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.
Similar content being viewed by others
References
Barbacid M (1987)Ras genes. Annu Rev Biochem 56:779–827
Bensch KG, Corrin B, Pariente R, Spencer H (1968) Oat-cell carcinoma of the lung: its origin and relationship to bronchial carcinoid. Cancer 22:1163–1172
Bos JL (1989)Ras oncogenes in human cancer: a review. Cancer Res 49:4682–4689
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 304:507–513
Gould VE, Linnoila RI, Memoli VA, Warren WH (1983a) Neuroendocrine cells and neuroendocrine neoplasms of the lung; review. Pathol Annu 18:287–330
Gould VE, Linnoila RI, Memoli VA, Warren WH (1983b) Neuroendocrine components of the bronchopulmonary tract: hyperplasias, dysplasias, and neoplasms. Lab Invest 49:519–537
Heighway J, Hasleton PS (1986) c-Ki-ras amplification in human lung cancer. Br J Cancer 53:285–287
Jackson-York GL, Davis BH, Warren WH, Gould VE, Memoli VA (1991) Flow cytometric DNA content analysis of neuroendocrine carcinoma of the lung. Cancer 68:374–379
Kurzrock R, Gallick GE, Gutterman JU (1986) Differential expression of p21ras gene product among histological subtypes of fresh primary human lung tumors. Cancer Res 46:1530–1534
McCoy MS, Toole JJ, Cunningham JM, Chang EH, Lowy DR, Weinberg RA (1983) Characterization of a human colon/lung carcinoma oncogene. Nature 302:79–81
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 304:501–506
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 51:4999–5002
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 6:1353–1362
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 81:71–75
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] 56:377–383
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 317:929–935
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 48:5738–5741
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 239:487–491
Sanger F, Nicklen S, Coulson AR (1977) DNA sequencing with chainterminating inhibitors. Proc Natl Acad Sci USA 74:5463–5467
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 223:661–664
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 51:3621–3623
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 135:697–702
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 304:497–500
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 323:561–565
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 5:1037–1043
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Wagner, S.N., Müller, R., Boehm, J. et al. Neuroendocrine neoplasms of the lung are not associated with point mutations at codon 12 of the Ki-ras gene. Virchows Archiv B Cell Pathol 63, 325–329 (1993). https://doi.org/10.1007/BF02899279
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02899279