Lawrence A. Loeb, M.D., Ph.D.
Department of Pathology and Biochemistry,Box 357705
University of Washington Seattle, WA 98195-7705
(Tel: 206-543-6015 FAX: 206-543-3967 Email: laloeb@u.washington.edu )
Based on the high frequencies of chromosomal abnormalities and mutations in human cancers, I offered the hypothesis that cancer is manifested by a mutator phenotype. Mutations in genes required to maintain genomic instability are early events in the evolution of a tumor. This hypothesis is based on the argument that the spontaneous mutation rate in normal cells is insufficient to account for the high frequency of mutations in human cancer cells.
Considering that cancers arise in one or a few cells, we argue that the normal background mutation rate of 1.4 X 10-10 nucleotides/cell division can account for only a few mutations in each tumor, and not the much larger number that are reported with increasing frequency, or the even greater numbers that are likely to be found as methods for detection become more sensitive. Recent evidence supporting the concept of a mutator phenotype includes: microsatellite instability, gene amplification, alterations in comparative genomic hybridization, loss of heterozygotes and aneuploidy -- each of which is characteristically elevated in tumors. Sources for a mutator phenotype in tumors include mutations in genes involved in DNA repair, DNA replication, nucleotide metabolism and chromosomal segregation. A knowledge of mechanisms that generate multiple mutations in cancer cells has important implications for prevention. For many tumors, a delay in the rate of accumulation of mutations by a factor of two could drastically reduce the death rates from these tumors.
References:
1. Loeb, L.A. (1991) Cancer Res. 51,3075-3079
2. Jackson, A.L. and Loeb, L.A., (1998) Genetics 148, 1483-1490
3. Mao, E.F., Lane, L., Lee, J.,. and Miller, J. H. (1997) I. Bacteriol. 179, 417-422
4. Jackson, A.L, Chen, R., and Loeb, L.A. (1998) Proc. Natl. Acad. Sci. USA 95, 12468-12473. 5. DNA polymerase active site is highly mutable: evolutionary consequences. P.H. Patel and L.A. Loeb. Proc. Natl. Acad. Sci. USA, 97: 5095-5 100, 2000.
6. Functional intraction between the Werner syndrome protein and DNA polymerase delta. A.S. Kamath-Loeb, E. Johansson, P.M.J. Burgers and L.A. Loeb. Proc. Natl. Acad. Sci. USA, 97: 4603-4608, 2000.
7. Improving enzymes for cancer gene therapy. L.P. Encell, D.M. Landis and L.A. Loeb. Nature Biotechnol., 17: 143-147, 1999.
8. Significance of multiple mutations in cancer. K.R. Loeb and L.A. Loeb, Carcinogenesis, 21: 279-385, 2000.
Lawrence A. Loeb, M.D., Ph.D. 1957 B.S. College of the City of New York, New York
1961 M.D. New York University, Bellevue Med. Schl., NYC
1964 Ph.D. University of California, Berkeley, CA
Professional Experience:
1961-1962 Internship in Medicine, Stanford-Palo Alto Medical Center, California
1962-1963 Research Associate with Dr. Harry V. Gelboin, NCI, Bethesda, MD
1964-1967 Research Associate with Dr. Daniel Mazia, Dept. Zoology, Univ. California, Berkeley, CA
1977-1978 Senior Member, Institute for Cancer Research, Philadelphia
1977-1978 Professor, Dept, Pathology, University of Pennsylvania
1978- Professor, Dept. Pathology, Director, Joseph Gottstein Memorial Cancer Research Laboratory, Adjunct Professor, Dept. Biochemistry, University of Washington, Seattle, WA
1988-1989 President, American Sssociation for Cancer Research
1988- Director, Medical Scientist Training Program, University of Washington, Seattle, WA
1993- Professor (joint appointment), Dept. Biochemistry, University of Washington, Seattle, WA
2001- President Elect, Environmental Mutagen Society