Prospective clinical study comparing DNA flow cytometry and HPV typing as predictive tests for persistence and progression of CIN I/II

Melsheimer, Peter; Klaes, Ruediger; Doeberitz, Magnus von Knebel; Bastert, G.

doi:10.1002/cyto.1101

Cited by 19 publications

(26 citation statements)

References 28 publications

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“…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. Therefore, Singh et al (37) proposed a conception of combining the DNA ploidy cytometry testing, which provides qualitative information and presence of aberrant aneuploid cells in cytologic specimen through flow cytometry by measuring the DNA content, and an HPV screening with reflex cytology would be an optimal method to detect progressive lesions with the greatest possible sensitivity and specificity.…”

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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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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“…The structural and numerical chromosomal changes result in an increasing shift of the overall DNA content of the cells, a phenomenon commonly referred to as aneuploidy. In cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (CxCa), DNA ploidy estimation has been established as a prognostic factor that allows to estimated the relative progression risk into more advanced lesions (3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

DNA Aneuploidy and Integration of Human Papillomavirus Type 16 E6/E7 Oncogenes in Intraepithelial Neoplasia and Invasive Squamous Cell Carcinoma of the Cervix Uteri

Melsheimer¹,

Vinokurova

Wentzensen

et al. 2004

Clinical Cancer Research

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126

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Purpose: Increasingly deregulated expression of the E6-E7 oncogenes of high-risk human papillomaviruses (HRHPVs) has been identified as the major transforming factor in the pathogenesis of cervical dysplasia and derived cancers. The expression of these genes in epithelial stem cells first results in chromosomal instability and induces chromosomal aneuploidy. It is speculated that this subsequently favors integration of HR-HPV genomes into cellular chromosomes. This in turn leads to expression of viral cellular fusion transcripts and further enhanced expression of the E6-E7 oncoproteins. Chromosomal instability and aneuploidization thus seems to precede and favor integration of HR-HPV genomes.Experimental Design: To prove this sequential concept, we analyzed here the sequence of events of DNA aneuploidization and integration in a series of HPV-16-positive cervical dysplastic lesions and carcinomas. Eighty-five punch biopsies of HPV-16-positive cervical lesions (20 CIN1/2, 50 CIN3, and 15 CxCa) were analyzed for DNA ploidy by DNA flow cytometry and for integration of HPV E6/E7 oncogenes using the amplification of papillomavirus oncogene transcripts assay, a reverse transcription-PCR method to detect integrate-derived human papillomavirus oncogene transcripts.Results: DNA aneuploidy and viral genome integration were both associated with increasing dysplasia (P < 0.001, 2 test for trend). In addition, DNA aneuploidy was associated with increased viral integration (P < 0.01, Fisher's exact test). Nineteen of 20 (95%) lesions with integrated viral genomes had aneuploid cell lines; however, only 19 of 32 (59%) lesions with aneuploid cell lines had integrated viral genomes.Conclusions: These data support the hypothesis that aneuploidization precedes integration of HR-HPV genomes in the progression of cervical dysplasia. Accordingly, deregulated viral oncogene expression appears to result first in chromosomal instability and aneuploidization and is subsequently followed by integration of HR-HPV genomes in the affected cell clones.

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“…Previous studies that attempted to determine whether these chromosomal changes could be used as a prognostic tool to identify women at an elevated risk of cervical carcinoma showed mixed results; several studies concluded that DNA content is of little predictive value in determining whether a tumor will metastasize or whether a patient will survive, 49,50 whereas other studies concluded that DNA content can predict accurately both the presence of high-grade lesions and patient survival. [51][52][53][54] One recent publication described the use of a laser-scanning cytometer to identify aneuploid cervical cells in women diagnosed with ASCUS/HPV-positive Pap smears. 55 Although the ASCUS/HPV-positive sample size in that study was small (n ϭ 16 patients), the identification of a proportion of these women who exhibited elevated levels of numerical chromosomal aberrations was quite similar to the results presented in the current study.…”

Section: Discussionmentioning

confidence: 99%

“…For PCR, the MY09 and MY11 primers were used to amplify HPV DNA, and the GH20 and PC04 primers were used to amplify human ␤-globin DNA (Qiagen, La Jolla, CA). Amplification of the L1 gene can allow for the identification of at least 20 HPV types (types 6,11,16,18,26,31,33,35,39,40,42,45,51,52,53,54,55,56,57, and 59). The DNA samples were extracted and purified for PCR using a proteinase K-phenol/chloroform procedure.…”

Section: Hpv Testingmentioning

confidence: 99%

Elevated levels of tetraploid cervical cells in human papillomavirus-positive Papanicolaou smears diagnosed as atypical squamous cells of undetermined significance

Olaharski

Eastmond

2004

Cancer

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Prospective clinical study comparing DNA flow cytometry and HPV typing as predictive tests for persistence and progression of CIN I/II

Cited by 19 publications

References 28 publications

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

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

DNA Aneuploidy and Integration of Human Papillomavirus Type 16 E6/E7 Oncogenes in Intraepithelial Neoplasia and Invasive Squamous Cell Carcinoma of the Cervix Uteri

Elevated levels of tetraploid cervical cells in human papillomavirus-positive Papanicolaou smears diagnosed as atypical squamous cells of undetermined significance

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