title: Chromosomal signatures of a subset of high-grade premalignant cervical lesions closely resemble invasive carcinomas.
abstract: Cervical cancer develops from precancerous high-grade cervical intraepithelial neoplasia (CIN) harboring a transforming infection with high-risk human papillomavirus, which is characterized by p16(INK4a) overexpression. Once such a lesion has developed, progression toward an invasive squamous cell carcinoma (SCC) may take one or more decades, underlining the heterogeneity of these lesions in terms of duration of existence and progression risk. We performed array-based comparative genomic hybridization (array CGH) on 46 p16(INK4a) immunopositive CIN2/3 lesions to determine whether this heterogeneity is reflected in their chromosomal profiles. Chromosomal profiles of CIN2/3 lesions were related to those of invasive cervical SCC and promoter methylation of CADM1, a tumor suppressor gene known to be functionally involved in the tumorigenic phenotype of cervical cancer cells. Frequent alterations found in CIN2/3 lesions included gains located at chromosome 1, 3, 7, and 20 and losses located at 4, 11, 16, 17, and 19. Unsupervised hierarchical clustering identified two subsets of CIN2/3 lesions, chromosomal profiles of one of which closely resembled invasive SCCs. Gains of 1, 3q, and 20 were characteristic for CIN2/3 lesions with chromosomal signatures resembling carcinomas. In addition, dense promoter methylation of the CADM1 gene was significantly more frequent in these CIN2/3 lesions (P = 0.004). No chromosomal alterations were detected in six CIN1 lesions, five of which were completely p16(INK4a) immunonegative. These findings suggest that biomarkers associated with gains at chromosomes 1, 3q, and 20 are potential hallmarks of advanced p16(INK4a)-positive CIN2/3 lesions with a high short-term risk of progression.
authors.affiliation: Departments of Pathology and Mathematics, VU University Medical Center, Amsterdam, the Netherlands, and Department of Obstetrics and Gynaecology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Saskia M
authors.initials: SM
authors.lastname: Wilting
authors.forename: Renske D M
authors.initials: RD
authors.lastname: Steenbergen
authors.forename: Marianne
authors.initials: M
authors.lastname: Tijssen
authors.forename: Wessel N
authors.initials: WN
authors.lastname: van Wieringen
authors.forename: Theo J M
authors.initials: TJ
authors.lastname: Helmerhorst
authors.forename: Folkert J
authors.initials: FJ
authors.lastname: van Kemenade
authors.forename: Maaike C G
authors.initials: MC
authors.lastname: Bleeker
authors.forename: Mark A
authors.initials: MA
authors.lastname: van de Wiel
authors.forename: Beatriz
authors.initials: B
authors.lastname: Carvalho
authors.forename: Gerrit A
authors.initials: GA
authors.lastname: Meijer
authors.forename: Bauke
authors.initials: B
authors.lastname: Ylstra
authors.forename: Chris J L M
authors.initials: CJ
authors.lastname: Meijer
authors.forename: Peter J F
authors.initials: PJ
authors.lastname: Snijders
mesh_terms: D000328:Adult; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis; D019175:DNA Methylation; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D009361:Neoplasm Invasiveness; D027383:Papillomaviridae; D030361:Papillomavirus Infections / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology; D002578:Uterine Cervical Dysplasia / Q000235:genetics* / Q000473:pathology / Q000821:virology
chemical_list: C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D019941:Cyclin-Dependent Kinase Inhibitor p16; D007136:Immunoglobulins; D008565:Membrane Proteins; D025521:Tumor Suppressor Proteins