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Cancer Cell International

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Open Access 01-12-2018 | Review

Predictive significance of TMRPSS2-ERG fusion in prostate cancer: a meta-analysis

Authors: Chunjiao Song, Huan Chen

Published in: Cancer Cell International | Issue 1/2018

Abstract

Background

Prostate cancer is a major malignancy in males. TMPRSS2-ERG is a high-frequency fusion gene expressed in prostate cancer and plays a vital role in carcinogenesis. Recent studies showed that TMPRSS2-ERG is a potential predictive biomarker for prostate cancer. However, the predictive value of TMPRSS2-ERG fusion is yet unclear.

Methods

A total of 76 relevant articles, published from 2015 to 2017, were obtained from PubMed, Web of Science, EMBASE, Scopus, the Cochrane Library, and CNKI databases to investigate the predictive significance of TMPRSS2-ERG fusion in prostate cancer. Pooled odds ratio (ORs) with 95% confidence intervals (CIs) were calculated to estimate the correlation between TMPRSS2-ERG fusion gene and tumor features.

Results

The pooled or stratified analysis showed that the TMPRSS2-ERG fusion gene had a highly predictive potential. First, TMPRSS2-ERG fusion was associated with T-stage at diagnosis (T3–4 vs. T1–2 OR: 1.40; 95% CI 1.33–1.48) and metastasis (M1 vs. M0 OR: 1.35; 95% CI 1.02–1.78) but not with biochemical recurrence or prostate cancer-specific mortality. Furthermore, the subgroup analysis found that the TMPRSS2-ERG fusion gene was correlated with Gleason (G) scores, and the fusion was common in prostate cancer with G ≤ 7. Additionally, the meta-analysis demonstrated that the fusion was likely to occur in young patients (> 65 vs. ≤ 65 OR: 0.68; 95% CI 0.52–0.89), in patients with high PSA levels (> 10 vs. ≤ 10 OR: 1.30; 95% CI 1.21–1.38), and in patients with peripheral involvement (positive vs. negative OR: 1.17; 95% CI 1.08–1.28), while not associated with tumor volume. Finally, the subgroup analysis of different fusion types demonstrated that the deletion-type fusion was significantly associated with the malignant degree of prostate cancer (pooled OR: 5.67; 95% CI 2.85–11.28). Moreover, the deletion-type was common in Africa patients, followed by Caucasian patients, and no significant difference was observed in the incidence of different fusion types in the Asian population.

Conclusions

The meta-analysis findings suggested that the TMPRSS2-ERG fusion gene might be a predictive marker for prostate cancer patients, and might be valuable for assessing the characteristics of prostate cancer for individualized treatment and prognosis evaluation.

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Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30. https://doi.org/10.3322/caac.21387 (Epub 2017 Jan 5).CrossRef

Qi JL, Wang LJ, Zhou MG, Liu YN, Liu JM, Liu SW, Zeng XY, Yin P. Disease burden of prostate cancer among men in China, from 1990 to 2013. Zhonghua Liu Xing Bing Xue Za Zhi. 2016;37(6):778–82. https://doi.org/10.3760/cma.j.issn.0254-6450.2016.06.007 (Chinese).CrossRefPubMed

Nadiminty N, Tummala R, Lou W, Zhu Y, Zhang J, Chen X, deVere White RW, Kung HJ, Evans CP, Gao AC. MicroRNA let-7c suppresses androgen receptor expression and activity via regulation of Myc expression in prostate cancer cells. J Biol Chem. 2012;287(2):1527–37. https://doi.org/10.1074/jbc.m111.278705 (Epub 2011 Nov 28).CrossRefPubMed

Loberg RD, Logothetis CJ, Keller ET, Pienta KJ. Pathogenesis and treatment of prostate cancer bone metastases: targeting the lethal phenotype. J Clin Oncol. 2005;23(32):8232–41 (Review).CrossRef

Center MM, Jemal A, Lortet-Tieulent J, Ward E, Ferlay J, Brawley O, Bray F. International variation in prostate cancer incidence and mortality rates. Eur Urol. 2012;61(6):1079–92. https://doi.org/10.1016/j.eururo.2012.02.054 (Epub 2012 Mar 8).CrossRefPubMed

Chun FK, Epstein JI, Ficarra V, Freedland SJ, Montironi R, Montorsi F, Shariat SF, Schröder FH, Scattoni V. Optimizing performance and interpretation of prostate biopsy: a critical analysis of the literature. Eur Urol. 2010;58(6):851–64. https://doi.org/10.1016/j.eururo.2010.08.041 (Epub 2010 Sep 4. Review).CrossRefPubMed

Crawford ED, Andriole GL, Marberger M, Rittmaster RS. Reduction in the risk of prostate cancer: future directions after the prostate cancer prevention trial. Urology. 2010;75(3):502–9. https://doi.org/10.1016/j.urology.2009.05.099 (Epub 2009 Dec 29. Review).CrossRefPubMed

Haas GP, Delongchamps NB, Jones RF, Chandan V, Serio AM, Vickers AJ, Jumbelic M, Threatte G, Korets R, Lilja H, de la Roza G. Needle biopsies on autopsy prostates: sensitivity of cancer detection based on true prevalence. J Natl Cancer Inst. 2007;99(19):1484–9 (Epub 2007 Sep 25).CrossRef

Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, Varambally S, Cao X, Tchinda J, Kuefer R, Lee C, Montie JE, Shah RB, Pienta KJ, Rubin MA, Chinnaiyan AM. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. 2005;310(5748):644–8.CrossRef

10.

Magi-Galluzzi C, Tsusuki T, Elson P, Simmerman K, LaFargue C, Esgueva R, Klein E, Rubin MA, Zhou M. TMPRSS2-ERG gene fusion prevalence and class are significantly different in prostate cancer of Caucasian, African-American and Japanese patients. Prostate. 2011;71(5):489–97. https://doi.org/10.1002/pros.21265 (Epub 2010 Sep 28).CrossRefPubMed

11.

Ren S, Peng Z, Mao JH, Yu Y, Yin C, Gao X, Cui Z, Zhang J, Yi K, Xu W, Chen C, Wang F, Guo X, Lu J, Yang J, Wei M, Tian Z, Guan Y, Tang L, Xu C, Wang L, Gao X, Tian W, Wang J, Yang H, Wang J, Sun Y. RNA-seq analysis of prostate cancer in the Chinese population identifies recurrent gene fusions, cancer-associated long noncoding RNAs and aberrant alternative splicings. Cell Res. 2012;22(5):806–21. https://doi.org/10.1038/cr.2012.30 (Epub 2012 Feb 21).CrossRefPubMedPubMedCentral

12.

Clinckemalie L, Spans L, Dubois V, Laurent M, Helsen C, Joniau S, Claessens F. Androgen regulation of the TMPRSS2 gene and the effect of a SNP in an androgen response element. Mol Endocrinol. 2013;27(12):2028–40. https://doi.org/10.1210/me.2013-1098 (Epub 2013 Oct 9).CrossRefPubMedPubMedCentral

13.

Clark JP, Cooper CS. ETS gene fusions in prostate cancer. Nat Rev Urol. 2009;6(8):429–39. https://doi.org/10.1038/nrurol.2009.127 (Review).CrossRefPubMed

14.

Hermans KG, van Marion R, van Dekken H, Jenster G, van Weerden WM, Trapman J. TMPRSS2:ERG fusion by translocation or interstitial deletion is highly relevant in androgen-dependent prostate cancer, but is bypassed in late-stage androgen receptor-negative prostate cancer. Cancer Res. 2006;66(22):10658–63.CrossRef

15.

Perner S, Demichelis F, Beroukhim R, Schmidt FH, Mosquera JM, Setlur S, Tchinda J, Tomlins SA, Hofer MD, Pienta KG, Kuefer R, Vessella R, Sun XW, Meyerson M, Lee C, Sellers WR, Chinnaiyan AM, Rubin MA. TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer. Cancer Res. 2006;66(17):8337–41.CrossRef

16.

Park K, Tomlins SA, Mudaliar KM, Chiu YL, Esgueva R, Mehra R, Suleman K, Varambally S, Brenner JC, MacDonald T, Srivastava A, Tewari AK, Sathyanarayana U, Nagy D, Pestano G, Kunju LP, Demichelis F, Chinnaiyan AM, Rubin MA. Antibody-based detection of ERG rearrangement-positive prostate cancer. Neoplasia. 2010;12(7):590–8.CrossRef

17.

Bories PN, Younes P, Zerbib M, Denjean L, Popovici T, Cynober L, Delongchamps NB. TMPRSS2-ERG fusion transcripts in matched urine and needle rinse material after biopsy for the detection of prostate cancer. Clin Chem. 2013;59(1):245–51. https://doi.org/10.1373/clinchem.2012.192260 (Epub 2012 Oct 8).CrossRefPubMed

18.

Stephan C, Jung K, Semjonow A, Schulze-Forster K, Cammann H, Hu X, Meyer HA, Bögemann M, Miller K, Friedersdorff F. Comparative assessment of urinary prostate cancer antigen 3 and TMPRSS2:ERG gene fusion with the serum [-2]proprostate-specific antigen-based prostate health index for detection of prostate cancer. Clin Chem. 2013;59(1):280–8. https://doi.org/10.1373/clinchem.2012.195560 (Epub 2012 Dec 4).CrossRefPubMed

19.

Pettersson A, Graff RE, Bauer SR, Pitt MJ, Lis RT, Stack EC, Martin NE, Kunz L, Penney KL, Ligon AH, Suppan C, Flavin R, Sesso HD, Rider JR, Sweeney C, Stampfer MJ, Fiorentino M, Kantoff PW, Sanda MG, Giovannucci EL, Ding EL, Loda M, Mucci LA. The TMPRSS2:ERG rearrangement, ERG expression, and prostate cancer outcomes: a cohort study and meta-analysis. Cancer Epidemiol Biomarkers Prev. 2012;21(9):1497–509. https://doi.org/10.1158/1055-9965.EPI-12-0042 (Epub 2012 Jun 26).CrossRefPubMedPubMedCentral

20.

Zhou H, Zhu D, Luo H, Jiang S, Wang Z, Xie J, Liu A. Expression significance of TMPRSS2, ERG and ETV1 in prostate cancer. J Clin Exp Pathol. 2015;31(8):855–9.

21.

Demichelis F, Fall K, Perner S, Andrén O, Schmidt F, Setlur SR, Hoshida Y, Mosquera JM, Pawitan Y, Lee C, Adami HO, Mucci LA, Kantoff PW, Andersson SO, Chinnaiyan AM, Johansson JE, Rubin MA. TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Oncogene. 2007;26(31):4596–9. Epub 2007 Jan 22. Erratum in: Oncogene. 2007;26(38):5692.CrossRef

22.

Attard G, Clark J, Ambroisine L, Fisher G, Kovacs G, Flohr P, Berney D, Foster CS, Fletcher A, Gerald WL, Moller H, Reuter V, De Bono JS, Scardino P, Cuzick J, Cooper CS, Transatlantic Prostate Group. Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer. Oncogene. 2008;27(3):253–63 (Epub 2007 Jul 16).CrossRef

23.

Hu Y, Dobi A, Sreenath T, Cook C, Tadase AY, Ravindranath L, Cullen J, Furusato B, Chen Y, Thangapazham RL, Mohamed A, Sun C, Sesterhenn IA, McLeod DG, Petrovics G, Srivastava S. Delineation of TMPRSS2-ERG splice variants in prostate cancer. Clin Cancer Res. 2008;14(15):4719–25. https://doi.org/10.1158/1078-0432.CCR-08-0531.CrossRefPubMed

24.

Sun WG, Xia L, Jiang LM, Yang WJ, Mo WF. Expression of TMPRSS2-ERG, AMACR and p63 in prostate cacinoma and their correlation Acta Universitatis Medicinalis Anhui 2012,47(11):1351-5.

25.

Kulda V, Topolcan O, Kucera R, Kripnerova M, Srbecka K, Hora M, Hes O, Klecka J, Babuska V, Rousarova M, Benson V, Pesta M. predictive significance of TMPRSS2-ERG fusion gene in prostate cancer. Anticancer Res. 2016;36(9):4787–93.CrossRef

26.

Ganie MA, Marwaha RK, Nisar S, Farooqi KJ, Jan RA, Wani SA, Gojwari T, Shah ZA. Impact of hypovitaminosis D on clinical, hormonal and insulin sensitivity parameters in normal body mass index polycystic ovary syndrome women. J Obstet Gynaecol. 2016;36(4):508–12. https://doi.org/10.3109/01443615.2015.1103715 (Epub 2016 Jan 15).CrossRefPubMed

27.

Barwick BG, Abramovitz M, Kodani M, Moreno CS, Nam R, Tang W, Bouzyk M, Seth A, Leyland-Jones B. Prostate cancer genes associated with TMPRSS2-ERG gene fusion and predictive of biochemical recurrence in multiple cohorts. Br J Cancer. 2010;102(3):570–6. https://doi.org/10.1038/sj.bjc.6605519 (Epub 2010 Jan 12).CrossRefPubMedPubMedCentral

28.

Steurer S, Mayer PS, Adam M, Krohn A, Koop C, Ospina-Klinck D, Tehrani AA, Simon R, Tennstedt P, Graefen M, Wittmer C, Brors B, Plass C, Korbel J, Weischenfeldt J, Sauter G, Huland H, Tsourlakis MC, Minner S, Schlomm T. TMPRSS2-ERG fusions are strongly linked to young patient age in low-grade prostate cancer. Eur Urol. 2014;66(6):978–81.CrossRef

29.

Young A, Palanisamy N, Siddiqui J, Wood David P, Wei John T, Chinnaiyan Arul M, Kunju Lakshmi P, Tomlins Scott A. Correlation of urine TMPRSS2:ERG and PCA3 to ERG+ and total prostate cancer burden. Am J Clin Pathol. 2012;138(5):685–96.CrossRef

30.

Tsourlakis MC, Stender A, Quaas A, Kluth M, Wittmer C, Haese A, Graefen M, Steurer S, Simon R, Korbel J, Weischenfeldt J, Huland H, Sauter G, Schlomm T, Minner S. Heterogeneity of ERG expression in prostate cancer: a large section mapping study of entire prostatectomy specimens from 125 patients. BMC Cancer. 2016;16:641. https://doi.org/10.1186/s12885-016-2674-6.CrossRefPubMedPubMedCentral

31.

Nam RK, Sugar L, Yang W, Srivastava S, Klotz LH, Yang LY, Stanimirovic A, Encioiu E, Neill M, Loblaw DA, Trachtenberg J, Narod SA, Seth A. Expression of the TMPRSS2:ERG fusion gene predicts cancer recurrence after surgery for localised prostate cancer. Br J Cancer. 2007;97(12):1690–5 (Epub 2007 Oct 30).CrossRef

32.

Wang J, Cai Y, Ren C, Ittmann M. Expression of variant TMPRSS2/ERG fusion messenger RNAs is associated with aggressive prostate cancer. Cancer Res. 2006;66(17):8347–51.CrossRef

33.

Yoshimoto M, Joshua AM, Cunha IW, Coudry RA, Fonseca FP, Ludkovski O, Zielenska M, Soares FA, Squire JA. Absence of TMPRSS2:ERG fusions and PTEN losses in prostate cancer is associated with a favorable outcome. Mod Pathol. 2008;21(12):1451–60. https://doi.org/10.1038/modpathol.2008.96 (Epub 2008 May 23).CrossRefPubMed

34.

Saramäki OR, Harjula AE, Martikainen PM, Vessella RL, Tammela TL, Visakorpi T. TMPRSS2:ERG fusion identifies a subgroup of prostate cancers with a favorable prognosis. Clin Cancer Res. 2008;14(11):3395–400. https://doi.org/10.1158/1078-0432.CCR-07-2051.CrossRefPubMed

35.

Lee K, Chae JY, Kwak C, Ku JH, Moon KC. TMPRSS2-ERG gene fusion and clinicopathologic characteristics of Korean prostate cancer patients. Urology. 2010;76(5):1268.e7–13. https://doi.org/10.1016/j.urology.2010.06.010 (Epub 2010 Aug 30).CrossRef

36.

Leinonen KA, Tolonen TT, Bracken H, Stenman UH, Tammela TL, Saramäki OR, Visakorpi T. Association of SPINK1 expression and TMPRSS2:ERG fusion with prognosis in endocrine-treated prostate cancer. Clin Cancer Res. 2010;16(10):2845–51. https://doi.org/10.1158/1078-0432.CCR-09-2505 (Epub 2010 May 4).CrossRefPubMed

37.

Gopalan A, Leversha MA, Satagopan JM, Zhou Q, Al-Ahmadie HA, Fine SW, Eastham JA, Scardino PT, Scher HI, Tickoo SK, Reuter VE, Gerald WL. TMPRSS2-ERG gene fusion is not associated with outcome in patients treated by prostatectomy. Cancer Res. 2009;69(4):1400–6. https://doi.org/10.1158/0008-5472.CAN-08-2467 (Epub 2009 Feb 3).CrossRefPubMedPubMedCentral

38.

Lapointe J, Kim YH, Miller MA, Li C, Kaygusuz G, van de Rijn M, Huntsman DG, Brooks JD, Pollack JR. A variant TMPRSS2 isoform and ERG fusion product in prostate cancer with implications for molecular diagnosis. Mod Pathol. 2007;20(4):467–73 (Epub 2007 Mar 2).CrossRef

39.

Rostad K, Hellwinkel OJ, Haukaas SA, Halvorsen OJ, Øyan AM, Haese A, Budäus L, Albrecht H, Akslen LA, Schlomm T, Kalland KH. TMPRSS2:ERG fusion transcripts in urine from prostate cancer patients correlate with a less favorable prognosis. APMIS. 2009;117(8):575–82. https://doi.org/10.1111/j.1600-0463.2009.02517.x.CrossRefPubMed

40.

Hofer MD, Kuefer R, Maier C, Herkommer K, Perner S, Demichelis F, Paiss T, Vogel W, Rubin MA, Hoegel J. Genome-wide linkage analysis of TMPRSS2-ERG fusion in familial prostate cancer. Cancer Res. 2009;69(2):640–6. https://doi.org/10.1158/0008-5472.CAN-08-2008.CrossRefPubMed

41.

Rubio-Briones J, Fernández-Serra A, Calatrava A, García-Casado Z, Rubio L, Bonillo MA, Iborra I, Solsona E, López-Guerrero JA. Clinical implications of TMPRSS2-ERG gene fusion expression in patients with prostate cancer treated with radical prostatectomy. J Urol. 2010;183(5):2054–61. https://doi.org/10.1016/j.juro.2009.12.096 (Epub 2010 Mar 19).CrossRefPubMed

42.

Toubaji A, Albadine R, Meeker AK, Isaacs WB, Lotan T, Haffner MC, Chaux A, Epstein JI, Han M, Walsh PC, Partin AW, De Marzo AM, Platz EA, Netto GJ. Increased gene copy number of ERG on chromosome 21 but not TMPRSS2-ERG fusion predicts outcome in prostatic adenocarcinomas. Mod Pathol. 2011;24(11):1511–20. https://doi.org/10.1038/modpathol.2011.111 (Epub 2011 Jul 8).CrossRefPubMedPubMedCentral

43.

Minner S, Enodien M, Sirma H, Luebke AM, Krohn A, Mayer PS, Simon R, Tennstedt P, Müller J, Scholz L, Brase JC, Liu AY, Schlüter H, Pantel K, Schumacher U, Bokemeyer C, Steuber T, Graefen M, Sauter G, Schlomm T. ERG status is unrelated to PSA recurrence in radically operated prostate cancer in the absence of antihormonal therapy. Clin Cancer Res. 2011;17(18):5878–88. https://doi.org/10.1158/1078-0432.CCR-11-1251 (Epub 2011 Jul 26).CrossRefPubMed

44.

Darnel AD, Lafargue CJ, Vollmer RT, Corcos J, Bismar TA. TMPRSS2-ERG fusion is frequently observed in Gleason pattern 3 prostate cancer in a Canadian cohort. Cancer Biol Ther. 2009;8(2):125–30 (Epub 2009 Feb 4).CrossRef

45.

Schaefer G, Mosquera JM, Ramoner R, Park K, Romanel A, Steiner E, Horninger W, Bektic J, Ladurner-Rennau M, Rubin MA, Demichelis F, Klocker H. Distinct ERG rearrangement prevalence in prostate cancer: higher frequency in young age and in low PSA prostate cancer. Prostate Cancer Prostatic Dis. 2013;16(2):132–8. https://doi.org/10.1038/pcan.2013.4 (Epub 2013 Feb 5).CrossRefPubMedPubMedCentral

46.

Dong J, Xiao L, Sheng L, Xu J, Sun ZQ. TMPRSS2:ETS fusions and clinicopathologic characteristics of prostate cancer patients from Eastern China. Asian Pac J Cancer Prev. 2014;15(7):3099–103.CrossRef

47.

Hermans KG, Boormans JL, Gasi D, van Leenders GJ, Jenster G, Verhagen PC, Trapman J. Overexpression of prostate-specific TMPRSS2(exon 0)-ERG fusion transcripts corresponds with favorable prognosis of prostate cancer. Clin Cancer Res. 2009;15(20):6398–403. https://doi.org/10.1158/1078-0432.CCR-09-1176 (Epub 2009 Oct 13).CrossRefPubMed

48.

Shah RB, Chinnaiyan AM. The discovery of common recurrent transmembrane protease serine 2 (TMPRSS2)-erythroblastosis virus E26 transforming sequence (ETS) gene fusions in prostate cancer: significance and clinical implications. Adv Anat Pathol. 2009;16(3):145–53. https://doi.org/10.1097/PAP.0b013e3181a12da7 (Review).CrossRefPubMed

Title: Predictive significance of TMRPSS2-ERG fusion in prostate cancer: a meta-analysis
Authors: Chunjiao Song
Huan Chen
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Cancer Cell International / Issue 1/2018
Electronic ISSN: 1475-2867
DOI: https://doi.org/10.1186/s12935-018-0672-2

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