Characterization of numerical chromosomal aberrations during cervical carcinogenesis

Tetraploidy and aneuploidy are two forms of chromosomal aberrations that accompany the development of cervical cancer. Aneuploidy is a late event which characterizes the chromosomal phenotype of advanced cervical cancer cells whereas tetraploidy appears to occur during the earlier stages of the disease. The molecular events leading up to and causing the development of aneuploidy during cervical carcinogenesis are poorly understood. We hypothesize that there is a sequential pattern to the development of these numerical chromosomal aberrations where tetraploid cervical cells undergo chromosomal loss forming the aneuploid cells characteristic of the later stages of the disease, that tetraploidy is an early event during cervical carcinogenesis that can be used as a secondary diagnostic tool to the ASCUS Pap smear, and that these chromosomal aberrations occur subsequent to HPV infection.; A molecular cytogenetic tool called fluorescence in situ hybridization (FISH) was used to simultaneously analyze alterations in chromosomes 3 and 17 in cervical cells from 400 different women. Polymerase chain reaction (PCR) and the Hybrid Capture II system, a commercially available kit, were used to analyze the cervical cells for the presence of the Human Papilloma Virus (HPV). The numerical chromosomal aberrations were identified to develop in a sequential pattern where tetraploidy preceded the development of aneuploidy. In addition, tetraploid cervical cells were determined to be chromosomally unstable and were identified to be prone to both chromosomal loss and breakage. We also identified that a small but significant number of women diagnosed as ASCUS HPV-positive exhibit elevated levels of tetraploid cervical cells. Furthermore, we were able to determine that both tetraploidy and aneuploidy appear only to occur subsequent to HPV infection.; These results indicate that tetraploidy is a transient and chromosomally unstable intermediate that can be used as a secondary diagnostic tool to the ASCUS Pap smear to identify women who may have an elevated risk of developing cervical malignancy. In addition, HPV infection appears to be a necessary but insufficient agent in the development of chromosomal instability during the process of cervical carcinogenesis.