Project description:Several copy number altered regions (CNA) have been identified in the genome of cervical cancer, especially amplifications of 3q and 5p. However, the contribution of those alterations to cervical carcinogenesis is still a matter of debate, since genome-wide, there is a lack of correlation between CNAs and gene expression. In this study, we investigated whether the CNAs in cell lines (CaLo, CasKi, HeLa, SiHa), at a gene-by-gene level, are related to changes in gene expression. On average 19.2% of the whole genome of cell lines had CNA. However, only 2.4% consisted of minimal recurrent regions (MRR), common to all cell lines. Whereas 3q had just some sparse common gains (13%), 5p was entirely duplicated recurrently. Genome-wide, only 11% of genes located in CNAs changed gene expression. In contrast, the rate increased over 3 fold times in MRRs. Chr 5p was confirmed entirely amplified by FISH. In spite of this, at most 32.9% of the explored genes in 5p (n=202) were de-regulated. In 3q, the rate was just 11.8%. Even in 3q26, which had five MRRs and 38.7% of SNPs was gained recurrently, the rate rose slightly to 13.6% (10 out of 73). Interestingly, up to 16% of de-regulated genes in 5p and 80% in 3q26 were down-regulated, suggesting additional factors are involved in gene repression. The de-regulated genes in 3q and 5p were found in clusters, suggesting local chromatin factors may also influence gene expression. In regions amplified discontinuously, the rate of down-regulated genes rose steadily as the number of amplified SNPs increased (p<0.01, Spearman's correlation). This suggests partial gene amplification as a mechanism of silencing gene expression. Additional genes were identified up- or down-regulated in 5p and 3q, which could be involved in cervical carcinogenesis, especially implicated in apoptosis. Those include CLPTM1L, AHRR, PDCD6 and DAP in 5p and TNFSF10 and ECT2 in 3q. Overall, the gene expression and copy number profiles suggest other factors, like epigenetic or chromatin domains, may influence gene expression within the entirely amplified genome segments. Further studies are needed to elucidate how these mechanisms regulate gene expression.

Project description:Several copy number altered regions (CNA) have been identified in the genome of cervical cancer, especially amplifications of 3q and 5p. However, the contribution of those alterations to cervical carcinogenesis is still a matter of debate, since genome-wide, there is a lack of correlation between CNAs and gene expression. In this study, we investigated whether the CNAs in cell lines (CaLo, CasKi, HeLa, SiHa), at a gene-by-gene level, are related to changes in gene expression. On average 19.2% of the whole genome of cell lines had CNA. However, only 2.4% consisted of minimal recurrent regions (MRR), common to all cell lines. Whereas 3q had just some sparse common gains (13%), 5p was entirely duplicated recurrently. Genome-wide, only 11% of genes located in CNAs changed gene expression. In contrast, the rate increased over 3 fold times in MRRs. Chr 5p was confirmed entirely amplified by FISH. In spite of this, at most 32.9% of the explored genes in 5p (n=202) were de-regulated. In 3q, the rate was just 11.8%. Even in 3q26, which had five MRRs and 38.7% of SNPs was gained recurrently, the rate rose slightly to 13.6% (10 out of 73). Interestingly, up to 16% of de-regulated genes in 5p and 80% in 3q26 were down-regulated, suggesting additional factors are involved in gene repression. The de-regulated genes in 3q and 5p were found in clusters, suggesting local chromatin factors may also influence gene expression. In regions amplified discontinuously, the rate of down-regulated genes rose steadily as the number of amplified SNPs increased (p<0.01, Spearman's correlation). This suggests partial gene amplification as a mechanism of silencing gene expression. Additional genes were identified up- or down-regulated in 5p and 3q, which could be involved in cervical carcinogenesis, especially implicated in apoptosis. Those include CLPTM1L, AHRR, PDCD6 and DAP in 5p and TNFSF10 and ECT2 in 3q. Overall, the gene expression and copy number profiles suggest other factors, like epigenetic or chromatin domains, may influence gene expression within the entirely amplified genome segments. Further studies are needed to elucidate how these mechanisms regulate gene expression. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from cell lines or peripheral blood samples. Copy number analysis of Affymetrix 100K SNP arrays was performed for 4 cervical cancer cell lines. DNA from 38 healty women were used as references for copy number inference.

Project description:Several copy number altered regions (CNA) have been identified in the genome of cervical cancer, especially amplifications of 3q and 5p. However, the contribution of those alterations to cervical carcinogenesis is still a matter of debate, since genome-wide, there is a lack of correlation between CNAs and gene expression. In this study, we investigated whether the CNAs in cell lines (CaLo, CasKi, HeLa, SiHa), at a gene-by-gene level, are related to changes in gene expression. On average 19.2% of the whole genome of cell lines had CNA. However, only 2.4% consisted of minimal recurrent regions (MRR), common to all cell lines. Whereas 3q had just some sparse common gains (13%), 5p was entirely duplicated recurrently. Genome-wide, only 11% of genes located in CNAs changed gene expression. In contrast, the rate increased over 3 fold times in MRRs. Chr 5p was confirmed entirely amplified by FISH. In spite of this, at most 32.9% of the explored genes in 5p (n=202) were de-regulated. In 3q, the rate was just 11.8%. Even in 3q26, which had five MRRs and 38.7% of SNPs was gained recurrently, the rate rose slightly to 13.6% (10 out of 73). Interestingly, up to 16% of de-regulated genes in 5p and 80% in 3q26 were down-regulated, suggesting additional factors are involved in gene repression. The de-regulated genes in 3q and 5p were found in clusters, suggesting local chromatin factors may also influence gene expression. In regions amplified discontinuously, the rate of down-regulated genes rose steadily as the number of amplified SNPs increased (p<0.01, Spearman's correlation). This suggests partial gene amplification as a mechanism of silencing gene expression. Additional genes were identified up- or down-regulated in 5p and 3q, which could be involved in cervical carcinogenesis, especially implicated in apoptosis. Those include CLPTM1L, AHRR, PDCD6 and DAP in 5p and TNFSF10 and ECT2 in 3q. Overall, the gene expression and copy number profiles suggest other factors, like epigenetic or chromatin domains, may influence gene expression within the entirely amplified genome segments. Further studies are needed to elucidate how these mechanisms regulate gene expression. We analyzed four cervical cancer cell lines and normal exocervix tissue from 10 healthy female subjects using the Affymetrix Human Exon 1.0 ST platform. Array data was processed by Affymetrix Exon Array Computational Tool. Biological replicates were performed for the cell lines. biological replicate: Calo-a, Calo-b biological replicate: Caski-a, Caski-b biological replicate: Hela-a, Hela-b biological replicate: Siha-a, Siha-b

Project description: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.

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Amplified genes are not necessarily over expressed, they can be unchanged or down regulated in cervical cancer cell lines

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