Genomic instability and tumor progression : a cytochemical, molecular biological and cytogenetic study of human tissue from uterine cervix, colon, breast and ovary

Disruption of cell cycle checkpoint control is believed to be common in human carcinomas. To elucidate how cell cycle defects and genomic instability cooperate we investigated the pathogenesis of carcinomas by using four different models of tumor progression in human tissue samples i.e. from the uterine cervix, colon, breast and ovary. We describe how cell cycle proteins with different functions (Ki-67, cyclin A, cyclin E, p27KIP1, p53 and p21WAF1) are associated with different aspects of genomic instability in different stages of the progression from normal cells to the invasive malignant phenotype. In cervical tumorigenesis we found an increase in proliferative activity and tetraploidisation already in the mild dysplastic lesions. In severe dysplasia/CIS one case (1/10) had a gain of chromosome 3q. In the invasive carcinomas of early stage 90% (9/10) of the cases had a recurrent gain of 3q and in advanced stage tumors this was found in 77% of the cases, often with high-level copy number alterations. This result was closely related to aneuploidy and HPV 16 infection. However, recurrent gains and losses were mapped to several other chromosomal regions. Subchromosomal amplifications were mapped to chromosome arms 8q, 3q, and 5p. The results indicate that p53 inactivation by HPV, rather than p53 mutation and gain of 3q represents pivotal alterations in the progression of cervical carcinoma. In colorectal adenomas we found crude aneuploidy and high proliferative activity as early events. The transition to invasive carcinoma was characterized by the emergence of multiple chromosomal aberrations. In adenocarcinomas recurrent gains were mapped to chromosomes 1, 13 and 20 and to chromosome arms 7p and 8q. Losses were mapped to chromosome 4 and chromosome arms 8p and 18q. Small breast cancers (T1b, <10 mm had a low proliferative activity (MIB-1, cyclin A) and frequently low levels of p53. T1c tumors (11-20 mm) were frequently aneuploid (75%), with increased proliferative activity and p53 expression. In aneuploid tumors increasing numbers of chromosomal aberrations and regional amplifications were found with increasing tumor size (T1b to T1c). This was not seen in diploid tumors. In patients with longterm (>10 years)- and short-term survival (