PHYSICAL STATUS AND EXPRESSION OF HPV GENES IN CERVICAL CANCERS

It is known that E2 protein of oncogenic human papillomavirus (HPV) in hibits the expression of E6 and E7 genes from their major promoters in vitro and suppresses the proliferation of cervical cancer cells, This suggests that the loss of functional E2 gene may provide selective ad vantages in the development of cervical cancer, Investigation of the r elationship between the disruption of HPV-16/18 E2 genes by DNA integr ation and clinical outcome of cervical cancer may not only help to und erstand the mechanism of HPV-related cervical carcinogenesis, but may also provide novel management of cervical cancer, It was noted that in tegrated HPV-16/18 DNA was predominant in most patients with cervical cancers, marking 51 of a total of 68 cases (75%); episomal HPV DNAs we re found in 5 cases (7.4%), and finally mixed forms of HPV DNAs with e pisome and integration were found in 12 cases (17.6%), Whole portions of E2 DNA of HPV-16 could be amplified by PCR in 19 (36.5%) of 52 case s of cervical intraepithelial neoplasia, It was shown that there was n ot statistically significant association with the different stages, bu t integrated HPV DNAs were detectable only in the patients with far-ad vanced stage of cervical cancers, which also means no episomal forms w ere detected. Episomal forms of HPV DNA were detectable in 14 (25.9%) of 54 squamous cell carcinomas (4 pure episomal forms and 10 mixed for ms), whereas only 1(8.3%) of 12 adenocarcinomas and adenosquamous cell carcinomas contained episomal viral DNA, When HPV DNA forms were comp ared with initial tumor size, lympho-vascular space involvement, and f requency of nodal metastasis, statistically significant relationships were not found. The association of DNA integration with invasive cervi cal cancers was seen regardless of HPV type; however, there were diffe rences between the integration profiles of HPV-16 and HPV-18 DNA. Of t he 51 HPV-16-containing cancers, 36 (70.6%) revealed purely integrated HPV DNA, and another 10 cases (19.6%) displayed both integrated and e pisomal HPV DNAs. However, 5 (9.8%) cases showed only episomal copies of the HPV-16 genome. In contrast, all 17 HPV-18-containing cancers (5 cases positive for HPV-18 and 12 cases positive for both HPV-16 and - 18) revealed only the integrated form of HPV-18 DNA. The expression of E6 and E7 transcripts of HPV-16/18 is uniformly correlated with the p hysical status of HPV DNAs. HPV E2 mRNAs were constantly expressed in the presence of the intact virus in cases with episome and mixed forms of HPV DNA, In general, amplified signals from HPV E2 RT-PCR are more intensive than those from DNA-PCR in the same patients, It is suggest ed that RT-PCR is a valuable method to evaluate dynamic expression of the specific gene and seems to be more sensitive than the DNA-PCR meth od in detecting intact E2 gene because of the gene copy numbers. (C) 1 997 Academic Press.