Skip to main content
British Journal of Cancer logoLink to British Journal of Cancer
. 2000 Jan 18;82(2):412–417. doi: 10.1054/bjoc.1999.0935

Detection of codon 12 K- ras mutations in non-neoplastic mucosa from bronchial carina in patients with lung adenocarcinomas

T Urban 1, S Ricci 2, C Danel 4, M Antoine 3, M Kambouchner 5, V Godard 2, R Lacave 2, J-F Bernaudin 2
PMCID: PMC2363273  PMID: 10646897

Abstract

K- ras activation by point mutation in codon 12 has been reported in lung adenocarcinomas in various models of experimental lung tumours induced by chemical carcinogens. The hypothesis of the presence of cells containing K- ras mutation in non neoplastic bronchial carina, the main site of impaction of airborne contaminants, was investigated by evaluating concurrent lung tumour and non-neoplastic proximal bronchial carinae from 19 patients with lung adenocarcinomas. The restriction fragment length polymorphism enriched PCR method used can detect one mutant allele among 103normal alleles. A mutation was detected in 42% of lung adenocarcinoma samples. No mutation was detected in either tumour or bronchial carinae in nine patients (47%). K- ras mutation was detected in the lung tumour but not in bronchial carinae in four patients (21%), in both the lung tumour and bronchial carinae in four other patients (21%). In two patients (11%), K- ras mutation was detected in at least one bronchial carina, but not in the lung tumour. Mutations of codon 12, confirmed by sequencing analysis of ten samples, were G to T transversion, mostly TGT and GTT in bronchial carinae and lung tumours. Our data show that activated K- ras by point mutation can be present in non-neoplastic bronchial carina mucosa even when no mutation is detected in tumour samples. © 2000 Cancer Research Campaign

Keywords: ras oncogene, polymerase chain reaction, adenocarcinoma, bronchial mucosa

Full Text

The Full Text of this article is available as a PDF (85.6 KB).

Selected References

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

  1. Auerbach O., Hammond E. C., Garfinkel L. Changes in bronchial epithelium in relation to cigarette smoking, 1955-1960 vs. 1970-1977. N Engl J Med. 1979 Feb 22;300(8):381–385. doi: 10.1056/NEJM197902223000801. [DOI] [PubMed] [Google Scholar]
  2. Barbacid M. ras genes. Annu Rev Biochem. 1987;56:779–827. doi: 10.1146/annurev.bi.56.070187.004023. [DOI] [PubMed] [Google Scholar]
  3. Behn M., Qun S., Pankow W., Havemann K., Schuermann M. Frequent detection of ras and p53 mutations in brush cytology samples from lung cancer patients by a restriction fragment length polymorphism-based "enriched PCR" technique. Clin Cancer Res. 1998 Feb;4(2):361–371. [PubMed] [Google Scholar]
  4. Bennett W. P., Colby T. V., Travis W. D., Borkowski A., Jones R. T., Lane D. P., Metcalf R. A., Samet J. M., Takeshima Y., Gu J. R. p53 protein accumulates frequently in early bronchial neoplasia. Cancer Res. 1993 Oct 15;53(20):4817–4822. [PubMed] [Google Scholar]
  5. Berthélemy P., Bouisson M., Escourrou J., Vaysse N., Rumeau J. L., Pradayrol L. Identification of K-ras mutations in pancreatic juice in the early diagnosis of pancreatic cancer. Ann Intern Med. 1995 Aug 1;123(3):188–191. doi: 10.7326/0003-4819-123-3-199508010-00005. [DOI] [PubMed] [Google Scholar]
  6. Bos J. L. ras oncogenes in human cancer: a review. Cancer Res. 1989 Sep 1;49(17):4682–4689. [PubMed] [Google Scholar]
  7. Brentnall T. A., Chen R., Lee J. G., Kimmey M. B., Bronner M. P., Haggitt R. C., Kowdley K. V., Hecker L. M., Byrd D. R. Microsatellite instability and K-ras mutations associated with pancreatic adenocarcinoma and pancreatitis. Cancer Res. 1995 Oct 1;55(19):4264–4267. [PubMed] [Google Scholar]
  8. Burmer G. C., Loeb L. A. Mutations in the KRAS2 oncogene during progressive stages of human colon carcinoma. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2403–2407. doi: 10.1073/pnas.86.7.2403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Carney D. N. Lung cancer biology. Curr Opin Oncol. 1991 Apr;3(2):288–296. doi: 10.1097/00001622-199104000-00009. [DOI] [PubMed] [Google Scholar]
  10. Carothers A. M., Grunberger D. DNA base changes in benzo[a]pyrene diol epoxide-induced dihydrofolate reductase mutants of Chinese hamster ovary cells. Carcinogenesis. 1990 Jan;11(1):189–192. doi: 10.1093/carcin/11.1.189. [DOI] [PubMed] [Google Scholar]
  11. Clements N. C., Jr, Nelson M. A., Wymer J. A., Savage C., Aguirre M., Garewal H. Analysis of K-ras gene mutations in malignant and nonmalignant endobronchial tissue obtained by fiberoptic bronchoscopy. Am J Respir Crit Care Med. 1995 Oct;152(4 Pt 1):1374–1378. doi: 10.1164/ajrccm.152.4.7551397. [DOI] [PubMed] [Google Scholar]
  12. Denissenko M. F., Pao A., Tang M., Pfeifer G. P. Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53. Science. 1996 Oct 18;274(5286):430–432. doi: 10.1126/science.274.5286.430. [DOI] [PubMed] [Google Scholar]
  13. Hruban R. H., van Mansfeld A. D., Offerhaus G. J., van Weering D. H., Allison D. C., Goodman S. N., Kensler T. W., Bose K. K., Cameron J. L., Bos J. L. K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am J Pathol. 1993 Aug;143(2):545–554. [PMC free article] [PubMed] [Google Scholar]
  14. Husgafvel-Pursiainen K., Hackman P., Ridanpä M., Anttila S., Karjalainen A., Partanen T., Taikina-Aho O., Heikkilä L., Vainio H. K-ras mutations in human adenocarcinoma of the lung: association with smoking and occupational exposure to asbestos. Int J Cancer. 1993 Jan 21;53(2):250–256. doi: 10.1002/ijc.2910530213. [DOI] [PubMed] [Google Scholar]
  15. Jiang W., Kahn S. M., Guillem J. G., Lu S. H., Weinstein I. B. Rapid detection of ras oncogenes in human tumors: applications to colon, esophageal, and gastric cancer. Oncogene. 1989 Jul;4(7):923–928. [PubMed] [Google Scholar]
  16. KNUDTSON K. P. The pathologic effects of smoking tobacco on the trachea and bronchial mucosa. Am J Clin Pathol. 1960 Apr;33:310–317. doi: 10.1093/ajcp/33.4.310. [DOI] [PubMed] [Google Scholar]
  17. Kahn S. M., Jiang W., Culbertson T. A., Weinstein I. B., Williams G. M., Tomita N., Ronai Z. Rapid and sensitive nonradioactive detection of mutant K-ras genes via 'enriched' PCR amplification. Oncogene. 1991 Jun;6(6):1079–1083. [PubMed] [Google Scholar]
  18. Kobayashi T., Tsuda H., Noguchi M., Hirohashi S., Shimosato Y., Goya T., Hayata Y. Association of point mutation in c-Ki-ras oncogene in lung adenocarcinoma with particular reference to cytologic subtypes. Cancer. 1990 Jul 15;66(2):289–294. doi: 10.1002/1097-0142(19900715)66:2<289::aid-cncr2820660216>3.0.co;2-6. [DOI] [PubMed] [Google Scholar]
  19. Leone-Kabler S., Wessner L. L., McEntee M. F., D'Agostino R. B., Jr, Miller M. S. Ki-ras mutations are an early event and correlate with tumor stage in transplacentally-induced murine lung tumors. Carcinogenesis. 1997 Jun;18(6):1163–1168. doi: 10.1093/carcin/18.6.1163. [DOI] [PubMed] [Google Scholar]
  20. Li Z. H., Zheng J., Weiss L. M., Shibata D. c-k-ras and p53 mutations occur very early in adenocarcinoma of the lung. Am J Pathol. 1994 Feb;144(2):303–309. [PMC free article] [PubMed] [Google Scholar]
  21. Loeb L. A., Ernster V. L., Warner K. E., Abbotts J., Laszlo J. Smoking and lung cancer: an overview. Cancer Res. 1984 Dec;44(12 Pt 1):5940–5958. [PubMed] [Google Scholar]
  22. Manenti G., De Gregorio L., Pilotti S., Falvella F. S., Incarbone M., Ravagnani F., Pierotti M. A., Dragani T. A. Association of chromosome 12p genetic polymorphisms with lung adenocarcinoma risk and prognosis. Carcinogenesis. 1997 Oct;18(10):1917–1920. doi: 10.1093/carcin/18.10.1917. [DOI] [PubMed] [Google Scholar]
  23. Mao L., Lee J. S., Kurie J. M., Fan Y. H., Lippman S. M., Lee J. J., Ro J. Y., Broxson A., Yu R., Morice R. C. Clonal genetic alterations in the lungs of current and former smokers. J Natl Cancer Inst. 1997 Jun 18;89(12):857–862. doi: 10.1093/jnci/89.12.857. [DOI] [PubMed] [Google Scholar]
  24. Mass M. J., Jeffers A. J., Ross J. A., Nelson G., Galati A. J., Stoner G. D., Nesnow S. Ki-ras oncogene mutations in tumors and DNA adducts formed by benz[j]aceanthrylene and benzo[a]pyrene in the lungs of strain A/J mice. Mol Carcinog. 1993;8(3):186–192. doi: 10.1002/mc.2940080309. [DOI] [PubMed] [Google Scholar]
  25. Minamoto T., Yamashita N., Ochiai A., Mai M., Sugimura T., Ronai Z., Esumi H. Mutant K-ras in apparently normal mucosa of colorectal cancer patients. Its potential as a biomarker of colorectal tumorigenesis. Cancer. 1995 Mar 15;75(6 Suppl):1520–1526. doi: 10.1002/1097-0142(19950315)75:6+<1520::aid-cncr2820751523>3.0.co;2-l. [DOI] [PubMed] [Google Scholar]
  26. Rodenhuis S., Boerrigter L., Top B., Slebos R. J., Mooi W. J., van't Veer L., van Zandwijk N. Mutational activation of the K-ras oncogene and the effect of chemotherapy in advanced adenocarcinoma of the lung: a prospective study. J Clin Oncol. 1997 Jan;15(1):285–291. doi: 10.1200/JCO.1997.15.1.285. [DOI] [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. Ronai Z., Yabubovskaya M. S., Zhang E., Belitsky G. A. K-ras mutation in sputum of patients with or without lung cancer. J Cell Biochem Suppl. 1996;25:172–176. [PubMed] [Google Scholar]
  29. Rosell R., Li S., Skacel Z., Mate J. L., Maestre J., Canela M., Tolosa E., Armengol P., Barnadas A., Ariza A. Prognostic impact of mutated K-ras gene in surgically resected non-small cell lung cancer patients. Oncogene. 1993 Sep;8(9):2407–2412. [PubMed] [Google Scholar]
  30. Slebos R. J., Hruban R. H., Dalesio O., Mooi W. J., Offerhaus G. J., Rodenhuis S. Relationship between K-ras oncogene activation and smoking in adenocarcinoma of the human lung. J Natl Cancer Inst. 1991 Jul 17;83(14):1024–1027. doi: 10.1093/jnci/83.14.1024. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. 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]
  33. 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]
  34. 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]
  35. Tada M., Ohashi M., Shiratori Y., Okudaira T., Komatsu Y., Kawabe T., Yoshida H., Machinami R., Kishi K., Omata M. Analysis of K-ras gene mutation in hyperplastic duct cells of the pancreas without pancreatic disease. Gastroenterology. 1996 Jan;110(1):227–231. doi: 10.1053/gast.1996.v110.pm8536861. [DOI] [PubMed] [Google Scholar]
  36. Urban T., Ricci S., Grange J. D., Lacave R., Boudghene F., Breittmayer F., Languille O., Roland J., Bernaudin J. F. Detection of c-Ki-ras mutation by PCR/RFLP analysis and diagnosis of pancreatic adenocarcinomas. J Natl Cancer Inst. 1993 Dec 15;85(24):2008–2012. doi: 10.1093/jnci/85.24.2008. [DOI] [PubMed] [Google Scholar]
  37. Urban T., Ricci S., Lacave R., Antoine M., Kambouchner M., Capron F., Bernaudin J. F. Codon 12 Ki-ras mutation in non-small-cell lung cancer: comparative evaluation in tumoural and non-tumoural lung. Br J Cancer. 1996 Oct;74(7):1051–1055. doi: 10.1038/bjc.1996.488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. 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]
  39. Wilentz R. E., Chung C. H., Sturm P. D., Musler A., Sohn T. A., Offerhaus G. J., Yeo C. J., Hruban R. H., Slebos R. J. K-ras mutations in the duodenal fluid of patients with pancreatic carcinoma. Cancer. 1998 Jan 1;82(1):96–103. doi: 10.1002/(sici)1097-0142(19980101)82:1<96::aid-cncr11>3.0.co;2-8. [DOI] [PubMed] [Google Scholar]
  40. Yanagisawa A., Ohtake K., Ohashi K., Hori M., Kitagawa T., Sugano H., Kato Y. Frequent c-Ki-ras oncogene activation in mucous cell hyperplasias of pancreas suffering from chronic inflammation. Cancer Res. 1993 Mar 1;53(5):953–956. [PubMed] [Google Scholar]
  41. You M., Candrian U., Maronpot R. R., Stoner G. D., Anderson M. W. Activation of the Ki-ras protooncogene in spontaneously occurring and chemically induced lung tumors of the strain A mouse. Proc Natl Acad Sci U S A. 1989 May;86(9):3070–3074. doi: 10.1073/pnas.86.9.3070. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. You M., Wang Y., Nash B., Stoner G. D. K-ras mutations in benzotrichloride-induced lung tumors of A/J mice. Carcinogenesis. 1993 Jun;14(6):1247–1249. doi: 10.1093/carcin/14.6.1247. [DOI] [PubMed] [Google Scholar]
  43. You M., Wang Y., Stoner G., You L., Maronpot R., Reynolds S. H., Anderson M. Parental bias of Ki-ras oncogenes detected in lung tumors from mouse hybrids. Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):5804–5808. doi: 10.1073/pnas.89.13.5804. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES