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Related Experiment Videos

p53 mutations in cyclophosphamide-associated bladder cancer

M A Khan1, L B Travis, C F Lynch

  • 1Laboratory of Human Carcinogenesis, Radiation Epidemiology Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.

Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology
|June 4, 1998
PubMed
Summary

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Cyclophosphamide-induced bladder cancers show specific p53 gene mutations. The mutation patterns suggest phosphoramide mustard, not acrolein, is the primary mutagen driving these tumors.

Area of Science:

  • Oncology
  • Molecular Carcinogenesis
  • Genetics

Background:

  • Cyclophosphamide is a known bladder carcinogen, with risk increasing with cumulative dose.
  • The specific metabolite responsible for cyclophosphamide-induced bladder cancer (acrolein or phosphoramide mustard) remains unclear.

Purpose of the Study:

  • To investigate the hypothesis that somatic mutations in the p53 tumor suppressor gene in cyclophosphamide-related bladder tumors can identify the causative metabolite.
  • To compare the p53 mutation spectrum in these tumors with those from other etiological factors.

Main Methods:

  • Analysis of p53 gene mutations in 19 cyclophosphamide-related bladder tumors.
  • Comparison of the observed mutation spectrum with published data for sporadic, smoking-related, schistosomiasis-linked, and arylamine-associated bladder cancers.

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  • Assessment of mutation patterns against known adduction sequences of cyclophosphamide metabolites.

    • Main Results:

    • p53 mutations were found in 43% of the tumors, predominantly at G:C base pairs with a preference for non-CpG sites and G:C-->A:T transitions.
    • The p53 mutation spectrum differed significantly from sporadic, smoking-related, and schistosomiasis-linked tumors, but not arylamine-associated tumors.
    • The observed mutation spectrum, particularly the absence of G:C-->T:A transversions and clustering of exon 6 mutations, aligns with phosphoramide mustard adduction patterns.

    Conclusions:

    • The p53 mutation spectrum in cyclophosphamide-associated bladder cancer suggests phosphoramide mustard is a key mutagen.
    • This finding helps elucidate the molecular mechanisms of cyclophosphamide-induced bladder carcinogenesis.