Журнал канцерогенеза и мутагенеза

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Genomic Instability or One-Gene Theory for Tumor Progression: A Breast Cancer Study

Roland B Sennerstam and Jan-Olov Strömberg

Objective: There is an ongoing debate in the literature as to whether human cancers originate from unique clones with single oncogene mutations or propagate from early established genomic instabilities due to intermediate metastable tetraploidization. The aim of this study was to investigate how far genomic instability, reflected in ploidy alterations, can explain tumor progression.
Methods: In total 1,280 patients were involved in this study. We defined DNA-index (DI) intervals for diploid, tetraploid and aneuploid tumors and made simulations based on increasing age of patients, from 30 to 60 years old. We related this information to four enhancement steps of a parameter reflecting genomic instability generated from the tumor G1 peak coefficient of variation, S-phase fraction and number of cells exceeding G2 phase DNA region (stemline-scatter-index; SSI). The change in ploidy entities was also simulated with respect to growing values of the parameter for genomic instability (SSI).
Results: Following the age-dependent alteration in ploidy there were, at the lowest level of genomic instability up to 45 years of age, only diploid (87%) and tetraploid (13%) tumors. In three SSI relative unit enlargements, along with increasing age, aneuploid tumors were mainly found to be derived from tetraploid tumors resulting in a growing number of hypotetra and hypertriploid tumors. The hypertriploid tumors (1.4 ≤ DI<1.8) increased 23-fold during the age interval 35 to 60 years, and a strong correlation was found between genomic instability and hypertriploid tumors. In the simulation experiments, it was found that tetraploidization occurred twice during tumor progression and it generated two populations of aneuploid tumors.
Conclusion: Our analysis indicates that genomic instability originates mainly in tetraploid tumors, in which
a state of high genomic instability results in the loss of genetic material due to mitotic failure. This generates selective competence and enhances the aggressiveness of tumors.