Br J Cancer. 1977 Jan;35(1):1–39. doi: 10.1038/bjc.1977.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Raycroft L., Wu H. Y., Lozano G. Transcriptional activation by wild-type but not transforming mutants of the p53 anti-oncogene. Science. 1990 Aug 31;249(4972):1049–1051. doi: 10.1126/science.2144364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Rodenhuis S., Slebos R. J., Boot A. J., Evers S. G., Mooi W. J., Wagenaar S. S., van Bodegom P. C., Bos J. L. Incidence and possible clinical significance of K-ras oncogene activation in adenocarcinoma of the human lung. Cancer Res. 1988 Oct 15;48(20):5738–5741. [PubMed] [Google Scholar]
  28. Selvakumaran M., Lin H. K., Miyashita T., Wang H. G., Krajewski S., Reed J. C., Hoffman B., Liebermann D. Immediate early up-regulation of bax expression by p53 but not TGF beta 1: a paradigm for distinct apoptotic pathways. Oncogene. 1994 Jun;9(6):1791–1798. [PubMed] [Google Scholar]
  29. Slebos R. J., Kibbelaar R. E., Dalesio O., Kooistra A., Stam J., Meijer C. J., Wagenaar S. S., Vanderschueren R. G., van Zandwijk N., Mooi W. J. K-ras oncogene activation as a prognostic marker in adenocarcinoma of the lung. N Engl J Med. 1990 Aug 30;323(9):561–565. doi: 10.1056/NEJM199008303230902. [DOI] [PubMed] [Google Scholar]
  30. Sugio K., Ishida T., Yokoyama H., Inoue T., Sugimachi K., Sasazuki T. ras gene mutations as a prognostic marker in adenocarcinoma of the human lung without lymph node metastasis. Cancer Res. 1992 May 15;52(10):2903–2906. [PubMed] [Google Scholar]
  31. Sugio K., Kurata S., Sasaki M., Soejima J., Sasazuki T. Differential expression of c-myc gene and c-fos gene in premalignant and malignant tissues from patients with familial polyposis coli. Cancer Res. 1988 Sep 1;48(17):4855–4861. [PubMed] [Google Scholar]
  32. Suzuki H., Takahashi T., Kuroishi T., Suyama M., Ariyoshi Y., Takahashi T., Ueda R. p53 mutations in non-small cell lung cancer in Japan: association between mutations and smoking. Cancer Res. 1992 Feb 1;52(3):734–736. [PubMed] [Google Scholar]
  33. Weinberg R. A. Oncogenes, antioncogenes, and the molecular bases of multistep carcinogenesis. Cancer Res. 1989 Jul 15;49(14):3713–3721. [PubMed] [Google Scholar]
  34. Xu H. J., Quinlan D. C., Davidson A. G., Hu S. X., Summers C. L., Li J., Benedict W. F. Altered retinoblastoma protein expression and prognosis in early-stage non-small-cell lung carcinoma. J Natl Cancer Inst. 1994 May 4;86(9):695–699. doi: 10.1093/jnci/86.9.695. [DOI] [PubMed] [Google Scholar]
  35. Yancopoulos G. D., Nisen P. D., Tesfaye A., Kohl N. E., Goldfarb M. P., Alt F. W. N-myc can cooperate with ras to transform normal cells in culture. Proc Natl Acad Sci U S A. 1985 Aug;82(16):5455–5459. doi: 10.1073/pnas.82.16.5455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. el-Deiry W. S., Tokino T., Velculescu V. E., Levy D. B., Parsons R., Trent J. M., Lin D., Mercer W. E., Kinzler K. W., Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993 Nov 19;75(4):817–825. doi: 10.1016/0092-8674(93)90500-p. [DOI] [PubMed] [Google Scholar]

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