Mitotic failure and genome stability in benign, premalignant and malignant human tissues

Abstract: Mitotic failure may occur throughout the human lifespan. Individual nuclear mistakes will escape detection within the mass of somatic cells. The probability of nondetection increases with progression in development. Cells not only in cancers, but already in precancers, are the result of repeated mitotic failure, preceded by genetic damage at different chromosomal sites. Tumors provide the topography in which genome stabili ty is severely endangered. Therefore, this study was focused on mitotic failure occurring in tumorigenesis. An exact determination of genomic capacity of individual cell nuclei was learned with microsections of appropriate depths. A close positive relation was observed between interphase nuclei in 8 µm sections with their imprinted counterparts (r = 0.99; nl = n2 = 73). Further 232 mitotic figures were measured in 15 µm sections of fetal liver and yielded 3.91 + 0.01 c DNA content when calibrated to endo genous Iymphocyte nuclei. Main results are listed in the following. Mitotic division contains 4.0 c DNA as a result of complete DNA replication, once per cell cycle. Mitoses occur predominantly in embryonic tissues, inflammations and hyperplasias. Chromosome division figures (CDFs) occur in human precancers and cancers. CDFs were defined by DNA contents deviating more or less than 0.5 c from 4.0 c values. The mass of CDFs were recorded above 4.5 c threshold and were described in lesions of uterine cervix, skin, oral mucosa, stomach, colon mucosa and breast. Psoriasis, pyogenic granuloma and bacterially induced colitis were found at maximum with 1.5% CDF frequency of total divisions. Low-grade dysplasia and well differentiated carcinoma showed 5% - 10% CDFs. The range of high-grade dysplasia was 30% - 60% CDFs. Poorly differentiated cancers comprised up to 70% CDFs of total divisions. A majority of telophase CDFs shows asymme tric morphology and unbalanced DNA contents in corresponding hemisphercs. Unbalanced telophases characterize cell kinetics, beginning early in precancer. CDFs precede DNA aneuploidy of interphase nuclei not only in precancers, but also in malignancies with a diploid modal distribution of interphase nuclei. Frequent chromatin bridges suggest that un balanced telophases and consecutive aneuploidy in interphase are caused by nondisjunction. Tumor progression from low-grade to high grade dysplasias and to cancer is characterized by recurrent shifts from modal 2 c interphase nuclei to 4 c nuclei and a remarkable increase in the 5 c exceeding rate. Clonal selection is the gateway in tumori genesis for aberrant karyotypes. Thus, few cancers are negative with CGH, but positive for CDFs with single cell microphotometry. Interphase DNA aneuploidy without CDFs characterizes noninvasive tumors. Nevertheless, they pose a potential for malignancy. Dysplastic nevi and atypical soft-tissue tumors are examples of effective control suppressing CDFs, but are leaky with respect to interphase aneuploidy. Mitotic failures result from multiple overrun of cell cycle checkpoints. CDFs are the pathological manifestation of mitotic failure. This study quan titatively confirmed asymmetric telophases detected by Hansemann ( 1890) in cancer. Mitotic failure was also monitored with prophase and metaphase CDFs; this was done not only in cancer, but also in precancer. The penetrance of mitotic failure decides on malignancy.