ERG rearrangement metastasis patterns in locally advanced prostate cancer

Abstract

Objectives: To interrogate multifocal prostate cancer (PCa) to determine its predilection for metastasis, using ERG rearrangement as marker of clonality. A hallmark of PCa is that distinct tumor foci may arise independently, which has important biological and clinical implications. Recent studies characterizing ERG-rearranged PCa possessing intrafocal homogeneity but interfocal heterogeneity support this hypothesis.

Methods: We studied 26 patients who underwent prostatectomy and lymphadenectomy with at least 2 distinct PCa foci and 1 lymph node (LN) metastasis. Each focus was assessed for size, Gleason score, ERG rearrangement, and TMPRSS2-ERG transcript.

Results: Fifteen of 26 cases exhibited interfocal homogeneity with regard to ERG rearrangement (ie, presence vs absence of ERG rearrangement). ERG rearrangement was present in all foci for 6 and absent in all foci for 9 cases. Two cases revealed interfocal heterogeneity with regard to rearrangement mechanism (ie, rearrangement through insertion or deletion). Eight of 26 cases revealed interfocal heterogeneity with regard to rearrangement status. In all cases with at least 1 ERG rearranged focus, we found the corresponding LN metastasis harboring an ERG rearrangement. Interestingly, in a subset of cases the rearrangement status in the LN did not correspond to size or Gleason score. All but 2 ERG rearranged foci had detectable TMPRSS2-ERG transcript levels.

Conclusions: When multifocal PCa demonstrates both ERG-positive and ERG-negative foci, the positive foci have a greater predilection for metastasis. Larger studies are needed to confirm the potential additional risk an ERG rearranged focus confers on the likelihood of disease progression.

Keywords: ERG rearrangements; TMPRSS2-ERG; metastatic; prostate cancer.

Figure 1. Matrix representation of ERG rearrangement and TMPRSS2-ERG mRNA expression status in multifocal PCa and corresponding LN mets

The numbers in the cells indicated primary and secondary Gleason grade of each focus. Green highlighted cells indicate ERG rearrangement through insertion, orange indicates rearrangement accompanied by a deletion, and blue indicates no ERG rearrangement, as assessed by FISH seen in the representative pictures for this study. B. PCa and accompanying LN foci from 9 samples that have bold labels in A were analyzed for TMPRSS2 (exon 1)-ERG (exon 4) mRNA expression. The assay that we used provides transcript copy number detected per reaction. Copy numbers for TMPRSS2-ERG mRNA were standardized using PSA mRNA copy numbers from the same sample. “neg” indicates the sample yielded copy numbers within the range of quantification for PSA but yielded no detected copy numbers for TMPRSS2-ERG mRNA. “pos” indicates that we obtained copy numbers within or above the quantifiable range for both PSA and TMPRSS2-ERG mRNAs.

Figure 2. Illustration of how metastatic dissemination of multifocal PCa depends on ERG rearrangement status rather than tumor size or Gleason grade

The blue focus represents the dominant focus with regard to size and Gleason grade but is negative for ERG rearrangement, while the secondary focus (with regard to size and Gleason grade) is positive for ERG rearrangement and drives regional metastatic dissemination.