Dataset Information

Detailed Analysis of Focal Chromosome Arm 1q and 6p Amplifications in Urothelial Carcinoma Reveals Complex Genomic Events on 1q, and SOX4 as a Possible Auxiliary Target on 6p.

ABSTRACT:

Background

Urothelial carcinoma shows frequent amplifications at 6p22 and 1q21-24. The main target gene at 6p22 is believed to be E2F3, frequently co-amplified with CDKAL1 and SOX4. There are however reports on 6p22 amplifications that do not include E2F3. Previous analyses have identified frequent aberrations occurring at 1q21-24. However, due to complex rearrangements it has been difficult to identify specific 1q21-24 target regions and genes.

Methods

We selected 29 cases with 6p and 37 cases with 1q focal genomic amplifications from 261 cases of urothelial carcinoma analyzed by array-CGH for high resolution zoom-in oligonucleotide array analyses. Genomic analyses were combined with gene expression data and genomic sequence analyses to characterize and fine map 6p22 and 1q21-24 amplifications.

Results

We show that the most frequently amplified gene at 6p22 is SOX4 and that SOX4 can be amplified and overexpressed without the E2F3 or CDKAL1 genes being included in the amplicon. Hence, our data point to SOX4 as an auxiliary amplification target at 6p22. We further show that at least three amplified regions are observed at 1q21-24. Copy number data, combined with gene expression data, highlighted BCL9 and CHD1L as possible targets in the most proximal region and MCL1, SETDB1, and HIF1B as putative targets in the middle region, whereas no obvious targets could be determined in the most distal amplicon. We highlight enrichment of G4 quadruplex sequence motifs and a high number of intraregional sequence duplications, both known to contribute to genomic instability, as prominent features of the 1q21-24 region.

Conclusions

Our detailed analyses of the 6p22 amplicon suggest SOX4 as an auxiliary target gene for amplification. We further demonstrate three separate target regions for amplification at 1q21-24 and identified BCL9, CHD1L, and MCL1, SETDB1, and HIF1B as putative target genes within these regions.

SUBMITTER: Eriksson P

PROVIDER: S-EPMC3688975 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

Detailed Analysis of Focal Chromosome Arm 1q and 6p Amplifications in Urothelial Carcinoma Reveals Complex Genomic Events on 1q, and SOX4 as a Possible Auxiliary Target on 6p.

Eriksson Pontus P Aine Mattias M Sjödahl Gottfrid G Staaf Johan J Lindgren David D Höglund Mattias M

PloS one 20130618 6

<h4>Background</h4>Urothelial carcinoma shows frequent amplifications at 6p22 and 1q21-24. The main target gene at 6p22 is believed to be E2F3, frequently co-amplified with CDKAL1 and SOX4. There are however reports on 6p22 amplifications that do not include E2F3. Previous analyses have identified frequent aberrations occurring at 1q21-24. However, due to complex rearrangements it has been difficult to identify specific 1q21-24 target regions and genes.<h4>Methods</h4>We selected 29 cases with 6 ...[more]

PMID: 23825644

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Project description:Background: Previous array CGH analyses have revealed several recurring genomic alterations in urothelial carcinoma. The most common genomic amplifications occur at 6p22 and 1q21-24. The main target gene at 6p22 is believed to be E2F3. This gene is frequently co-amplified with CDKAL1 and SOX4 and there are reports on 6p22 amplifications that do not include the E2F3 locus. Previous array CGH analyses have indicated multiple possible target regions at 1q21-24. However, due to complex rearrangements it has been difficult to identify specific 1q21-24 target regions and target genes. Results: We show that the most commonly amplified gene at 6p22 is SOX4 and that SOX4 can be amplified and over expressed without E2F3 or CDKAL1 being included in the amplicon. Hence, our data point to SOX4 as an auxiliary amplification target at 6p22. We further show that at least three amplified regions are observed at 1q21-24. Copy number data, combined with gene expression data, highlighted BCL9 and CHD1L as possible targets in the most proximal region and MCL1, SETDB1, and HIF1B as targets in the middle region, whereas no obvious gene targets could be determined in the most distal amplicon. We also highlight the enrichment of G4 quadruplex sequence motifs and the high number of intraregional sequence duplications, both known to contribute to genomic instability, as prominent features of the 1q21-24 region. Conclusions: Our detailed analyses of the 6p22 amplicon in urothelial carcinomas suggest SOX4 as an auxiliary target gene for amplification. We further demonstrate three separate target regions for amplification at 1q21-24 and identified BCL9, CHD1L, MCL1, SETDB1, and HIF1B as likely target genes within these regions. The study was conducted on genomic DNA from 68 primary fresh-frozen urothelial carcinoma tumors analysed using a Agilent SurePrint G3 4x180k Custom CGH Microarray Platform (028432). Samples were selected based on the presence of copy number alterations observed on lower resolution genomic data (32K BAC array). The majority of the BAC data is publicly available in GEO submissions GSE32535 and GSE19915. CN profiles for a minority of samples were derived from Illumina Methylation27k arrays according to Lauss et al 2012 [PMID: 22705924] and can be recreated from the data deposited in GSE33510 (derived CN data). Sample names are the same between all studies. This dataset also partly overlaps with Series GSE32894 (gene expression data). Names of the overlapping sample names are the same and indicated in the description field. Data from GSE32894 was used to calculate correlations between CN and gene expression.

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Dataset Information

Detailed Analysis of Focal Chromosome Arm 1q and 6p Amplifications in Urothelial Carcinoma Reveals Complex Genomic Events on 1q, and SOX4 as a Possible Auxiliary Target on 6p.

Background

Methods

Results

Conclusions

Publications

Detailed Analysis of Focal Chromosome Arm 1q and 6p Amplifications in Urothelial Carcinoma Reveals Complex Genomic Events on 1q, and SOX4 as a Possible Auxiliary Target on 6p.

Similar Datasets

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