Molecular characterisation of ERG, ETV1 and PTEN gene loci identifies patients at low and high risk of death from prostate cancer

A H M Reid, G Attard, L Ambroisine, G Fisher, G Kovacs, D Brewer, J Clark, P Flohr, S Edwards, D M Berney, C S Foster, A Fletcher, W L Gerald, H Møller, V E Reuter, P T Scardino, J Cuzick, J S de Bono, C S Cooper, Transatlantic Prostate Group, A H M Reid, G Attard, L Ambroisine, G Fisher, G Kovacs, D Brewer, J Clark, P Flohr, S Edwards, D M Berney, C S Foster, A Fletcher, W L Gerald, H Møller, V E Reuter, P T Scardino, J Cuzick, J S de Bono, C S Cooper, Transatlantic Prostate Group

Abstract

Background: The discovery of ERG/ETV1 gene rearrangements and PTEN gene loss warrants investigation in a mechanism-based prognostic classification of prostate cancer (PCa). The study objective was to evaluate the potential clinical significance and natural history of different disease categories by combining ERG/ETV1 gene rearrangements and PTEN gene loss status.

Methods: We utilised fluorescence in situ hybridisation (FISH) assays to detect PTEN gene loss and ERG/ETV1 gene rearrangements in 308 conservatively managed PCa patients with survival outcome data.

Results: ERG/ETV1 gene rearrangements alone and PTEN gene loss alone both failed to show a link to survival in multivariate analyses. However, there was a strong interaction between ERG/ETV1 gene rearrangements and PTEN gene loss (P<0.001). The largest subgroup of patients (54%), lacking both PTEN gene loss and ERG/ETV1 gene rearrangements comprised a 'good prognosis' population exhibiting favourable cancer-specific survival (85.5% alive at 11 years). The presence of PTEN gene loss in the absence of ERG/ETV1 gene rearrangements identified a patient population (6%) with poorer cancer-specific survival that was highly significant (HR=4.87, P<0.001 in multivariate analysis, 13.7% survival at 11 years) when compared with the 'good prognosis' group. ERG/ETV1 gene rearrangements and PTEN gene loss status should now prospectively be incorporated into a predictive model to establish whether predictive performance is improved.

Conclusions: Our data suggest that FISH studies of PTEN gene loss and ERG/ETV1 gene rearrangements could be pursued for patient stratification, selection and hypothesis-generating subgroup analyses in future PCa clinical trials and potentially in patient management.

Figures

Figure 1
Figure 1
Haematoxylin and eosin (H & E), fluorescence in-situ hybridisation (FISH) and P63/alpha-methylacyl-CoA racemase (AMACR) on adjacent slides (A) a prostate cancer gland with H & E staining; (B) ETV1 FISH in the same gland on an adjacent slide. Cartoon and magnified images of two nuclei are also shown. The upper nucleus has four paired (ploidy) ETV1 probes and the lower nucleus has two paired ETV1 probes indicating wild-type ETV1; FISH for ERG also showed paired probes indicating wild-type ERG (image not shown); (C) PTEN FISH in the same gland on an adjacent slide. Cartoon and magnified images of one nucleus is shown. The nucleus has four (ploidy) chromosome, 10 centromeric probes (in red) and two PTEN probes (in green) indicating heterozygous loss of PTEN; and (D) the same prostate cancer gland on an adjacent slide, which has absent P63 staining and AMACR positivity.
Figure 2
Figure 2
Fluorescence in-situ hybridisation (FISH) detection of PTEN loss. (A) Position of two ‘PTEN’ BAC probes shown in green. The PTEN gene and flanking gene C10orf59 are shown in dark blue. Arrows indicate the direction of transcription. (B) PTEN loss patterns. Green signals are probes that detect PTEN and red signals are probes that detect the chromosome 10 centromere. Nuclei with normal PTEN complement are visualised in interphase as two green and two red signals (left). Heterozygous PTEN loss results in the loss of one green signal (centre) and homozygous PTEN loss, the loss of two green signals (right).
Figure 3
Figure 3
(A) Prostate cancer survival according to PTEN gene status and (B) according to PTEN and ERG/ETV1 gene status.

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