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Cancers Exhibit a Mutator Phenotype: Clinical Implications

¹ Department of Pathology, University of Washington School of Medicine, Seattle, Washington; ² Oncology Clinical Research, Merck Research Laboratories, North Wales, Pennsylvania; and ³ Simons Center for Systems Biology, Institute for Advanced Study, Princeton, New Jersey

Requests for reprints: Lawrence A. Loeb, Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195-7470. Phone: 206-543-6015; Fax: 206-543-3967; E-mail: larryloeb{at}earthlink.net.

Abstract

Malignancies are characterized by mutations. We have hypothesized that the thousands of mutations in most human cancers do not result from the low mutation rates exhibited by normal human cells. Instead, cancer cells express a mutator phenotype (i.e., the mutation rate in the cancer cells is much greater than that in normal cells). We consider the following points: (a) Mutations in genes that govern genetic stability could be the cause of a mutator phenotype exhibited by human cancers. (b) A mutator phenotype increases the efficiency of acquiring mutations including those associated with cancer. (c) Recent experimental evidence indicates that human tumors contain a vast array of both clonal mutations and nonexpanded (random) mutations. (d) The presence of nonexpanded mutations in tumors has fundamental clinical implications for cancer risk assessment, grading, and prognosis including the rapid emergence of resistance to chemotherapeutic agents. Lastly, (e) if a mutator phenotype drives carcinogenesis, drugs that target mutator pathways might prevent cancer by delay. [Cancer Res 2008;68(10):3551–7]

Reviews

Cancers Exhibit a Mutator Phenotype: Clinical Implications

¹ Department of Pathology, University of Washington School of Medicine, Seattle, Washington; ² Oncology Clinical Research, Merck Research Laboratories, North Wales, Pennsylvania; and ³ Simons Center for Systems Biology, Institute for Advanced Study, Princeton, New Jersey

Requests for reprints: Lawrence A. Loeb, Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195-7470. Phone: 206-543-6015; Fax: 206-543-3967; E-mail: larryloeb{at}earthlink.net.

Abstract

Malignancies are characterized by mutations. We have hypothesized that the thousands of mutations in most human cancers do not result from the low mutation rates exhibited by normal human cells. Instead, cancer cells express a mutator phenotype (i.e., the mutation rate in the cancer cells is much greater than that in normal cells). We consider the following points: (a) Mutations in genes that govern genetic stability could be the cause of a mutator phenotype exhibited by human cancers. (b) A mutator phenotype increases the efficiency of acquiring mutations including those associated with cancer. (c) Recent experimental evidence indicates that human tumors contain a vast array of both clonal mutations and nonexpanded (random) mutations. (d) The presence of nonexpanded mutations in tumors has fundamental clinical implications for cancer risk assessment, grading, and prognosis including the rapid emergence of resistance to chemotherapeutic agents. Lastly, (e) if a mutator phenotype drives carcinogenesis, drugs that target mutator pathways might prevent cancer by delay. [Cancer Res 2008;68(10):3551–7]

I. Walter Bodmer

Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom

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