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. 2001 Jul;85(2):235–241. doi: 10.1054/bjoc.2001.1913

Topographic analysis of K-ras mutations in histologically normal lung tissues and tumours of lung cancer patients

P Keohavong 1,5, H H Mady 2,6, W M Gao 1, J M Siegfried 3,5, J D Luketich 4,5, M F Melhem 2,6
PMCID: PMC2364035  PMID: 11461083

Abstract

Mutations in the K-ras gene are very common in lung tumours and are implicated in the development of lung cancer, but the timing of their occurrence remains poorly understood. We investigated K-ras mutations in cell samples microdissected by laser capture microscopy at multiple sites from lung tissue sections representing tumour tissue and matched histologically normal tissue obtained from 48 lung cancer patients. K-ras mutations were detected in cell samples from 10 of 38 (26.3%) lung adenocarcinomas and in none of the histologically normal or tumour cell samples taken from 10 lung squamous cell carcinomas. Of the K-ras mutation-positive adenocarcinomas, in 4 cases a mutation was found in only the tumour tissue, in 1 case a mutation was found only in the histologically normal tissue, and in 5 cases mutations were found in both the tumour tissue and histologically normal tissue. Among these 5 cases, 2 had identical mutations in both the tumour tissue and histologically normal tissue, 2 had 1 mutation in the tumour tissue and 2 mutations in the histologically normal tissue, 1 of which was identical to the mutation found in the tumour, and 1 case had 2 codon 12 mutations in tumour tissue and 2 mutations, in codons 9 and 11, in histologically normal tissue. These results showed that K-ras mutations are frequent in histologically normal cells taken from outside lung adenocarcinomas and suggest that some of these mutations may represent early events which could pave the way of lung carcinogenesis. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: lung carcinoma, ras oncogene, laser capture microdissection, denaturing gradient gel electrophoresis

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Selected References

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  1. Barbacid M. ras genes. Annu Rev Biochem. 1987;56:779–827. doi: 10.1146/annurev.bi.56.070187.004023. [DOI] [PubMed] [Google Scholar]
  2. 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]
  3. Bishop J. M. Molecular themes in oncogenesis. Cell. 1991 Jan 25;64(2):235–248. doi: 10.1016/0092-8674(91)90636-d. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. 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]
  6. Der C. J., Finkel T., Cooper G. M. Biological and biochemical properties of human rasH genes mutated at codon 61. Cell. 1986 Jan 17;44(1):167–176. doi: 10.1016/0092-8674(86)90495-2. [DOI] [PubMed] [Google Scholar]
  7. Emmert-Buck M. R., Bonner R. F., Smith P. D., Chuaqui R. F., Zhuang Z., Goldstein S. R., Weiss R. A., Liotta L. A. Laser capture microdissection. Science. 1996 Nov 8;274(5289):998–1001. doi: 10.1126/science.274.5289.998. [DOI] [PubMed] [Google Scholar]
  8. Gazdar A. F. The molecular and cellular basis of human lung cancer. Anticancer Res. 1994 Jan-Feb;14(1B):261–267. [PubMed] [Google Scholar]
  9. Harris C. C. Chemical and physical carcinogenesis: advances and perspectives for the 1990s. Cancer Res. 1991 Sep 15;51(18 Suppl):5023s–5044s. [PubMed] [Google Scholar]
  10. 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]
  11. 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]
  12. Keohavong P., DeMichele M. A., Melacrinos A. C., Landreneau R. J., Weyant R. J., Siegfried J. M. Detection of K-ras mutations in lung carcinomas: relationship to prognosis. Clin Cancer Res. 1996 Feb;2(2):411–418. [PubMed] [Google Scholar]
  13. Keohavong P., Zhu D., Melacrinos A. C., DeMichele M. A., Weyant R. J., Luketich J. D., Testa J. R., Fedder M., Siegfried J. M. Detection of low-fraction K-ras mutations in primary lung tumors using a sensitive method. Int J Cancer. 1997 Apr 22;74(2):162–170. doi: 10.1002/(sici)1097-0215(19970422)74:2<162::aid-ijc4>3.0.co;2-x. [DOI] [PubMed] [Google Scholar]
  14. Keohavong P., Zhu D., Whiteside T. L., Swalsky P., Bakker A., Elder E. M., Siegfried J. M., Srivastava S., Finkelstein S. D. Detection of infrequent and multiple K-ras mutations in human tumors and tumor-adjacent tissues. Anal Biochem. 1997 May 1;247(2):394–403. doi: 10.1006/abio.1997.2100. [DOI] [PubMed] [Google Scholar]
  15. Khosravi-Far R., Der C. J. The Ras signal transduction pathway. Cancer Metastasis Rev. 1994 Mar;13(1):67–89. doi: 10.1007/BF00690419. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Marshall C. J. Tumor suppressor genes. Cell. 1991 Jan 25;64(2):313–326. doi: 10.1016/0092-8674(91)90641-b. [DOI] [PubMed] [Google Scholar]
  18. Mills N. E., Fishman C. L., Rom W. N., Dubin N., Jacobson D. R. Increased prevalence of K-ras oncogene mutations in lung adenocarcinoma. Cancer Res. 1995 Apr 1;55(7):1444–1447. [PubMed] [Google Scholar]
  19. 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]
  20. Pretlow T. P., Barrow B. J., Ashton W. S., O'Riordan M. A., Pretlow T. G., Jurcisek J. A., Stellato T. A. Aberrant crypts: putative preneoplastic foci in human colonic mucosa. Cancer Res. 1991 Mar 1;51(5):1564–1567. [PubMed] [Google Scholar]
  21. 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]
  22. Rosell R., Monzó M., Pifarré A., Ariza A., Sánchez J. J., Moreno I., Maurel J., López M. P., Abad A., de Anta J. M. Molecular staging of non-small cell lung cancer according to K-ras genotypes. Clin Cancer Res. 1996 Jun;2(6):1083–1086. [PubMed] [Google Scholar]
  23. SLAUGHTER D. P., SOUTHWICK H. W., SMEJKAL W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer. 1953 Sep;6(5):963–968. doi: 10.1002/1097-0142(195309)6:5<963::aid-cncr2820060515>3.0.co;2-q. [DOI] [PubMed] [Google Scholar]
  24. Santos E., Martin-Zanca D., Reddy E. P., Pierotti M. A., Della Porta G., Barbacid M. Malignant activation of a K-ras oncogene in lung carcinoma but not in normal tissue of the same patient. Science. 1984 Feb 17;223(4637):661–664. doi: 10.1126/science.6695174. [DOI] [PubMed] [Google Scholar]
  25. Seeburg P. H., Colby W. W., Capon D. J., Goeddel D. V., Levinson A. D. Biological properties of human c-Ha-ras1 genes mutated at codon 12. Nature. 1984 Nov 1;312(5989):71–75. doi: 10.1038/312071a0. [DOI] [PubMed] [Google Scholar]
  26. Sozzi G., Miozzo M., Pastorino U., Pilotti S., Donghi R., Giarola M., De Gregorio L., Manenti G., Radice P., Minoletti F. Genetic evidence for an independent origin of multiple preneoplastic and neoplastic lung lesions. Cancer Res. 1995 Jan 1;55(1):135–140. [PubMed] [Google Scholar]
  27. Stanley L. A. Molecular aspects of chemical carcinogenesis: the roles of oncogenes and tumour suppressor genes. Toxicology. 1995 Feb 27;96(3):173–194. doi: 10.1016/0300-483x(94)02991-3. [DOI] [PubMed] [Google Scholar]
  28. Strong M. S., Incze J., Vaughan C. W. Field cancerization in the aerodigestive tract--its etiology, manifestation, and significance. J Otolaryngol. 1984 Feb;13(1):1–6. [PubMed] [Google Scholar]
  29. 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]
  30. Sugio K., Kishimoto Y., Virmani A. K., Hung J. Y., Gazdar A. F. K-ras mutations are a relatively late event in the pathogenesis of lung carcinomas. Cancer Res. 1994 Nov 15;54(22):5811–5815. [PubMed] [Google Scholar]
  31. Suzuki Y., Orita M., Shiraishi M., Hayashi K., Sekiya T. Detection of ras gene mutations in human lung cancers by single-strand conformation polymorphism analysis of polymerase chain reaction products. Oncogene. 1990 Jul;5(7):1037–1043. [PubMed] [Google Scholar]
  32. 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]
  33. Urban T., Ricci S., Danel C., Antoine M., Kambouchner M., Godard V., Lacave R., Bernaudin J. F. Detection of codon 12 K-ras mutations in non-neoplastic mucosa from bronchial carina in patients with lung adenocarcinomas. Br J Cancer. 2000 Jan;82(2):412–417. doi: 10.1054/bjoc.1999.0935. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. 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]
  35. Westra W. H., Baas I. O., Hruban R. H., Askin F. B., Wilson K., Offerhaus G. J., Slebos R. J. K-ras oncogene activation in atypical alveolar hyperplasias of the human lung. Cancer Res. 1996 May 1;56(9):2224–2228. [PubMed] [Google Scholar]
  36. 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]
  37. 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]
  38. Yakubovskaya M. S., Spiegelman V., Luo F. C., Malaev S., Salnev A., Zborovskaya I., Gasparyan A., Polotsky B., Machaladze Z., Trachtenberg A. C. High frequency of K-ras mutations in normal appearing lung tissues and sputum of patients with lung cancer. Int J Cancer. 1995 Dec 11;63(6):810–814. doi: 10.1002/ijc.2910630611. [DOI] [PubMed] [Google Scholar]
  39. 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]
  40. Zhu D., Keohavong P., Finkelstein S. D., Swalsky P., Bakker A., Weissfeld J., Srivastava S., Whiteside T. L. K-ras gene mutations in normal colorectal tissues from K-ras mutation-positive colorectal cancer patients. Cancer Res. 1997 Jun 15;57(12):2485–2492. [PubMed] [Google Scholar]

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