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Heterogeneity and clinical significance of ETV1 translocations in human prostate cancer.

Attard G, Clark J, Ambroisine L, Mills IG, Fisher G, Flohr P, Reid A, Edwards S, Kovacs G, Berney D, Foster C, Massie CE, Fletcher A, De Bono JS, Scardino P, Cuzick J, Cooper CS, Transatlantic Prostate Gro - Br. J. Cancer (2008)

Bottom Line: The presence of ETV1 gene alterations (found in 23 cases, 5.4%) was correlated with higher Gleason Score (P=0.001), PSA level at diagnosis (P=<0.0001) and clinical stage (P=0.017) but was not linked to poorer survival.We found that the six previously characterised translocation partners of ETV1 only accounted for 34% of ETV1 re-arrangements (eight out of 23) in this series, with fusion to the androgen-repressed gene C15orf21 representing the commonest event (four out of 23).In 5'-RACE experiments on RNA extracted from formalin-fixed tissue we identified the androgen-upregulated gene ACSL3 as a new 5'-translocation partner of ETV1.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cancer Research, Male Urological Cancer Research Centre, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.

ABSTRACT
A fluorescence in situ hybridisation (FISH) assay has been used to screen for ETV1 gene rearrangements in a cohort of 429 prostate cancers from patients who had been diagnosed by trans-urethral resection of the prostate. The presence of ETV1 gene alterations (found in 23 cases, 5.4%) was correlated with higher Gleason Score (P=0.001), PSA level at diagnosis (P=<0.0001) and clinical stage (P=0.017) but was not linked to poorer survival. We found that the six previously characterised translocation partners of ETV1 only accounted for 34% of ETV1 re-arrangements (eight out of 23) in this series, with fusion to the androgen-repressed gene C15orf21 representing the commonest event (four out of 23). In 5'-RACE experiments on RNA extracted from formalin-fixed tissue we identified the androgen-upregulated gene ACSL3 as a new 5'-translocation partner of ETV1. These studies report a novel fusion partner for ETV1 and highlight the considerable heterogeneity of ETV1 gene rearrangements in human prostate cancer.

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FISH detection of translocation of ETV1 to chromosome 14(q13.3–21.1). Top: Interphase nuclei are hybridised to probes that detect sequences immediately 3′ to the ETV1 gene on chromosome 7 (probe I, red) and a green probe (probe V) consisting of six BACS spanning the 14q13.3–21.1 region. (A). Red and green signals are normally separated. (B) Co-localisation of red and green probes indicate juxtaposition of chr 7 ETV1 sequences with chr 14 (q 13.3–21.1). The lower panel shows the position of the BACs used for probe V: C1 (RP11-945C4), C2 (RP11-381L10), C3 (RP11-666J24), C4 (RP11-796F21), C5 (RP11-588D7), C6 (RP11-107E23) labelled with FITC. The relative position and direction of transcription of genes are indicated by the arrows.
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fig2: FISH detection of translocation of ETV1 to chromosome 14(q13.3–21.1). Top: Interphase nuclei are hybridised to probes that detect sequences immediately 3′ to the ETV1 gene on chromosome 7 (probe I, red) and a green probe (probe V) consisting of six BACS spanning the 14q13.3–21.1 region. (A). Red and green signals are normally separated. (B) Co-localisation of red and green probes indicate juxtaposition of chr 7 ETV1 sequences with chr 14 (q 13.3–21.1). The lower panel shows the position of the BACs used for probe V: C1 (RP11-945C4), C2 (RP11-381L10), C3 (RP11-666J24), C4 (RP11-796F21), C5 (RP11-588D7), C6 (RP11-107E23) labelled with FITC. The relative position and direction of transcription of genes are indicated by the arrows.

Mentions: We constructed a TMA block containing cores from all of the cancers harbouring ETV1 re-arrangements (23 tumours) and six randomly selected cancers with an ERG gene rearrangement. We used slices of this TMA to carry out break-apart assays for the 5′-fusion partners previously identified by Tomlins et al (2005, 2006, 2007): namely TMPRSS2, SLC45A3, HERV-K, C15orf21 and HNRPA2B1 (Table 2). We also used FISH assays to confirm co-localisation of 3′-ETV1 with 5′-sequences from each of the above partners as previously described by Tomlins et al (2007) (results not shown). To identify tumours with translocation of ETV1 to the androgen-regulated prostate-specific region at 14q13.3–14q21.1 we co-hybridised a TMA slice with a 3′-ETV1 FISH probe (red) and a FISH probe consisting of six BACs spanning the entire region of 14q13.3–q21.1 (green). Co-localisation of the red and green signals was taken as evidence of translocation of ETV1 to this region (Figure 2). The FISH probes used in all of these assays are listed in Supplementary Table 1.


Heterogeneity and clinical significance of ETV1 translocations in human prostate cancer.

Attard G, Clark J, Ambroisine L, Mills IG, Fisher G, Flohr P, Reid A, Edwards S, Kovacs G, Berney D, Foster C, Massie CE, Fletcher A, De Bono JS, Scardino P, Cuzick J, Cooper CS, Transatlantic Prostate Gro - Br. J. Cancer (2008)

FISH detection of translocation of ETV1 to chromosome 14(q13.3–21.1). Top: Interphase nuclei are hybridised to probes that detect sequences immediately 3′ to the ETV1 gene on chromosome 7 (probe I, red) and a green probe (probe V) consisting of six BACS spanning the 14q13.3–21.1 region. (A). Red and green signals are normally separated. (B) Co-localisation of red and green probes indicate juxtaposition of chr 7 ETV1 sequences with chr 14 (q 13.3–21.1). The lower panel shows the position of the BACs used for probe V: C1 (RP11-945C4), C2 (RP11-381L10), C3 (RP11-666J24), C4 (RP11-796F21), C5 (RP11-588D7), C6 (RP11-107E23) labelled with FITC. The relative position and direction of transcription of genes are indicated by the arrows.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2480965&req=5

fig2: FISH detection of translocation of ETV1 to chromosome 14(q13.3–21.1). Top: Interphase nuclei are hybridised to probes that detect sequences immediately 3′ to the ETV1 gene on chromosome 7 (probe I, red) and a green probe (probe V) consisting of six BACS spanning the 14q13.3–21.1 region. (A). Red and green signals are normally separated. (B) Co-localisation of red and green probes indicate juxtaposition of chr 7 ETV1 sequences with chr 14 (q 13.3–21.1). The lower panel shows the position of the BACs used for probe V: C1 (RP11-945C4), C2 (RP11-381L10), C3 (RP11-666J24), C4 (RP11-796F21), C5 (RP11-588D7), C6 (RP11-107E23) labelled with FITC. The relative position and direction of transcription of genes are indicated by the arrows.
Mentions: We constructed a TMA block containing cores from all of the cancers harbouring ETV1 re-arrangements (23 tumours) and six randomly selected cancers with an ERG gene rearrangement. We used slices of this TMA to carry out break-apart assays for the 5′-fusion partners previously identified by Tomlins et al (2005, 2006, 2007): namely TMPRSS2, SLC45A3, HERV-K, C15orf21 and HNRPA2B1 (Table 2). We also used FISH assays to confirm co-localisation of 3′-ETV1 with 5′-sequences from each of the above partners as previously described by Tomlins et al (2007) (results not shown). To identify tumours with translocation of ETV1 to the androgen-regulated prostate-specific region at 14q13.3–14q21.1 we co-hybridised a TMA slice with a 3′-ETV1 FISH probe (red) and a FISH probe consisting of six BACs spanning the entire region of 14q13.3–q21.1 (green). Co-localisation of the red and green signals was taken as evidence of translocation of ETV1 to this region (Figure 2). The FISH probes used in all of these assays are listed in Supplementary Table 1.

Bottom Line: The presence of ETV1 gene alterations (found in 23 cases, 5.4%) was correlated with higher Gleason Score (P=0.001), PSA level at diagnosis (P=<0.0001) and clinical stage (P=0.017) but was not linked to poorer survival.We found that the six previously characterised translocation partners of ETV1 only accounted for 34% of ETV1 re-arrangements (eight out of 23) in this series, with fusion to the androgen-repressed gene C15orf21 representing the commonest event (four out of 23).In 5'-RACE experiments on RNA extracted from formalin-fixed tissue we identified the androgen-upregulated gene ACSL3 as a new 5'-translocation partner of ETV1.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cancer Research, Male Urological Cancer Research Centre, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.

ABSTRACT
A fluorescence in situ hybridisation (FISH) assay has been used to screen for ETV1 gene rearrangements in a cohort of 429 prostate cancers from patients who had been diagnosed by trans-urethral resection of the prostate. The presence of ETV1 gene alterations (found in 23 cases, 5.4%) was correlated with higher Gleason Score (P=0.001), PSA level at diagnosis (P=<0.0001) and clinical stage (P=0.017) but was not linked to poorer survival. We found that the six previously characterised translocation partners of ETV1 only accounted for 34% of ETV1 re-arrangements (eight out of 23) in this series, with fusion to the androgen-repressed gene C15orf21 representing the commonest event (four out of 23). In 5'-RACE experiments on RNA extracted from formalin-fixed tissue we identified the androgen-upregulated gene ACSL3 as a new 5'-translocation partner of ETV1. These studies report a novel fusion partner for ETV1 and highlight the considerable heterogeneity of ETV1 gene rearrangements in human prostate cancer.

Show MeSH
Related in: MedlinePlus