Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Computer simulation of the impact of the genome structure on multistep tumorigenesis based on unequal sister chromatide exchange

AF Rübben MD

Dept Dermatology, Rheinisch-Westfalische Technische Hochschule, Aachen, Germany,

AIMS: Mutations within a malignant cell clone do not only represent the selective pressures exerted by the tumor cell microenvironment but they may also reflect the constraints imposed by the genomic structure of the malignant cell. We have designed and analyzed a computer simulation of 4-step tumorigenesis where mutations only arise through unequal sister chromatide exchange leading to deletions or duplications of strings of genes. METHODS: The model starts with a tumor cell with one chromosome harboring a set of 4 tumor suppressor genes, 4 oncogenes, 4 essential genes as well as 4 neutral genes. Genetic variability arises through unequal chromatide exchange. Tumor progression proceeds through two steps of complete loss of tumor suppressor genes as well as two steps of duplications of oncogenes. Loss of essential genes is lethal to the cells. The computer simulation allows to vary the sequence of genes, the mutation rate and the maximum length of deletions or duplications during unequal sister chromatide exchange. RESULTS: The data provided by multiple runs of the computer simulation confirmed that tumorigenesis of cells only mutating through unequal sister chromatide exchange is strongly influenced by the sequence of the genes and especially by the distance between tumor suppressor genes and essential genes. CONCLUSIONS: The exact nature of genomic instability of human tumor cells is not known. Yet, our computer simulation suggests that the structure of the genome may strongly modify tumorigenesis and tumor progression and may be used in the future to define alternative anticancer strategies.

KEY WORDS: mathematical modeling.

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Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on genetic instability.