ERG overexpression plus SLC45A3 (prostein) and PTEN expression loss: Strong association of the triple hit phenotype with an aggressive pathway of prostate cancer progression

Abstract

<i>TMPRSS2</i> and <i>SLC45A3</i> rearrangements may coexist in the same tumor. <i>ERG</i> rearrangements and <i>PTEN</i> loss are concomitant events in prostate cancer (PrCa), and can cooperate in progression. We have reported that mRNA expression of <i>TMPRSS2-ERG</i> and <i>SLC45A3-ERG</i> rearrangements plus <i>PTEN</i> loss define an aggressive tumor subset. The aim of this study has been to validate these results by immunohistochemistry in a large cohort of tumors. ERG, SLC45A3 and PTEN immunostaining and their association with pathological features and PSA progression-free survival were analyzed in 220 PrCa (PSMAR-Biobank, Barcelona, Spain). ERG protein expression was found in 46.8% and SLC45A3 and PTEN loss in 30% and 34% tumors, respectively. Single ERG positive immunostaining was associated with GS = 6 tumors (<i>p</i> = 0.016), double ERG+/PTEN loss with GS = 7 (<i>p</i> = 0.008) and Grade Group 2 (GG) or GG3 cases (<i>p</i> = 0.042), ERG+/SLC45A3 loss/PTEN loss ("triple hit") with GS ≥ 8 (<i>p</i> < 0.0001) and GG4 or GG5 tumors (<i>p</i> = 0.0003). None of GS = 6 nor = GG1 cases showed this combination. In the GS ≥ 8 group, ERG+ (<i>p</i> = 0.002), PTEN loss (<i>p</i> = 0.009) and "triple hit" (<i>p</i> = 0.003) were associated with Gleason pattern 3 component, and single SLC45A3 loss (<i>p</i> = 0.036) with GS ≥ 8 without pattern 3. The number of aberrant events and the triple hit were strongly associated with shorter PSA progression-free survival. In GS = 6 PrCa, single ERG+ was also associated with progression. ERG+ identifies a distinct pathway of PrCa. Additional assessment of PTEN and SLC45A3 adds relevant prognostic information. The triple hit phenotype (ERG+/SLC45A3 loss/PTEN loss) is associated with progression and could be used for patient stratification, treatment and follow-up.