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-P.

doi:10.1593/neo.03439

Cited by 111 publications

(59 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Among these 23 tumor samples with combined TRAF4 gene amplification and overexpression, 17 (74%) showed a strong TRAF4 immunostaining (2 þ ), which suggests that increased TRAF4 gene copy number is associated to higher level of TRAF4 protein expression. Aside from high levels of amplification of known oncogenes, genome-wide analysis of gene copy number alterations in cancer revealed that the majority of transcriptional variations are due to low level copy number changes (Hyman et al, 2002;Wolf et al, 2004). In our study, the TRAF4 gain observed in 22% of all cases was moderate (up to 10 copies) but it was significantly associated with gene expression.…”

supporting

confidence: 45%

TRAF4 overexpression is a common characteristic of human carcinomas

et al. 2006

View full text Add to dashboard Cite

Tumor necrosis factor receptor (TNFR) associated factor 4 (TRAF4) was initially identified as a gene amplified and overexpressed in breast carcinomas. Our aim was to evaluate whether TRAF4 protein overexpression exists in other cancer types. Immunohistochemistry analysis of tumor samples from 623 patients with 20 different tumor types showed that TRAF4 was overexpressed in 268 tumors (43%), including 82 of 137 lung adenocarcinomas (60%). Interestingly, 32 primary tumors and their matching metastases exhibited mostly similar TRAF4 expression pattern. TRAF4 protein overexpression was limited to cancer cells and the subcellular localization was consistently cytoplasmic in a large majority of cases. To investigate changes in TRAF4 gene copy number, 125 cases from six different types of carcinomas were also analysed by fluorescence in situ hybridization. Out of the 28 cases (22%) showing an increased TRAF4 gene copy number, 23 (82%) were overexpressing the protein. Thus, TRAF4 gene amplification is one of the mechanisms responsible for TRAF4 protein overexpression in human cancers. Considering that TRAF4 is located at 17q11.2 in a region of amplification devoid of known oncogenes and is commonly overexpressed in cancer, our data support an oncogenic role for TRAF4. Oncogene Keywords: TRAF4; chromosome 17q11; ERBB2; amplification; lung TRAF proteins belong to a family of cytoplasmic adaptors involved in the signalling cascade activated by receptors of the TNFR and interleukin-1/Toll-like receptor (IL-1R/TLR) families (Chung et al., 2002). Six TRAF proteins that share common structural features, including a carboxy-terminal TRAF domain, are encoded by the mammalian genome. Their main functions are exerted in the immune system where they regulate intracellular signalling pathways leading to the activation of a common set of transcription factors including NF-kB and AP-1 (Aggarwal, 2003).Unlike other members of the TRAF family, the biological function of TRAF4 remains elusive. Several reports suggested that TRAF4 could be recruited to different TNFR and TLR signalling pathways (Krajewska et al., 1998;Ye et al., 1999;Esparza and Arch, 2004;Takeshita et al., 2005), and in mitogen-activated protein kinase (MAPK) pathways (Xu et al., 2002;Abell and Johnson, 2005;Li et al., 2005) but in vivo evidence of such a role is still missing. Mice deficient for TRAF4 exhibit clear ontogenic defects affecting neural tube closure, tracheal formation and skeletal patterning, phenotypes that might be linked to abnormal cell migration (Regnier et al., 2002).TRAF4 was the first member of the TRAF protein family found upregulated in human carcinomas. Indeed, the TRAF4 cDNA was initially isolated from metastatic breast cancer Tomasetto et al., 1995), where the TRAF4 gene was amplified, leading to overexpression of the gene product (Bieche et al., 1996). Detailed analysis of the amplification pattern of five genes located on the long arm of the chromosome 17, including the ERBB2 oncogene (Slamon et al., 1989), revealed the existence of at least...

show abstract

supporting

confidence: 45%

TRAF4 overexpression is a common characteristic of human carcinomas

et al. 2006

View full text Add to dashboard Cite

show abstract

“…8,39 The increase in mRNA level caused by amplification is not always proportional to the number of gene copies; 33 and the effects of the gene copy number on expression levels were more relevant for high-level amplifications in a gene-by-gene analysis; results that were also found in breast and prostate cancers. 40,41 In our series, only the cases with dmin amplification, present in more than 10% of the cells, showed an increase of RNA expression.…”

Section: Discussionmentioning

confidence: 47%

New pattern of EGFR amplification in glioblastoma and the relationship of gene copy number with gene expression profile

et al. 2010

View full text Add to dashboard Cite

Gene amplification is a process that is characterized by an increase in the copy number of a restricted region in a chromosome arm, and is frequently associated with an overexpression of the corresponding amplified gene. Amplified DNA can be organized either as extrachromosomal elements, repeated units at a single locus or scattered throughout the genome. The amplification of the gene for epidermal growth factor receptor (EGFR) is a common finding in glioblastomas and the amplified gene copies appears as double minutes. The aim of this study was to investigate the different patterns of EGFR amplification in 40 cases of glioblastoma using FISH analysis in metaphases and paraffin sections, and to investigate the relationship of gene copy number with gene expression profile. The analysis of copy number alterations of EGFR was validated by quantitative PCR and SNP microarrays. We observed that in 42% of the cases, the type of amplification of EGFR was as double minute chromosomes. In addition, we detected another type of amplification, with extra copies of EGFR inserted in different loci of chromosome 7, present in 28% of cases. In this form of amplification, the number of copies is small, and the percentage of cells with EGFR amplification is rarely more than 15%. This model of amplification could correspond to a variant of the insertion mechanism, or a consequence of a process of duplication. Our results suggest that this mechanism could represent an early stage of amplification in glioblastomas. Overall, we found a close correlation between EGFR gene copy-number alterations and the level of EGFR protein expression. However, all cases with a high level of mRNA exhibited strong expression for the EGFR protein, and most cases with a low level of mRNA showed no overexpression of EGFR protein.

show abstract

“…MALDI-TOF MS-based identification of the nuclear proteins bound to ANXA7-promoter (F, À1086/À890) in prostate cancer (PC3) versus normal prostate cells (PrEC) The more abundant bands in the DNA-affinity pattern for the F-segment in PC3 (as shown in Figure 3) correspond to the uniquely high ANXA7 gene copy number (Wolf et al, 2004) and complementary DNA (cDNA) expression in PC3 among other NCI-60 cells (Stanford Microarray Database, Stanford, CA, USA, as shown in Supplementary Figure S1). Accordingly, PC3 shows greater than threefold increase of ANXA7 protein expression compared with other tested cells, including PrEC, DU145, and LNCaP (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…In particular, although the specifically high gene copy number of ANXA7 (Wolf et al, 2004) can explain the increase in total gene and protein expression of ANXA7 in PC3, multiple ANXA7 products in PC3 versus PrEC indicate additional hnRNP-associated effects on ANXA7 splicing in PC3. According to ANXA7 expression profiling in cancer cells (Gene Expression Omnibus and Stanford Microarray Database), only PC3 and PPC-1 cells, that share similar karyotypes, have ANXA7 elevation, and an ANXA7 expression profile in general is not concordant with hnRNPs ( Supplementary Figure S2-S3).…”

Section: Discussionmentioning

confidence: 98%

“…Hence, the regulatory mechanisms in ANXA7 transcription and splicing in different cell environments, including neoplastic transformation, need to be elucidated. The androgen-resistant PC3 prostate cancer cells, in particular, have been shown to possess an intriguingly high ANXA7 gene copy number (Wolf et al, 2004) that questions the tumor suppressor role of endogenous ANXA7 in these cells. Hence, we undertook a study on ANXA7 transcription in normal and cancerous prostate cells, including PC3, and analyzed ANXA7-promoter activity in juxtaposition to the Genomatix-derived mapping of putative regulatory matrixes.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Role of multi-hnRNP nuclear complex in regulation of tumor suppressor ANXA7 in prostate cancer cells

Torosyan

Dobi²,

Glasman

et al. 2010

Oncogene

View full text Add to dashboard Cite

Annexin-A7 (ANXA7) tumor suppressor role has been shown in various tumors, and ANXA7 expression has been particularly lost in androgen-resistant prostate cancers. In this study, we studied ANXA7 regulation in normal prostate versus androgen-sensitive and -resistant prostate cancer cells. Deletion mapping analysis showed lowest ANXA7-promoter activities in androgen-sensitive LNCaP prostate cancer cells. Genomatix analysis of ANXA7 promoter identified a cluster of steroid nuclear hormone receptor elements, including V$GREF (V$GRE.02/ ARE.02). Gelshift analysis clearly indicated distinct nuclear protein occupancy at this ANXA7-promoter site (À1086/À890) in prostate cancer (LNCaP, DU145, and PC3) versus normal prostate (PrEC) cells. In matrixassisted laser desorption time-of-flight mass spectrometrybased search for ANXA7 nuclear regulators, we identified several heterogeneous nuclear ribonucleoproteins (hnRNPs) (A1, A2/B1 and K) attached to the steroidassociated ANXA7-promoter site in the androgen-resistant PC3 prostate cancer cells with high ANXA7 gene copy number, but not in PrEC. The hnPNP role in ANXA7 regulation (that was validated by hnRNPA2/B1 antibody interference) resulted in multiple ANXA7 cDNA and protein products in PC3, but not in PrEC. Ingenuity pathways analysis showed plausible molecular paths between ANXA7 and the hnRNP-associated network in prostate cancer progression. Thus, a multi-hnRNP complex can be responsible for aberrant ANXA7 transcription and splicing, thereby affecting ANXA7 expression pattern and tumor suppressor function in prostate cancer.

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 111 publications

References 18 publications

TRAF4 overexpression is a common characteristic of human carcinomas

TRAF4 overexpression is a common characteristic of human carcinomas

New pattern of EGFR amplification in glioblastoma and the relationship of gene copy number with gene expression profile

Role of multi-hnRNP nuclear complex in regulation of tumor suppressor ANXA7 in prostate cancer cells

Contact Info

Product

Resources

About