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High-Risk HPV Infection and CIN Grade Correlates to the Expression of c-myc, CD4(+), FHIT, E-cadherin, Ki-67, and p16(INK4a)
Department of Obstetrics and Gynecology, Falun Hospital.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Department of Pathology and Clinical Cytology, Falun Hospital.
Department of Pathology and Clinical Cytology, Falun Hospital.
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2011 (English)In: Journal of Lower Genital Tract Disease, ISSN 1089-2591, E-ISSN 1526-0976, Vol. 15, no 4, 280-286 p.Article in journal (Refereed) Published
Abstract [en]

Objective. This study aimed to investigate correlations between a panel of biomarkers/tumor markers and high-risk (HR) human papillomavirus (HPV)-positive versus HR-HPV-negative cervical lesions.

Materials and Methods. The study included 188 women who consecutively attended a colposcopy clinic because of PAP smears suggesting cervical intraepithelial neoplasia (CIN), and 40 women with normal vaginal cytology. Tissue microarray blocks were prepared from representative cervical cone or punch biopsies. Sections were stained for 12 biological markers, previously shown to be relevant in cervical neoplasms, and expression was correlated to the presence or absence of HR-HPV in cervical lesions.

Results. No correlations between expression of biomarkers and HPV status were found in normal epithelium. Expression of c-myc, CD4(+), Ki-67, and p16(INK4a) correlated significantly to HR-HPVYinfected epithelium compared with HR-HPV-negative epithelium. When adjustment was made for CIN grade, only the expression of Ki-67 correlated significantly with HPV status and CIN grade. Human papillomavirus status was stratified to normal epithelium, low-grade CIN, and high-grade CIN. Fragile histidine triad (FHIT), E-cadherin, Rb, Ki-67, and p16(INK4a) expression was significantly increased in HPV-positive tissue by increasing CIN grade. No correlation to tumor marker expression was observed in the HPV-negative tissue. Conclusions. This study described correlations, previously not investigated, between HPV status and tumor marker expression, that is, E-cadherin, Rb, and fragile histidine triad. Surprisingly, p16(INK4a) was not, although Ki-67 expression was, independently correlated to HPV positivity. The results of this study suggest that p16(INK4a) instead correlates independently with increasing CIN grade.

Place, publisher, year, edition, pages
2011. Vol. 15, no 4, 280-286 p.
Keyword [en]
human papillomavirus, cervical intraepithelial neoplasia, cervical epithelium, tumor markers
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-160386DOI: 10.1097/LGT.0b013e318215170cISI: 000295398800005OAI: oai:DiVA.org:uu-160386DiVA: diva2:450991
Available from: 2011-10-24 Created: 2011-10-24 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Tissue tumor marker expression in normal cervical tissue and in cervical intraepithelial neoplasia, for women who are at high risk of human papilloma virus infection, are smokers, contraceptive users or in fertile age
Open this publication in new window or tab >>Tissue tumor marker expression in normal cervical tissue and in cervical intraepithelial neoplasia, for women who are at high risk of human papilloma virus infection, are smokers, contraceptive users or in fertile age
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aim of this research was to study the correlation between tissue tumor marker expression and HR-HPV infection, smoking, hormonal contraceptive use and sex steroids in women with cervical intraepithelial neoplasia or normal epithelium. The study investigated the expression of 11 tumor markers in cervical biopsies obtained from 228 women with different diagnoses ranging from normal cervical epithelium to various stages of CIN. 188 women were recruited at our colposcopy clinic (out-patient surgery, Department of Obstetrics and Gynecology, Falun Hospital) for laser cervical conization or a directed punch biopsy, either because of a vaginal smear (Pap smear) that showed cytological findings suggesting CIN, or because of repeated findings showing atypical squamous cells of undetermined significance (ASCUS). For 40 volunteers, punch biopsies were taken from the normal cervical epithelium. The time period for this study was 2005-2007.

Study I :  228 women, of whom 116 were tested, 64 were positive to HR-HPV. The results showed that Ki67 tumor cell proliferation index was the only marker that independently correlated to both the presence of HR-HPV and the severity of cervical lesions.

Study II:  228 women, of whom 83 were smokers (36, 9%). Smokers showed lower expression of p53, FHIT (tumor suppressor markers) and interleukin-10 .Higher expression of Cox-2 and Ki-67 (tumor proliferation markers).

Study III:  195 women who were premenopausal. There was increased p53 expression (tumor suppressor) in the progestin-IUD users compared to non-users. Decreased IL-10 expression (immunological marker) was observed in both COC users and any progestin-only users.

Study IV: Serum from 80 premenopausal women was available. The main finding was that the increased levels of serum progesterone and estradiol were associated with increased Cox-2 expression (proliferation marker). Serum progesterone and estradiol levels influence cellular and extracellular proteins which have been associated with neoplastic development in normal epithelium and CIN.

Conclusion: The results of these studies support previous epidemiological findings on the role of smoking, contraceptive use and sex steroids as co-factors in development of CIN and that tumor marker expression varies in different grades of CIN.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 74 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1137
Keyword
tumor markers, cervical intraepithelial neoplasia, smoking, contraceptive use, sex steroid hormones, HPV infection
National Category
Health Sciences
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:uu:diva-262889 (URN)978-91-554-9348-6 (ISBN)
Public defence
2015-11-16, Rosénsalen, ingång 95/96, Akademiska sjukhuset, Uppsala, 13:00 (English)
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Available from: 2015-10-21 Created: 2015-09-22 Last updated: 2015-10-27

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Pekar, GyulaHellberg, Dan

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