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

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 (Po0.001). 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 ¼ 4.87, Po0.001 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.

Detection ofERGgene rearrangements andPTENdeletions in unsuspected prostate cancer of the transition zone

“…Recently, we and others have confirmed significant association between ERG rearrangements and PTEN deletions in localized and metastatic/hormone refractory disease. 15,16,19 This observation was also supported by in-vivo studies using transgenic mouse models demonstrating that double transgenic mice for aberrant ERG and PTEN deletions develop frank invasive prostate cancer vs. high grade prostatic intraepithelial neoplasia (HGPIN) in either PTEN deletions or TMPRSS2-ERG gene fusion (the most common form of ERG rearrangement). These murine studies underscore the potential value of PTEN and ERG as early biomarkers of progression in human PCA.…”

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14] More recently, several studies demonstrated significant association between ERG rearrangements and PTEN genomic deletions in localized PCA with prognostic implications. [15][16][17][18][19][20] Moreover, studies in transgenic mouse models confirmed that both aberrant expression of ERG and deletion of PTEN are required to develop frank invasive carcinoma, indicating that both genetic aberrations play an important role in driving prostate cancer development and progression. More comprehensive studies are, however required to determine the prognostic significance of these biomarkers for the future clinical management of PCA.…”

PTEN losses exhibit heterogeneity in multifocal prostatic adenocarcinoma and are associated with higher Gleason grade

“…TMPRSS2 rearrangements seem to be reproducibly associated with a less favorable prognosis only when accompanied by PTEN loss. 14,39 The present study was not designed to further assess the association between PTEN deletions, TMPRSS2-ERG rearrangements and clinical outcome. Rather, the aim was to define the incidence of heterogeneity for PTEN deletions and TMPRSS2-ERG fusion rearrangements within and between separate cancer foci in the same prostate, and to determine whether there was any association with modified Gleason pattern.…”

“…[29][30][31] PTEN deletions are found in approximately 40% of localized prostate cancers. 8,14,[31][32][33][34][35][36][37][38][39][40][41][42][43][44] In advanced disease, fluorescence in situ hybridization (FISH) has identified hemizygous (loss of one copy) and homozygous (loss of both copies) PTEN deletions, 31,39,43,45,46 with the incidence of PTEN deletion approaching 70-80% of castrate-resistant tumors. 33,40,42,43 It has been shown that hemizygous PTEN deletions are associated with earlier biochemical relapse.…”

“…Homozygous PTEN deletions are strongly linked to metastasis and androgen-independent progression. 20,33,39,40,47,48 Genomic loss and inactivation of the PTEN gene most likely lead to an adverse clinical course through haploinsufficiency and reduced levels of the PTEN protein. 49 Loss of PTEN leads to upregulation of PI3K/AKT, a pathway strongly associated with disease progression in prostate cancer.…”