Marked heterogeneity of ERG expression in large primary prostate cancers

Abstract

Approximately 50% of prostate cancers are characterized by TMPRSS2 (transmembrane protease serine 2)-ERG (avian v-ets erythroblastosis virus E26 oncogene homolog) gene fusions resulting in an androgen-regulated overexpression of the transcription factor ERG. Some studies have suggested prognostic or predictive relevance of ERG status in prostate cancer. Such concepts could be impaired by extensive ERG heterogeneity in analyzed tumors. The aim of this study was to analyze the extent of heterogeneity for TMPRSS2-ERG fusion in prostate cancer. To enable large-scale studies on the extent of heterogeneity of biomarkers in prostate cancer, a heterogeneity tissue microarray containing samples from 10 different tumor blocks of 190 large prostate cancers selected from a consecutive series of 480 radical prostatectomies was developed. ERG expression was analyzed by immunohistochemistry. Positive ERG immunostaining was found in arrayed cancer-containing samples from 103 of the 178 analyzable patients (58%). ERG immunostaining was homogeneously positive in 29 prostate cancers (16%), whereas heterogeneous ERG positivity was seen in 74 cancers (42%). ERG heterogeneity was within one tumor focus (intrafocal heterogeneity) in 69 cases (93% of heterogeneous cases) and between different tumor foci (interfocal heterogeneity) in 5 cases (7%). Marked intrafocal heterogeneity challenges the concept of TMPRSS2-ERG fusion always representing an early step in prostate cancer development. Marked heterogeneity also compromises the concept of analyzing ERG status for treatment decisions in diagnostic needle core biopsies.

Genomic Predictors of Outcome in Prostate Cancer

“…Genetic prediction tools may also add significant costs to the PCa diagnostic and therapeutic algorithms, but these costs might be justified if indeed they lead to a reduction in unnecessary treatments for localized disease or a more appropriate selection of therapy for advanced disease. An important aspect of biomarker and genetics research is the heterogeneity of PCa both within a single tumor locus (intrafocal heterogeneity) and between different tumor deposits (interfocal heterogeneity) [96][97][98]. In addition to intra/interfocal heterogeneity, a field effect of genetic changes should also be considered because cancer-related genetic changes are also detected in benign areas of the same prostate [99].…”

Heterogeneity and chronology of PTEN deletion and ERG fusion in prostate cancer

“…To facilitate such whole tumor analyses, we have previously developed a prostate cancer heterogeneity tissue microarray (tissue microarray) platform. 2 This tissue microarray platform contains samples from 10 distant tumor areas each of 189 large prostate cancers, thus enabling a high-throughput mapping of molecular features across the entire tumors. Our initial analysis of this tissue microarray revealed that the prostate cancer-specific TMPRSS2:ERG fusions is heterogeneous in 470% of ERG-positive prostate cancers.…”

“…Our initial analysis of this tissue microarray revealed that the prostate cancer-specific TMPRSS2:ERG fusions is heterogeneous in 470% of ERG-positive prostate cancers. 2 Inactivation of the phosphatase and tensin homolog (PTEN) gene by genomic deletion or rearrangement, including intragenic breakage and translocation, is another key molecular event in prostate cancer. PTEN deletion or rearrangement has been reported in 20-30% of prostate carcinomas, and is linked to particularly aggressive cancers.…”

Clinical relevance of prostate cancer genetic characterization: literature review

“…Современные данные [61][62][63][64] показывают, что в от-дельных опухолевых очагах почти всегда имеется значи-мая внутриочаговая гетерогенность в отношении образо-вания слияний TMРRSS2: ERG и его структуры, в отношении потери PTEN, геномных аберраций и эпигенетических изменений всего генома. В большин-стве случаев эти генетически различные опухоли кажутся идентичными внешне и по степени дифферен цировки будут классифицированы одинаково.…”