The Role of Chromosomal Instability in Tumor Initiation

Chromosomal instability (CIN) is a defining characteristic of most human cancers. Mutation of CIN genes increases the probability that whole chromosomes or large fractions of chromosomes are gained or lost during cell division. The consequence of CIN is an imbalance in the number of chromosomes per...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 99; no. 25; pp. 16226 - 16231
Main Authors Nowak, Martin A., Komarova, Natalia L., Sengupta, Anirvan, Jallepalli, Prasad V., Shih, le-Ming, Vogelstein, Bert, Lengauer, Christoph
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 10.12.2002
National Acad Sciences
Subjects
Animals
Biological Sciences
Cancer
Cell division
Cell lines
Cell Transformation, Neoplastic - genetics
Chromosome Aberrations
Chromosome Breakage
Chromosome Fragility - genetics
Colorectal cancer
Colorectal Neoplasms - genetics
Crypts
Genes
Genes, APC
Genes, Tumor Suppressor
Genetic mutation
Human genetics
Humans
Loss of Heterozygosity
Medical research
Mice
Models, Genetic
Mutagenesis
Point Mutation
Retinoblastoma - genetics
Stem cells
Stochastic Processes
Tumors
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Summary:Chromosomal instability (CIN) is a defining characteristic of most human cancers. Mutation of CIN genes increases the probability that whole chromosomes or large fractions of chromosomes are gained or lost during cell division. The consequence of CIN is an imbalance in the number of chromosomes per cell (aneuploidy) and an enhanced rate of loss of heterozygosity. A major question of cancer genetics is to what extent CIN, or any genetic instability, is an early event and consequently a driving force for tumor progression. In this article, we develop a mathematical framework for studying the effect of CIN on the somatic evolution of cancer. Specifically, we calculate the conditions for CIN to initiate the process of colorectal tumorigenesis before the inactivation of tumor suppressor genes.
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To whom correspondence should be addressed. E-mail: nowak@ias.edu.
Contributed by Bert Vogelstein
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.202617399