Frequent gain of the human telomerase gene TERC at 3q26 in cervical adenocarcinomas.

The level of genomic amplification of the human telomerase gene TERC, which maps to chromosome band 3q26, was determined in primary cervical adenocarcinomas. Interphase nuclei prepared from archival material of 12 primary cervical adenocarcinomas, eight of which were human papillomavirus positive, were hybridised with a triple colour probe set specific for centromeres of chromosomes 3 and 7 and the TERC gene. We observed high proportions of nuclei with increased absolute copy numbers for TERC in all tumours (mean 3.3; range 2.3-5.2). Amplification of the human telomerase gene TERC is a consistent aberration in cervical adenocarcinomas. Therefore, application of our probe set may provide an objective genetic test for the assessment of glandular cells in Pap smears and hence for the diagnosis of cervical adenocarcinomas.

Detection of adeno-associated virus type 2 genome in cervical carcinoma.

Adeno-associated virus (AAV) can impair the replication of other viruses. Adeno-associated virus seroprevalences have been reported to be lower among women with cervical cancer. In-vitro, AAV can interfere with the production of human papillomavirus virions. Adeno-associated virus-2 DNA has also been detected in cervical cancer tissue, although not consistently. To evaluate the role of AAV infection in relation to invasive cervical cancer, we performed a nested case-control study within a retrospectively followed population-based cohort. A total of 104 women who developed invasive cervical cancer on average 5.6 years of follow-up (range: 0.5 months-26.2 years) and 104 matched control-women who did not develop cervical cancer during the same follow-up time were tested for AAV and human papillomavirus by polymerase chain reaction. At baseline, two (2%) case-women and three (3%) control-women were positive for AAV-2 DNA. At the time of cancer diagnosis, 12 (12%) case-women and 3 (3%) matched control-women were positive for AAV-2 DNA. Persisting AAV infection was not evident. In conclusion, AAV-2 DNA was present in a low proportion of cervical cancers and we found no evidence that the presence of AAV in cervical smears of healthy women would be associated with reduced risk of cervical cancer.

Parallel cyclin E and cyclin A expression in neoplastic lesions of the uterine cervix.

Cyclin E levels are high during late G1 and early S-phase in normal cells. The cyclin E expression over the cell cycle in tumours is not fully known. The impact on patient outcome by high cyclin E levels during other parts of the cell cycle than late G1- and early S-phase is unknown. We set out to study the expression of cyclin E over the cell cycle in cervical carcinomas. Using immunofluorescence staining of cyclin A, digital microscopy, and digital image analysis, we determined which cells in a tissue section that were in S- or G2-phase. M-phase cells were detected by morphology. By simultaneously staining for cyclin E, we investigated the variation in cyclin E levels over the cell cycle in cervical carcinoma lesions. In a case-control study, in which each deceased patient was matched with a patient still alive and well after >5 years of follow-up, we found that the deceased patients had a considerably higher fraction of cyclin A-positive cells staining for cyclin E than the survivors (n = 36). We conclude that parallel cyclin E and cyclin A expression is an indicator for poor outcome in cervical carcinomas. In addition, we investigated the expression pattern of cyclin E and cyclin A in consecutive biopsy samples from cervical carcinomas at different stages, as well as in human papillomavirus positive or negative adenocarcinomas in order to further study the cyclin E and cyclin A expression pattern in neoplastic lesions of the uterine cervix.

The clinicopathologic significance of laminin-5 gamma2 chain expression in cervical squamous carcinoma and adenocarcinoma.

Carcinoma of the uterine cervix is one of the most prevalent malignancies among women in developing countries and the third most common type worldwide. Squamous cell carcinoma predominates in the cervix uteri, while adenocarcinoma and adenosquamous carcinomas represent about 10-15% of all cervical cancers. Many studies have confirmed that the human papillomavirus (HPV) is the most important etiologic factor in the development of cervical cancer. The aim of our study was to investigate the expression of the laminin-5 gamma2 chain in primary malignancies of the cervix uteri and to focus on the clinicopathologic significance of the expression of the laminin-5 gamma2 chain in cervical squamous carcinoma and adenocarcinoma with respect to age and survival of the patients. The study consisted of a total of 89 cases of invasive cervical cancer (54 squamous carcinomas and 35 adenocarcinomas). The laminin-5 gamma2 chain was found in 80% of all the squamous carcinoma and in 66% of cervical adenocarcinoma. There was no correlation of the high expression of laminin-5 with survival. The univariate analysis in squamous cell carcinoma showed that factors such as the stage of the disease and positive lymph nodes had an impact on the survival of the patients, whereas in the multivariate analysis, only age at diagnosis was an independent prognostic factor. However, in cases with cervical adenocarcinoma, only the stage of the disease was an independent prognostic factor. There was no difference between HPV-positive and HPV-negative tumors concerning the high expression of laminin-5 gamma2 chain. Our results indicate that the majority of the primary cervical tumors, especially squamous cell carcinoma, showed expression of laminin-5 gamma2 chain immunoreactivity. Independent prognostic values for the survival of the patients were age and stage of the disease.

Human papillomavirus infection, risk for subsequent development of cervical neoplasia and associated population attributable fraction.

BACKGROUND: Human papillomavirus (HPV) is the major cause of cervical neoplasia but estimates of the population attributable fraction (PAR%), of HPV vary. PAR% has not been derived from longitudinal studies although assessment of HPV exposure prior to the neoplasia diagnosis should increase validity of such estimates. AIMS: Systematic review and meta-analysis of longitudinal studies on HPV associated relative risk (RR) for and PAR% of HPV16 in cervical neoplasia. METHODS: Pertinent data from longitudinal studies was made available through Medline and substituted by various hand searches. HPV associated weighted mean RR, with 95% confidence interval (CI) of cervical neoplasia, and the PAR% of HPV16 in cervical carcinoma were estimated both for unselected and low HPV prevalence populations. RESULTS: HPV associated RR of cervical carcinoma in PCR-based studies was 17 (95% CI 8.2-33). HPV16 associated RRs in seroepidemiological studies were 3.3 (95% CI 2.2-4.9) for the unselected population, HPV16 seroprevalence 11.0%, and 12.5 (95% CI 5.5-29) for a population with low HPV16 seroprevalence of 5.3%. Corresponding PAR% estimates of HPV16 were 27 and 44%, respectively. CONCLUSION: Protective vaccination against HPV16 infection would prevent up to 44% of cervical carcinoma.

HIV-1 in placentas of untreated HIV-1-infected women in relation to viral transmission, infectious HIV-1 and RNA load in plasma.

The presence of HIV in the placenta was analysed in relation to virological and immunological factors and vertical transmission of HIV in 39 pregnancies between 1989 and 1993 among 37 HIV-1-infected women without zidovudine prophylaxis. HIV-1 was detected in 12 of 37 (31%) placentas by immunohistochemistry and in 3 of 18 by PCR. Altogether 14/39 (36%) placentas bore evidence of HIV-1 infection, although there was no relation with the outcome of HIV infection in the child. Neither was there a relation between placental infection and either CD4 cell counts or HIV-1 RNA levels. However, HIV-1 was isolated from plasma in 20 of 39 (50%) pregnancies, which was inversely related to the presence of HIV in the placenta. When HIV-1 was identified in the placenta, HIV-1 was isolated from plasma in 3/14 (21%) pregnancies, vs 17/25 (68%) when it was not (p = 0.01), with a relative risk of having a placenta positive for HIV of 3.9 in pregnancies with a negative plasma HIV isolation. This inverse relation may point to differences in tropism between HIV-1 in placenta and plasma. The results show that the placental barrier prevents HIV transmission, irrespective of whether HIV enters the placenta or not.

Seroepidemiology of human papillomavirus type 73: a sexually transmitted low-risk virus.

Human papillomavirus type 73 (HPV 73) has been detected in some invasive cervical cancers and has been cloned from a squamous-cell carcinoma of the esophagus, but the epidemiology of this infection and its associated risk of cancer is unknown. We investigated the seroepidemiology of this virus using virus-like particles. The IgG response to HPV 73 appeared to be HPV type-specific, since a comparison of HPV 73 antibody levels before and after infection with HPV 6, 11, 16, 18 or 33 found no evidence of cross-induction of HPV 73 antibodies and since there was little correlation between the antibody levels to HPV 73 and the other 5 investigated HPV types. In both a cross-sectional serosurvey that included 274 women and a 7-year follow-up study that enrolled 98 women, HPV 73 seropositivity was found to be strongly dependent on the number of lifetime sexual partners [OR for > 4 vs. 0 to 1 partners: 6.0 (95%CI: 1.4-53.6) and 7.9 (95% CI: 2.8-28.3), respectively]. Finally, the risk for HPV 73 seropositive women to develop CIN was investigated in a prospective study nested in a cohort of 15,234 Swedish women. The population-based HPV 73 seroprevalence in Sweden was 14%. No excess risk for CIN was found (OR: 0.77). We conclude that HPV 73 is a mainly sexually transmitted, probably mostly transient, infection that does not confer any measurably increased risk for CIN development.

Type-specific persistence of human papillomavirus DNA before the development of invasive cervical cancer.

BACKGROUND: Infection with the human papillomavirus (HPV) has been established as a cause of cervical cancer, but the association between a positive test for HPV DNA and the risk of the subsequent development of invasive cervical cancer is unknown. METHODS: In a study of women who participated in a population-based screening program for cancer of the cervix in Sweden from 1969 to 1995, we compared the proportion of normal cervical smears (Pap smears) that were positive for HPV DNA among 118 women in whom invasive cervical cancer developed an average of 5.6 years later (range, 0.5 month to 26.2 years) with the proportion of HPV DNA-positive smears from 118 women who remained healthy during a similar length of follow-up (controls). The control women were matched for age to the women with cancer, and they had had two normal Pap smears obtained at time points that were similar to the times of the baseline smear and the diagnosis of cancer confirmed by biopsy in the women with cancer. RESULTS: At baseline, 35 of the women with cancer (30 percent) and 3 of the control women (3 percent) were positive for HPV DNA (odds ratio, 16.4; 95 percent confidence interval, 4.4 to 75.1). At the time of diagnosis, 80 of the 104 women with cancer for whom tissue samples were available (77 percent) and 4 of the 104 matched control women (4 percent) were positive for HPV DNA. The HPV DNA type was the same in the base-line smear and the biopsy specimen in all of the women with cancer in whom HPV DNA was detected at base line. None of the control women had the same type of HPV in both smears. CONCLUSIONS: A single positive finding of HPV DNA in a Pap smear confers an increased risk of future invasive cervical cancer that is positive for the same type of virus as identified earlier.

Sexual behaviour and papillomavirus exposure in cervical intraepithelial neoplasia: a population-based case-control study.

Sexual history is an established risk determinant for cervical neoplasia. It is not clear if human papillomavirus (HPV) exposure entirely explains the sexual behaviour-related risk or if other sexually transmitted agents may act as cofactors for HPV in carcinogenesis. The aim of this study was to elucidate whether HPV exposure or HPV persistence explains the sexual history-related risk of high-grade cervical intraepithelial neoplasia (CIN) using a population-based case-control study of most of the 254 women referred to colposcopy in the Vasterbotten county in Sweden because of an abnormal cervical smear during October 1993 to December 1995 and 320 age-matched women from the general population. The women were interviewed for sexual history and tested for presence of serum antibodies to HPV-16, -18 and -33 as well as for presence of HPV DNA in cervical brush samples. HPV-16, -18 and -33 seropositivity was specific for the corresponding type of HPV DNA, dependent on the lifetime sexual history and associated with a two- to threefold increased risk of CIN 3. There was no sexual history-related risk of CIN among HPV-seropositive women and adjustment for HPV DNA presence explained the sexual history-related risk of CIN. In conclusion, HPV exposure appeared to explain the sexual history-related risk of high-grade CIN.