Conditional mutators and tumorigenesis

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Publication Type dissertation
School or College School of Medicine
Department Oncological Sciences
Author Richards, Burt T.
Title Conditional mutators and tumorigenesis
Date 1999-08
Description The clonal population model of tumorigenesis depends on selection of genetically unstable cells with advantageous mutations. The number of mutations in tumor suppressor genes and proto-oncogenes in many cancers is much higher than can be accounted for by spontaneous mutation rates. This has lead to the idea that a mutator phenotype or increased mutation rate is an early event during tumorigenesis. Tumor samples from patients with hereditary nonpolyposis colorectal cancer (HNPCC) exhibit an increased mutation rate and microsatellite instability and have mutations in genes involved in DNA mismatch repair. The hMSH2 protein is proposed to be the central mismatch repair protein when complexed with either hMSH3 or hMSH6. Biochemical studies using nuclear extracts from hMSH2-deficient cell lines are unable to correct single base pair mismatches or insertion/deletion errors common to microsatellite repeats. We examined hMSH2-deficient cell lines for increased mutation rates at coding sequences and microsatellite repeats to determine the role of hMSH2 protein in maintaining genome stability. Surprisingly, two of the four hMSH2-deficient cell lines tested did not exhibit a mutator phenotype. However, it was discovered that the mutation rate was significantly increased in these cells when they were maintained in suboptimal, high-density culture conditions or in different lots of fetal bovine serum. This conditional mutator phenotype has important implications for understanding accumulation of mutations during tumorigenesis and may mimic conditions of the tumor microenvironment.
Type Text
Publisher University of Utah
Subject Cancer; DNA
Subject MESH Carcinogens; Genetics
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Conditional mutators and tumorigenesis". Spencer S. Eccles Health Sciences Library. Print version of "Conditional mutators and tumorigenesis" available at J. Willard Marriott Library Special Collection. RC39.5 1999 .R53.
Rights Management © Burt T. Richards.
Format Medium application/pdf
Format Extent 2,452,651 bytes
Identifier undthes,3961
Source Original University of Utah Spencer S. Eccles Health Sciences Library (no longer available)
Master File Extent 2,452,673 bytes
ARK ark:/87278/s6959k9h
Setname ir_etd
Date Created 2012-04-24
Date Modified 2012-04-24
ID 190503
Reference URL
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