Molecular biology underlying the clinical heterogeneity of prostate cancer: an update.
* Context.--Recent studies have uncovered a number of possible
mechanisms by which prostate cancers can become resistant to systemic
androgen deprivation, most involving androgen-independent reactivation
of the androgen receptor. Genome-wide expression analysis with
microarrays has identified a wide array of genes that are differentially
expressed in metastatic prostate cancers compared to primary
nonrecurrent tumors. Recently, recurrent gene fusions between TMPRSS2
and ETS family genes have been identified and extensively studied for
their role in prostatic carcinoma.
Objective.--To review the recent developments in the molecular biology of prostate cancer, including those pertaining to the androgen receptor and the newly identified TMPRSS2-related translocations.
Data Sources.--Literature review and personal experience.
Conclusions.--Prostatic adenocarcinoma is a heterogeneous group of neoplasms with a broad spectrum of pathologic and molecular characteristics and clinical behaviors. Numerous mechanisms contribute to the development of resistance to androgen ablation therapy, resulting in ligand-independent reactivation of the androgen receptor, including amplification, mutation, phosphorylation, and activation of coreceptors. Multiple translocations of members of the ETS oncogene family are present in approximately half of clinically localized prostate cancers.
TMPRSS2:ERG gene rearrangement appears to be an early event in prostate cancer and is not observed in benign or hyperplastic prostatic epithelium. Duplication of
TMPRSS2:ERG appears to predict a worse prognosis. The relationship between TMPRSS2:ERG gene rearrangement and other morphologic and prognostic parameters of prostate cancer is still unclear.
Prostate cancer (Development and progression)
Prostate cancer (Care and treatment)
Molecular biology (Usage)
Androgens (Physiological aspects)
Gene mutations (Research)
Gene mutations (Physiological aspects)
Mackinnon, A. Craig
Yan, Benjamin C.
Joseph, Loren J.
Al-Ahmadie, Hikmat A.
|Publication:||Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 College of American Pathologists ISSN: 1543-2165|
|Issue:||Date: July, 2009 Source Volume: 133 Source Issue: 7|
|Topic:||Event Code: 310 Science & research|
|Product:||Product Code: 8521213 Molecular Biology NAICS Code: 54171 Research and Development in the Physical, Engineering, and Life Sciences SIC Code: 2833 Medicinals and botanicals|
|Geographic:||Geographic Scope: United States Geographic Code: 1USA United States|
Prostate cancer is the most common noncutaneous malignancy in men
and the second most common cause of cancer deaths, accounting for 186
320 new annual cases and 28 660 deaths in America and an annual
incidence of 679023 cases and 221002 deaths worldwide in 2008. (1,2) The
highest incidence of prostate cancer is found in the United States,
Canada, and Scandinavia, and the lowest in China and other parts of
Asia. (3,4) Risk factors include advancing age, African American
ethnicity, family history, and diet. (5-9) The increasingly widespread
testing for serum levels of prostate-specific antigen (PSA) has allowed
for the increasing detection of prostate cancers at earlier stages of
development. As a result, prostatic adenocarcinoma has become a
clinically heterogeneous entity, with some early carcinomas following an
indolent clinical course, remaining confined to the prostate with little
effect on overall lifespan, while other cases can lead to the
development of lethal metastatic disease. Despite the recent advances in
treatment modalities, surgical, radiation, and hormonal therapies for
prostate cancer are not without complications, making the development of
methods for distinguishing indolent cancers from their aggressive
counterparts necessary to avoid excessive treatment that may lead to
significant morbidity. (10) Furthermore, current methods of treating
advanced metastatic disease often prove to be insufficient in the
long-term. Recent research has therefore sought to identify new
molecular pathways by which investigators can distinguish indolent
prostate cancers from those that go on to pursue a more aggressive
clinical course, as well as to discover new targets for the treatment of
Previous cytogenetic and molecular studies (11-21) had shown that prostatic adenocarcinomas tend to incur frequent and consistent losses of specific chromosomal loci, including chromosomes 8p, 10q, 13q, and 17p, and, less commonly, 6q, 7q, 16q, and 18q, as well as gains in chromosomes 7 and 8q. More recently, investigators compared the gene expression profiles of primary nonrecurrent prostatic adenocarcinomas and metastatic prostate cancers by using microarrays. (22) Genes that were more highly expressed in metastatic carcinomas included those involved in DNA synthesis and repair, mitosis, and cell cycle regulation, such as RFC5, TOP2A, RFC4, and MAD2L1, which have previously been shown to be highly expressed in proliferating cells. (23) Other differentially expressed genes included those involved in signal transduction, transcriptional regulation, chromatin modification, RNA processing, protein synthesis, posttranslational protein modification, cell adhesion, cell migration, cytoskeletal regulatory elements, extracellular matrix proteins, biosynthetic enzymes, and transport proteins. (22) Several unclassified genes with unknown functions were also found to be differentially expressed. (22)
PROSTATIC ADENOCARCINOMA RESISTANT TO ANDROGEN ABLATION THERAPY
Prostate cancer affects 1 of 9 men older than 65 years. (24) Age correlates with a decrease in the ratio of androgens to estrogens in men, suggesting that a physiologic change in hormonal status may contribute to the progression of preneoplastic lesions to adenocarcinoma. (25-27) Androgen ablation therapy is the most common systemic treatment for metastatic disease; it prevents testosterone production by the testes and thereby causes tumor regression during the short-term by depleting androgen-dependent carcinoma cells. (28,29) Androgen deprivation can be achieved surgically or by medical castration, which can be performed by the administration of estrogens and gonadotropin-releasing agonists and antagonists, and has been shown to be effective in treating advanced and metastatic disease in several large clinical trials. (30-33) However, most prostatic adenocarcinomas become refractory to androgen ablation. (34) Experiments with animal models of prostatic adenocarcinomas, (34,35) such as Dunning R-3327-H rat prostate carcinomas and the transgenic adenocarcinoma mouse prostate model, have shown that androgen therapy ultimately selects for androgen-independent carcinoma cells during the long-term, leading to the development of highly aggressive, androgen-resistant tumors. Despite this progression to more aggressive disease, it is still advised that patients with hormone-resistant cancers continue to receive androgen ablation therapy. (36)
Aberrant activation of the androgen receptor (AR) can result from gene amplification, mutation, phosphorylation, activation of coregulators, or androgen-independent activation. Most cases of prostatic carcinoma resistant to androgen ablation therapy demonstrate activation of AR by one of these mechanisms. (37-39) The AR gene is either mutated or amplified in 20% to 30% of androgen-resistant prostate carcinomas. (40-42) Further, 20% of hormone-resistant carcinomas contain gene amplifications as compared to just 2% of hormone-sensitive tumors, suggesting that aberrant activation in response to low levels of androgens or other ligands may underlie the progression to aggressive disease that is refractory to androgen ablation therapy. (43) Specific mutations, such as the T877A and H874Y substitutions, confer increased sensitivity to AR for steroid hormones such as progesterone, 17p-estradiol, or hydroxyflutamide in prostate cancer cell lines and xenografts. (44,45) Mutant AR containing the E231G substitution has also been shown to predispose transgenic mice to the development of prostatic intraepithelial neoplasia (PIN), adenocarcinoma, and metastases. (46) Experiments have shown that AR hyperactivity results in the formation of prostatic neoplasms: overexpression of AR leads to the development of focal PIN, whereas AR overexpression in LAPC-4 prostate cancer cells and xenografts results in a transition from androgen-sensitive disease to androgen-resistant cancer. (47,48) Phosphorylation of AR at different specific serine residues may cause stabilization of the protein against proteolytic degradation or induce transcriptional activation of the receptor protein. (49)
Inappropriate AR hyperactivity may also be caused by activation of coregulators. Recurrent CWR22 tumors were found to harbor overexpressed transcriptional intermediary factor 2 and steroid receptor coactivator 1, which increased AR transactivation at physiologic androgen concentrations. (37) Other coregulators of AR function include ARA70, p300, CBP, Tip60, ARA55, ARA54, gelsolin, Stat3, and RAC3. (50-53) The Foxa1 and Foxa2 proteins are transcription factors belonging to the forkhead box A (Foxa) superfamily (also known as hepatocyte nuclear factor 3 proteins) that are essential for endodermal development and are involved in respiratory, intestinal, and hepatic gene expression. (54-60) Although Foxa1 was found to be expressed in prostatic carcinomas of different grades, Foxa2 stimulates transactivation of the PSA promoter in an androgen and AR-independent manner and has been identified in small cell carcinomas and high-grade adenocarcinomas of the prostate, suggesting that Foxa2 regulation of gene expression may contribute to progression of prostatic carcinomas to a more aggressive and androgen-independent state. (58)
Genome-wide expression analyses (61) have identified genes that are differentially expressed in prostate cancers from patients who had received the gonadotropin-releasing agonist goserelin and AR antagonist flutamide for 3 months. Hierarchical clustering algorithms that analyzed gene expression profiles classified the specimens according to treatment status, suggesting that distinct transcriptional programs are activated in prostate carcinomas in response to androgen therapy. The genes that were more highly expressed in carcinomas treated with androgen ablation agents included those encoding AR and steroid biosynthetic enzymes, as well as a suite of genes that have been previously shown to be targets of AR or have been implicated as being regulated by it, including the gene encoding PSA (kallikrein-related peptidase 3), KLK3, and KLK2, as well as DBI, FASN, IL6, SERPINB5, TGFBR3, TMPRSS2, TUBA1, HOXC6, TRG ,and FOLH1. (61-66) Other upregulated genes may represent secondary, indirect effects of androgen ablation that occur later than reactivation of AR. To identify only those genes that are subject to transcriptional regulation by AR, gene expression profiles of LNCaP human prostatic adenocarcinoma cells were examined after androgen withdrawal. (61) Approximately 25% of the genes differentially expressed in carcinomas after chronic androgen ablation therapy also showed an altered transcript level in the carcinoma cell line. Finally, comparison of the gene expression profiles of androgen-resistant cancers to those of cancers that had not developed resistance demonstrated that prostatic adenocarcinomas resistant to androgen ablation therapy had gene expression profiles more similar to those of untreated, androgen-dependent tumors than of cancers under conditions of androgen deprivation. This finding suggests a reversal in the gene expression profile of androgen-refractory cancers that is caused by androgen deprivation therapy, possibly by ligand-independent reactivation of AR, a mechanism that has been proposed by several authors. (67-70) Furthermore, a unique set of genes was expressed in androgen-resistant prostatic carcinomas that was not expressed in primary androgen-dependent tumors or in other metastatic carcinomas. (61)
Activation of AR can be highlighted by immunohisto chemistry as a strong nuclear expression in androgen-resistant prostate cancers. (61) Moreover, reactivation of AR gene was not due to gene amplification in most cases, as it was shown by FISH analysis that only a minority of the androgen-resistant carcinomas studied contained amplified AR genes. The human prostatic adenocarcinoma xenograft CWR22, which is propagated in nude mice, recapitulates the properties of in vivo prostate cancers, with an initial period of androgen-dependent proliferation followed by persistent growth several months after androgen deprivation. (71,72) Androgen receptor protein from a relapsed CWR22 carcinoma has a half-life that is 2 to 4 times that of AR from LNCaP cells, demonstrating that recurrent tumors have hyperstabilized AR as compared to androgen-dependent neoplasms. (73) The increased expression, greater stability, and nuclear localization of AR in recurrent prostate cancers resistant to androgen deprivation correlated with hypersensitivity to low levels of androgens in these tumors; androgen ablation-resistant prostate cancers required a significantly much lower concentration of dihydrotestosterone than that required by androgen-dependent tumors for stimulation of proliferative activity.
Several of the genes that were found by the microarray study to be more highly transcribed in androgen ablation-resistant tumors encoded biosynthetic enzymes involved in the synthesis of cholesterol, including HMG-CoA synthase, squalene synthase, lanosterol synthase, and squalene monooxygenase, the rate-limiting enzyme in sterol synthesis. (61,74) Androgen ablation-resistant tumors were shown to be more strongly immunoreactive for squalene monooxygenase than were androgen-dependent tumors. (61) The increased production of steroid biosynthetic enzymes in resistant tumors suggests that one mechanism by which these carcinomas overcome androgen deprivation is by compensatory synthesis of androgens, with consequently increased AR activity. Recurrent prostatic carcinomas consistently exhibit decreased expression of the tumor suppressor gene PTEN (phosphatase and tensin homolog), which carries loss-of-function mutations in advanced prostate cancers. (75) The PTEN protein dephosphorylates phosphatidylinositol-3,4,5-trisphosphate ([PIP.sub.3]), resulting in inhibition of the Akt (protein kinase B) cell survival signaling pathway. (76)
Besides reactivation of AR and loss of PTEN tumor suppressor activity, other mechanisms for the development of hormone-resistant prostate cancers have been proposed. Aberrant overexpression or amplification of the HER2/neu gene has been identified in prostatic carcinomas (77) and elevated serum levels of the HER2/neu extracellular domain were found in androgen ablation-refractory prostate cancers. (78) Overexpression of the HER2/neu (ERBB2, CD340) receptor tyrosine kinase was capable of rescuing LNCaP cells from the antiproliferative effect of androgen deprivation and also shortened the latency period for tumor formation in castrated mice with severe combined immunodeficiency by 50%. (77) Furthermore, HER2/neu can enhance by 15-fold the expression of the AR target PSA in the absence of androgens in LAPC-4 cells. (77) HER2/neu can also activate MAP kinase and PIP3/Akt signaling cascades, culminating in the phosphorylation of serines 213 and 791 of AR. (79,80) Constitutive Akt activity led to increased neoplastic growth in LNCaP xenografts. (81) Other growth factors that may contribute to the development of hormone-resistant cancers include insulin-like growth factor 1, epidermal growth factor, keratinocyte growth factor, and factors secreted by neuroendocrine cells. (82-84)
The conserved basic helix-loop-helix transcription factor TWIST has been shown to be highly expressed in the majority (90%) of prostate cancers and only in a minority (6.7%) of benign prostatic hyperplasia cases. (85) TWIST expression levels were also found to be proportional to Gleason grade, and higher levels correlated with metastasis. (85) Experiments with DU145 and PC-3 androgen-resistant prostatic adenocarcinoma cell lines (85) found that down-regulation of TWIST expression by RNA interference led to suppression of invasiveness and a reduction in E-cadherin expression, as well as loss of the morphologic and molecular changes that signify the epithelial-mesenchymal transition.
In summary, a major clinical challenge presented by prostate cancer is the treatment of androgen ablation-resistant carcinomas. Recent experimental evidence suggests that there are multiple avenues leading to the development of this aggressive form of prostatic carcinoma, which subvert the molecular mechanisms of the cell to reactivate AR, activate its targets, gain inappropriate HER2/ neu activity, lose PTEN-mediated tumor suppression, or stimulate the epithelial-mesenchymal transition via TWIST. Other authors postulate the existence of androgen-resistant prostate cancer stem cells that contribute to the growth of aggressive tumors. Future molecular studies will help further elucidate the diverse signaling pathways underlying the pathogenesis of prostate cancers refractory to systemic hormonal deprivation and may lead to the development of multiple pharmacologic agents and therapeutic modalities that will halt progression of hormone-naive tumors.
MOLECULAR BIOLOGY OF TMPRSS2:ERG
A significant role for the ETS gene family, which encodes transcription factors in prostate cancer, was recently discovered by using a novel bioinformatics approach known as COPA (cancer outlier profile analysis) (86) that identified the oncogenes ERG (21q22.2), ETV1 (7p21.2), ETV4 (17q21), and ETV5 (3q27) as very highly expressed in a subset of prostate cancers on the basis of a large set of microarray data. (86-88) ERG, ETV1, ETV4, and ETV5 are members of the ETS family of transcription factors, which are characterized by an evolutionarily conserved, 85-amino acid DNA-binding domain that facilitates binding to purine-rich DNA with a GGAA/T core consensus sequence. (89) ETS proteins function cooperatively with other transcription factors in the regulation of a diversity of cellular functions including proliferation, differentiation, angiogenesis, hematopoiesis, oncogenic transformation, and apoptosis. (90) Importantly, translocations involving members of the ETS family have been identified in human leukemia and solid tumors. (89) A mechanism underlying ETS overexpression in prostate cancer was established once it was recognized that the androgen-responsive gene TMPRSS2 (see below) is fused to the coding region of an ETS family member (for example ERG) as a result of gene rearrangement, which was also demonstrated directly by studies in vitro. (86,91,92) The TMPRRSS2:ERG gene fusion is observed in greater than 90% of prostate cancers with ETS-family gene rearrangements, (93) whereas TMPRSS2: ETV1, TMPRSS2:ETV4, and TMPRSS2:ETV5 rearrangements occur more rarely. Furthermore, ETV1, ETV4, and ETV5 have additional fusion partners other than TMPRSS2, including SLC45A3, HERV-KJ22q11.3, C15orf21, and HNRPA2B1. (94)
TMPRSS2 is located at 21q22.2, (95) and TMPRSS2 is predominantly expressed in luminal epithelial prostate cells, with much lower expression in pancreas, kidney, lung, colon, and liver and no measurable expression in testes, ovary, placenta, spleen, thymus, circulating leukocytes, brain, heart, or skeletal muscle. (96,97) TMPRSS2 and ERG are located 3Mb apart on chromosome 21q22.2-22.3 (Figure, A through E). The 5' ends of both genes are orientated toward the telomere, and TMPRSS2 is positioned telomerically relative to ERG. Interstitial deletion of the intervening intronic genomic DNA is the most common mechanism for fusion and is observed in 60% to 90% of TMPRSS2: ERG fusion-positive prostate cancers (see below). Regions of microhomology exist in the TMPRSS2 and ERG loci, suggesting that they might underlie rearrangement events during defective homologous recombination. (98)
Seventeen different types of TMPRSS2:ERG fusion transcripts involving various regions of the TMPRSS2 and ERG genes have been identified (86,99-102); however, 8 of these transcripts are unlikely to result in the translation of functional ERG proteins due to the introduction of premature stop codons. Of the 9 predicted functional TMPRSS2:ERG fusion transcripts, 2 code for normal ERG proteins, 6 code for amino-terminal-truncated ERG proteins, and 1 codes for a bona fide TMPRSS2:ERG fusion protein. (101) These studies demonstrate that expression of multiple fusion mRNAs is common, with TMPRSS2 exon 1 fused to ERG exon 4 being the most frequently expressed type of TMPRSS2:ERG fusion. Alternative splicing of the TMPRSS2:ERG gene is proposed as the most likely basis for the multiple different types of fusion mRNAs ob served. (99,101)
DETECTION AND PREVALENCE OF TMPRSS2:ERG GENE FUSION IN PROSTATE CANCER
Most TMPRSS2:ERG gene fusion events in patients with clinically localized prostate cancer (ie, patients identified through PSA screening who have potentially curable disease by surgical resection) are characterized by using either fluorescence in situ hybridization (FISH) or quantitative reverse transcription-polymerase chain reaction (RT-PCR). One common FISH method uses break-apart probes that bind the 5' (ie, green) and 3' (ie, red) ends of the ERG gene (Figure). In normal prostate tissue, both of these probes hybridize to the ERG locus and generate adjacent green and red fluorescent signals in the nucleus. In contrast, prostate cancer cells harboring rearranged ERG demonstrate distinct, separate green and red fluorescent signals, as the probes are split because of change in chromosome structure. One advantage of this method is that it also reveals the mechanism underlying the rearrangement by detection of the commonly occurring 3-Mb interstitial deletion between TMPRSS2 and ERG. In such cases, this deletion manifests by the loss of the 5' (green) signal in nuclei of malignant cells.
The initial report (86) identifying the TMPRSS2:ERG gene rearrangement demonstrated that 47% of clinically localized prostate cancers contain the TMPRSS2:ERG fusion, and two-thirds of these translocations are formed secondary to interstitial deletion between the TMPRSS2 and ERG genes on chromosome 21q22.2-22.3. Subsequent work (101,103-106) confirms that the TMPRSS2:ERG rearrangement is present in approximately 50% of primary prostate cancer samples with interstitial deletion of the 5' region of ERG occurring in 60% of the TMPRSS2:ERG-positive primary prostate cancers. Gene rearrangements involving ETV1 and ETV4 are rare, accounting for approximately 2% of all observed gene alterations.
MORPHOLOGY OF TMPRSS2:ERG PROSTATE CANCER
Initially, morphologic analysis of prostate cancer cases (107) identified 5 features strongly associated with the presence of the TMPRSS2:ERG fusion, which included blue-tinged mucin, cribriform growth pattern, macronucleoli, intraductal tumor spread, and signet ring cell features. Of the cases demonstrating none of these features, 24% were TMPRSS2:ERG fusion-positive. Conversely, 55%, 86%, and 93% of cases with 1, 2, or 3+ features, respectively, were TMPRSS2:ERG fusion-positive.
The association of the TMPRSS2:ERG fusion with high-grade prostatic intraepithelial neoplasia (HGPIN) was observed in up to 21% of cases in several studies. (94,108,109) Unlike localized prostate cancer, in which TMPRSS2:ERG fusion-positive prostate cancers typically demonstrate overexpression of ERG, overexpression of ERG is less constant in TMPRSS2:ERG fusion-positive HGPIN. (109) TMPRSS2: ERG fusions were not present in benign prostatic epithelium or other lesions not associated with prostate cancer, specifically, benign prostatic hyperplasia and proliferative inflammatory atrophy. Furthermore, all TMPRSS2:ERGpositive HGPlN cases identified by FISH showed the same fusion pattern as the matching prostate cancer from the same patient, and no fusion-positive HGPIN cases associated with fusion-negative prostate cancer were identified by FISH, (108,110) suggesting TMPRSS2:ERG may play a role in the progression from HGPIN to adenocarcinoma. (92)
Based upon (1) the homogenous distribution of the fusion gene throughout the cancer, (2) the absence of detectable TMPRSS2:ERG fusion events in normal and hyperplastic prostate tissue, (3) the finding that TMPRSS2: ERG-positive HGPIN lesions show the same fusion pattern with the matching prostate cancer, and (4) the fact that TMPRSS2:ERG fusion-positive HGPIN is never observed with fusion-negative matching prostate cancer, it can be suggested that TMPRSS2:ERG fusion is an early event in the development of prostate adenocarcinoma. In support of these findings, transgenic mice expressing the equivalent truncated ERG gene coded by human TMPRSS2:ERG develop mouse PIN (mPIN), along with loss of the p63-positive basal layer adjacent to mPIN foci. (92) These findings strongly suggest that TMPRSS2:ERG fusion HGPIN is a true precursor for TMPRSS2:ERG-positive prostate cancer.
TMPRSS2:ERG AND CLINICAL PROGNOSIS
As a wide array of distinct TMPRSS2:ERG fusions have been identified, several studies have explored whether specific gene fusion isoforms correlate with aggressive clinical behavior. One group (101) observed that expression of TMPRSS2:ERG fusion variants consisting of exons 1 and 2 of TMPRSS2 fused to exon 4 of ERG (T2E4) and, to a lesser extent, exon 1 of TMPRSS2 juxtaposed to exons 2 or 3 of ERG (T1E2/3) are associated with early recurrence and seminal vesicle invasion. Interestingly, these fusion isoforms all contain the native ATG translation initiation codon from either TMPRSS2 or ERG, raising the possibility that increased efficiency of translation from native translation start codons may underlie the correlation between TMPRSS2:ERG fusion type and aggressive clinical course. Alternatively, it may represent altered biochemical properties of the TMPRSS2:ERG fusion protein.
A comprehensive FISH analysis of TMPRSS2:ERG rearrangement in 445 cases (111) has demonstrated that prostate cancer in which the 5' portion of ERG is deleted has significantly worse cause-specific and overall survival than prostate cancer in which ERG is either not disrupted (ie, normal EGR) or contains a balanced ERG translocation (ie, split EGR). When ERG-deleted prostate cancers were further analyzed, the authors observed that prostate cancer with 2 or more copies of the 3' ERG region showed much worse clinical behavior: the survival rate of patients with duplication of the TMPRSS2:ERG gene rearrangement was 25% at 8 years compared to 90% for patients with prostate cancer without ERG rearrangement. A separate study examining 521 patients (112) reported similar results in which duplication of TMPRSS2:ERG was associated with higher clinical stage and aggressive disease. Furthermore, analysis of 214 patients with prostate cancer suggested that multiple copies of TMPRSS2:ERG were associated with greater prostate cancer-specific mortality, although this study (113) was not statistically significant. Taken together, these results demonstrate that ERG gene copy number may provide useful prognostic information for patients with prostate cancer.
The association of TMPRSS2:ERG gene rearrangement with Gleason score, aggressive disease, and prognosis is unclear, as multiple studies with conflicting findings have been described. A population-based study (114) of 252 men followed up expectantly with low-stage (T1a-bNXM0) prostate cancer explored the risk of metastasis or prostate cancer-specific death based upon the presence of the TMPRSS2:ERG fusion. These authors determined that TMPRSS2:ERG fusion-positive prostate cancer is associated with higher Gleason score (>7) than fusion-negative prostate cancer. Furthermore, cumulative incidence regression analysis demonstrated a significant association between TMPRSS2:ERG fusion-positive prostate cancer and metastases or disease-specific death. Another study (115) reported similar findings. However, several other studies (98,110,116-118) failed to establish any correlation between TMPRSS2:ERG gene fusion status and Gleason score, tumor stage, or clinical outcomes. Lastly, using a xenograft model system, Hermans et al (119) demonstrated that advanced, AR-negative tumors did not express the TMPRSS2:ERG fusion transcript despite its presence in the genomic DNA, indicating that TMPRSS2:ERG is not involved in androgen-independent growth of these xenografts. This finding suggests that the TMPRSS2:ERG fusion is important during the early, androgen-sensitive stage of tumor growth, but androgen-dependent TMPRSS2:ERG expression is bypassed and down-regulated as tumor growth progresses and becomes androgen resistant. (119)
In summary, the discovery of TMPRSS2 gene rearrangements helped broaden our understanding of the molecular pathology of prostate cancer, and the numerous studies that followed the initial report confirmed the high prevalence of TMPRSS2:ETS gene alterations in prostate cancer, as well as advanced our understanding of androgen signaling during prostate cancer progression. Mouse and human studies clearly demonstrate the occurrence of TMPRSS2:ETS gene fusion events in early HGPIN lesions; however, no evidence to date demonstrates a direct role for TMPRSS2:ETS fusion genes in the progression to adenocarcinoma, a fact suggesting a requirement for additional genetic mutations in the course of prostate cancer development.
(1.) Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58:71-96.
(2.) Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74-108.
(3.) Gronberg H. Prostate cancer epidemiology. Lancet. 2003;361:859-864.
(4.) Quinn M, Babb P. Patterns and trends in prostate cancer incidence, survival, prevalence and mortality--part I: international comparisons. BJU Int. 2002;90: 162-173.
(5.) American Cancer Society. Cancer Facts and Figures, 2003. Atlanta, GA: American Cancer Society; 2003.
(6.) Bratt O. Hereditary prostate cancer: clinical aspects. J Urol. 2002;168:906 913.
(7.) Carter BS, Beaty TH, Steinberg GD, Childs B, Walsh PC. Mendelian inheritance of familial prostate cancer. Proc Natl Acad SciU SA. 1992;89:3367-3371.
(8.) Haas GP, Sakr WA. Epidemiology of prostate cancer. CA Cancer J Clin. 1997;47:273-287.
(9.) Steinberg GD, Carter BS, Beaty TH, Childs B, Walsh PC. Family history and the risk of prostate cancer. Prostate. 1990;17:337-347.
(10.) Michaelson MD, Cotter SE, Gargollo PC, Zietman AL, Dahl DM, Smith MR. Management of complications of prostate cancer treatment. CA Cancer J Clin. 2008;58:196-213.
(11.) Alcaraz A, Takahashi S, Brown JA, et al. Aneuploidy and aneusomy of chromosome 7 detected by fluorescence in situ hybridization are markers of poor prognosis in prostate cancer. Cancer Res. 1994;54:3998-4002.
(12.) Bandyk MG, Zhao L, Troncoso P, et al. Trisomy 7: a potential cytogenetic marker of human prostate cancer progression. Genes Chromosomes Cancer. 1994;9:19-27.
(13.) Cooney KA, Wetzel JC, Consolino CM, Wojno KJ. Identification and characterization of proximal 6q deletions in prostate cancer. Cancer Res. 1 996;56: 4150-4153.
(14.) Cunningham JM, Shan A, Wick MJ, et al. Allelic imbalance and microsatellite instability in prostatic adenocarcinoma. Cancer Res. 1996;56:4475-4482.
(15.) Elo JP, Harkonen P, Kyllonen AP, et al. Loss of heterozygosity at 16q24.1q24.2 is significantly associated with metastatic and aggressive behavior of prostate cancer. Cancer Res. 1997;57:3356-3359.
(16.) Latil A, Baron JC, Cussenot O, et al. Genetic alterations in localized prostate cancer: identification of a common region of deletion on chromosome arm 18q. Genes Chromosomes Cancer. 1994;11:119-125.
(17.) Latil A, Cussenot O, Fournier G, Driouch K, Lidereau R. Loss of hetero zygosity at chromosome 16q in prostate adenocarcinoma: identification of three independent regions. Cancer Res. 1997;57:1058-1062.
(18.) Saric T, Brkanac Z, Troyer DA, et al. Genetic pattern of prostate cancer progression. Int J Cancer. 1999;81:219-224.
(19.) Takahashi S, Shan AL, Ritland SR, et al. Frequent loss of heterozygosity at 7q31.1 in primary prostate cancer is associated with tumor aggressiveness and progression. Cancer Res. 1995;55:4114-4119.
(20.) Van Den Berg C, Guan XY, Von Hoff D, et al. DNA sequence amplification in human prostate cancer identified by chromosome microdissection: potential prognostic implications. Clin Cancer Res. 1995;1:11-18.
(21.) Zenklusen JC, Thompson JC, Troncoso P, Kagan J, Conti CJ. Loss of heterozygosityin human primary prostate carcinomas: a possible tumor suppressor gene at 7q31.1. CancerRes. 1994;54:6370-6373.
(22.) LaTulippe E, Satagopan J, Smith A, et al. Comprehensive gene expression analysis of prostate cancer reveals distinct transcriptional programs associated with metastatic disease. Cancer Res. 2002;62:4499-4506.
(23.) Ross DT, Scherf U, Eisen MB, et al. Systematic variation in gene expression patterns in human cancer cell lines. Nat Genet. 2000;24:227-235.
(24.) Coffey DS. Prostate cancer: an over view of an increasing dilemma. Cancer. 1993;71:880-886.
(25.) Dai WS, Kuller LH, LaPorte RE, Gutai JP, Falvo-Gerard L, Caggiula A. The epidemiology of plasma testosterone levels in middle-aged men. Am J Epidemiol. 1981;114:804-816.
(26.) Mawhinney MG, Neubauer BL. Actions of estrogen in the male. Invest Urol. 1979;16:409-420.
(27.) Prehn RT. On the prevention and therapy of prostate cancer by androgen administration. Cancer Res. 1999;59:4161-4164.
(28.) Huggins C, Hodges CV. Studies on prostatic cancer, effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1:293-297.
(29.) Huggins C, Hodges CV. Studies on prostatic cancer--I: The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. CA Cancer J Clin. 1972;22:232-240.
(30.) Byar DP. Proceedings: The Veterans Administration Cooperative Urological Research Group's studies of cancer of the prostate. Cancer. 1973;32:1 126-1 130.
(31.) Sharifi N, Gulley JL, Dahut WL. Androgen deprivation therapy for prostate cancer. JAMA. 2005;294:238-244.
(32.) The Medical Research Council Prostate Cancer Working Party Investigators Group. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial--The Medical Research Council Prostate Cancer Working Party Investigators Group. Br J Urol. 1997;79:235-246.
(33.) The Veterans Administration Co-operative Urological Research Group. Treatment and survival of patients with cancer of the prostate: The Veterans Administration Co-operative Urological Research Group. Surg Gynecol Obstet. 1967;124:1011-1017.
(34.) Gingrich JR, Barrios RJ, Kattan MW, Nahm HS, Finegold MJ, Greenberg NM. Androgen-independent prostate cancer progression in the TRAMP model. Cancer Res. 1997;57:4687-4691.
(35.) Isaacs JT, Coffey DS. Adaptation versus selection as the mechanism responsible for the relapse of prostatic cancer to androgen ablation therapy as studied in the Dunning R-3327-H adenocarcinoma. CancerRes. 1981;41:5070-5075.
(36.) Chang SS, Benson MC, Campbell SC, et al. Society of Urologic Oncology position statement: redefining the management of hormone-refractory prostate carcinoma. Cancer. 2005;103:11-21.
(37.) Gregory CW, He B, Johnson RT, et al. A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy. Cancer Res. 2001;61:4315-4319.
(38.) Linja MJ, Savinainen KJ, Saramaki OR, Tammela TL, Vessella RL, Visakorpi T. Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer. Cancer Res. 2001;61:3550-3555.
(39.) Palmberg C, Koivisto P, Kakkola L, Tammela TL, Kallioniemi OP, Visakorpi T. Androgen receptor gene amplification at primary progression predicts response to combined androgen blockade as second line therapy for advanced prostate cancer. J Uurol. 2000;164:1992-1995.
(40.) Feldman BJ, Feldman D. The development of androgen-independent prostate cancer. Nat Rev Cancer. 2001;1:34-45.
(41.) Fenton MA, Shuster TD, Fertig AM, et al. Functional characterization of mutant androgen receptors from androgen-independent prostate cancer. Clin Cancer Res. 1997;3:1383-1388.
(42.) Koivisto P, Kononen J, Palmberg C, et al. Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. Cancer Res. 1997;57:314-319.
(43.) Edwards J, Krishna NS, Grigor KM, Bartlett JM. Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer. Br J Cancer. 2003;89:552-556.
(44.) Tan J, Sharief Y, Hamil KG, et al. Dehydroepiandrosterone activates mutant androgen receptors expressed in the androgen-dependent human prostate cancer xenograft CWR22 and LNCaP cells. Mol Endocrinol. 1997;11:450-459.
(45.) Veldscholte J, Ris-Stalpers C, Kuiper GG, et al. A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens. Biochem Biophys Res Commun. 1990;173:534-540.
(46.) Han G, Buchanan G, Ittmann M, et al. Mutation of the androgen receptor causes oncogenic transformation of the prostate. Proc Natl AcadSci U SA. 2005; 102:1151-1156.
(47.) Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10:33-39.
(48.) Stanbrough M, Leav I, Kwan PW, Bubley GJ, Balk SP. Prostatic intraepithelial neoplasia in mice expressing an androgen receptor transgene in prostate epithelium. Proc Natl Acad Sci U SA. 2001;98:10823-10828.
(49.) Edwards J, Bartlett JM. The androgen receptor and signal-transduction path-ways in hormone-refractory prostate cancer--part 1: modifications to the androgen receptor. BJU Int. 2005;95:1320-1326.
(50.) Culig Z, Comuzzi B, Steiner H, Bartsch G, Hobisch A. Expression and function of androgen receptor coactivators in prostate cancer. J Steroid Biochem Mol Biol. 2004;92:265-271.
(51.) Culig Z, Steiner H, Bartsch G, Hobisch A. Mechanisms of endocrine therapy-responsive and -unresponsive prostate tumours. Endocr Relat Cancer. 2005; 12:229-244.
(52.) Debes JD, Comuzzi B, Schmidt LJ, Dehm SM, Culig Z, Tindall DJ. P300 regulates androgen receptor-independent expression of prostate-specific qantigen in prostate cancer cells treated chronically with interleukin-6. Cancer Res. 2005; 65:5965-5973.
(53.) Edwards J, Bartlett JM. The androgen receptor and signal-transduction pathways in hormone-refractory prostate cancer--part 2: androgen-receptor cofactors and bypass pathways. BJU Int. 2005;95:1327-1335.
(54.) Carlsson P, Mahlapuu M. Forkhead transcription factors: key players in development and metabolism. Dev Biol. 2002;250:1-23.
(55.) Costa RH, Kalinichenko VV, Lim L. Transcription factors in mouse lung development and function. Am J Physiol Lung Cell Mol Physiol. 2001;280:823L 838L.
(56.) Kaestner KH. The hepatocyte nuclear factor 3 (HNF3 or FOXA) family in metabolism. Trends Endocrinol Metab. 2000;11:281-285.
(57.) Kaestner KH, Knochel W, Martinez DE. Unified nomenclature for the winged helix/forkhead transcription factors. Genes Dev. 2000;14:142-146.
(58.) Mirosevich J, Gao N, Gupta A, Shappell SB, Jove R, Matusik RJ. Expression and role of Foxa proteins in prostate cancer. Prostate. 2006;66:1013-1028.
(59.) Tomaru Y, Kondo S, Suzuki M, Hayashizaki Y. A comprehensive search for HNF-3alpha-regulated genes in mouse hepatoma cells by 60K cDNA microarray and chromatin immunoprecipitation/PCR analysis. Biochem Biophys Res Commun. 2003;310:667-674.
(60.) Zaret K. Developmental competence of the gutendoderm: genetic potentiation by GATA and HNF3/fork head proteins. Dev Biol. 1999;209:1-10.
(61.) Holzbeierlein J, Lal P, LaTulippe E, et al. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am J Pathol. 2004;164:217-227.
(62.) De Primo SE, Diehn M, Nelson JB, et al. Transcriptional programs activated by exposure of human prostate cancer cells to androgen. Genome Biol. 2002;3: research0032.1.
(63.) Moore SM, Nelson PS. Gene expression profiling of the human prostate androgen response program. J Androl. 2002;23:163-169.
(64.) Nelson PS, Clegg N, Arnold H, et al. The program of androgen-responsive genes in neoplastic prostate epithelium. Proc Natl Acad Sci U S A. 2002;99: 11890-11895.
(65.) Vaarala MH, Porvari K, Kyllonen A, Vihko P. Differentially expressed genes in two LNCaP prostate cancer cell lines reflecting changes during prostate cancer progression. Lab Invest. 2000;80:1259-1268.
(66.) Xu LL, Su YP, Labiche R, et al. Quantitative expression profile of androgen-regulated genes in prostate cancer cells and identification of prostate-specific genes. Int J Cancer. 2001;92:322-328.
(67.) Amler LC, Agus DB, LeDuc C, et al. Dysregulated expression of androgen-responsive and nonresponsive genes in the androgen-independent prostate cancer xenograft model CWR22-R1. Cancer Res. 2000;60:6134-6141.
(68.) Bubendorf L, Kolmer M, Kononen J, et al. Hormone therapy failure in human prostate cancer: analysis by complementary DNA and tissue microarrays. J Natl Cancer Inst. 1999;91:1758-1764.
(69.) Mousses S, Wagner U, Chen Y, et al. Failure of hormone therapy in prostate cancer involves systematic restoration of androgen responsive genes and activation of rapamycin sensitive signaling. Oncogene. 2001;20:6718-6723.
(70.) Zegarra-Moro OL, Schmidt LJ, Huang H, Tindall DJ. Disruption of androgen receptor function inhibits proliferation of androgen-refractory prostate cancer cells. Cancer Res. 2002;62:1008-1013.
(71.) Nagabhushan M, Miller CM, Pretlow TP, et al. CWR22: the first human prostate cancer xenograft with strongly androgen-dependent and relapsed strains both in vivo and in soft agar. Cancer Res. 1996;56:3042-3046.
(72.) Wainstein MA, He F, Robinson D, et al. CWR22: androgen-dependent xenograft model derived from a primary human prostatic carcinoma. Cancer Res. 1994;54:6049-6052.
(73.) Gregory CW, Johnson RT Jr, Mohler JL, French FS, Wilson EM. Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Res. 2001;61:2892-2898.
(74.) Chugh A, Ray A, Gupta JB. Squalene epoxidase as hypocholesterolemic drug target revisited. Progr Lipid Res. 2003;42:37-50.
(75.) Steck PA, Pershouse MA, Jasser SA, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 1997;15:356-362.
(76.) Yamada KM, Araki M. Tumor suppressor PTEN: modulator of cell signaling, growth, migration and apoptosis. J Cell Sci. 2001;114:2375-2382.
(77.) Craft N, Shostak Y, Carey M, Sawyers CL. A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat Med. 1999;5:280-285.
(78.) Arai Y, Yoshiki T, Yoshida O. c-erbB-2 oncoprotein: a potential biomarker of advanced prostate cancer. Prostate. 1997;30:195-201.
(79.) Wen Y, Hu MC, Makino K, et al. HER-2/neu promotes androgen-independent survival and growth of prostate cancer cells through the Akt pathway. Cancer Res. 2000;60:6841-6845.
(80.) Yeh S, Lin HK, Kang HY, Thin TH, Lin MF, ChangC. From HER2/Neu signal cascade to androgen receptor and its coactivators: a novel pathway by induction of androgen targetgenes through MAP kinase in prostate cancer cells. Proc Natl Acad Sci U S A. 1999;96:5458-5463.
(81.) Graff JR, Konicek BW, McNulty AM, et al. Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression. J Biol Chem. 2000;275:24500 24505.
(82.) Chan JM, Stampfer MJ, Giovannucci E, et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science. 1998;279:563 566.
(83.) Culig Z, Hobisch A, Cronauer MV, et al. Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor, and epidermal growth factor. Cancer Res. 1994;54:5474-5478.
(84.) Jin RJ, WangY, Masumori N, etal. NE-10 neuroendocrine cancer promotes the LNCaP xenograft growth in castrated mice. Cancer Res. 2004;64:5489-5495.
(85.) Kwok WK, Ling MT, Lee TW, et al. Up-regulation of TWIST in prostate cancer and its implication as a therapeutic target. Cancer Res. 2005;65:5153 5162.
(86.) Tomlins SA, Rhodes DR, Perner S, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. 2005;310:644-648.
(87.) Helgeson BE, Tomlins SA, Shah N, et al. Characterization of TMPRSS2: ETV5 and SLC45A3:ETV5 gene fusions in prostate cancer. Cancer Res. 2008;68: 73-80.
(88.) Tomlins SA, Mehra R, Rhodes DR, et al. TMPRSS2:ETV4 gene fusions define a third molecular subtype of prostate cancer. Cancer Res. 2006;66:3396 3400.
(89.) Oikawa T, Yamada T. Molecular biology of the Ets family of transcription factors. Gene. 2003;303:11-34.
(90.) Seth A, Watson DK. ETS transcription factors and their emerging roles in human cancer. Eur J Cancer. 2005;41:2462-2478.
(91.) Korenchuk S, Lehr JE, MClean L, et al. VCaP, a cell-based model system of human prostate cancer. In Vivo. 2001;15:163-168.
(92.) Tomlins SA, Laxman B, Varambally S, et al. Role of the TMPRSS2-ERG gene fusion in prostate cancer. Neoplasia. 2008;10:177-188.
(93.) Kumar-Sinha C, Tomlins SA, Chinnaiyan AM. Recurrent gene fusions in prostate cancer. Nat Rev Cancer. 2008;8:497-511.
(94.) Tomlins SA, Laxman B, Dhanasekaran SM, et al. Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature. 2007;448:595-599.
(95.) Paoloni-Giacobino A, Chen H, Peitsch MC, Rossier C, Antonarakis SE. Cloning of the TMPRSS2 gene, which encodes a novel serine protease with transmembrane, LDLRA, and SRCR domains and maps to 21q22.3. Genomics. 1997; 44:309-320.
(96.) Lin B, Ferguson C, White JT, et al. Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2. Cancer Res. 1999;59:4180-4184.
(97.) Vaarala MH, Porvari KS, Kellokumpu S, Kyllonen AP, Vihko PT. Expression of transmembrane serine protease TMPRSS2 in mouse and human tissues. J Pathol. 2001;193:134-140.
(98.) Yoshimoto M, Joshua AM, Chilton-Macneill S, et al. Three-color FISH analysis of TMPRSS2/ERG fusions in prostate cancer indicates that genomic micro-deletion of chromosome 21 is associated with rearrangement. Neoplasia. 2006; 8:465-469.
(99.) Clark J, Merson S, Jhavar S, et al. Diversity of TMPRSS2-ERG fusion transcripts in the human prostate. Oncogene. 2007;26:2667-2673.
(100.) Soller MJ, Isaksson M, Elfving P, Soller W, Lundgren R, Panagopoulos I. Confirmation of the high frequency of the TMPRSS2/ERG fusion gene in prostate cancer. Genes Chromosomes Cancer. 2006;45:717-719.
(101.) 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;66:8347-8351.
(102.) Clark J, Attard G, Jhavar S, et al. Complex patterns of ETS gene alteration arise during cancer development in the human prostate. Oncogene. 2008;27: 1993-2003.
(103.) Iljin K, Wolf M, Edgren H, et al. TMPRSS2 fusions with oncogenic ETS factors in prostate cancer involve unbalanced genomic rearrangements and are associated with HDAC1 and epigenetic reprogramming. Cancer Res. 2006;66: 10242-10246.
(104.) Mehra R, Tomlins SA, Shen R, et al. Comprehensive assessment of TMPRSS2 and ETS family gene aberrations in clinically localized prostate cancer. Mod Pathol. 2007;20:538-544.
(105.) Perner S, Demichelis F, Beroukhim R, et al. TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer. Cancer Res. 2006;66:8337-8341.
(106.) Schlesinger C, Bostwick DG, Iczkowski KA. High-grade prostatic intra epithelial neoplasia and atypical small acinar proliferation: predictive value for cancer in current practice. Am J Surg Pathol. 2005;29:1201-1207.
(107.) Mosquera JM, Perner S, Demichelis F, et al. Morphological features of TMPRSS2-ERG gene fusion prostate cancer. J Pathol. 2007;212:91-101.
(108.) Mosquera JM, Perner S, Genega EM, et al. Characterization of TMPRSS2ERG fusion high-grade prostatic intraepithelial neoplasia and potential clinical implications. Clin Cancer Res. 2008;14:3380-3385.
(109.) Cerveira N, Ribeiro FR, Peixoto A, et al. TMPRSS2-ERG genefusion causing ERG overexpression precedes chromosome copy number changes in prostate carcinomas and paired HGPIN lesions. Neoplasia. 2006;8:826-832.
(110.) Perner S, Mosquera JM, Demichelis F, et al. TMPRSS2-ERG fusion prostate cancer: an early molecular event associated with invasion. Am J Surg Pathol. 2007;31:882-888.
(111.) Attard G, Clark J, Ambroisine L, et al. Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer. Oncogene.
112. Gopalan A, Leversha M, Satagopan JM, et al. TMPRSS2-ERG gene fusion is not associated with outcome in patients treated by prostatectomy. Cancer Res. 2009. In press.
113. FitzGerald LM, Agalliu I, Johnson K, et al. Association of TMPRSS2-ERG gene fusion with clinical characteristics and outcomes: results from a population-based study of prostate cancer. BMC Cancer. 2008;8:230.
114. Demichelis F, Fall K, Perner S, et al. TMPRSS2:ERG genefusion associated with lethal prostate cancer in a watchful waiting cohort. Oncogene. 2007;26: 4596-4599.
115. 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. 2007;60:1238-1243.
116. Nam RK, Sugar L, Yang W, et al. Expression of the TMPRSS2:ERG fusion gene predicts cancer recurrence after surgery for localised prostate cancer. Br J Cancer. 2007;97:1690-1695.
117. Fine SW, Gopalan A, Al-Ahmadie HA, et al. Does TMPRSS2-ERG gene fusion status in prostate cancer correlate with Gleason score? Mod Pathol. 2008; 21:156A.
118. Lapointe J, Kim YH, Miller MA, et al. A variant TMPRSS2 isoform and ERG fusion product in prostate cancer with implications for molecular diagnosis. Mod Pathol. 2007;20:467-473.
119. 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;66:10658 10663.
A. Craig Mackinnon, MD, PhD; Benjamin C. Yan, MD, PhD; Loren J. Joseph, MD; Hikmat A. Al-Ahmadie, MD Accepted for publication February 5, 2009.
From the Department of Pathology, University of Chicago, Chicago, Illinois. Dr Al-Ahmadie is now with the Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Hikmat A. Al-Ahmadie, MD, Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (e-mail: firstname.lastname@example.org).
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