発がんと突然変異誘発のジャーナル

概要

Hyperdiploidy Tetraploidization and Genomic Instability in Breast Cancer–A Case Report Study

Roland B Sennerstam and Jan-Olov Strömberg

Introduction: Several reports have indicated that tetraploidization is an intermediate step of tumor progression between diploid cells and genomically reorganized aneuploid tumor cells. Tetraploidization is a conserved phenomenon in both plants and animals, which occurs in the human body in reaction to various stress factors.
Methods: A breast cancer population was divided into groups according to DNA Index (DI) interval, and three ploidy entities were defined as three different tumor groups: diploid (D-type), tetraploid (T-type) and aneuploid (A-type) tumors. Using a parameter reflecting genomic instability and proliferative activity (Stemline Scatter Index, SSI), we stepwise simulated the ploidy alterations following increase in SSI values. The percentage of each tumor type at each level of accumulated SSI value was estimated and the slopes of the generated curves were compared in linear regression analysis.
Results: At diagnosis, 32% of the patients had T-type tumors some of which were established in a pre-diagnostic period. During simulation guided by increasing SSI values a second step of tetraploidization was found during a tumor size interval of 10–20 mm caused by a presumed reaction to anoxic stress. The generated tetraploid cell populations were recruited from diploid cancer cells, indicating that already transformed cells loaded tetraploidgenerated cells with genomic instability. These genomically unstable and altered tetraploid cells were postulated to generate aneuploid cells within a hypotetraploid DI region. A narrow DI interval among D-type tumors was suggested to be responsible for the recruitment of T-type tumors.
Conclusion: We present a two-step model in which the first tetraploidization occurs early in breast cancer tumor progression and might represent a reaction to stress factors in benign epithelial tumors and epithelial hyperplasia and a later process of tumor size dependent origin for tetraploidization.