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Journal of Molecular Diagnostics 2007, Vol. 9, No. 5
Copyright © 2007 American Society for Investigative Pathology & Association for Molecular Pathology
DOI: 10.2353/jmoldx.2007.070007

Chromosomal Biomarkers for Detection of Human Papillomavirus Associated Genomic Instability in Epithelial Cells of Cervical Cytology Specimens

Irina Sokolova*, Alicia Algeciras-Schimnich*, Minghao Song*, Svetlana Sitailo*, Frank Policht*, Benjamin R. Kipp{dagger}, Jesse S. Voss{dagger}, Kevin C. Halling{dagger}, Adam Ruth*, Walter King*, Dawn Underwood{ddagger}, Jennifer Brainard{ddagger} and Larry Morrison*

From Abbott Molecular, * Des Plaines, Illinois; the Department of Laboratory Medicine and Pathology, {dagger} Mayo Clinic, Rochester, Minnesota; and the Department of Anatomic Pathology, {ddagger} The Cleveland Clinic Foundation, Cleveland, Ohio

The goal of this study was to compare how accumulation of chromosomal aberrations in human papillomavirus (HPV)-infected cells correlates with the severity of cervical dysplastic lesions. We assessed the frequency of genomic alterations for 35 different loci in a pilot biopsy study and selected two loci (3q26 and 8q24) with the highest frequency of copy number gains found in high-grade dysplasia and cancer. These probes were labeled with gold and red fluorophores and combined with HPV biotin-labeled probes for subsequent detection using a tyramide signal amplification system with a green fluorophore. Cells that were both HPV positive and chromosomally abnormal were designated as "double-positive cells." Cervical cytology specimens from 235 patients were used for this blinded study. The average number of double-positive cells increased from two cells in patients with a cytological interpretation of atypical squamous cells of undetermined significance to 22 cells in low-grade squamous intraepithelial lesion and 99 cells in high-grade squamous intraepithelial lesion, reflecting an accumulation of chromosomal abnormality with disease progression. Using a cutoff of four or more double-positive cells as the criterion for the presence of a cervical intraepithelial neoplasia 2 or 3 lesion, we demonstrated that low-grade squamous intraepithelial lesion and high-grade squamous intraepithelial lesion cytology specimens with underlying cervical intraepithelial neoplasia 2/3 histology showed positive test results in more than 80% of cases. Correlation of 3q26 and 8q24 aneusomy with concurrent HPV infection may thus serve as a biomarker of genetic instability in HPV-infected cells.




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S. Andersson, P. Sowjanya, D. Wangsa, A. Hjerpe, B. Johansson, G. Auer, P. E. Gravitt, C. Larsson, K.-L. Wallin, T. Ried, et al.
Detection of Genomic Amplification of the Human Telomerase Gene TERC, a Potential Marker for Triage of Women with HPV-Positive, Abnormal Pap Smears
Am. J. Pathol., November 1, 2009; 175(5): 1831 - 1847.
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Copyright © 2007 by the American Society for Investigative Pathology and the Association for Molecular Pathology.