Nature Medicine
2, 676 - 681 (1996)
doi:10.1038/nm0696-676
Somatic microsatellite mutations as molecular tumor clocksDarryl Shibata1, 5, William Navidi2, Reijo Salovaara3, Zhi-Hua Li1
& Lauri A. Aaltonen4
1Department of Pathology, University of Southern California School of Medicine, 1200 North State Street, No. 736, Los Angeles, California 90033, USA
2Department of Preventive Medicine, University of Southern California, 1540 Alcazar Street #220, Los Angeles, California 90033, USA
3Department of Pathology, Haartman Institute, P.O. Box 21, FIN-00014 University of Helsinki, Finland
4Department of Medical Genetics, Haartman Institute, P.O. Box 21, FIN-00014 University of Helsinki, Finland
5Correspondence should be addressed to D.S. Microsatellite (MS) mutations can potentially unravel the past of mutator phenotype tumors, with greater genetic diversity expected in older regions. Rapid clonal expansions of xenografts were characterized by relatively homogenous MS alleles, whereas greater diversity was observed in a colorectal cancer with the greatest variation in its adjacent adenoma. A subcutaneous lung cancer metastasis demonstrated diversity consistent with its one−month clinical duration and evidence of active mitosis during dormancy. The genetic legacy inherent to multistep tumorigenesis provides direct estimates of tumor ages, with up to thousands of cell divisions and high death rates necessary to yield the observed diversities. MS molecular tumor clocks have the unique potential to systematically reconstruct the early and occult evolution of individual human mutator phenotype tumors.
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