Absence of TMPRSS2:ERG fusions and PTEN losses in prostate cancer is associated with a favorable outcome

Yoshimoto, Maisa; Joshua, Anthony M.; Cunha, Isabela Werneck da; Coudry, Renata A.; Fonseca, Francisco Paulo da; Ludkovski, Olga; Zieleńska, Maria; Soares, Fernando Augusto; Squire, Jeremy A.

doi:10.1038/modpathol.2008.96

Cited by 256 publications

(228 citation statements)

References 51 publications

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“…As the incidence of ERG gene alterations have been linked to clinical stage and Gleason score, these differences may be explained, at least in part, by the distinct clinical compositions of the prostate tumor sets surveyed in each study, as suggested by Attard et al 8 Among our positive cases, deletion, rather than translocation, was found to be the main mechanism for TMPRSS2-ERG gene fusion in both transition zone prostate cancers (57%) and peripheral zone prostate cancers (58%), as previously reported in other studies. 2,24,25,33,40,41 We observed duplication of the rearranged sequence with deletion in one prostate cancer from the peripheral zone. Yoshimoto et al 3 observed duplication of TMPRSS2-ERG fusion in 6% of tumors and reported an association with worse prognosis.…”

Section: Discussionmentioning

confidence: 78%

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

et al. 2010

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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.

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Section: Discussionmentioning

confidence: 78%

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

et al. 2010

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“…30 Using logistic regression, we did not find a statistically significant predictive value of immunohistochemical ERG expression on radical prostatectomy with subsequent biochemical or clinical recurrence, overall death or disease-specific death. Although predictive value of TMPRSS2-ERG fusion for biochemical recurrence and death has been reported by some studies, 6,7,31,32 ERG fusion with deletion and duplication of the 5 0 end (Edel and 2 þ Edel) has specifically been associated with worse outcome. 6,7,31,32 Obviously, immunohistochemistry is not able to identify the genetic aberration leading to ERG overexpression.…”

Section: Discussionmentioning

confidence: 96%

“…Although predictive value of TMPRSS2-ERG fusion for biochemical recurrence and death has been reported by some studies, 6,7,31,32 ERG fusion with deletion and duplication of the 5 0 end (Edel and 2 þ Edel) has specifically been associated with worse outcome. 6,7,31,32 Obviously, immunohistochemistry is not able to identify the genetic aberration leading to ERG overexpression. It remains to be elucidated whether TMPRSS2-ERG fusion by deletion or duplication is causally related to worse outcome, or merely reflect general genetic imbalance.…”

Section: Discussionmentioning

confidence: 96%

ERG immunohistochemistry is not predictive for PSA recurrence, local recurrence or overall survival after radical prostatectomy for prostate cancer

et al. 2012

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In prostate cancer genomic rearrangements involving genes encoding ETS transcription factors are commonly present, with androgen-regulated transmembrane protease, serine 2 (TMPRSS2)-v-ets erythroblastosis virus E26 oncogen homologue (ERG) gene fusion occurring in 40-70%. Studies on the predictive value of ERG rearrangement as detected by in-situ hybridization or polymerase chain reaction have resulted in varying outcomes. The objective of this study was to correlate immunohistochemical ERG protein expression with clinico-pathological parameters at radical prostatectomy specimens, and to determine its predictive value for postoperative disease recurrence and progression in a prostate cancer screening cohort. Since androgen receptor is downregulated by ERG in cell lines, we also compared the expression of respective proteins. We selected 481 participants from the European Randomized Study of Screening for Prostate Cancer treated by radical prostatectomy for prostate adenocarcinoma. A tissue microarray was constructed containing representative cores of all prostate cancer specimens as well as 22 xenografts and seven cell lines. Immunohistochemical expression of ERG and androgen receptor was correlated with prostate-specific antigen (PSA), Gleason sum, pT-stage, surgical margins, biochemical recurrence, local recurrence, overall death and disease-specific death. ERG expression was detected in 284 patients (65%). Expression occurred significantly more frequent in patients with PSA r10 ng/ml (P ¼ 0.024). There was no significant association between ERG and Gleason sum, pT-stage or surgical margin status. PSA (P ¼ 0.011), Gleason sum (P ¼ 0.003), pT-stage (P ¼ 0.001) and surgical margin status (Po0.001) all had independent value for postoperative biochemical recurrence, while positive surgical margin (P ¼ 0.021) was the only independent predictor for local recurrence. ERG protein expression did not have prognostic value for the clinical end points in uni-and multivariate analyses. A positive correlation existed between ERG and androgen receptor expression in single tissue cores (Po0.001). In conclusion, immunohistochemical ERG expression has no predictive value for prostate cancer recurrence or progression after radical prostatectomy. Increasing ERG levels are associated with the upregulation of androgen receptor expression in clinical specimens.

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“…16,17 Mehra et al 18 first reported that the TMPRSS2:ERG fusion could be heterogeneous in multifocal prostate cancer. 28 There can be heterogeneity between different tumor foci, not only in the presence or absence of the fusion, but also in the mechanism of the fusion, that is, deletion or translocation. This interfocal or internodular heterogeneity has been confirmed by several follow-up studies.…”

Section: Discussionmentioning

confidence: 99%

ETS family-associated gene fusions in Japanese prostate cancer: analysis of 194 radical prostatectomy samples

Miyagi

Sasaki

Fujinami³

et al. 2010

Modern Pathology

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The incidence and clinical significance of the TMPRSS2:ERG gene fusion in prostate cancer has been investigated with contradictory results. It is now common knowledge that significant variability in gene alterations exists according to ethnic background in various kinds of cancer. In this study, we evaluated gene fusions involving the ETS gene family in Japanese prostate cancer. Total RNA from 194 formalin-fixed and paraffin-embedded prostate cancer samples obtained by radical prostatectomy was subjected to reversetranscriptase polymerase chain reaction to detect the common TMPRSS2:ERG T1-E4 and T1-E5 fusion transcripts and five other non-TMPRSS2:ERG fusion transcripts. We identified 54 TMPRSS2:ERG-positive cases (54/194, 28%) and two HNRPA2B1:ETV1-positive cases (2/194, 1%). The SLC45A3-ELK4 transcript, a fusion transcript without structural gene rearrangement, was detectable in five cases (5/194, 3%). The frequencies of both TMPRSS2:ERG-and non-TMPRSS2:ERG-positive cases were lower than those reported for European, North American or Brazilian patients. Internodular heterogeneity of TMPRSS2:ERG was observed in 5 out of 11 multifocal cases (45%); a frequency similar to that found in European and North American cases. We found a positive correlation between the TMPRSS2:ERG fusion and a Gleason score of r7 and patient age, but found no relationship with pT stage or plasma prostate-specific antigen concentration. To exclude the possibility that Japanese prostate cancer displays novel TMPRSS2:ERG transcript variants or has unique 5 0 fusion partners for the ETS genes, we performed 5 0 RACE using fresh-frozen prostate cancer samples. We identified only the normal 5 0 cDNA ends for ERG, ETV1 and ETV5 in fusion-negative cases. Because we identified a relatively low frequency of TMPRSS2:ERG and other fusions, further evaluation is required before this promising molecular marker should be introduced into the management of Japanese prostate cancer patients.

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Absence of TMPRSS2:ERG fusions and PTEN losses in prostate cancer is associated with a favorable outcome

Cited by 256 publications

References 51 publications

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

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

ERG immunohistochemistry is not predictive for PSA recurrence, local recurrence or overall survival after radical prostatectomy for prostate cancer

ETS family-associated gene fusions in Japanese prostate cancer: analysis of 194 radical prostatectomy samples

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