Herpes Simplex Virus and Risk of Cervical Cancer: A Longitudinal, Nested Case-Control Study in the Nordic Countries

Matti Lehtinen1, Pentti Koskela2, Egil Jellum3, Aini Bloigu2, Tarja Anttila4, Göran Hallmans5, Tiina Luukkaala1, Steinar Thoresen6, Linda Youngman7, Joakim Dillner8 and Matti Hakama9

1 School of Public Health, University of Tampere, Tampere, Finland.
2 National Public Health Institute, Oulu, Finland.
3 Institute of Clinical Biochemistry, University of Oslo, Oslo, Norway.
4 Department of Microbiology, University of Oulu, Finland.
5 Department of Nutrition Research, University of Umeå, Umeå, Sweden.
6 The Cancer Registry of Norway, Oslo, Norway.
7 Clinical Trial Service Unit, University of Oxford, Oxford, United Kingdom.
8 Department of Clinical Microbiology, University of Lund, Malmö, Sweden.
9 Finnish Cancer Registry, Helsinki, Finland.

Received for publication November 19, 2001; accepted for publication May 28, 2002.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Human papillomaviruses (HPVs) play the major role in cervical carcinogenesis. The authors reevaluated the role of herpes simplex virus type 2 (HSV-2) in this multistage process by conducting a longitudinal, nested case-control study using 1974–1993 data and comparing the results with those from a meta-analysis of studies. A Nordic cohort of 550,000 women was followed up for an average of 5 years, after which 178 cervical carcinoma cases and 527 controls were identified. HSV-2; HPV-16, HPV-18, and HPV-33; and Chlamydia trachomatis antibodies were determined at baseline by HSV-2 glycoprotein gG-2 and HPV virus-like-particle enzyme immunoassays and by using the microimmunofluorescence method. The relative risk of cervical carcinoma was calculated by conditional logistic regression. Longitudinal studies on HSV-2 and cervical neoplasia were identified through MEDLINE (National Library of Medicine, Bethesda, Maryland), and weighted mean relative risks were calculated. Smoking (relative risk = 1.6, 95% confidence interval (CI): 1.1, 2.3) and HPV-16/HPV-18/HPV-33 (relative risk = 2.9, 95% CI: 1.9, 4.3) were both associated with cervical carcinoma. The smoking- and HPV-16/HPV-18/HPV-33–adjusted relative risks for HSV-2 were 1.0 (95% CI: 0.6, 1.7) and 0.7 (95% CI: 0.3, 1.6), respectively, for HPV seropositives. In the meta-analysis, the relative risk for HSV-2 was 0.9 (95% CI: 0.6, 1.3). In both sets of data, HSV-2 did not play a role in cervical carcinogenesis.

cervix neoplasms; herpes simplex; longitudinal studies; meta-analysis; retrospective studies

Abbreviations: Abbreviations: CI, confidence interval; ELISA, enzyme-linked immunosorbent assay; HPV, human papillomavirus; HSV-2, herpes simplex virus type 2; RR, relative risk.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Since the end of the 1960s, herpes simplex virus type 2 (HSV-2) had been considered the major cause of invasive cervical carcinoma, but a longitudinal seroepidemiologic study (1), together with inconsistent detection of HSV-2 DNA and consistent identification of human papillomavirus (HPV) DNA in cervical carcinoma (2), revised this paradigm in the early 1980s. However, assessing an infectious etiology of chronic disorders is difficult, and cohort studies that include complete follow-up are less vulnerable to different biases (3). Hence, most reliable results are provided by a combination of longitudinal design, a population-based setting, and state-of-the-science exposure assessment.

During the 1990s, considerable improvements took place in the serologic diagnosis of herpes simplex and HPV infections. HSV-2 antibodies can now be determined by a glycoprotein gG-2 enzyme-linked immunosorbent assay (ELISA) that suffers only minimally from cross-reactivity between herpes simplex virus type 1 and HSV-2 because a majority of glycoprotein gG-2 is coded by a unique segment of the HSV-2 genome (4–6). The HPV virus-like particle ELISA is a highly type-specific and reproducible, albeit not very sensitive, marker of cumulative HPV exposure (7–9). These assay developments have substantially improved the potential of serum sample banks to identify causes of anogenital cancers.

Natural history studies have been conducted with only cervical intraepithelial neoplasia as the endpoint (10). Linkage of population-based cancer registries with population-based serum banks overcomes ethical problems related to invasive cervical carcinoma being the endpoint. Application of incidence density sampling for matched controls increases the power to detect effects without bias. The lag between serum withdrawal and diagnosis accounts for the long latency period of invasive cervical carcinoma. By using state-of-the-science laboratory assays and a nested case-control design, we analyzed by far the largest known quantity of serum sample material collected since the 1970s in the Nordic countries (1974–1993) and compared the results systematically with those from other longitudinal studies on HSV-2 and cervical carcinoma.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Serum banks
The study cohort consisted of 550,000 women who donated blood samples to population-based serum banks in Finland, Norway, and Sweden (table 1). In 1983, the Finnish Maternity Cohort started to collect first-trimester blood samples to screen for congenital infections (11). The blood samples are drawn at all maternity clinics, and about 98 percent of all pregnant women donate samples to the Finnish Maternity Cohort bank. In 1993, this cohort had collected 710,000 samples from 390,000 women; the samples were stored at –25°C.


View this table:
[in this window]
[in a new window]
 
TABLE 1. Characteristics of the Nordic cohort for a nested case-control study of the cervical carcinoma risk associated with previous exposure to sexually transmitted microorganisms, 1974–1993
 
The Janus Project was established in Norway in 1973 (12). In 1991, the Janus Serum Bank had collected 424,000 serum samples from 293,000 donors; again, the samples were stored at –25°C. About 145,000 women were recruited during routine health examinations. During phase I (1974–1978) and phase II (1986–1991), the participation rates were 85 percent and 75 percent, respectively.

The Västerbotten Project was established in northern Sweden in 1986 (13). Each year, all residents of Västerbotten County aged 30, 40, 50, 60, and 69 years are invited to participate in the health-promotion project, which includes donating biologic samples for future medical research. From 1986 to 1993, the participation rate was about 65 percent. In 1993, the Västerbotten serum bank had collected samples from 15,000 women; the samples were stored at –80°C.

Cancer registries
The Finnish Cancer Registry, the Cancer Registry of Norway, and the cancer registry at the Oncological Centre in Umeå, which covers northern Sweden, are population based and country- or countywide (14, 15). Notifications are received from hospitals, laboratories, and physicians, and reporting coverage is practically 100 percent.

Identification of cases and controls
Women with invasive cervical carcinoma as the primary cancer diagnosis were identified by linkage of the serum banks and cancer registries. The linkages were performed in 1994 by using personal identification numbers and resulted in identification of 220 cases. Forty-two cases were excluded: 24 did not have enough sera, two could not be located, four had donated sera less than 15 days before the diagnosis, and, for 12, the disease was not invasive.

For each case, three female controls who were cancer free at the time of the case’s diagnosis were selected randomly and were matched for age at serum sampling (±2 years), length of time that the serum sample was stored (±2 months), and cohort area (Finland, Sweden, and subcohorts of the Janus Serum Bank in Norway). The earliest prediagnostic sample was chosen. If three controls could not be found, the matching criteria were widened: the age of six controls differed by more than 4 years (maximum, 4.4 years) from that of the case; the maximum difference in storage time was 5 months. Samples from seven (1.3 percent) of 527 controls could not be located.

Laboratory methods
Immunoglobulin G antibodies to HSV-2 were determined by using a commercially available HSV-2 glycoprotein gG-2 ELISA (Biokit SA, Barcelona, Spain) according to the manufacturer’s recommendations. Immunoglobulin G antibodies to HPV-16, HPV-18, and HPV-33 were determined by a standard virus-like particle ELISA using predetermined cutoff levels as an indication of exposure to the HPV types (8, 9). Chlamydia trachomatis antibodies were determined by using a standard microimmunofluorescence test (11).

Current smoking was defined by serum cotinine levels using a quantitative ELISA modification (STC Technologies, Bethlehem, Pennsylvania). Because smoking is a risk factor for passive smoking, the cutoff level of 20 µg/liter was used to distinguish active smokers from nonsmokers.

Criteria for selecting studies for the meta-analysis
We followed the BMJ recommendations (16) for selecting studies for review. All longitudinal studies on HSV-2 and cervical neoplasia available until June 2001 were eligible for inclusion. The studies were required to fulfill the following two criteria: 1) follow-up with use of a cohort, nested case-control approach among initially healthy women; and 2) definition of cumulative exposure (previous or present infection measured by serology for HSV-2 among either the total cohort or cases and controls) with a report of a relative risk and its variance (confidence interval), corresponding odds ratio, or pertinent frequency data (use of endpoints that could be categorized into the following three groups: 1) invasive cervical carcinoma, 2) inseparable invasive cervical carcinoma/carcinoma in situ (alone or included in cervical intraepithelial neoplasia), or 3) squamous cell carcinoma). Unless otherwise indicated, we used smoking-adjusted and/or matched (age, length of time of sample storage, country) point estimates based on individual data.

In addition to manual searches, we searched through MEDLINE (National Library of Medicine, Bethesda, Maryland) from 1966 to June 2001 by using the following search terms from Medical Subject Headings (MeSH) of Index Medicus and their combinations: herpes simplex virus and cervical neoplasia, and case-cohort or cohort or follow-up or longitudinal or prospective or retrospective study.

Statistical analysis
Relative risks and their 95 percent confidence intervals were estimated for invasive cervical carcinoma and squamous cell carcinoma by using conditional logistic regression (17) with Stata computer software (version 5.0; Stata Corporation, College Station, Texas). Unconditional logistic regression analysis was applied for HPV-seropositive cases and controls, including the matching variables in the model.

The weighted mean relative risk was calculated by taking a weighted average of the log relative risk (RR) from eligible studies, the weight assigned to each log RR being proportional to the inverse of its variance (18). The variances were derived from the published confidence intervals or from the pertinent frequency data by means of standard formulae. The homogeneity of log(RRi) across the studies was tested by using {chi}2 statistics.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We identified 178 cases with invasive cervical carcinoma, 150 of whom had cervical squamous cell carcinoma. Mean lag time between serum sampling and diagnosis was 5 years (range, 0.1–18) (table 1).

In univariate analysis, C. trachomatis, smoking, and HPV-16/HPV-18/HPV-33 were associated with an increased risk of invasive cervical carcinoma (RR = 2.5, 95 percent CI: 1.7, 3.9; RR = 1.6, 95 percent CI: 1.1, 2.4; and RR = 2.8, 95 percent CI: 1.9, 4.3, respectively). HSV-2 was associated with a moderately increased risk (RR = 1.3, 95 percent CI: 0.8, 2.1). The crude risk of squamous cell carcinoma was also low (RR = 1.4, 95 percent CI: 0.9, 2.4).

Stepwise adjustment for C. trachomatis, smoking, HPV-16/HPV-18/HPV-33, and a combination of the latter two factors removed the excess risk of both invasive cervical carcinoma and squamous cell carcinoma (RR = 1.0, 95 percent CI: 0.6, 1.7 and RR = 1.1, 95 percent CI: 0.6, 1.9, respectively; table 2). Among HPV-16/HPV-18/HPV-33 seropositives, HSV-2 was not associated with any excess risk of invasive cervical carcinoma or squamous cell carcinoma (RR = 0.7, 95 percent CI: 0.3, 1.6 and RR = 0.7, 95 percent CI: 0.3, 1.7, respectively).


View this table:
[in this window]
[in a new window]
 
TABLE 2. Relative risk of cervical carcinoma associated with previous exposure to herpes simplex virus type 2, overall and among human papillomavirus* seropositives, the Nordic countries, 1974–1993
 
Finally, with the exception of an increased risk (RR = 2.2, 95 percent CI: 0.5, 9.4) just prior to diagnosis, the lag did not affect the point estimates for invasive cervical carcinoma when the data were divided into four lag categories: 1–12, 13–59, 60–119, and >=120 months (figure 1). On the other hand, the point estimates for squamous cell carcinoma tended to increase with increasing lag.



View larger version (10K):
[in this window]
[in a new window]
 
FIGURE 1. Human papillomavirus types 16, 18, and 33 and smoking-adjusted relative risks of invasive cervical carcinoma (ICC, n = 178) and squamous cell carcinoma of the uterine cervix (SCC, n = 150) associated with herpes simplex virus type 2 infection, by lag between serum sampling and cancer diagnosis in a Nordic cohort of 550,000 women followed up for an average of 5 years between 1974 and 1993. Relative risks for lag categories 1–12, 13–59, 60–119, and >=120 months: ICC (downward triangles)—2.2 (95% confidence interval (CI): 0.5, 9.4), 0.5 (95% CI: 0.2, 1.1), 1.6 (95% CI: 0.5, 5.7), and 1.7 (95% CI: 0.4, 6.5), respectively; SCC (upward triangles)—2.2 (95% CI: 0.5, 9.5), 0.5 (95% CI: 0.2, 1.2), 1.6 (95% CI: 0.4, 5.5), and 3.1 (95% CI: 0.7, 15), respectively.

 
Six longitudinal seroepidemiologic studies (1, 19, 20–22, the present study) on the association of HSV-2 with cervical neoplasia (invasive cervical carcinoma and/or carcinoma in situ) were identified. Altogether, more than 3 million person-years of follow-up resulted in about 200 matched case-control pairs, triplets, or quadruplets (table 3). Three studies had applied glycoprotein gG-2 ELISA, and four studies had applied the older serologic methods by using a ratio of HSV-2 and herpes simplex virus type 1 antibody levels with a predefined cutoff level of 0.85 (also known as the II/I ratio (23)). Weighted mean relative risks of 0.7 (95 percent CI: 0.4, 1.3) and 0.9 (95 percent CI: 0.5, 1.9), respectively, were obtained, indicating lack of any increased risk of cervical neoplasia, irrespective of the method used to determine HSV-2 antibodies (table 3). When the glycoprotein gG-2 ELISA was used, the grand mean relative risk for all longitudinal studies was 0.9 (95 percent CI: 0.6, 1.3).


View this table:
[in this window]
[in a new window]
 
TABLE 3. Meta-analysis of longitudinal seroepidemiologic studies of herpes simplex virus type 2 and cervical neoplasia* using the II/I ratio{dagger} or glycoprotein gG-2 enzyme-linked immunosorbent assay to determine previous herpes simplex virus type 2 infection with serum antibodies
 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In the present study, previous HSV-2 infection was not associated with any excess risk of subsequent development of cervical carcinoma. Similarly, in a meta-analysis of comparable longitudinal seroepidemiologic studies that yielded a remarkably narrow confidence interval, HSV-2 was not associated with any excess risk of cervical carcinoma. Since the study by Choi et al. (19) was conducted, not one of the longitudinal seroepidemiologic studies on HSV-2 and cervical neoplasia (1, 20–22) has found a significantly increased relative risk, but all were underpowered to detect a small excess risk. However, the upper 95 percent confidence limit of our final meta-analysis, 1.3, indicates that if an excess risk of cervical neoplasia were associated with HSV-2, it would be very small.

Our results also indicate that the previous estimates of the effect of HSV-2 on cervical neoplasia found in many cross-sectional case-control studies (23–26) were biased. Possible sources of bias include the cross-sectional design, inadequate power, misclassification, and confounding due to uncontrolled risk factors, for example, HPV. Adjustment for smoking and C. trachomatis, known risk factors for cervical neoplasia/surrogates of risk-taking behavior (11, 27), reduced our point estimates; further adjustment for HPV-16/HPV-18/HPV-33 removed the excess risk from the point estimate for women who tested positive for HSV-2 antibodies. Moreover, HSV-2 antibodies were associated with no excess risk for HPV-16/HPV-18/HPV-33–seropositive women, also indicating that HSV-2 is not a cause of invasive cervical carcinoma.

With few exceptions, HSV glycoprotein gG-2 ELISAs are now considered highly sensitive (>95 percent) and reproducible (coefficient of variation, <=5 percent) (6, 28). The test we used should not have biased the relative risk toward unit risk. Although our final relative risk estimates were consistent with all of the previous longitudinal study results based on the early nonstandardized tests, our increased crude relative risk estimates for invasive cervical carcinoma and squamous cell carcinoma suggest that the previous results were indeed affected by a lack of test validity. Together with lower specificity and sensitivity of the II/I assays and the early glycoprotein gG-2 ELISAs, regression toward the mean probably biased the previous results toward unit risk. In our longitudinal study, we were able to assess a more accurate crude relative risk; however, it proved to be confounded by HPV exposure, as indicated by both adjusting for HPV-16/HPV-18/HPV-33 antibodies and restricting the analysis to HPV-seropositive cases and controls only. Thus, the meta-analysis of the previous longitudinal studies yielded a probably correct result for the wrong reasons or as a result of chance.

Why, then, did the cross-sectional studies find an association? Invasive cervical carcinoma patients produce an autoantibody response to an HSV-2–inducible tumor-specific tissue polypeptide that is recognized by the II/I assay (29). This finding also applies to the antibodies determined by HSV-2 nonstructural antigens (25, 26, 30, 31) suggested to be found in invasive cervical carcinoma (32). Cross-reactivity between viral infected cell protein (ICP) 8 and a homologous/functionally identical cellular protein, proliferating cell nuclear antigen, which is abundant in invasive cervical carcinoma, is one possible explanation (33–37). It is plausible that ICP8 antibodies and proliferating cell nuclear antigen autoantibodies, as well as the HSV-2 antibodies and autoantibodies measured by the II/I assay, were both indistinguishable and readily detectable in the incident invasive cervical carcinoma cases.

Although our study did not associate a short time period from serum sampling to cancer diagnosis with a significantly increased risk, the possibility that cervical neoplasia predisposes to HSV-2 infection, that is, reverse causality, should not be neglected as an explanation for the association found in the previous cross-sectional case-control studies. Longitudinal design removes much of the possible bias due to antibody response to the cross-reactive tumor-specific antigens, or amplification of the virus by the occult neoplasia, irrespective of the serologic test used (1, 20, 30). Although the nonsignificant increase of HSV-2–associated risk of squamous cell carcinoma by increasing lag may deserve consideration in even larger studies, we conclude that HSV-2 is not likely to be causally associated with invasive cervical carcinoma or squamous cell carcinoma.


    ACKNOWLEDGMENTS
 
This study was supported by the Nordic Cancer Union and the Academy of Finland. The Janus Serum Bank is owned by the Norwegian Cancer Society. The serum samples were provided following approval by the institutional review boards.

The authors thank Prof. Vladimir Vonka for stimulating discussions and Dr. Vera Abeler for histologic classification.

This is publication number 20 of the Nordic Biological Specimen Banks study group on Cancer Causes and Control (NBSBCCC).


    NOTES
 
Reprint requests to Dr. Matti Lehtinen, University of Tampere, School of Public Health, POB 607, FI-33101 Tampere, Finland (e-mail: llmale{at}uta.fi). Back


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Vonka V, Kanka J, Jelinek I, et al. Prospective study on the relationship between cervical neoplasia and herpes simplex type-2 virus. Int J Cancer 1984;33:61–8.[ISI][Medline]
  2. Durst M, Gissmann L, Ikenberg H, et al. A new papillomavirus DNA from cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proc Natl Acad Sci U S A 1983;80:3812–15.[Abstract]
  3. Rothman KJ, Greenland S, eds. Modern epidemiology. 2nd ed. Philadelphia, PA: Lippincott-Raven Publishers, 1998.
  4. McGeoch DJ, Moss HWM, McNab D, et al. DNA sequence and genetic content of the HindIII 1 region in the short unique component of the herpes simplex virus type 2 genome: identification of the gene encoding glycoprotein G, and evolutionary comparisons. J Gen Virol 1987;68:19–38.[Abstract]
  5. Sanchez-Martinez D, Schmid DS, Whittington W, et al. Evaluation of a test based on baculovirus-expressed glycoprotein G for detection of herpes simplex virus type-specific antibodies. J Infect Dis 1991;164:1196–9.[ISI][Medline]
  6. Arvaja M, Lehtinen M, Koskela P, et al. Serological evaluation of herpes simplex virus type 1 and type 2 infections in pregnancy. Sex Transm Infect 1999;75:168–71.[Abstract]
  7. Strickler HD, Hildesheim A, Viscidi RP, et al. Interlaboratory agreement among results of human papillomavirus type 16 enzyme-linked immunosorbent assays. J Clin Microbiol 1997;35:1751–6.[Abstract]
  8. Dillner J, Lehtinen M, Bjorge T, et al. Prospective seroepidemiological study of human papillomavirus infection as a risk factor for invasive cervical cancer. J Natl Cancer Inst 1997;89:1293–9.[Abstract/Free Full Text]
  9. Kjellberg L, Wang Z, Wiklund F, et al. Sexual behaviour and papillomavirus exposure in cervical intraepithelial neoplasia: a population-based case-control study. J Gen Virol 1999;80:391–8.[Abstract]
  10. Human papillomaviruses. IARC monographs on the evaluation of carcinogenic risks to humans. Vol 64. Lyon, France: International Agency for Research on Cancer, 1995.
  11. Koskela P, Anttila T, Bjorge T, et al. Chlamydia trachomatis infection as a risk factor for invasive cervical cancer. Int J Cancer 2000;85:35–9.[ISI][Medline]
  12. Jellum E, Andersen A, Lund-Larsen P, et al. Experiences of the Janus Serum Bank in Norway. Environ Health Perspect 1995;103:85–8.[ISI][Medline]
  13. Dillner J, Lenner P, Lehtinen M, et al. A population-based seroepidemiological study of cervical cancer. Cancer Res 1994;54:134–41.[Abstract]
  14. Engeland A, Haldorsen T, Tretli S, et al. Prediction of cancer incidence in the Nordic countries up to years 2000 and 2010. A collaborative study of the five Nordic cancer registries. (Supplement). APMIS 1993;101:S38.
  15. Lenner P, Jonsson H, Gardfjell O. Trends in cancer incidence, survival and mortality in northern Sweden 1960–1986. Med Oncol Tumor Pharmacother 1991;8:105–12.[ISI][Medline]
  16. Egger M, Davey-Smith G, Phillips AN. Meta-analysis. Principles and procedures. BMJ 1997;315:1533–7.[Free Full Text]
  17. Breslow NE, Day NE, eds. Statistical methods in cancer research. Vol 1. The analysis of case-control studies. Lyon, France: International Agency for Research on Cancer, 1980. (IARC scientific publication no. 32).
  18. Der Simonian R, Laird M. Meta-analysis in controlled trials. Control Clin Trials 1986;7:177–88.[ISI][Medline]
  19. Choi NW, Shettigara PT, Abu-Zeid HAH, et al. Herpesvirus infection and cervical anaplasia—a seroepidemiological study. Int J Cancer 1977;119:167–71.
  20. Lehtinen M, Hakama M, Aaran RK, et al. Herpes simplex virus type 2 infection and cervical cancer: a prospective study of 12 years of follow-up in Finland. Cancer Causes Control 1992;3:333–8.[ISI][Medline]
  21. Adam E, Kaufman RH, Alder-Storthz K, et al. A prospective study of association of herpes simplex virus and human papillomavirus infection with cervical neoplasia in women exposed to diethylstilbestrol in utero. Int J Cancer 1985;35:19–26.[ISI][Medline]
  22. Lehtinen M, Dillner J, Knekt P, et al. Serologically diagnosed infection with human papillomavirus type 16 and risk for subsequent development of cervical carcinoma: nested case-control study. BMJ 1996;312:537–9. [Abstract/Free Full Text]
  23. Rawls WE, Adam E, Melnick JL. An analysis of seroepidemiological studies of herpes virus type 2 and carcinoma of the cervix. Cancer Res 1972;33:1479–82.
  24. Nahmias AJ, Josey WE, Naib ZM, et al. Antibodies to herpesvirus hominis types 1 and 2 in humans. II. Women with cervical cancer. Am J Epidemiol 1970;91:547–52.[ISI][Medline]
  25. Melnick JL, Courtney RJ, Powell KL, et al. Studies on herpes simplex virus and cancer. Cancer Res 1976;36:845–56.[Abstract]
  26. Aurelian L, Kessler II, Rosenshein NB, et al. Viruses and gynecologic cancers: herpesvirus protein (ICP10/AG-4), a cervical tumor antigen that fulfills the criteria for a marker of carcinogenicity. Cancer 1980;48(2 suppl):455–71.[ISI]
  27. Szarewski A, Cuzick J. Smoking and cervical cancer: a review of the evidence. J Epidemiol Biostat 1998;3:229–56.
  28. Ribes JA, Hayes M, Smith A, et al. Comparative performance of herpes simplex virus type 2-specific serologic assays from Meridian Diagnostics and MRL Diagnostics. J Clin Microbiol 2001;39:3740–2.[Abstract/Free Full Text]
  29. Macnab JCM, Nelson JS, Daw S, et al. Patients with cervical cancer produce an antibody response to an HSV inducible tumour-specific polypeptide. Int J Cancer 1992;50:578–84.[ISI][Medline]
  30. Lehtinen M, Hakama M, Knekt P, et al. Lack of serum antibodies to the major HSV-2 specified DNA-binding protein before diagnosis of cervical neoplasia. J Med Virol 1989;27:131–6.[ISI][Medline]
  31. Evans LA, Sheppard M, May JT. Analysis of the HSV-2 early AG-4 antigen. Arch Virol 1985;85:13–23.[ISI][Medline]
  32. Dreesman GR, Burek J, Adam E, et al. Expression of herpesvirus-induced antigens in human cervical cancer. Nature 1980;283:591–3.[ISI][Medline]
  33. Mittall KR, Demopoulos RI, Goswami S. PCNA expression in cervical neoplasia. Am J Surg Pathol 1993;17:117–22.[ISI][Medline]
  34. Bravo R, Frank R, Blundell PA, et al. Cyclin/PCNA is the auxiliary protein of DNA polymerase delta. Nature 1987;326:515–17.[ISI][Medline]
  35. Kulomaa P, Paavonen J, Lehtinen M. Herpes simplex virus induces unscheduled DNA synthesis in virus-infected cervical cancer cell lines. Res Virol 1992;143:351–9.[ISI][Medline]
  36. Zuber M, Tan EM, Ryoji M. Involvement of proliferating cell nuclear antigen (cyclin) in DNA replication in living cells. Mol Cell Biol 1989;9:57–66.[ISI][Medline]
  37. Galloway DA, McDougall JK. Alterations in the cellular phenotype induced by herpes simplex viruses. J Med Virol 1990;31:36–42.[ISI][Medline]




This Article
Abstract
FREE Full Text (PDF)
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (9)
Disclaimer
Request Permissions
Google Scholar
Articles by Lehtinen, M.
Articles by Hakama, M.
PubMed
PubMed Citation
Articles by Lehtinen, M.
Articles by Hakama, M.