Skip to main content
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1994 Feb;144(2):303–309.

c-k-ras and p53 mutations occur very early in adenocarcinoma of the lung.

Z H Li 1, J Zheng 1, L M Weiss 1, D Shibata 1
PMCID: PMC1887136  PMID: 8311114

Abstract

The topographical distribution of a mutation provides insight into past patterns of tumor evolution. This approach was applied to two loci commonly mutated in adenocarcinoma of the lung--p53 and c-K-ras. In 41 primary adenocarcinomas, c-K-ras codon 12 point mutations were detected in 8 (19.5%) tumors and p53 point mutations were detected in 10 (24.4%) tumors, with one tumor harboring both mutations. These mutations were only detected in malignant cells and with a homogeneous topographical distribution throughout 16 tumors, including metastasis. Intratumor heterogeneity was detected in only one tumor in which a small portion lacked the specific p53 mutation. Based on this topographical analysis, it is likely that when these mutations occur in adenocarcinoma of the lung, they are usually acquired during the very earliest phases of tumor formation before the bulk of clonal expansion, and in very small precursor lesions.

Full text

PDF
303

Images in this article

Selected References

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

  1. 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]
  2. Hensel C. H., Xiang R. H., Sakaguchi A. Y., Naylor S. L. Use of the single strand conformation polymorphism technique and PCR to detect p53 gene mutations in small cell lung cancer. Oncogene. 1991 Jun;6(6):1067–1071. [PubMed] [Google Scholar]
  3. 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]
  4. 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]
  5. 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]
  6. 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]
  7. Mitsudomi T., Steinberg S. M., Oie H. K., Mulshine J. L., Phelps R., Viallet J., Pass H., Minna J. D., Gazdar A. F. ras gene mutations in non-small cell lung cancers are associated with shortened survival irrespective of treatment intent. Cancer Res. 1991 Sep 15;51(18):4999–5002. [PubMed] [Google Scholar]
  8. Nowell P. C. The clonal evolution of tumor cell populations. Science. 1976 Oct 1;194(4260):23–28. doi: 10.1126/science.959840. [DOI] [PubMed] [Google Scholar]
  9. Rodenhuis S., Slebos R. J. Clinical significance of ras oncogene activation in human lung cancer. Cancer Res. 1992 May 1;52(9 Suppl):2665s–2669s. [PubMed] [Google Scholar]
  10. Rodenhuis S., van de Wetering M. L., Mooi W. J., Evers S. G., van Zandwijk N., Bos J. L. Mutational activation of the K-ras oncogene. A possible pathogenetic factor in adenocarcinoma of the lung. N Engl J Med. 1987 Oct 8;317(15):929–935. doi: 10.1056/NEJM198710083171504. [DOI] [PubMed] [Google Scholar]
  11. Shibata D., Hawes D., Li Z. H., Hernandez A. M., Spruck C. H., Nichols P. W. Specific genetic analysis of microscopic tissue after selective ultraviolet radiation fractionation and the polymerase chain reaction. Am J Pathol. 1992 Sep;141(3):539–543. [PMC free article] [PubMed] [Google Scholar]
  12. Shibata D., Schaeffer J., Li Z. H., Capella G., Perucho M. Genetic heterogeneity of the c-K-ras locus in colorectal adenomas but not in adenocarcinomas. J Natl Cancer Inst. 1993 Jul 7;85(13):1058–1063. doi: 10.1093/jnci/85.13.1058. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Sozzi G., Miozzo M., Donghi R., Pilotti S., Cariani C. T., Pastorino U., Della Porta G., Pierotti M. A. Deletions of 17p and p53 mutations in preneoplastic lesions of the lung. Cancer Res. 1992 Nov 1;52(21):6079–6082. [PubMed] [Google Scholar]
  15. 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]
  16. Sundaresan V., Ganly P., Hasleton P., Rudd R., Sinha G., Bleehen N. M., Rabbitts P. p53 and chromosome 3 abnormalities, characteristic of malignant lung tumours, are detectable in preinvasive lesions of the bronchus. Oncogene. 1992 Oct;7(10):1989–1997. [PubMed] [Google Scholar]
  17. Verlaan-de Vries M., Bogaard M. E., van den Elst H., van Boom J. H., van der Eb A. J., Bos J. L. A dot-blot screening procedure for mutated ras oncogenes using synthetic oligodeoxynucleotides. Gene. 1986;50(1-3):313–320. doi: 10.1016/0378-1119(86)90335-5. [DOI] [PubMed] [Google Scholar]
  18. Vähäkangas K. H., Samet J. M., Metcalf R. A., Welsh J. A., Bennett W. P., Lane D. P., Harris C. C. Mutations of p53 and ras genes in radon-associated lung cancer from uranium miners. Lancet. 1992 Mar 7;339(8793):576–580. doi: 10.1016/0140-6736(92)90866-2. [DOI] [PubMed] [Google Scholar]
  19. Westra W. H., Offerhaus G. J., Goodman S. N., Slebos R. J., Polak M., Baas I. O., Rodenhuis S., Hruban R. H. Overexpression of the p53 tumor suppressor gene product in primary lung adenocarcinomas is associated with cigarette smoking. Am J Surg Pathol. 1993 Mar;17(3):213–220. doi: 10.1097/00000478-199303000-00001. [DOI] [PubMed] [Google Scholar]
  20. Westra W. H., Slebos R. J., Offerhaus G. J., Goodman S. N., Evers S. G., Kensler T. W., Askin F. B., Rodenhuis S., Hruban R. H. K-ras oncogene activation in lung adenocarcinomas from former smokers. Evidence that K-ras mutations are an early and irreversible event in the development of adenocarcinoma of the lung. Cancer. 1993 Jul 15;72(2):432–438. doi: 10.1002/1097-0142(19930715)72:2<432::aid-cncr2820720219>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES