High-Resolution Analysis of Gene Copy Number Alterations in Human Prostate Cancer Using CGH on cDNA Microarrays: Impact of Copy Number on Gene Expression

Wolf, Maija; Mousses, Spyro; Hautaniemi, Sampsa; Karhu, Ritva; Huusko, Pia; Allinen, Minna; Elkahloun, Abdel G.; Monni, Outi; Chen, Yidong; Kallioniemi, Anne; Kallioniemi, Olli

doi:10.1593/neo.3439

Cited by 63 publications

(62 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As only very little is known about the function of this gene, it is not possible to speculate on the basis of this phenomenon. Overall, our findings are in good agreement with previous studies that have implicated gene copy number alterations as significant determinants of gene expression patterns (Hyman et al, 2002;Pollack et al, 2002;Wolf et al, 2004;Fridlyand et al, 2006). However, it has to be noted that the tumour group with moderate amplification showed expression levels similar to those seen in the non-amplified tumours, indicating that low level copy number increases at this region did not have a significant effect on gene expression levels.…”

Section: Discussionsupporting

confidence: 93%

High-level amplification at 17q23 leads to coordinated overexpression of multiple adjacent genes in breast cancer

et al. 2007

View full text Add to dashboard Cite

Increased copy numbers of 17q23 chromosomal region have been shown to occur in different tumour types and to be associated with tumour progression and with poor prognosis. Several genes have earlier been proposed as potential oncogenes at this region largely on the grounds of cell lines studies. In this study, we performed a systematic gene expression survey on 26 primary breast tumours with known 17q23 amplification status by quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR). The 17q23 amplicon is restricted to an B5 MB region in breast cancer and contains 29 known genes. Our survey revealed a statistically significant (Po0.01) difference between the high level and no amplification groups in a set of eleven genes whereas no difference between the moderate and the non-amplified tumour groups were observed. Interestingly, these 11 genes were located adjacent to one another within a 1.56 Mb core region in which all except one of the genes were overexpressed. These data suggest that only high-level amplification at the 17q23 amplicon core leads to elevated gene expression in breast cancer. Moreover, our results highlight the fact that 17q23 amplicon carries multiple candidate genes and that this may be a more common event in gene amplification than previously thought.

show abstract

Section: Discussionsupporting

confidence: 93%

High-level amplification at 17q23 leads to coordinated overexpression of multiple adjacent genes in breast cancer

et al. 2007

View full text Add to dashboard Cite

show abstract

“…These cell lines have been previously proWled using Spectral Karyotyping (SKY), G-banding, megabase-interval resolution array CGH as well as cDNA array CGH (Clark et al 2003;Wolf et al 2004;Zhao et al 2005). In this study, we not only detected the previously identiWed structural chromosomal alterations and mapped the boundaries of the deletions and duplications, but discovered novel regions of genomic rearrangement that have eluded detection in previous studies (Supplemental Table 1).…”

Section: Prostate Cancer Cell Genomesmentioning

confidence: 87%

“…We examined the genomes of three cell lines commonly used in the study of prostate cancer in order to evaluate the frequency of such an association. As the LNCaP, PC3, and DU145 prostate cell line karyotypes have been well characterized cytogenetically, they were chosen to demonstrate this methodology (Beheshti et al 2000(Beheshti et al , 2001(Beheshti et al , 2002Clark et al 2003;Hu et al 2004;Lim et al 2004;StreVord et al 2001;Wolf et al 2004;Zhao et al 2005). We Wnd that there is a high correlation of CNA associated with boundaries of "balanced" translocation events and demonstrate that a combined cytogenetic and tiling path array CGH approach is an eVective method for precise localization of translocation breakpoints on a genome-wide basis.…”

Section: Introductionmentioning

confidence: 98%

Cytogenetically balanced translocations are associated with focal copy number alterations

et al. 2006

View full text Add to dashboard Cite

Current cytogenetic methods (e.g., G-banding and multicolor chromosomal painting) allow detection of translocation events but lack the resolution to (a) locate the breakpoints precisely at the chromosome band level or (b) discriminate balanced translocations from translocations with copy number alterations not previously reported, or imperfectly balanced translocations. In this study, we demonstrate that cytogenetically balanced translocations are in fact frequently associated with segmental gain or loss of DNA. The recent development of a whole genome tiling path BAC array has enabled tiling resolution analysis of genomic segmental copy number status. Combining tiling resolution BAC array comparative genomic hybridization (array CGH) with G-Banding analysis and multicolor chromosomal painting approaches such as spectral karyotyping (SKY) facilitates high-resolution mapping of genomic alterations associated with imperfectly balanced translocations. Using a refined version of our CGH array we have deduced the copy number status throughout the genomes of three cytogenetically well-characterized prostate cancer cell lines (PC3, DU145, LNCaP) to determine whether translocations are associated with focal gains and losses of DNA. At 78 kb tiling resolution we identified the boundaries of 170, 80, and 34 known and novel copy number alterations (CNA) in these cell line genomes, respectively. Thirty-three of the 36 known translocations (92%, P < 0.001) in DU145 were associated with segmental CNA. Likewise, 80% (P < 0.001) of the known translocations showed association in LNCaP. Although many translocation breakpoints exhibit segmental alteration in PC3, the pattern of chromosomal rearrangements is too complex for use in comprehensive association with CNA boundaries. Our results reveal that imperfectly balanced translocations in tumor genomes are a phenomenon that occurs at frequencies much higher than previously demonstrated.

show abstract

“…With CGH, consistent gains and losses can be identified in prostate tumors and cancer lines, at a 10Y20 Mbp resolution (James 1999, Gray & Collins 2000. Currently, array-based comparative genomic hybridization (aCGH), using cDNA (Pollack et al 1999, Fritz et al 2002, Clark et al 2003, Wolf et al 2004, oligonucleotides (Bignell et al 2004) or ordered bacterial artificial chromosome (BAC) arrays spanning the entire human genome are being used to study genomic alterations (Snijders et al 2001, Clark et al 2003, Lapuk et al 2004. Unlike cDNA or oligonucleotide arrays, the genomewide BAC array CGH (BAC aCGH) approaches provide gain/loss information on both gene-rich regions and regions that are not well studied with regard to transcriptionally active genes (gene deserts) (Mantripragada et al 2004).…”

Section: Introductionmentioning

confidence: 99%

The impact of genomic alterations on the transcriptome: a prostate cancer cell line case study

Chaudhary

Schmidt

2006

Chromosome Res

View full text Add to dashboard Cite

Genetic instability may lead to the loss/gain of transcriptional control. Here we investigated the effect of genomic instability, that is loss/gain of chromosomal regions on the global transcriptome of prostate cancer cell line DU145. The genomic loss/gain map obtained through BAC array-based CGH was superimposed on the dynamic transcriptome of DU145 cells treated with serum for 0 h (serum starved), 2 h and 12 h. The genomic analysis suggested that in DU145 cells: (1) chromosomal gains are prominent than losses and (2) copy number changes are associated with chromosome-specific and dynamic gene expression regulatory mechanisms. A significant proportion of the genes in the stable regions of the chromosome were up-regulated whereas a higher proportion of genes were down-regulated at 2 and 12 h in the deleted regions of the chromosomes following serum treatment. No change in expression was observed for the genes in the gained regions over a period of time. This analysis led us to propose that loss of heterozygosity leads to an overall transcriptional down-regulation that may further lead to a decrease in the expression of putative tumor suppressors. The genomic profile of DU145 is similar to pathological specimens of prostate cancer, hence the genomic/transcriptomic signature of DU145 can be used to understand the pathology of prostate cancer. It is expected that this analysis will allow a better understanding of transcriptional regulatory mechanisms in the context of genomic loss and gain and may lead to the discovery of novel oncogenes and tumor suppressors and the underlying regulatory pathways.

show abstract

High-Resolution Analysis of Gene Copy Number Alterations in Human Prostate Cancer Using CGH on cDNA Microarrays: Impact of Copy Number on Gene Expression

Cited by 63 publications

References 19 publications

High-level amplification at 17q23 leads to coordinated overexpression of multiple adjacent genes in breast cancer

High-level amplification at 17q23 leads to coordinated overexpression of multiple adjacent genes in breast cancer

Cytogenetically balanced translocations are associated with focal copy number alterations

The impact of genomic alterations on the transcriptome: a prostate cancer cell line case study

Contact Info

Product

Resources

About