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PNAS 103 (48): 18238-18242

Copyright © 2006 by the National Academy of Sciences.

From the Cover

BIOLOGICAL SCIENCES / MEDICAL SCIENCES

Human cancers express a mutator phenotype

Jason H. Bielas, Keith R. Loeb*, Brian P. Rubin, Lawrence D. True, and Lawrence A. Loeb{dagger}

Department of Pathology, University of Washington, Seattle, WA 98195

Edited by Mary-Claire King, University of Washington, Seattle, WA, and approved September 29, 2006

Received for publication August 15, 2006.

Abstract: Cancer cells contain numerous clonal mutations, i.e., mutations that are present in most or all malignant cells of a tumor and have presumably been selected because they confer a proliferative advantage. An important question is whether cancer cells also contain a large number of random mutations, i.e., randomly distributed unselected mutations that occur in only one or a few cells of a tumor. Such random mutations could contribute to the morphologic and functional heterogeneity of cancers and include mutations that confer resistance to therapy. We have postulated that malignant cells exhibit a mutator phenotype resulting in the generation of random mutations throughout the genome. We have recently developed an assay to quantify random mutations in human tissue with unprecedented sensitivity. Here, we report measurements of random single-nucleotide substitutions in normal and neoplastic human tissues. In normal tissues, the frequency of spontaneous random mutations is exceedingly low, less than 1 x 10–8 per base pair. In contrast, tumors from the same individuals exhibited an average frequency of 210 x 10–8 per base pair, an elevation of at least two orders of magnitude. Our data document tumor heterogeneity at the single-nucleotide level, indicate that accelerated mutagenesis prevails late into tumor progression, and suggest that elevation of random mutation frequency in tumors might serve as a novel prognostic indicator.

Key Words: genetic instability • random mutation frequency • tumor heterogeneity • point mutation instability (PIN) • carcinogenesis

Freely available online through the PNAS open access option.

Author contributions: J.H.B. and L.A.L. designed research; J.H.B. and K.R.L. performed research; K.R.L., B.P.R., and L.D.T. contributed new reagents/analytic tools; J.H.B., K.R.L., B.P.R., L.D.T., and L.A.L. analyzed data; and J.H.B. wrote the paper.

*Present address: Department of Laboratory Medicine, Box 357110, University of Washington, Seattle, WA 98115-7110.

The authors declare no conflict of interest.

This article is a PNAS direct submission.

See Commentary on page 18033.

{dagger}To whom correspondence should be addressed at: Department of Pathology, Box 357705, University of Washington, Seattle, WA 98115-7705. E-mail: laloeb{at}u.washington.edu

© 2006 by The National Academy of Sciences of the USA

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