title: Chromosomal biomarkers for detection of human papillomavirus associated genomic instability in epithelial cells of cervical cytology specimens.
abstract: 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.
authors.affiliation: Abbott Molecular Inc., 1300 E. Touhy Avenue, Des Plaines, IL 60018, USA. irina.sokolova@abbott.com
authors.forename: Irina
authors.initials: I
authors.lastname: Sokolova
authors.forename: Alicia
authors.initials: A
authors.lastname: Algeciras-Schimnich
authors.forename: Minghao
authors.initials: M
authors.lastname: Song
authors.forename: Svetlana
authors.initials: S
authors.lastname: Sitailo
authors.forename: Frank
authors.initials: F
authors.lastname: Policht
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Kipp
authors.forename: Jesse S
authors.initials: JS
authors.lastname: Voss
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Halling
authors.forename: Adam
authors.initials: A
authors.lastname: Ruth
authors.forename: Walter
authors.initials: W
authors.lastname: King
authors.forename: Dawn
authors.initials: D
authors.lastname: Underwood
authors.forename: Jennifer
authors.initials: J
authors.lastname: Brainard
authors.forename: Larry
authors.initials: L
authors.lastname: Morrison
mesh_terms: D052685:Alphapapillomavirus / Q000502:physiology*; D002869:Chromosome Aberrations; D002877:Chromosomes, Human / Q000235:genetics*; D002893:Chromosomes, Human, Pair 3; D002898:Chromosomes, Human, Pair 8; D004847:Epithelial Cells / Q000378:metabolism* / Q000821:virology*; D005260:Female; D018628:Gene Dosage; D005819:Genetic Markers; D042822:Genomic Instability; D006801:Humans; D014626:Vaginal Smears
chemical_list: D005819:Genetic Markers