title: Amplified genes may be overexpressed, unchanged, or downregulated in cervical cancer cell lines.
abstract: Several copy number-altered regions (CNAs) have been identified in the genome of cervical cancer, notably, amplifications of 3q and 5p. However, the contribution of copy-number alterations to cervical carcinogenesis is unresolved because genome-wide there exists a lack of correlation between copy-number alterations and gene expression. In this study, we investigated whether CNAs in the cell lines CaLo, CaSki, HeLa, and SiHa were associated with changes in gene expression. On average, 19.2% of the cell-line genomes had CNAs. However, only 2.4% comprised minimal recurrent regions (MRRs) common to all the cell lines. Whereas 3q had limited common gains (13%), 5p was entirely duplicated recurrently. Genome-wide, only 15.6% of genes located in CNAs changed gene expression; in contrast, the rate in MRRs was up to 3 times this. Chr 5p was confirmed entirely amplified by FISH; however, maximum 33.5% of the explored genes in 5p were deregulated. In 3q, this rate was 13.4%. Even in 3q26, which had 5 MRRs and 38.7% recurrently gained SNPs, the rate was only 15.1%. Interestingly, up to 19% of deregulated genes in 5p and 73% in 3q26 were downregulated, suggesting additional factors were involved in gene repression. The deregulated genes in 3q and 5p occurred in clusters, suggesting local chromatin factors may also influence gene expression. In regions amplified discontinuously, downregulated genes increased steadily as the number of amplified SNPs increased (p<0.01, Spearman's correlation). Therefore, partial gene amplification may function in silencing gene expression. Additional genes in 1q, 3q and 5p could be involved in cervical carcinogenesis, specifically in apoptosis. These include PARP1 in 1q, TNFSF10 and ECT2 in 3q and CLPTM1L, AHRR, PDCD6, and DAP in 5p. Overall, gene expression and copy-number profiles reveal factors other than gene dosage, like epigenetic or chromatin domains, may influence gene expression within the entirely amplified genome segments.
authors.affiliation: Unidad de Medicina Genómica, Facultad de Medicina, Hospital General de México, Universidad Nacional Autónoma de México, México, Distrito Federal, México.
authors.forename: Oscar
authors.initials: O
authors.lastname: Vazquez-Mena
authors.forename: Ingrid
authors.initials: I
authors.lastname: Medina-Martinez
authors.forename: Eligia
authors.initials: E
authors.lastname: Juárez-Torres
authors.forename: Valeria
authors.initials: V
authors.lastname: Barrón
authors.forename: Ana
authors.initials: A
authors.lastname: Espinosa
authors.forename: Nicolás
authors.initials: N
authors.lastname: Villegas-Sepulveda
authors.forename: Laura
authors.initials: L
authors.lastname: Gómez-Laguna
authors.forename: Karem
authors.initials: K
authors.lastname: Nieto-Martínez
authors.forename: Lorena
authors.initials: L
authors.lastname: Orozco
authors.forename: Edgar
authors.initials: E
authors.lastname: Roman-Basaure
authors.forename: Sergio
authors.initials: S
authors.lastname: Muñoz Cortez
authors.forename: Manuel
authors.initials: M
authors.lastname: Borges Ibañez
authors.forename: Carlos
authors.initials: C
authors.lastname: Venegas-Vega
authors.forename: Mariano
authors.initials: M
authors.lastname: Guardado-Estrada
authors.forename: Angélica
authors.initials: A
authors.lastname: Rangel-López
authors.forename: Susana
authors.initials: S
authors.lastname: Kofman
authors.forename: Jaime
authors.initials: J
authors.lastname: Berumen
mesh_terms: D002460:Cell Line; D002869:Chromosome Aberrations; D056915:DNA Copy Number Variations; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D058977:Molecular Sequence Annotation; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction; D002583:Uterine Cervical Neoplasms / Q000235:genetics*