DNA cytometry confirms the utility of the Bethesda system for the classification of Papanicolaou smears

Bollmann, R.; Bollmann, Magdolna; Henson, Donald E.; Bodó, M

doi:10.1002/cncr.9033

Cited by 27 publications

(9 citation statements)

References 62 publications

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“…The perturbation of the mitotic apparatus in replicating cells that express HPV oncogenes leads to the formation of multiple centrosomes that cause multipolar mitosis with severe numerical and structural aberrations of the chromosomes, a hallmark of aneuploidy. Aneuploidy is a significant progression marker in cervical precancer, suggesting that aneuploid cell clones are more likely to survive and progress to more advanced dysplasia, as compared with euploid cell clones (4). Similarly, integration of high-risk HPV genomes and the expression of iPOTs emerged as strong progression factor (16,28).…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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

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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Section: Discussionmentioning

confidence: 99%

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

126

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“…14,52,53,56 Intervals between the detection of DNA aneuploidy and histologic follow-up in these studies were up to 3 years.…”

Section: Clinical Application In Cervical Premalignant Lesions and Inmentioning

confidence: 93%

“…In a series of 170 seemingly falsepositive routine cervical smears, DNA aneuploidy was found in 47 smears without histologic explanation. 56 Using DNA aneuploidy as a solid marker of malignancy in uterine epithelia, the authors classified those DNA-ICM also may be used as a method for quality control in histologic diagnosis. In patients with positive cytologic tumor cell diagnoses and negative histologic follow-up, the detection of DNA aneuploidy should motivate the pathologist to work-up more thoroughly a given conization or biopsy specimen.…”

Section: Quality Assurance Of Cytologic and Histologic Diagnosesmentioning

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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“…97,98 Now there are only low and high grade cervical lesions. This simplified classification scheme has also been recommended for neoplastic lesions of esophagus, stomach, colon, and rectum.…”

Section: Transformation (Cancer)mentioning

confidence: 99%

DATE analysis: A general theory of biological change applied to microarray data

Rasnick¹

2009

Biotechnology Progress

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In contrast to conventional data mining, which searches for specific subsets of genes (extensive variables) to correlate with specific phenotypes, DATE analysis correlates intensive state variables calculated from the same datasets. At the heart of DATE analysis are two biological equations of state not dependent on genetic pathways. This result distinguishes DATE analysis from other bioinformatics approaches. The dimensionless state variable F quantifies the relative overall cellular activity of test cells compared to well-chosen reference cells. The variable pi(i) is the fold-change in the expression of the ith gene of test cells relative to reference. It is the fraction phi of the genome undergoing differential expression-not the magnitude pi-that controls biological change. The state variable phi is equivalent to the control strength of metabolic control analysis. For tractability, DATE analysis assumes a linear system of enzyme-connected networks and exploits the small average contribution of each cellular component. This approach was validated by reproducible values of the state variables F, RNA index, and phi calculated from random subsets of transcript microarray data. Using published microarray data, F, RNA index, and phi were correlated with: (1) the blood-feeding cycle of the malaria parasite, (2) embryonic development of the fruit fly, (3) temperature adaptation of Killifish, (4) exponential growth of cultured S. pneumoniae, and (5) human cancers. DATE analysis was applied to aCGH data from the great apes. A good example of the power of DATE analysis is its application to genomically unstable cancers, which have been refractory to data mining strategies.

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DNA cytometry confirms the utility of the Bethesda system for the classification of Papanicolaou smears

Cited by 27 publications

References 62 publications

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

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

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

DATE analysis: A general theory of biological change applied to microarray data

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