ERG rearrangement is present in a subset of transition zone prostatic tumors

Abstract

A majority of prostate cancers exhibit a recurrent gene rearrangement involving chromosome 21. In approximately 90% of cases, the rearrangement is characterized by fusion of the androgen-regulated gene TMPRSS2 with the oncogene ERG. A recent study suggested that TMPRSS2-ERG gene fusion is lacking in cancers arising from the transition zone of the prostate. A dominant transition zone cancer was detected in 62/397 (16%) patients who underwent radical prostatectomy at our institution and were reviewed and mapped by a single pathologist. In 46/62 specimens, a secondary tumor was identified in the peripheral zone of the prostate. A tissue microarray containing both transition and peripheral zone tumors was constructed and evaluated for gene fusion analysis. TMPRSS2-ERG fusion status was determined using a multicolor interphase fluorescence in situ hybridization assay for ERG break-apart. The median age of the patients was 59 years. Prostatectomy Gleason score was 6 in 21, 7 in 34, and Z8 in 7 cases. Median tumor volume was 200 mm 2 . TMPRSS2-ERG gene fusion was present in 7/59 (12%) transition zone, and in 12/35 (34%) peripheral zone tumors. Transition zone fusion-positive cases were larger than their negative counterparts. No significant correlation was found between fusion status and Gleason score or pathologic stage. Gene fusion through deletion occurred in 4/7 transition zone and 7/12 peripheral zone tumors. Transition zone prostate cancers are considered biologically and genetically different from peripheral zone tumors. Although ERG rearrangement is more common in peripheral zone tumors, we have detected TMPRSS2-ERG fusion in a subset of transition zone cancers (12%). The lower frequency of gene fusion in transition zone prostate cancer may suggest distinct molecular alterations from peripheral zone tumors and the association with a high tumor volume may indicate a growth advantage for transition zone tumors harboring the gene fusion. Further studies are necessary to confirm this hypothesis.

TMPRSS2-ERG gene fusion in transition zone prostate cancer

“…Since the publication of our study, several other independent studies (reported in abstract form) have evaluated TMPRSS2-ERG gene fusion in tumors of TZ origin. [5][6][7] Although a distinctively small number of such tumors expressed the TMPRSS2-ERG gene fusion, the overwhelming majority (78-94%) of TZ tumors in these studies lacked the TMPRSS2-ERG gene fusion, thus confirming the zonal differences reported in our study.…”

“…This rate of ERG gene rearrangements in unsuspected and incidental prostate cancers in TURP specimens is similar to the finding of 15%, recently shown in a large watchful waiting cohort from Sweden, which similarly included only TURP specimens. 7 In summary, although we agree that biological difference may exist between transitional and peripheral zone tumors, we caution against the conclusion of complete absence of TMPRSS2-ERG gene fusion within the prostate transition zone tumors. To the Editor: We read with great interest the comments by Bismar and Trpkov 1 in reference to our paper, 'Prostate cancer of transition zone origin lacks TMPRSS2-ERG gene fusion,' published in Modern Pathology.…”

“…Although cutoff levels in FISH analyses may vary for different probes and among different laboratories, we used the widely accepted definition of a proper cutoff as being the mean of false-positive findings in at least five negative control specimens plus three times the standard deviation. [7][8] Hence, we analyzed ERG rearrangement in normal prostate glands and established a cutoff level of 10% for our FISH analyses. In other words, if more than 90% of the evaluated nuclei in a TZ tumor focus showed no evidence of ERG rearrangement, then that TZ focus was considered to lack the TMPRSS2-ERG gene fusion.…”

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

“…37 A second study confirmed that the detection of ERG rearrangements in a subset of transition zone tumors was significantly lower (12%) than in the peripheral zone tumors (34%). 38 Several other studies investigated ERG rearrangements in watchful waiting cohorts, in which the incidence of ERG rearrangements was reported to be at much lower rates compared to radical prostatectomy cohorts (15 vs. 40-60%). 8,9,11,14,19,39 In the current study, we sought to investigate the frequency of ERG gene rearrangements and PTEN genomic deletions in a cohort of 54 patients whose tumors were detected un-expectantly during a TURP for benign prostate hyperplasia (BPH).…”

ERG protein expression and genomic rearrangement status in primary and metastatic prostate cancer—a comparative study of two monoclonal antibodies

“…1 --3 The most prominent gene rearrangement in PCa arises between the androgen-regulated serine protease TMPRSS2 and the transcription factor ERG, resulting in an overexpression of a truncated oncoprotein. 2,4 --6 Depending on factors, such as, cohort design (PSA-screened PCa versus incidentally diagnosed PCa), zonal tumor origin (PCa originating from the transitional zone versus PCa originating from the peripheral zone) 7,8 and various histologic variants of PCa, 9 --12 ERG rearrangements occur in 15 --80% of PCa. Furthermore, despite its high prevalence and clonal nature, 13 --17 the ERG rearrangement is highly specific to PCa.…”