DNA aneuploidy and infection of human papillomavirus type 16 in preneoplastic lesions of the uterine cervix: correlation with progression to malignancy

Kashyap, Veena; Das, Bhudev C.

doi:10.1016/s0304-3835(97)00396-0

Cited by 18 publications

(17 citation statements)

References 21 publications

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“…Selection of tetraploidy at passage 14 may therefore have been due to an increase in the effects of integrated HPV16 rather than to a selective advantage conferred by tetraploidy per se. The argument that polyploidy may not be of particular importance in cervical neoplastic progression is supported by some in vivo evidence, albeit from small studies, suggesting that it is aneuploidy rather than polyploidy that predicts progression of cervical SILs (45,46). Several aspects of our study reinforce the evidence (10, 21) that W12 is an accurate model of progression of HPV16-associated cervical neoplasia.…”

Section: Discussionsupporting

confidence: 84%

Acquisition of High-Level Chromosomal Instability Is Associated with Integration of Human Papillomavirus Type 16 in Cervical Keratinocytes

et al. 2004

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Whereas two key steps in cervical carcinogenesis are integration of high-risk human papillomavirus (HR-HPV) and acquisition of an unstable host genome, the temporal association between these events is poorly understood. Chromosomal instability is induced when HR-HPV E7 oncoprotein is overexpressed from heterologous promoters in vitro. However, it is not known whether such events occur at the "physiologically" elevated levels of E7 produced by deregulation of the homologous HR-HPV promoter after integration. Indeed, an alternative possibility is that integration in vivo is favored in an already unstable host genome. We have addressed these issues using the unique human papillomavirus (HPV) 16-containing cervical keratinocyte cell line W12, which was derived from a low-grade squamous intraepithelial lesion and thus acquired HPV16 by "natural" infection. Whereas W12 at low passage contains HPV16 episomes only, long-term culture results in the emergence of cells containing integrated HPV16 only. We show that integration of HPV16 in W12 is associated with 3 deletion of the E2 transcriptional repressor, resulting in deregulation of the homologous promoter of the integrant and an increase in E7 protein levels. We further demonstrate that high-level chromosomal instability develops in W12 only after integration and that the forms of instability observed correlate with the physical state of HPV16 DNA and the level of E7 protein. Whereas intermediate E7 levels are associated with numerical chromosomal abnormalities, maximal levels are associated with both numerical and structural aberrations. HR-HPV integration is likely to be a critical event in cervical carcinogenesis, preceding the development of chromosomal abnormalities that drive malignant progression.

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Section: Discussionsupporting

confidence: 84%

Acquisition of High-Level Chromosomal Instability Is Associated with Integration of Human Papillomavirus Type 16 in Cervical Keratinocytes

et al. 2004

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“…The persistence of aneuploidy of cells is a pivotal characteristic for cervical carcinoma development (34), of which reflects a situation of uncontrolled increase of DNA and loss of crucial information and plays an essential role in neoplastic transformation (35). The increased aneuploid DNA value with the increase in grades of cervical dysplasia has long been considered to be a specific prognostic marker of malignancy (34).…”

Section: Discussionmentioning

confidence: 99%

“…The increased aneuploid DNA value with the increase in grades of cervical dysplasia has long been considered to be a specific prognostic marker of malignancy (34). In 2001, Melsheimer and colleagues (36) reported that flow cytometric analysis of DNA ploidy may be a potential means providing a strategic diagnostic tool for early detection of cervical cancer.…”

Section: Discussionmentioning

confidence: 99%

DNA Ploidy Cytometry Testing for Cervical Cancer Screening in China (DNACIC Trial): a Prospective Randomized, Controlled Trial

Tong

Shen²,

Wang³

et al. 2009

Clinical Cancer Research

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Purpose: This randomized, controlled trial was designed to determine whether the DNA cytometry testing is superior to the conventional cytologic testing for mass cervical cancer screening. Experimental Design: After approval by the institutional ethics review boards from three separate screening centers, a total of 23,993 Chinese women ages 20 to 65 years were randomly assigned into one of the two groups: a DNA cytometry testing group (11,999 women) and a cytologic testing group (11,994 women). Each woman underwent the other testing after first attending the assigned screening test. Women with positive results after assigned testing additionally underwent colposcopy and human papillomaviruses detections, and those with cervical precancerous or cancerous lesions received appropriate treatment. Sensitivity and specificity estimates were adjusted for verification bias. Analyses were by intention to treat and per protocol ways. Results: In the cytometric DNA testing group, cervical cancer was diagnosed in 40 subjects, compared with 24 subjects in the cytologic testing group [hazard ratio for the detection of advanced cancer in the DNA cytometry testing group, 0.42; 95% confidence interval (CI), 0.27-0.60]. The sensitivity of the DNA cytometry testing for cervical cancer was 91.7% (95% CI, 64.3-95.8), whereas the sensitivity of cytologic testing was 44.5% (95% CI, 25.2-61.3; P = 0.008). The specificity was 54.1% (95% CI, 31.6-69.0) for DNA cytometry testing and 70.6% (95% CI, 46.8-82.5; P = 0.003) for cytologic testing. The sensitivity of both tests used together was 100%, and the specificity was 91.8%. A total of 187 subjects reported mild to severe adverse events after treatment with positive results in 319 women. Conclusions: Our results highlight the benefit of the DNA cytometry testing strategy in mass cervical cancer screening with greater sensitivity and positive predicted value than the conventional cytologic testing in developing settings. (Clin Cancer Res 2009;15(20):6438-45) Cervical cancer remains the leading cause of cancer death among women in low-resource countries. Approximately 320,000 of cervical cancer cases are diagnosed in the developing world every year, of which takes over 80% of all the cases of cervical cancer that are diagnosed annually worldwide (1). As thus, how the cervical cancer is sieved through effective methods during mass population screening is an essential question for global researchers investigating the effectiveness October 14, 2009; DOI: 10.1158/1078-0432.CCR-09-1689 and accuracy of currently available means-particularly for predicting the emergence of the cancer after a single round of screening.Cervical cytologic testing with the Bethesda System has proved to be one of the most successful examples of cancer screening over the simple Papanicolaou (Pap) smear test and has resulted in significant decreases in incidence and mortality from cervical cancer (2). Besides, numerous studies recommended that human papillomavirus (HPV) testing is an appropriate method when...

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“…In 2001, Sudbø et al showed that the progression rate from oral dysplasia to invasive oral carcinoma based on the detection of DNA aneuploidy was only 10% after 1 year but increased significantly, to 90%, after 5 years. 77 Thus, this interval should be taken into account in the evaluation of the diagnostic and prognostic value of DNA-ICM.…”

Section: Latency Periodmentioning

confidence: 99%

Diagnostic and prognostic use of DNA image cytometry in cervical squamous intraepithelial lesions and invasive carcinoma

Böcking

Nguyen

2003

Cancer

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In the fight against cervical malignancy and its precursors, several adjuvant diag- In patients with borderline lesions (mild and moderate dysplasias) of the uterine cervix, cytomorphology alone often is not sufficient for the early and definite cytologic detection of malignancy. Cervical dysplasia describes squamous cells or tissues that potentially may lead to malignancy but do not exhibit sufficient evidence for a definite assumption. Resulting from weakness of morphologic criteria to identify malignant transformation in epithelial cells early and unequivocally, dysplasias are not a disease entity. The widely accepted assumption is that the higher the grade of dysplasia is, the higher the probability of progression to carcinoma is.1 However, as a result of insufficient morphologic criteria, neither histologic nor cytologic evaluation can predict whether a lesion will progress to cancer in an individual patient.2 Rates of regression and progression of cervical dysplasia (positive and negative predictive values) are quite different from one study to another. 1 Insufficient interobserver reproducibility in diagnostic cytology and histology represents another dilemma in the microscopic diagnosis of precancerous cervical intraepithelial lesions.Because the diagnosis of cervical squamous intraepithelial lesions (SILs) is not only poorly reproducible but also of limited biologic meaning for the individual patient, the number of resulting control procedures usually is high. These range from repeated cytologic smears and biopsies to unnecessary operations (conizations). Missed early diagnoses of cancers may result from cytomorphologic uncertainties. This also results in unnecessary costs and avoidable anxiety for the patients.In the late 1970s, zur Hausen suggested that there may be an association between human papillomavirus (HPV) and cervical carcinoma.3 Large numbers of subsequent epidemiologic, clinicopathologic, and molecular studies have linked the presence of specific types of HPV to the development of anogenital carcinoma and its precursors. A recent study estimated the worldwide HPV prevalence in cervical carcinomas at 99.7%. 4 Today, it is widely accepted that HPVs play a critical role in the pathogenesis of most cervical carcinomas and their precursor lesions. The infection of cervical epithelial cells with HPV itself is necessary but still insufficient for neoplastic progression. Other factors, especially genetic alterations, are needed to enter into the process of neoplastic transformation. 5Several adjuvant diagnostic methods currently are proposed to increase the diagnostic accuracy and reproducibility of cytology and histology. These range from clinical procedures, like colposcopy, to laboratory methods, like assays for the detection of HPV DNA and HPV typing 6 or DNA image cytometry (DNA-ICM). 1,7,8 In the current review, we focus on the technical performance and application of DNA-ICM in diagnosis and prognosis of cervical SILs and invasive cervical carcinoma. Biologic BackgroundChromosomal aneuploi...

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DNA aneuploidy and infection of human papillomavirus type 16 in preneoplastic lesions of the uterine cervix: correlation with progression to malignancy

Cited by 18 publications

References 21 publications

Acquisition of High-Level Chromosomal Instability Is Associated with Integration of Human Papillomavirus Type 16 in Cervical Keratinocytes

Acquisition of High-Level Chromosomal Instability Is Associated with Integration of Human Papillomavirus Type 16 in Cervical Keratinocytes

DNA Ploidy Cytometry Testing for Cervical Cancer Screening in China (DNACIC Trial): a Prospective Randomized, Controlled Trial

Diagnostic and prognostic use of DNA image cytometry in cervical squamous intraepithelial lesions and invasive carcinoma

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