TMPRSS2-ERG gene fusion is not associated with outcome in patients treated by prostatectomy.

A significant number of prostate cancers have been shown to have recurrent chromosomal rearrangements resulting in the fusion of the androgen-regulated TMPRSS2 promoter to a member of the ETS transcription factor family, most commonly ERG. This results in ERG overexpression, which may have a direct causal role in prostate tumorigenesis or progression. However, the clinical significance of the rearrangement is unclear, and in particular, relationship to outcome has been inconsistent in recent reports. We analyzed TMPRSS2-ERG gene rearrangement status by fluorescence in situ hybridization in 521 cases of clinically localized surgically treated prostate cancer with 95 months of median follow-up and also in 40 unmatched metastases. Forty-two percent of primary tumors and 40% of metastases had rearrangements. Eleven percent had copy number increase (CNI) of the TMPRRS2-ERG region. Rearrangement alone was associated with lower grade, but not with stage, biochemical recurrence, metastases, or death. CNI with and without rearrangement was associated with high grade and advanced stage. Further, a subgroup of cancers with CNI and rearrangement by deletion, with two or more copies of the deleted locus, tended to be more clinically aggressive. DNA index assessment revealed that the majority of tumors with CNI of TMPRSS2-ERG had generalized aneuploidy/tetraploidy in contrast to tumors without TMPRSS2-ERG CNI, which were predominantly diploid. We therefore conclude that translocation of TMPRSS2-ERG is not associated with outcome, and the aggressive clinical features associated with CNI of chromosome 21 reflect generalized aneuploidy and are not due to CNI specifically of rearranged TMPRSS2-ERG.

[1]  Hans Garmo,et al.  Radical prostatectomy versus watchful waiting in early prostate cancer. , 2005, The New England journal of medicine.

[2]  John T. Wei,et al.  The role of SPINK1 in ETS rearrangement-negative prostate cancers. , 2008, Cancer cell.

[3]  T. Tammela,et al.  TMPRSS2:ERG Fusion Identifies a Subgroup of Prostate Cancers with a Favorable Prognosis , 2008, Clinical Cancer Research.

[4]  J Cuzick,et al.  Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer , 2008, Oncogene.

[5]  M. Rubin,et al.  TMPRSS2-ERG fusion heterogeneity in multifocal prostate cancer: clinical and biologic implications. , 2007, Urology.

[6]  J. Brooks,et al.  Genomic profiling reveals alternative genetic pathways of prostate tumorigenesis. , 2007, Cancer research.

[7]  Adam S. Kibel,et al.  TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort , 2007 .

[8]  R. Shah,et al.  Heterogeneity of TMPRSS2 gene rearrangements in multifocal prostate adenocarcinoma: molecular evidence for an independent group of diseases. , 2007, Cancer research.

[9]  J. Witjes,et al.  Detection of TMPRSS2-ERG Fusion Transcripts and Prostate Cancer Antigen 3 in Urinary Sediments May Improve Diagnosis of Prostate Cancer , 2007, Clinical Cancer Research.

[10]  S. Dhanasekaran,et al.  Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer , 2007, Nature.

[11]  Yao-Tseng Chen,et al.  Gene fusions between TMPRSS2 and ETS family genes in prostate cancer: frequency and transcript variant analysis by RT-PCR and FISH on paraffin-embedded tissues , 2007, Modern Pathology.

[12]  Debashis Ghosh,et al.  Comprehensive assessment of TMPRSS2 and ETS family gene aberrations in clinically localized prostate cancer , 2007, Modern Pathology.

[13]  R. Eeles,et al.  Diversity of TMPRSS2-ERG fusion transcripts in the human prostate , 2007, Oncogene.

[14]  L. Klotz,et al.  Expression of TMPRSS2:ERG gene fusion in prostate cancer cells is an important prognostic factor for cancer progression , 2007, Cancer biology & therapy.

[15]  M. Rubin,et al.  TMPRSS2-ERG Fusion Prostate Cancer: An Early Molecular Event Associated With Invasion , 2006, The American journal of surgical pathology.

[16]  V. Srikantan,et al.  Frequent overexpression of ETS-related gene-1 (ERG1) in prostate cancer transcriptome , 2006, Oncogene.

[17]  G. Jenster,et al.  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. , 2006, Cancer research.

[18]  O. Kallioniemi,et al.  TMPRSS2 fusions with oncogenic ETS factors in prostate cancer involve unbalanced genomic rearrangements and are associated with HDAC1 and epigenetic reprogramming. , 2006, Cancer research.

[19]  J. Cuzick,et al.  Long-term outcome among men with conservatively treated localised prostate cancer , 2006, British Journal of Cancer.

[20]  R. Henrique,et al.  TMPRSS2-ERG gene fusion causing ERG overexpression precedes chromosome copy number changes in prostate carcinomas and paired HGPIN lesions. , 2006, Neoplasia.

[21]  Lei Wang,et al.  Noninvasive detection of TMPRSS2:ERG fusion transcripts in the urine of men with prostate cancer. , 2006, Neoplasia.

[22]  Michael Ittmann,et al.  Expression of variant TMPRSS2/ERG fusion messenger RNAs is associated with aggressive prostate cancer. , 2006, Cancer research.

[23]  J. Tchinda,et al.  TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer. , 2006, Cancer research.

[24]  Arul M Chinnaiyan,et al.  TMPRSS2:ETV4 gene fusions define a third molecular subtype of prostate cancer. , 2006, Cancer research.

[25]  J. Tchinda,et al.  Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. , 2006, Science.

[26]  W. Gerald,et al.  Integration of gene expression profiling and clinical variables to predict prostate carcinoma recurrence after radical prostatectomy , 2005, Cancer.

[27]  W. Gerald,et al.  Gene expression profiling predicts clinical outcome of prostate cancer. , 2004, The Journal of clinical investigation.

[28]  Arul M Chinnaiyan,et al.  Multiplex biomarker approach for determining risk of prostate-specific antigen-defined recurrence of prostate cancer. , 2003, Journal of the National Cancer Institute.

[29]  S. Dhanasekaran,et al.  The polycomb group protein EZH2 is involved in progression of prostate cancer , 2002, Nature.

[30]  J. Martínez-Jabaloyas,et al.  Prognostic value of DNA ploidy and nuclear morphometry in prostate cancer treated with androgen deprivation. , 2002, Urology.

[31]  J. Cheville,et al.  Factors That Influence the Measurement of Prostate Cancer DNA Ploidy and Proliferation in Paraffin Embedded Tissue Evaluated by Flow Cytometry , 2001, Modern Pathology.

[32]  S. Dhanasekaran,et al.  Delineation of prognostic biomarkers in prostate cancer , 2001, Nature.

[33]  M. Leversha.  Mapping of genomic clones by fluorescence in situ hybridization. , 2001, Methods in molecular biology.

[34]  E. Bergstralh,et al.  Use of Gleason score, prostate specific antigen, seminal vesicle and margin status to predict biochemical failure after radical prostatectomy. , 2001, The Journal of urology.

[35]  L. Truong,et al.  Caveolin-1 expression in clinically confined human prostate cancer: a novel prognostic marker. , 1999, Cancer research.

[36]  M. Kattan,et al.  Postoperative nomogram for disease recurrence after radical prostatectomy for prostate cancer. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  J. Overgaard,et al.  DNA ploidy and survival of patients with clinically localized prostate cancer treated without intent to cure , 1998, The Prostate.

[38]  D. Bostwick,et al.  Comparison of fluorescence in situ hybridization analysis of isolated nuclei and routine histological sections from paraffin-embedded prostatic adenocarcinoma specimens. , 1996, The American journal of pathology.

[39]  F. Marshall,et al.  Selection of men at high risk for disease recurrence for experimental adjuvant therapy following radical prostatectomy. , 1995, Urology.

[40]  M. Lieber.  Practical clinical utility of DNA ploidy for managing patients with prostate carcinoma. , 1995, Urology.

[41]  G. Haas,et al.  Flow cytometric DNA analysis of fresh prostatic resections: Correlation with conventional prognostic parameters in patients with prostate cancer , 1993, Cancer.

[42]  N. Tinari,et al.  DNA and S‐phase fraction analysis by flow cytometry in prostate cancer. Clinicopathologic implications , 1993, Cancer.

[43]  J. Adolfsson,et al.  The prognostic value of modal deoxyribonucleic acid in low grade, low stage untreated prostate cancer. , 1990, The Journal of urology.

[44]  L. Layfield,et al.  Relationship of DNA content to conventional prognostic factors in clinically localised carcinoma of the prostate. , 1988, British journal of urology.

[45]  J. Chin,et al.  Relationship between DNA ploidy, glandular differentiation, and tumor spread in human prostate cancer. , 1985, Cancer research.