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Related Experiment Videos

Human cancers express a mutator phenotype.

Jason H Bielas1, Keith R Loeb, Brian P Rubin

  • 1Department of Pathology, University of Washington, Seattle, WA 98195, USA.

Proceedings of the National Academy of Sciences of the United States of America
|November 17, 2006
PubMed
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Cancer cells exhibit a significantly higher rate of random mutations compared to normal tissues. This accelerated mutagenesis, observed at the single-nucleotide level, may contribute to tumor heterogeneity and serve as a prognostic indicator.

Area of Science:

  • Genetics
  • Oncology
  • Molecular Biology

Background:

  • Cancer cells accumulate clonal mutations conferring proliferative advantages.
  • The presence and significance of random, unselected mutations in tumors remain under investigation.
  • Such mutations may drive tumor heterogeneity and therapeutic resistance.

Purpose of the Study:

  • To quantify random single-nucleotide substitutions in normal and neoplastic human tissues.
  • To investigate the prevalence and frequency of accelerated mutagenesis in tumors.
  • To explore the potential of mutation frequency as a prognostic indicator.

Main Methods:

  • Development of a sensitive assay to quantify random mutations in human tissue.
  • Measurement of spontaneous random mutation frequencies in normal tissues.

Related Experiment Videos

  • Measurement of spontaneous random mutation frequencies in neoplastic (tumor) tissues from the same individuals.

    • Main Results:

    • Normal human tissues exhibit an exceedingly low frequency of spontaneous random mutations (< 1 x 10^-8 per base pair).
    • Human tumors displayed a significantly elevated average frequency of random mutations (210 x 10^-8 per base pair), an increase of at least two orders of magnitude.
    • Data demonstrate tumor heterogeneity at the single-nucleotide level and indicate accelerated mutagenesis persists late in tumor progression.

    Conclusions:

    • Tumors exhibit a mutator phenotype with a substantially elevated frequency of random mutations compared to normal tissues.
    • Accelerated mutagenesis is prevalent throughout tumor progression, contributing to genomic instability and heterogeneity.
    • Elevated random mutation frequency in tumors may represent a novel prognostic biomarker for cancer.