Genetic mechanisms in tumour initiation and progression, no. 10
The ras gene family and human carcinogenesis

https://doi.org/10.1016/0165-1110(88)90004-8Get rights and content

Abstract

It has been well established that specific alterations in members of the ras gene family, H-ras, K-ras and N-ras, can convert them into active oncogenes. These alterations are either point mutations occurring in either codon 12, 13 or 61 or, alternatively, a 5- to 50-fold amplification of the wild-type gene. Activated ras oncogenes have been found in a significant proportion of all tumors but the incidence varies considerably with the tumor type: it is relatively frequent (20–40%) in colorectal cancer and acute myeloid leukemia, but absent or present only rarely in, for example, breast tumors and stomach cancer. No correlation has been found, yet, between the presence or absence of an activated ras gene and the clinical or biological features of the malignancy.

The activation of ras oncogenes is only one step in the multistep process of tumor formation. The presence of mutated ras genes in benign polyps of the colon indicates that activation can be an early event, possibly even the initiating event. However, it can also occur later in the course of carcinogenesis to initiate for instance the transition of a benign polyp of the colon into a malignant carcinoma or to convert a primary melanoma into a metastatic tumor. Apparently, the activation of ras genes is not an obligatory event but when it occurs it can contribute to both early and advanced stages of human carcinogenesis.

References (136)

  • M. Perucho et al.

    Human tumor-derived cell lines contain common and different transforming genes

    Cell

    (1981)
  • S. Rodenhuis et al.

    Absence of oncogene amplifications and occasional activation of N-ras in lymphoblastic leukemia of childhood

    Blood

    (1986)
  • R.T. Schimke

    Gene amplification in cultured cells

    Cell

    (1984)
  • B.M. Sefton et al.

    The transforming proteins of Rous sarcoma virus: Harvey sarcoma virus and Abelson virus contain tightly bound lipid

    Cell

    (1982)
  • C. Shih et al.

    Isolation of transforming sequence from a human bladder carcinoma cell line

    Cell

    (1982)
  • A.P. Albino et al.

    Transforming ras genes from human melanoma: a manifestation of tumour heterogeneity?

    Nature (London)

    (1984)
  • J.M. Bishop

    The molecular genetics of cancer

    Science

    (1987)
  • D.G. Blair et al.

    New method of detecting cellular transforming genes

    Science

    (1982)
  • J.L. Bos et al.

    Three different mutations in codon 61 of the human N-ras gene detected by synthetic oligonucleotide hybridization

    Nucleic Acids Res.

    (1984)
  • J.L. Bos et al.

    Amino-acid substitutions at codon 13 of the N-ras oncogene in human acute myeloid leukaemia

    Nature (London)

    (1985)
  • J.L. Bos et al.

    A human gastric carcinoma contains a single mutated and an amplified normal allele of the Ki-ras oncogene

    Nucleic Acids Res.

    (1986)
  • J.L. Bos et al.

    Prevalence of ras mutations in human colorectal cancers

    Nature (London)

    (1987)
  • G.M. Brodeur et al.

    Amplification of the N-myc in untreated human neuroblastomas correlated with advanced disease stage

    Science

    (1984)
  • R. Brown et al.

    Mechanism of activation of an N-ras gene in the human fibrosarcoma cell line HT1080

    EMBO J.

    (1984)
  • J.E. Buss et al.

    Direct identification of palmitic acid as a lipid attached to p21 ras

    Mol. Cell. Biol.

    (1986)
  • D.J. Capon et al.

    Complete nucleotide sequences of the T24 human bladder carcinoma oncogene and its normal homologue

    Nature (London)

    (1983)
  • D.J. Capon et al.

    Activation of Ki-ras2 gene in human colon and lung carcinomas by two different point mutations

    Nature (London)

    (1983)
  • W.P. Carney et al.

    Monoclonal antibody specific for an activated ras protein

  • K. Cichutek et al.

    Harvey ras genes transform without mutant codons, apparently activated by truncation of a 5′ exon (exon-1)

  • E.H. Chang et al.

    Tumorigenic transformation of mammalian cells induced by a normal human gene homologous to the oncogene of Harvey murine sarcoma virus

    Nature (London)

    (1982)
  • P. Chardin et al.

    N-ras gene activation in the RD human rhabdomyosarcoma cell line

    Int. J. Cancer

    (1985)
  • Z.Q. Chen et al.

    Posttranslational processing of p21 ras proteins involves palmitylation of the C-terminal tetrapeptide containing cysteine-186

    J. Virol.

    (1985)
  • R.G. Chipperfield et al.

    Activation of H-ras p21 by substitution, deletion, and insertion mutations

    Mol. Cell. Biol.

    (1985)
  • D.J. Clanton et al.

    Mutations of the ras gene product p21 that abolish guanine nucleotide binding

  • R. Clark et al.

    Antibodies specific for amino acid 12 of the ras oncogene product inhibit GTP binding

  • B.J. Conner et al.

    Detection of sickle cell βs-globin allele by hybridization with synthetic oligonucleotides

  • C.J. Der et al.

    Transforming genes of human bladder and lung carcinoma cell lines are homologous to the ras genes of Harvey and Kirsten sarcoma viruses

  • C.J. Der et al.

    Biological and biochemical properties of human rasH genes mutated at codon 61

    Cell

    (1985)
  • R. Dhar et al.

    Nucleotide sequence of the p21 transforming protein of Harvey murine sarcoma virus

    Science

    (1982)
  • G.P. Dotto et al.

    Specific growth response of ras-transformed embryo fibroblasts to tumour promoters

    Nature (London)

    (1985)
  • A. Eva et al.

    Transforming genes of human hematopoietic tumors: frequent detection of ras-related oncogenes whose activation appears to be independent of tumor phenotype

  • O. Fasano et al.

    New human transforming genes detected by a tumorigenicity assay

    Mol. Cell. Biol.

    (1984)
  • O. Fasano et al.

    Analysis of the transforming potential of the human H-ras gene by random mutagenesis

  • E.R. Fearon et al.

    Loss of genes on the short arm of chromosome 11 in bladder cancer

    Nature (London)

    (1985)
  • L.F. Fleischman et al.

    Rastransformed cells: altered levels of phosphatidylinositol-4,5-bisphosphate and catabolites

    Science

    (1986)
  • K. Forrester et al.

    Detection of high incidence of K-ras oncogenes during human carcinogenesis

    Nature (London)

    (1987)
  • J. Fujita et al.

    Frequency of molecular alterations affecting ras protooncogenes in human urinary tract tumors

  • M. Fukui et al.

    Detection of a raf-related and two other transforming DNA sequences in human tumors maintained in nude mice

  • C. Gambke et al.

    Activation of an N-ras gene in acute myeloblastic leukemia through somatic mutation in the first exon

  • D.L. George et al.

    Enhanced c-Ki-ras expression associated with Friend virus integration in a bone marrow-derived mouse cell line

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