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How aneuploidy affects metabolic control and causes cancer
1Department of Molecular and Cell Biology, 229 Stanley Hall, University of California Berkeley, Berkeley, CA 94720, USA. rasnick@mindspring.com
The Biochemical Journal
|June 9, 1999
Summary
Aneuploidy, an abnormal number of chromosomes, is proposed as the cause of cancer. This condition drives cancer phenotypes by altering gene expression fractions, not magnitudes, leading to cellular transformation and genetic instability.
Area of Science:
- Oncology
- Genetics
- Cell Biology
Background:
- Cancer exhibits complex phenotypes like invasiveness and metastasis, lacking a unified explanation.
- Aneuploidy (abnormal chromosome number) has been hypothesized as a cause of cancer for over a century.
Purpose of the Study:
- To test the hypothesis that aneuploidy causes cancer using an adaptation of Metabolic Control Analysis.
- To explain cancer-specific phenotypes through the lens of aneuploidy.
Main Methods:
- Adaptation of Metabolic Control Analysis to model gene expression changes.
- Analysis of the relationship between gene dose, differential expression, and phenotypic transformation.
Main Results:
- Phenotypic transformation to cancer is driven by the fraction of the genome differentially expressed, not the magnitude.
- A twofold increase in gene product expression due to aneuploidy causes non-linear physiological and metabolic changes.
- Aneuploidy disrupts mitosis, explaining cancer cells' genetic instability and chromosome aberrations.
Conclusions:
- Cancer is the phenotype of cells exceeding a specific aneuploidy threshold.
- This threshold can be reached through gradual aneuploidy increase or tetraploidization followed by chromosome loss.
- Aneuploidy provides a coherent explanation for all cancer phenotypes, including invasiveness, altered morphology, and genetic instability.
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