ERG oncoprotein expression in prostate carcinoma patients of different ethnicities

Kelly,Gregory  M.; Kong,Yink  Heay; Dobi,Albert; Srivastava,Shiv; Sesterhenn,Isabell  A.; Pathmanathan,Rajadurai; Tan,Hui  Meng; Tan,Shyh‑Han; Cheong,Sok  Ching

doi:10.3892/mco.2014.418

ERG oncoprotein expression in prostate carcinoma patients of different ethnicities

Authors:
- Gregory M. Kelly
- Yink Heay Kong
- Albert Dobi
- Shiv Srivastava
- Isabell A. Sesterhenn
- Rajadurai Pathmanathan
- Hui Meng Tan
- Shyh‑Han Tan
- Sok Ching Cheong
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Affiliations: Oral Cancer Research Team, Cancer Research Initiatives Foundation (CARIF), 2nd Floor Outpatient Centre, Sime Darby Medical Centre, Subang Jaya, Selangor 47500, Malaysia, Department of Surgery, Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA, Joint Pathology Center, Silver Spring, MD 20910, USA, Sime Darby Medical Centre, Subang Jaya, Selangor 47500, Malaysia
Published online on: September 18, 2014 https://doi.org/10.3892/mco.2014.418
Pages: 23-30

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Abstract

overexpression of the erythroblast transformation‑specific‑related gene (ERG) oncoprotein due to transmembrane protease, serine 2 (TMPRSS2)‑ERG fusion, the most prevalent genomic alteration in prostate cancer (CaP), is more frequently observed among Caucasian patients compared to patients of African or Asian descent. To the best of our knowledge, this is the first study to investigate the prevalence of ERG alterations in a multiethnic cohort of CaP patients. A total of 191 formalin‑fixed paraffin‑embedded sections of transrectal ultrasound‑guided prostate biopsy specimens, collected from 120 patients treated at the Sime Darby Medical Centre, Subang Jaya, Malaysia, were analyzed for ERG protein expression by immunohistochemistry using the anti‑ERG monoclonal antibody 9FY as a surrogate for the detection of ERG fusion events. The overall frequency of ERG protein expression in the population evaluated in this study was 39.2%. Although seemingly similar to rates reported in other Asian communities, the expression of ERG was distinct amongst different ethnic groups (p=0.004). Malaysian Indian (MI) patients exhibited exceedingly high expression of ERG in their tumors, almost doubling that of Malaysian Chinese (MC) patients, whereas ERG expression was very low amongst Malay patients (12.5%). When collectively analyzing data, we observed a significant correlation between younger patients and higher ERG expression (p=0.04). The prevalence of ERG expression was significantly different amongst CaP patients of different ethnicities. The higher number of ERG‑expressing tumors among MI patients suggested that the TMPRSS2‑ERG fusion may be particularly important in the pathogenesis of CaP amongst this group of patients. Furthermore, the more frequent expression of ERG among the younger patients analyzed suggested an involvement of ERG in the early onset of CaP. The results of this study underline the value of using ERG status to better understand the differences in the etiology of CaP initiation and progression between ethnic groups.

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1	Zainal Ariffin O and Nor Saleha IT: Nationa. Cancer Registry Report 2007. Malaysia Cancer Statistics - Data and Figure. National Cancer Registry, Ministry of Health, Putrajaya Malaysia: 2011
2	Othman NH, Nor ZM and Biswal BM: Is Kelantan joining the global cancer epidemic? - experience from hospital Universiti Sains Malaysia; 1987–2007. Asian Pac J Cancer Prev. 9:473–478. 2008.PubMed/NCBI
3	Farrell J, Petrovics G, McLeod DG and Srivastava S: Genetic and molecular differences in prostate carcinogenesis between African American and Caucasian American men. Int J Mol Sci. 14:15510–15531. 2013. View Article : Google Scholar : PubMed/NCBI
4	Mononen N and Schleutker J: Polymorphisms in genes involved in androgen pathways as risk factors for prostate cancer. J Urol. 181:1541–1549. 2009. View Article : Google Scholar : PubMed/NCBI
5	Rosen P, Pfister D, Young D, et al: Differences in frequency of ERG oncoprotein expression between index tumors of Caucasian and African American patients with prostate cancer. Urology. 80:749–753. 2012. View Article : Google Scholar
6	Martin DN, Starks AM and Ambs S: Biological determinants of health disparities in prostate cancer. Curr Opin Oncol. 25:235–241. 2013.PubMed/NCBI
7	Amundadottir LT, Sulem P, Gudmundsson J, et al: A common variant associated with prostate cancer in European and African populations. Nat Genet. 38:652–658. 2006. View Article : Google Scholar : PubMed/NCBI
8	Freedman ML, Haiman CA, Patterson N, et al: Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men. Proc Natl Acad Sci USA. 103:14068–14073. 2006. View Article : Google Scholar : PubMed/NCBI
9	Taioli E, Sears V, Watson A, et al: Polymorphisms in CYP17 and CYP3A4 and prostate cancer in men of African descent. Prostate. 73:668–676. 2013. View Article : Google Scholar : PubMed/NCBI
10	Rubin MA, Maher CA and Chinnaiyan AM: Common gene rearrangements in prostate cancer. J Clin Oncol. 29:3659–3668. 2011. View Article : Google Scholar : PubMed/NCBI
11	Rosen P, Sesterhenn IA, Brassell SA, McLeod DG, Srivastava S and Dobi A: Clinical potential of the ERG oncoprotein in prostate cancer. Nat Rev Urol. 9:131–137. 2012. View Article : Google Scholar : PubMed/NCBI
12	Magi-Galluzzi C, Tsusuki T, Elson P, et al: TMPRSS2-ERG gene fusion prevalence and class are significantly different in prostate cancer of Caucasian, African-American and Japanese patients. Prostate. 71:489–497. 2011. View Article : Google Scholar
13	Lee K, Chae JY, Kwak C, Ku JH and Moon KC: TMPRSS2-ERG gene fusion and clinicopathologic characteristics of Korean prostate cancer patients. Urology. 76(1268): e7–e13. 2010.PubMed/NCBI
14	Mao X, Yu Y, Boyd LK, et al: Distinct genomic alterations in prostate cancers in Chinese and Western populations suggest alternative pathways of prostate carcinogenesis. Cancer Res. 70:5207–5212. 2010. View Article : Google Scholar
15	Miyagi Y, Sasaki T, Fujinami K, et al: ETS family-associated gene fusions in Japanese prostate cancer: analysis of 194 radical prostatectomy samples. Mod Pathol. 23:1492–1498. 2010. View Article : Google Scholar
16	Furusato B, van Leenders GJ, Trapman J, et al: Immunohistochemical ETS-related gene detection in a Japanese prostate cancer cohort: diagnostic use in Japanese prostate cancer patients. Pathol Int. 61:409–414. 2011. View Article : Google Scholar : PubMed/NCBI
17	Kimura T, Furusato B, Miki J, et al: Expression of ERG oncoprotein is associated with a less aggressive tumor phenotype in Japanese prostate cancer patients. Pathol Int. 62:742–748. 2012. View Article : Google Scholar : PubMed/NCBI
18	Suh JH, Park JW, Lee C and Moon KC: ERG immunohistochemistry and clinicopathologic characteristics in Korean prostate adenocarcinoma patients. Korean J Pathol. 46:423–428. 2012. View Article : Google Scholar : PubMed/NCBI
19	Rawal S, Young D, Williams M, et al: Low frequency of the ERG oncogene alterations in prostate cancer patients from India. J Cancer. 4:468–472. 2013. View Article : Google Scholar : PubMed/NCBI
20	Qi M, Yang X, Zhang F, et al: ERG rearrangement is associated with prostate cancer-related death in Chinese prostate cancer patients. PLoS One. 9:e849592014. View Article : Google Scholar : PubMed/NCBI
21	Petrovics G, Liu A, Shaheduzzaman S, et al: Frequent overexpression of ETS-related gene-1 (ERG1) in prostate cancer transcriptome. Oncogene. 24:3847–3852. 2005. View Article : Google Scholar : PubMed/NCBI
22	Tomlins SA, Rhodes DR, Perner S, et al: Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. 310:644–648. 2005. View Article : Google Scholar : PubMed/NCBI
23	Dobi A, Sreenath T and Srivastava S: Androgen-dependent oncogenic activation of ETS transcription factors by recurrent gene fusions in prostate cancer: biological and clinical implicationsAndrogen-Responsive Genes in Prostate Cancer. WangZ: Springer; New York, NY: pp. 307–328. 2013, View Article : Google Scholar
24	Sreenath TL, Dobi A, Petrovics G and Srivastava S: Oncogenic activation of ERG: a predominant mechanism in prostate cancer. J Carcinog. 10(37)2011.PubMed/NCBI
25	Furusato B, Tan SH, Young D, et al: ERG oncoprotein expression in prostate cancer: clonal progression of ERG-positive tumor cells and potential for ERG-based stratification. Prostate Cancer Prostatic Dis. 13:228–237. 2010. View Article : Google Scholar : PubMed/NCBI
26	Sun C, Dobi A, Mohamed A, et al: TMPRSS2-ERG fusion, a common genomic alteration in prostate cancer activates C-MYC and abrogates prostate epithelial differentiation. Oncogene. 27:5348–5353. 2008. View Article : Google Scholar : PubMed/NCBI
27	Gupta S, Iljin K, Sara H, et al: FZD4 as a mediator of ERG oncogene-induced WNT signaling and epithelial-to-mesenchymal transition in human prostate cancer cells. Cancer Res. 70:6735–6745. 2010. View Article : Google Scholar : PubMed/NCBI
28	Carver BS, Tran J, Gopalan A, et al: Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nat Genet. 41:619–624. 2009. View Article : Google Scholar : PubMed/NCBI
29	King JC, Xu J, Wongvipat J, et al: Cooperativity of TMPRSS2-ERG with PI3-kinase pathway activation in prostate oncogenesis. Nat Genet. 41:524–526. 2009. View Article : Google Scholar : PubMed/NCBI
30	Rahim S and Uren A: Emergence of ETS transcription factors as diagnostic tools and therapeutic targets in prostate cancer. Am J Transl Res. 5:254–268. 2013.PubMed/NCBI
31	Park K, Tomlins SA, Mudaliar KM, et al: Antibody-based detection of ERG rearrangement-positive prostate cancer. Neoplasia. 12:590–598. 2010.PubMed/NCBI
32	Braun M, Goltz D, Shaikhibrahim Z, et al: ERG protein expression and genomic rearrangement status in primary and metastatic prostate cancer - a comparative study of two monoclonal antibodies. Prostate Cancer Prostatic Dis. 15:165–169. 2012. View Article : Google Scholar
33	Svensson MA, Perner S, Ohlson AL, et al: A comparative study of ERG status assessment on DNA, mRNA, and protein levels using unique samples from a Swedish biopsy cohort. Appl Immunohistochem Mol Morphol. 22:136–141. 2014. View Article : Google Scholar : PubMed/NCBI
34	Gsponer JR, Braun M, Scheble VJ, et al: ERG rearrangement and protein expression in the progression to castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. 17:126–131. 2014. View Article : Google Scholar : PubMed/NCBI
35	Fontugne J, Lee D, Cantaloni C, et al: Recurrent prostate cancer genomic alterations predict response to brachytherapy treatment. Cancer Epidemiol Biomarkers Prev. 23:594–600. 2014. View Article : Google Scholar : PubMed/NCBI
36	Hasan ARb: Statistica. Handbook Malaysia 2013. Department of Statistics; Malaysia: 2013
37	Attard G, Clark J, Ambroisine L, et al: Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer. Oncogene. 27:253–263. 2008. View Article : Google Scholar
38	Rajput AB, Miller MA, De Luca A, et al: Frequency of the TMPRSS2:ERG gene fusion is increased in moderate to poorly differentiated prostate cancers. J Clin Pathol. 60:1238–1243. 2007. View Article : Google Scholar : PubMed/NCBI
39	Demichelis F, Fall K, Perner S, et al: TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Oncogene. 26:4596–4599. 2007. View Article : Google Scholar : PubMed/NCBI
40	Darnel AD, Lafargue CJ, Vollmer RT, Corcos J and Bismar TA: TMPRSS2-ERG fusion is frequently observed in Gleason pattern 3 prostate cancer in a Canadian cohort. Cancer Biol Ther. 8:125–130. 2009. View Article : Google Scholar : PubMed/NCBI
41	Perner S, Demichelis F, Beroukhim R, et al: TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer. Cancer Res. 66:8337–8341. 2006. View Article : Google Scholar : PubMed/NCBI
42	Mehra R, Tomlins SA, Shen R, et al: Comprehensive assessment of TMPRSS2 and ETS family gene aberrations in clinically localized prostate cancer. Mod Pathol. 20:538–544. 2007. View Article : Google Scholar : PubMed/NCBI
43	Schaefer G, Mosquera JM, Ramoner R, et al: Distinct ERG rearrangement prevalence in prostate cancer: higher frequency in young age and in low PSA prostate cancer. Prostate Cancer Prostatic Dis. 16:132–138. 2013.PubMed/NCBI
44	Fromont G, Godet J, Peyret A, et al: 8q24 amplification is associated with Myc expression and prostate cancer progression and is an independent predictor of recurrence after radical prostatectomy. Hum Pathol. 44:1617–1623. 2013. View Article : Google Scholar : PubMed/NCBI
45	Gopalan A, Leversha MA, Satagopan JM, et al: TMPRSS2-ERG gene fusion is not associated with outcome in patients treated by prostatectomy. Cancer Res. 69:1400–1406. 2009. View Article : Google Scholar : PubMed/NCBI
46	Mosquera JM, Mehra R, Regan MM, et al: Prevalence of TMPRSS2-ERG fusion prostate cancer among men undergoing prostate biopsy in the United States. Clin Cancer Res. 15:4706–4711. 2009. View Article : Google Scholar : PubMed/NCBI
47	Setlur SR, Mertz KD, Hoshida Y, et al: Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer. J Natl Cancer Inst. 100:815–825. 2008. View Article : Google Scholar : PubMed/NCBI
48	Sboner A, Demichelis F, Calza S, et al: Molecular sampling of prostate cancer: a dilemma for predicting disease progression. BMC Med Genomics. 3(8)2010. View Article : Google Scholar : PubMed/NCBI
49	Hofer MD, Kuefer R, Maier C, et al: Genome-wide linkage analysis of TMPRSS2-ERG fusion in familial prostate cancer. Cancer Res. 69:640–646. 2009. View Article : Google Scholar : PubMed/NCBI
50	Xue L, Mao X, Ren G, et al: Chinese and Western prostate cancers show alternate pathogenetic pathways in association with ERG status. Am J Cancer Res. 2:736–744. 2012.PubMed/NCBI