Searching for new biomarkers for cervical cancer: Molecular accidents and the interplay of papillomavirus oncogenes and epithelial differentiation. Part I

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Abstract

High-risk human papillomaviruses have been identified as the causal agents of cervical cancer. The detection of viral infection therefore creates the potential to identify patients at risk. However, at least 10% of normal women harbour these viruses yet only very few develop clinically important lesions. Implementation of HPV-DNA testing as the primary test in cervical cancer screening is therefore unlikely to be cost-effective and its use is still actively debated. Initiation of cervical precancer is tightly linked to deregulated expression of the viral E6-E7 oncogenes. During a normal acute HPV infection, expression of these genes is restricted to terminally differentiated cells in the stratum spinosum or above which have been withdrawn from the cell cycle. In dysplastic cervical lesions, the viral E6-E7 genes are expressed in replicating basal cells due to the failure of the intracellular control machinery, which is normally active in the basal cells. Once expressed in mitotically active cells, the E6-E7 gene products disrupt control of the cell cycle at the G1/S phase restriction points due to a complex interaction with many cellular binding partners, including p53 and pRB. This initiates a state of chromosomal instability and favours neoplastic transformation. In the search for a specific biomarker to identify dysplastic cells, it was found that, among many other features, E7 induces a cellular marker protein (p16ink4a) that is strongly expressed in dysplastic cells. Monoclonal antibodies directed against p16ink4a allow specific identification of dysplastic cells in histological sections and cytological smears. Increasing chromosomal instability induced by aberrant expression of the viral oncogenes E6 and E7 in advanced cervical precancers often results later on in integration of the viral genome into cellular chromosomes. The detection of specific viral mRNAs derived from integrated HPV genomes can be used to identify pre-neoplastic lesions with a particularly high risk for progression into invasive cancers (APOT-assay). The detailed analysis of the biochemical and molecular interactions of the HR-HPV oncogene products E6 and E7 with their cellular binding partners has provided a theoretical basis for new improved molecular markers of dysplastic lesions and of further progression to invasive cancer. These findings allow the development of new, highly sensitive, specific and therefore cost-effective cervical cancer screening assays.

Original languageEnglish (US)
Pages (from-to)35-41
Number of pages7
JournalPapillomavirus Report
Volume13
Issue number2
StatePublished - Jan 1 2002

Fingerprint

Oncogenes
Uterine Cervical Neoplasms
Accidents
Biomarkers
Chromosomal Instability
Early Detection of Cancer
Cyclin-Dependent Kinase Inhibitor p16
G1 Phase Cell Cycle Checkpoints
Costs and Cost Analysis
Viral Genome
Oncogene Proteins
Virus Diseases
Cell Cycle Checkpoints
S Phase
Genes
Neoplasms
Cell Cycle
Chromosomes
Monoclonal Antibodies
Genome

ASJC Scopus subject areas

  • Virology

Cite this

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title = "Searching for new biomarkers for cervical cancer: Molecular accidents and the interplay of papillomavirus oncogenes and epithelial differentiation. Part I",
abstract = "High-risk human papillomaviruses have been identified as the causal agents of cervical cancer. The detection of viral infection therefore creates the potential to identify patients at risk. However, at least 10{\%} of normal women harbour these viruses yet only very few develop clinically important lesions. Implementation of HPV-DNA testing as the primary test in cervical cancer screening is therefore unlikely to be cost-effective and its use is still actively debated. Initiation of cervical precancer is tightly linked to deregulated expression of the viral E6-E7 oncogenes. During a normal acute HPV infection, expression of these genes is restricted to terminally differentiated cells in the stratum spinosum or above which have been withdrawn from the cell cycle. In dysplastic cervical lesions, the viral E6-E7 genes are expressed in replicating basal cells due to the failure of the intracellular control machinery, which is normally active in the basal cells. Once expressed in mitotically active cells, the E6-E7 gene products disrupt control of the cell cycle at the G1/S phase restriction points due to a complex interaction with many cellular binding partners, including p53 and pRB. This initiates a state of chromosomal instability and favours neoplastic transformation. In the search for a specific biomarker to identify dysplastic cells, it was found that, among many other features, E7 induces a cellular marker protein (p16ink4a) that is strongly expressed in dysplastic cells. Monoclonal antibodies directed against p16ink4a allow specific identification of dysplastic cells in histological sections and cytological smears. Increasing chromosomal instability induced by aberrant expression of the viral oncogenes E6 and E7 in advanced cervical precancers often results later on in integration of the viral genome into cellular chromosomes. The detection of specific viral mRNAs derived from integrated HPV genomes can be used to identify pre-neoplastic lesions with a particularly high risk for progression into invasive cancers (APOT-assay). The detailed analysis of the biochemical and molecular interactions of the HR-HPV oncogene products E6 and E7 with their cellular binding partners has provided a theoretical basis for new improved molecular markers of dysplastic lesions and of further progression to invasive cancer. These findings allow the development of new, highly sensitive, specific and therefore cost-effective cervical cancer screening assays.",
author = "{von Knebel Doeberitz}, Magnus",
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N2 - High-risk human papillomaviruses have been identified as the causal agents of cervical cancer. The detection of viral infection therefore creates the potential to identify patients at risk. However, at least 10% of normal women harbour these viruses yet only very few develop clinically important lesions. Implementation of HPV-DNA testing as the primary test in cervical cancer screening is therefore unlikely to be cost-effective and its use is still actively debated. Initiation of cervical precancer is tightly linked to deregulated expression of the viral E6-E7 oncogenes. During a normal acute HPV infection, expression of these genes is restricted to terminally differentiated cells in the stratum spinosum or above which have been withdrawn from the cell cycle. In dysplastic cervical lesions, the viral E6-E7 genes are expressed in replicating basal cells due to the failure of the intracellular control machinery, which is normally active in the basal cells. Once expressed in mitotically active cells, the E6-E7 gene products disrupt control of the cell cycle at the G1/S phase restriction points due to a complex interaction with many cellular binding partners, including p53 and pRB. This initiates a state of chromosomal instability and favours neoplastic transformation. In the search for a specific biomarker to identify dysplastic cells, it was found that, among many other features, E7 induces a cellular marker protein (p16ink4a) that is strongly expressed in dysplastic cells. Monoclonal antibodies directed against p16ink4a allow specific identification of dysplastic cells in histological sections and cytological smears. Increasing chromosomal instability induced by aberrant expression of the viral oncogenes E6 and E7 in advanced cervical precancers often results later on in integration of the viral genome into cellular chromosomes. The detection of specific viral mRNAs derived from integrated HPV genomes can be used to identify pre-neoplastic lesions with a particularly high risk for progression into invasive cancers (APOT-assay). The detailed analysis of the biochemical and molecular interactions of the HR-HPV oncogene products E6 and E7 with their cellular binding partners has provided a theoretical basis for new improved molecular markers of dysplastic lesions and of further progression to invasive cancer. These findings allow the development of new, highly sensitive, specific and therefore cost-effective cervical cancer screening assays.

AB - High-risk human papillomaviruses have been identified as the causal agents of cervical cancer. The detection of viral infection therefore creates the potential to identify patients at risk. However, at least 10% of normal women harbour these viruses yet only very few develop clinically important lesions. Implementation of HPV-DNA testing as the primary test in cervical cancer screening is therefore unlikely to be cost-effective and its use is still actively debated. Initiation of cervical precancer is tightly linked to deregulated expression of the viral E6-E7 oncogenes. During a normal acute HPV infection, expression of these genes is restricted to terminally differentiated cells in the stratum spinosum or above which have been withdrawn from the cell cycle. In dysplastic cervical lesions, the viral E6-E7 genes are expressed in replicating basal cells due to the failure of the intracellular control machinery, which is normally active in the basal cells. Once expressed in mitotically active cells, the E6-E7 gene products disrupt control of the cell cycle at the G1/S phase restriction points due to a complex interaction with many cellular binding partners, including p53 and pRB. This initiates a state of chromosomal instability and favours neoplastic transformation. In the search for a specific biomarker to identify dysplastic cells, it was found that, among many other features, E7 induces a cellular marker protein (p16ink4a) that is strongly expressed in dysplastic cells. Monoclonal antibodies directed against p16ink4a allow specific identification of dysplastic cells in histological sections and cytological smears. Increasing chromosomal instability induced by aberrant expression of the viral oncogenes E6 and E7 in advanced cervical precancers often results later on in integration of the viral genome into cellular chromosomes. The detection of specific viral mRNAs derived from integrated HPV genomes can be used to identify pre-neoplastic lesions with a particularly high risk for progression into invasive cancers (APOT-assay). The detailed analysis of the biochemical and molecular interactions of the HR-HPV oncogene products E6 and E7 with their cellular binding partners has provided a theoretical basis for new improved molecular markers of dysplastic lesions and of further progression to invasive cancer. These findings allow the development of new, highly sensitive, specific and therefore cost-effective cervical cancer screening assays.

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