Human papillomavirus infection, genetic instability and invasive properties of cervical lesions

Cancer of the uterine cervix is one of the most frequent malignancies in women worldwide. Approximately half a million new cases of cervical cancer are diagnosed each year, and about 200 000 women die from the disease. Human papillomavirus (HPV) DNA has been shown to be present in about 90 % of all cervical cancers. Using molecular biological techniques, about 80 human genotypes have now been characterized, of which about 30 are genital types. The ISH method developed by us has been shown to be able to detect and type HPV DNA, using our own biotinylated probes, in both cell and tissue specimens, with high sensitivity and very good specificity compared with PCR. The ISH method was used for HPV typing of biopsies, which were further tested for expression of the HPV capsid antigens by immunostaining. The identification and characterization of antigenic sites on the HPV capsids can be useful for the design of immunogens for vaccination studies. We found that cytology is insufficient for HPV detection in latent infections of cell specimens and that DNA detection systems, such as PCR and ISH, are needed as a complement in the gynaecological screening programs. In our material an HPV DNA prevalence of 13.4 % was detected by PCR, which may be the method of choice for screening. The ISH method, less sensitive than PCR, is useful, however, when few cells are infected and morphological relationships need to be clarified. Comparing biopsies of cervical adenocarcinoma from Ireland and Sweden, it has been demonstrated that, irrespective of geographical differences, HPV infection is highly correlated to patient age. The binding of p53 and pRB to high risk HPV E6-E7 gene products is an important factor for carcinogenesis, indicated by DNA ploidy disturbances and proliferative aberrations. Our studies clearly show that carcinogenic progression is correlated to increasing centrosomal aberration and a transition of diploid into aneuploid cell populations. Invasive capacity, as reflected by laminin-5 accumulation in the cytoplasmic compartment of a subpopulation of cervical lesions, occurs late in the carcinogenic process and definitely after numerical centrosomal aberration, cell cycle disturbance and aneuploidy. The data indicate that the demonstration of laminin-5 accumulation in the tumor cells can be used as a sensitive method for diagnosing early invasiveness.