Virchows Archiv B

, 63:325 | Cite as

Neuroendocrine neoplasms of the lung are not associated with point mutations at codon 12 of the Ki-ras gene

  • Stephan N. Wagner
  • Rupert Müller
  • Joachim Boehm
  • Barbara Pütz
  • Peter H. Wünsch
  • Heinz Höfler
Article

Summary

The most prominent abnormality ofras proto-oncogenes in human lung tumours has involved point mutations at codon 12 of the Ki-ras gene. We have analysed 35 tumour samples of neuroendocrine lung neoplasms (ten carcinoid tumours, ten well-differentiated neuroendocrine carcinomas, and 15 intermediate/small cell neuroendocrine carcinomas) for a point mutation at this site. For this purpose, formalin-fixed and paraffin-embedded tissue sections were microdissected to remove non-tumorous areas. DNA in the remaining tumour tissue was amplified in vitro by the polymerase chain reaction (PCR) and double-stranded PCR products were subjected to sequence analysis. Neither point mutations at codon 12 nor additional structural alterations at codons 1–32 were detected in the Ki-ras gene. Our results suggest that point mutations at codon 12 of the Ki-ras gene do not seem to be involved in the pathogenesis of pulmonary neuroendocrine neoplasms.

Key words

Lung Neuroendocrine neoplasms Ki-ras Point mutation Sequencing 

References

  1. Barbacid M (1987)Ras genes. Annu Rev Biochem 56:779–827PubMedCrossRefGoogle Scholar
  2. Bensch KG, Corrin B, Pariente R, Spencer H (1968) Oat-cell carcinoma of the lung: its origin and relationship to bronchial carcinoid. Cancer 22:1163–1172PubMedCrossRefGoogle Scholar
  3. Bos JL (1989)Ras oncogenes in human cancer: a review. Cancer Res 49:4682–4689PubMedGoogle Scholar
  4. Capon DJ, Seeburg PH, McGrath JP, Hayflick JS, Edman U, Levinson AD, Goeddel DV (1983) Activation of Ki-ras 2 gene in human colon and lung carcinomas by two different point mutations. Nature 304:507–513PubMedCrossRefGoogle Scholar
  5. Gould VE, Linnoila RI, Memoli VA, Warren WH (1983a) Neuroendocrine cells and neuroendocrine neoplasms of the lung; review. Pathol Annu 18:287–330PubMedGoogle Scholar
  6. Gould VE, Linnoila RI, Memoli VA, Warren WH (1983b) Neuroendocrine components of the bronchopulmonary tract: hyperplasias, dysplasias, and neoplasms. Lab Invest 49:519–537PubMedGoogle Scholar
  7. Heighway J, Hasleton PS (1986) c-Ki-ras amplification in human lung cancer. Br J Cancer 53:285–287PubMedGoogle Scholar
  8. Jackson-York GL, Davis BH, Warren WH, Gould VE, Memoli VA (1991) Flow cytometric DNA content analysis of neuroendocrine carcinoma of the lung. Cancer 68:374–379PubMedCrossRefGoogle Scholar
  9. Kurzrock R, Gallick GE, Gutterman JU (1986) Differential expression of p21ras gene product among histological subtypes of fresh primary human lung tumors. Cancer Res 46:1530–1534PubMedGoogle Scholar
  10. McCoy MS, Toole JJ, Cunningham JM, Chang EH, Lowy DR, Weinberg RA (1983) Characterization of a human colon/lung carcinoma oncogene. Nature 302:79–81PubMedCrossRefGoogle Scholar
  11. McGrath JP, Capon DJ, Smith DH, Chen EY, Seeburg PH, Goeddel DV, Levinson AD (1983) Structure and organization of the human Ki-ras proto-oncogene and a related processed pseudogene. Nature 304:501–506PubMedCrossRefGoogle Scholar
  12. Mitsudomi T, Steinberg SM, Oie HK, Mulshine JL, Phelps R, Viallet J, Pass H, Minna JD, Gazdar AF (1991a)Ras gene mutations in non-small cell lung cancers are associated with shortened survival irrespective of treatment intent. Cancer Res 51:4999–5002PubMedGoogle Scholar
  13. Mitsudomi T, Viallet J, Mulshine JL, Linnoila RI, Minna JD, Gazdar AF (1991 b) Mutations ofras genes distinguish a subset of non-small-cell lung cancer cell lines from small-cell lung cancer cell lines. Oncogene 6:1353–1362PubMedGoogle Scholar
  14. Nakano H, Yamamoto F, Neville C, Evans D, Mizuno T, Perucho M (1984) Isolation of transforming sequences of two human lung carcinomas: structural and functional analysis of the activated c-K-ras oncogenes. Proc Natl Acad Sci USA 81:71–75PubMedCrossRefGoogle Scholar
  15. Radosevich JA, Gould VE, Ma Y, Lee I, Thor A, Carney WP, Warren WH, Schlom J, Rosen ST (1989) Immunohistochemical analysis of normal and mutatedras oncogene p21 expression in human pulmonary and pleural neoplasms. Virchows Arch [B] 56:377–383CrossRefGoogle Scholar
  16. Rodenhuis S, Wetering ML van de Mooi WJ, Evers SG, Zandwijk N van, Bos JL (1987) Mutational activation of the K-ras oncogene: a possible pathogenetic factor in adenocarcinoma of the lung. N Engl J Med 317:929–935PubMedGoogle Scholar
  17. Rodenhuis S, Slebos RJC, Boot AJM, Evers SG, Mooi WJ, Wagenaar SS, Bodegom PC van, Bos JL (1988) Incidence and possible clinical significance of K-ras oncogene activation in adenocarcinoma of the human lung. Cancer Res 48:5738–5741PubMedGoogle Scholar
  18. Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Ehrlich HA (1988) Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 239:487–491PubMedCrossRefGoogle Scholar
  19. Sanger F, Nicklen S, Coulson AR (1977) DNA sequencing with chainterminating inhibitors. Proc Natl Acad Sci USA 74:5463–5467PubMedCrossRefGoogle Scholar
  20. Santos E, Martin-Zanca D, Reddy EP, Pierotti MA, Delia Porta G, Barbacid M (1984) Malignant activation of a K-ras oncogene in lung carcinoma but not in normal tissue of the same patient. Science 223:661–664PubMedCrossRefGoogle Scholar
  21. Sethi T, Rozengurt E (1991) Multiple neuropeptides stimulate clonal growth of small cell lung cancers: effects of bradykinin, vasopressin, cholecystokinin, galanin, and neurotensin. Cancer Res 51:3621–3623PubMedGoogle Scholar
  22. Shibata D, Brynes RK, Nathwani BN, Kwok S, Sninsky J, Arnheim N (1989) Human immunodeficiency viral DNA is readily found in lymph node biopsies from seropositive individuals: analysis of fixed using the polymerase chain reaction. Am J Pathol 135:697–702PubMedGoogle Scholar
  23. Shimizu K, Birnbaum D, Ruley MA, Fasano O, Suard Y, Edlund L, Taparowsky E, Goldfarb M, Wigler M (1983) Structure of the Ki-ras gene of the human lung carcinoma cell line Calu-1. Nature 304:497–500PubMedCrossRefGoogle Scholar
  24. Slebos RJC, Kibbelaar RE, Dalesio O, Kooistra A, Stam J, Meijer CJLM, Wagenaar SS, Vanderschueren RGJRA, Zandwijk N van, Mooi WJ, Bos JL, Rodenhuis S (1990) K-ras oncogene activations as a prognostic marker in adenocarcinoma of the lung. N Engl J Med 323:561–565PubMedGoogle Scholar
  25. Suzuki Y, Orita M, Shiraishi M, Hayashi K, Sekiya T (1990) Detection ofras gene mutations in human lung cancers by singlestrand conformation polymorphism analysis of polymerase chain reaction products. Oncogene 5:1037–1043PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • Stephan N. Wagner
    • 1
  • Rupert Müller
    • 2
  • Joachim Boehm
    • 2
  • Barbara Pütz
    • 2
  • Peter H. Wünsch
    • 3
  • Heinz Höfler
    • 1
    • 2
  1. 1.Institute of PathologyGSF-Forschungszentrum für Umwelt und GesundheitNeuherberg-MunichGermany
  2. 2.Institute of Pathology, School of MedicineTechnische Universität MünchenMunich 80Germany
  3. 3.Institute of PathologySchool of Medicine NürnbergNürnberg 90Germany

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