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. 1987 Sep;40(9):1055–1063. doi: 10.1136/jcp.40.9.1055

Cellular oncogenes in neoplasia.

V T Chan 1, J O McGee 1
PMCID: PMC1141173  PMID: 3312299

Abstract

In recent years cellular homologues of many viral oncogenes have been identified. As these genes are partially homologous to viral oncogenes and are activated in some tumour cell lines they are termed "proto-oncogenes". In tumour cell lines proto-oncogenes are activated by either quantitative or qualitative changes in gene structure: activation of these genes was originally thought to be a necessary primary event in carcinogenesis, but activated cellular oncogenes, unlike viral oncogenes, do not transform normal cells in culture. In experimental models cooperation between two oncogenes can induce transformation of early passage cells, and this has become the basis of an hypothesis for multistep carcinogenesis. Proto-oncogene products also show sequence homology to various components in the mitogenic pathway (growth factors, growth factor receptors, signal transducing proteins and nuclear proteins), and it has been postulated that they may cause deregulation of the various components of this pathway. In human tumours single or multiple oncogene activation occurs. The pattern of oncogene activation in common solid malignancies is not consistent within any one class of tumour, nor is it uniform between classes, with three exceptions. In neuroblastoma, breast cancer, and perhaps in lung cancer there is relatively consistent activation of N-myc, neu, and c-myc/N-myc, respectively. Amplification of these genes generally correlates with poor prognosis. The introduction of methods for the direct study of oncogene transcription and their products will undoubtedly broaden our vision of cancer biology in man and, hopefully, add diagnostic and prognostic precision to tumour typing.

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Selected References

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  1. Alitalo K., Winqvist R., Lin C. C., de la Chapelle A., Schwab M., Bishop J. M. Aberrant expression of an amplified c-myb oncogene in two cell lines from a colon carcinoma. Proc Natl Acad Sci U S A. 1984 Jul;81(14):4534–4538. doi: 10.1073/pnas.81.14.4534. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Baldwin G. S. Epidermal growth factor precursor is related to the translation product of the Moloney sarcoma virus oncogene mos. Proc Natl Acad Sci U S A. 1985 Apr;82(7):1921–1925. doi: 10.1073/pnas.82.7.1921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bechade C., Calothy G., Pessac B., Martin P., Coll J., Denhez F., Saule S., Ghysdael J., Stéhelin D. Induction of proliferation or transformation of neuroretina cells by the mil and myc viral oncogenes. Nature. 1985 Aug 8;316(6028):559–562. doi: 10.1038/316559a0. [DOI] [PubMed] [Google Scholar]
  4. Bishop J. M. Enemies within: the genesis of retrovirus oncogenes. Cell. 1981 Jan;23(1):5–6. doi: 10.1016/0092-8674(81)90263-4. [DOI] [PubMed] [Google Scholar]
  5. Brodeur G. M., Seeger R. C., Schwab M., Varmus H. E., Bishop J. M. Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science. 1984 Jun 8;224(4653):1121–1124. doi: 10.1126/science.6719137. [DOI] [PubMed] [Google Scholar]
  6. Burns J., Chan V. T., Jonasson J. A., Fleming K. A., Taylor S., McGee J. O. Sensitive system for visualising biotinylated DNA probes hybridised in situ: rapid sex determination of intact cells. J Clin Pathol. 1985 Oct;38(10):1085–1092. doi: 10.1136/jcp.38.10.1085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Clarke M. F., Westin E., Schmidt D., Josephs S. F., Ratner L., Wong-Staal F., Gallo R. C., Reitz M. S., Jr Transformation of NIH 3T3 cells by a human c-sis cDNA clone. 1984 Mar 29-Apr 4Nature. 308(5958):464–467. doi: 10.1038/308464a0. [DOI] [PubMed] [Google Scholar]
  8. Cooper C. S., Park M., Blair D. G., Tainsky M. A., Huebner K., Croce C. M., Vande Woude G. F. Molecular cloning of a new transforming gene from a chemically transformed human cell line. Nature. 1984 Sep 6;311(5981):29–33. doi: 10.1038/311029a0. [DOI] [PubMed] [Google Scholar]
  9. Cooper G. M., Neiman P. E. Transforming genes of neoplasms induced by avian lymphoid leukosis viruses. Nature. 1980 Oct 16;287(5783):656–659. doi: 10.1038/287656a0. [DOI] [PubMed] [Google Scholar]
  10. Coussens L., Van Beveren C., Smith D., Chen E., Mitchell R. L., Isacke C. M., Verma I. M., Ullrich A. Structural alteration of viral homologue of receptor proto-oncogene fms at carboxyl terminus. Nature. 1986 Mar 20;320(6059):277–280. doi: 10.1038/320277a0. [DOI] [PubMed] [Google Scholar]
  11. Croce C. M., Thierfelder W., Erikson J., Nishikura K., Finan J., Lenoir G. M., Nowell P. C. Transcriptional activation of an unrearranged and untranslocated c-myc oncogene by translocation of a C lambda locus in Burkitt. Proc Natl Acad Sci U S A. 1983 Nov;80(22):6922–6926. doi: 10.1073/pnas.80.22.6922. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Downward J., Yarden Y., Mayes E., Scrace G., Totty N., Stockwell P., Ullrich A., Schlessinger J., Waterfield M. D. Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature. 1984 Feb 9;307(5951):521–527. doi: 10.1038/307521a0. [DOI] [PubMed] [Google Scholar]
  13. Escot C., Theillet C., Lidereau R., Spyratos F., Champeme M. H., Gest J., Callahan R. Genetic alteration of the c-myc protooncogene (MYC) in human primary breast carcinomas. Proc Natl Acad Sci U S A. 1986 Jul;83(13):4834–4838. doi: 10.1073/pnas.83.13.4834. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Eva A., Aaronson S. A. Isolation of a new human oncogene from a diffuse B-cell lymphoma. Nature. 1985 Jul 18;316(6025):273–275. doi: 10.1038/316273a0. [DOI] [PubMed] [Google Scholar]
  15. Finkel T., Der C. J., Cooper G. M. Activation of ras genes in human tumors does not affect localization, modification, or nucleotide binding properties of p21. Cell. 1984 May;37(1):151–158. doi: 10.1016/0092-8674(84)90310-6. [DOI] [PubMed] [Google Scholar]
  16. Furth M. E., Aldrich T. H., Cordon-Cardo C. Expression of ras proto-oncogene proteins in normal human tissues. Oncogene. 1987 Mar;1(1):47–58. [PubMed] [Google Scholar]
  17. Gallick G. E., Kurzrock R., Kloetzer W. S., Arlinghaus R. B., Gutterman J. U. Expression of p21ras in fresh primary and metastatic human colorectal tumors. Proc Natl Acad Sci U S A. 1985 Mar;82(6):1795–1799. doi: 10.1073/pnas.82.6.1795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gazit A., Igarashi H., Chiu I. M., Srinivasan A., Yaniv A., Tronick S. R., Robbins K. C., Aaronson S. A. Expression of the normal human sis/PDGF-2 coding sequence induces cellular transformation. Cell. 1984 Nov;39(1):89–97. doi: 10.1016/0092-8674(84)90194-6. [DOI] [PubMed] [Google Scholar]
  19. Goubin G., Goldman D. S., Luce J., Neiman P. E., Cooper G. M. Molecular cloning and nucleotide sequence of a transforming gene detected by transfection of chicken B-cell lymphoma DNA. Nature. 1983 Mar 10;302(5904):114–119. doi: 10.1038/302114a0. [DOI] [PubMed] [Google Scholar]
  20. Hayward W. S., Neel B. G., Astrin S. M. Activation of a cellular onc gene by promoter insertion in ALV-induced lymphoid leukosis. Nature. 1981 Apr 9;290(5806):475–480. doi: 10.1038/290475a0. [DOI] [PubMed] [Google Scholar]
  21. Huebner R. J., Todaro G. J. Oncogenes of RNA tumor viruses as determinants of cancer. Proc Natl Acad Sci U S A. 1969 Nov;64(3):1087–1094. doi: 10.1073/pnas.64.3.1087. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kingston R. E., Baldwin A. S., Jr, Sharp P. A. Regulation of heat shock protein 70 gene expression by c-myc. Nature. 1984 Nov 15;312(5991):280–282. doi: 10.1038/312280a0. [DOI] [PubMed] [Google Scholar]
  23. Klein G., Klein E. Oncogene activation and tumor progression. Carcinogenesis. 1984 Apr;5(4):429–435. doi: 10.1093/carcin/5.4.429. [DOI] [PubMed] [Google Scholar]
  24. Klein G., Klein E. Oncogene activation and tumor progression. Carcinogenesis. 1984 Apr;5(4):429–435. doi: 10.1093/carcin/5.4.429. [DOI] [PubMed] [Google Scholar]
  25. Klein G. Specific chromosomal translocations and the genesis of B-cell-derived tumors in mice and men. Cell. 1983 Feb;32(2):311–315. doi: 10.1016/0092-8674(83)90449-x. [DOI] [PubMed] [Google Scholar]
  26. Klein G. The role of gene dosage and genetic transpositions in carcinogenesis. Nature. 1981 Nov 26;294(5839):313–318. doi: 10.1038/294313a0. [DOI] [PubMed] [Google Scholar]
  27. Kraus M. H., Yuasa Y., Aaronson S. A. A position 12-activated H-ras oncogene in all HS578T mammary carcinosarcoma cells but not normal mammary cells of the same patient. Proc Natl Acad Sci U S A. 1984 Sep;81(17):5384–5388. doi: 10.1073/pnas.81.17.5384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Krontiris T. G., DiMartino N. A., Colb M., Parkinson D. R. Unique allelic restriction fragments of the human Ha-ras locus in leukocyte and tumour DNAs of cancer patients. 1985 Jan 31-Feb 6Nature. 313(6001):369–374. doi: 10.1038/313369a0. [DOI] [PubMed] [Google Scholar]
  29. Land H., Parada L. F., Weinberg R. A. Cellular oncogenes and multistep carcinogenesis. Science. 1983 Nov 18;222(4625):771–778. doi: 10.1126/science.6356358. [DOI] [PubMed] [Google Scholar]
  30. Lee W. H., Murphree A. L., Benedict W. F. Expression and amplification of the N-myc gene in primary retinoblastoma. 1984 May 31-Jun 6Nature. 309(5967):458–460. doi: 10.1038/309458a0. [DOI] [PubMed] [Google Scholar]
  31. Lidereau R., Mathieu-Mahul D., Theillet C., Renaud M., Mauchauffé M., Gest J., Larsen C. J. Presence of an allelic EcoRI restriction fragment of the c-mos locus in leukocyte and tumor cell DNAs of breast cancer patients. Proc Natl Acad Sci U S A. 1985 Oct;82(20):7068–7070. doi: 10.1073/pnas.82.20.7068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Manne V., Bekesi E., Kung H. F. Ha-ras proteins exhibit GTPase activity: point mutations that activate Ha-ras gene products result in decreased GTPase activity. Proc Natl Acad Sci U S A. 1985 Jan;82(2):376–380. doi: 10.1073/pnas.82.2.376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Martin G. S., Duesberg P. H. The a subunit in the RNA of transforming avian tumor viruses. I. Occurrence in different virus strains. II. Spontaneous loss resulting in nontransforming variants. Virology. 1972 Feb;47(2):494–497. doi: 10.1016/0042-6822(72)90287-5. [DOI] [PubMed] [Google Scholar]
  34. Martin G. S. Rous sarcoma virus: a function required for the maintenance of the transformed state. Nature. 1970 Sep 5;227(5262):1021–1023. doi: 10.1038/2271021a0. [DOI] [PubMed] [Google Scholar]
  35. Mavilio F., Sposi N. M., Petrini M., Bottero L., Marinucci M., De Rossi G., Amadori S., Mandelli F., Peschle C. Expression of cellular oncogenes in primary cells from human acute leukemias. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4394–4398. doi: 10.1073/pnas.83.12.4394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. McGrath M. S., Weissman I. L. AKR leukemogenesis: identification and biological significance of thymic lymphoma receptors for AKR retroviruses. Cell. 1979 May;17(1):65–75. doi: 10.1016/0092-8674(79)90295-2. [DOI] [PubMed] [Google Scholar]
  37. Mellon P., Pawson A., Bister K., Martin G. S., Duesberg P. H. Specific RNA sequences and gene products of MC29 avian acute leukemia virus. Proc Natl Acad Sci U S A. 1978 Dec;75(12):5874–5878. doi: 10.1073/pnas.75.12.5874. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Mertz E. T., Hassen M. M., Cairns-Whittern C., Kirleis A. W., Tu L., Axtell J. D. Pepsin digestibility of proteins in sorghum and other major cereals. Proc Natl Acad Sci U S A. 1984 Jan;81(1):1–2. doi: 10.1073/pnas.81.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Nau M. M., Brooks B. J., Battey J., Sausville E., Gazdar A. F., Kirsch I. R., McBride O. W., Bertness V., Hollis G. F., Minna J. D. L-myc, a new myc-related gene amplified and expressed in human small cell lung cancer. Nature. 1985 Nov 7;318(6041):69–73. doi: 10.1038/318069a0. [DOI] [PubMed] [Google Scholar]
  40. Neiman P., Payne L. N., Weiss R. A. Viral DNA in bursal lymphomas induced by avian leukosis viruses. J Virol. 1980 Apr;34(1):178–186. doi: 10.1128/jvi.34.1.178-186.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Padua R. A., Barrass N., Currie G. A. A novel transforming gene in a human malignant melanoma cell line. Nature. 1984 Oct 18;311(5987):671–673. doi: 10.1038/311671a0. [DOI] [PubMed] [Google Scholar]
  42. Pawson T., Guyden J., Kung T. H., Radke K., Gilmore T., Martin G. S. A strain of Fujinami sarcoma virus which is temperature-sensitive in protein phosphorylation and cellular transformation. Cell. 1980 Dec;22(3):767–775. doi: 10.1016/0092-8674(80)90553-x. [DOI] [PubMed] [Google Scholar]
  43. Pulciani S., Santos E., Lauver A. V., Long L. K., Aaronson S. A., Barbacid M. Oncogenes in solid human tumours. Nature. 1982 Dec 9;300(5892):539–542. doi: 10.1038/300539a0. [DOI] [PubMed] [Google Scholar]
  44. Quintanilla M., Brown K., Ramsden M., Balmain A. Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis. Nature. 1986 Jul 3;322(6074):78–80. doi: 10.1038/322078a0. [DOI] [PubMed] [Google Scholar]
  45. Rabbitts T. H., Forster A., Hamlyn P., Baer R. Effect of somatic mutation within translocated c-myc genes in Burkitt's lymphoma. Nature. 1984 Jun 14;309(5969):592–597. doi: 10.1038/309592a0. [DOI] [PubMed] [Google Scholar]
  46. Rassoulzadegan M., Naghashfar Z., Cowie A., Carr A., Grisoni M., Kamen R., Cuzin F. Expression of the large T protein of polyoma virus promotes the establishment in culture of "normal" rodent fibroblast cell lines. Proc Natl Acad Sci U S A. 1983 Jul;80(14):4354–4358. doi: 10.1073/pnas.80.14.4354. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Rothberg P. G., Erisman M. D., Diehl R. E., Rovigatti U. G., Astrin S. M. Structure and expression of the oncogene c-myc in fresh tumor material from patients with hematopoietic malignancies. Mol Cell Biol. 1984 Jun;4(6):1096–1103. doi: 10.1128/mcb.4.6.1096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Ruley H. E. Adenovirus early region 1A enables viral and cellular transforming genes to transform primary cells in culture. Nature. 1983 Aug 18;304(5927):602–606. doi: 10.1038/304602a0. [DOI] [PubMed] [Google Scholar]
  49. Schechter A. L., Stern D. F., Vaidyanathan L., Decker S. J., Drebin J. A., Greene M. I., Weinberg R. A. The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature. 1984 Dec 6;312(5994):513–516. doi: 10.1038/312513a0. [DOI] [PubMed] [Google Scholar]
  50. Shih T. Y., Weeks M. O., Young H. A., Scolnick E. M. p21 of Kirsten murine sarcoma virus is thermolabile in a viral mutant temperature sensitive for the maintenance of transformation. J Virol. 1979 Aug;31(2):546–546. doi: 10.1128/jvi.31.2.546-546.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Slamon D. J., Clark G. M., Wong S. G., Levin W. J., Ullrich A., McGuire W. L. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987 Jan 9;235(4785):177–182. doi: 10.1126/science.3798106. [DOI] [PubMed] [Google Scholar]
  52. Slamon D. J., deKernion J. B., Verma I. M., Cline M. J. Expression of cellular oncogenes in human malignancies. Science. 1984 Apr 20;224(4646):256–262. doi: 10.1126/science.6538699. [DOI] [PubMed] [Google Scholar]
  53. Spandidos D. A., Kerr I. B. Elevated expression of the human ras oncogene family in premalignant and malignant tumours of the colorectum. Br J Cancer. 1984 Jun;49(6):681–688. doi: 10.1038/bjc.1984.108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Tabin C. J., Bradley S. M., Bargmann C. I., Weinberg R. A., Papageorge A. G., Scolnick E. M., Dhar R., Lowy D. R., Chang E. H. Mechanism of activation of a human oncogene. Nature. 1982 Nov 11;300(5888):143–149. doi: 10.1038/300143a0. [DOI] [PubMed] [Google Scholar]
  55. Wakelam M. J., Davies S. A., Houslay M. D., McKay I., Marshall C. J., Hall A. Normal p21N-ras couples bombesin and other growth factor receptors to inositol phosphate production. Nature. 1986 Sep 11;323(6084):173–176. doi: 10.1038/323173a0. [DOI] [PubMed] [Google Scholar]
  56. Whittaker J. L., Walker R. A., Varley J. M. Differential expression of cellular oncogenes in benign and malignant human breast tissue. Int J Cancer. 1986 Nov 15;38(5):651–655. doi: 10.1002/ijc.2910380506. [DOI] [PubMed] [Google Scholar]
  57. Wong A. J., Ruppert J. M., Eggleston J., Hamilton S. R., Baylin S. B., Vogelstein B. Gene amplification of c-myc and N-myc in small cell carcinoma of the lung. Science. 1986 Jul 25;233(4762):461–464. doi: 10.1126/science.3014659. [DOI] [PubMed] [Google Scholar]
  58. Yancopoulos G. D., Nisen P. D., Tesfaye A., Kohl N. E., Goldfarb M. P., Alt F. W. N-myc can cooperate with ras to transform normal cells in culture. Proc Natl Acad Sci U S A. 1985 Aug;82(16):5455–5459. doi: 10.1073/pnas.82.16.5455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Yokota J., Tsunetsugu-Yokota Y., Battifora H., Le Fevre C., Cline M. J. Alterations of myc, myb, and rasHa proto-oncogenes in cancers are frequent and show clinical correlation. Science. 1986 Jan 17;231(4735):261–265. doi: 10.1126/science.3941898. [DOI] [PubMed] [Google Scholar]
  60. Zarbl H., Sukumar S., Arthur A. V., Martin-Zanca D., Barbacid M. Direct mutagenesis of Ha-ras-1 oncogenes by N-nitroso-N-methylurea during initiation of mammary carcinogenesis in rats. 1985 May 30-Jun 5Nature. 315(6018):382–385. doi: 10.1038/315382a0. [DOI] [PubMed] [Google Scholar]
  61. Zerlin M., Julius M. A., Cerni C., Marcu K. B. Elevated expression of an exogenous c-myc gene is insufficient for transformation and tumorigenic conversion of established fibroblasts. Oncogene. 1987 Mar;1(1):19–27. [PubMed] [Google Scholar]

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