title: Genomic imbalances in 70 snap-frozen cervical squamous intraepithelial lesions: associations with lesion grade, state of the HPV16 E2 gene and clinical outcome.
abstract: Host genomic abnormalities may determine the natural history of cervical squamous intraepithelial lesions (SILs). We undertook comparative genomic hybridisation analysis of epithelium carefully microdissected from 70 cervical SILs, the largest series to date. In contrast to previous studies, we used frozen sections for optimal DNA quality and examined whether patterns of DNA copy number imbalance (CNI) are characteristic of SIL grade, human papillomavirus (HPV) status and postoperative recurrence. We identified more CNIs in cervical SIL than previously described, with more CNIs per case in high-grade squamous intraepithelial lesion (HG-SIL) than in low-grade squamous intraepithelial lesion (LG-SIL) (P=0.04). While some CNIs were seen at similar frequencies in HG-SIL and LG-SIL, others, including gain on 1q, 3q and 16q, were found frequently in HG-SIL but not in LG-SIL. There were significantly more CNIs per case in HG-SILs showing loss of the HPV16 E2 gene (a repressor of viral oncogene transcription) (P=0.026) and in HG-SILs that subsequently recurred (P=0.04). Our data are consistent with sequential acquisition of CNIs in cervical SIL progression. Higher frequency of CNI in association with E2 gene loss supports in vitro evidence that high-risk HPV integration is associated with genomic instability. Further investigation of the clinical value of specific host genomic abnormalities in cervical SIL is warranted.
authors.affiliation: Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 2XZ, UK.
authors.forename: W
authors.initials: W
authors.lastname: Alazawi
authors.forename: M
authors.initials: M
authors.lastname: Pett
authors.forename: S
authors.initials: S
authors.lastname: Strauss
authors.forename: R
authors.initials: R
authors.lastname: Moseley
authors.forename: J
authors.initials: J
authors.lastname: Gray
authors.forename: M
authors.initials: M
authors.lastname: Stanley
authors.forename: N
authors.initials: N
authors.lastname: Coleman
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005629:Frozen Sections; D018628:Gene Dosage; D006801:Humans; D042282:Microdissection; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology / Q000821:virology; D009693:Nucleic Acid Hybridization; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D027383:Papillomaviridae / Q000302:isolation & purification; D030361:Papillomavirus Infections / Q000150:complications; D014412:Tumor Virus Infections / Q000150:complications; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology*; D002578:Uterine Cervical Dysplasia / Q000235:genetics* / Q000473:pathology / Q000821:virology*
chemical_list: D004268:DNA-Binding Proteins; C054855:E2 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral