PROSTA-GEN DX™A NEW Biopsy-based tool for prostate cancer management

Examines two major mechanisms of carcinogenesis

P-TEN

LOSS OF TUMOR SUPPRESSOR

GENE

TMPRSS2:ERG

GENE FUSION/ TRANSLOCATION

ANEUPLOIDY

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TMPRss2-eRG and PTen loss in prostate cancerJeremy A Squire

Two studies show that the common recurrent gene fusion between TMPRSS2 and ERG promotes prostate cancer in both mouse and humans when PTEN is concurrently lost. in human prostate cancer, the presence of both these aberrations may be indicative of poor prognosis, suggesting that preclinical therapeutic research should target both of these pathways.

Recommendations over screening for early diagnosis of prostate cancer have recently gained attention, with increasing concern that the introduction of routine prostate-specific antigen (PSA) blood testing has led to significant overtreatment of prostate cancer1. This debate highlights the need to better understand the primary molecular determinants that drive prostate cancer. Two papers on pages 524 and 619 of this issue2,3 now draw attention to a close col-laboration between ETS transcription fac-tors and the PTEN tumor suppressor, which together seem to be pivotal in both human and murine prostate cancer.

Proteins of the ETS family are a group of related signal-dependent transcriptional reg-ulators mediating cellular proliferation, dif-ferentiation and tumorigenesis4. In human prostate cancer, genomic alterations of ETS-related genes (principally ERG) as a result of a fusion between an androgen receptor– regulated gene promoter of TMPRSS2 and ETS transcription factors is present in about half of tumors5. Given this high frequency of ETS genetic rearrangements in prostate can-cer, it is plausible that overexpression of ETS factors per se may represent a crucial event in prostate tumorigenesis. However, important details of the biological role of aberrant ETS expression in prostate cancer initiation and progression need to be clarified.

Since this discovery was made, there has been considerable interest in understanding the mechanism by which the TMPRSS2-

ERG fusion may promote progression to prostate cancer. Studies have used various mouse models that often take advantage of the probasin promoter to drive prostate-specific expression of the TMPRSS2-ERG transgene. An early indication that the ini-tial steps of cancer have been triggered in the mouse is when a transgene elicits the formation of benign prostatic intraepithe-lial neoplasia (PIN) in the prostate gland. In human disease, the presence of high-grade PIN is strongly associated with the develop-ment of cancer. However, deriving a precise morphological definition of PIN that can be identified in different mouse models can be problematic6, and this has led to various interpretations concerning the stage in the

disease process that TMPRSS2-ERG activa-tion leads to cancer7,8.

Concurrent loss of PTENThe two reports in this issue2,3 now dem-onstrate that the role of the PTEN pathway is crucial in understanding the interplay between TMPRSS2-ERG activation, PIN and prostate cancer oncogenesis. PTEN is among the most commonly mutated tumor suppres-sor genes in human cancer, and like many other tumor suppressors, PTEN targets pro-teins in signaling pathways that regulate cell growth and survival and contributes to can-cer when lost or inactivated. Mouse models have shown that Pten-deficient mice develop high-grade PIN, but without progression to

Jeremy A. Squire is in the Department of Pathology and Molecular Medicine and the NCIC Clinical Trials Group at Queen’s University, Kingston, Ontario, Canada. e-mail: squirej@queensu.ca

nature genetics | volume 41 | number 5 | may 2009 509

TF TFTA

TF TFTA

Normalprostate

Unregulated activationof AKT and

downstream targetsPTEN

TMPRSS2 ERG

AKT

ARE

ERG Overexpressionof ETS targets

Proliferation

Anti-apoptosis

Genomic instability

Differentiation

Angiogenesis

Cell migration

Invasion

PIN

Prostatecarcinoma

Figure 1 A path to prostate cancer progression. Loss of PTEN and concomitant activation of AKT could act in partnership with the TMPRSS2-ERG fusion protein to promote progression to prostate cancer through downstream pathways that increase the selective advantage of premalignant prostatic intraepithelial neoplasia (PIN) cells. ARE, androgen response elements; TA, transcriptional activator; TF, transcription factor.

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d. PROSTATE CANCER PROGRESSION

ONLY TECHNOLOGY THAT COMBINES HISTOLOGIC, MOLECULAR AND

CLINICAL PARAMETERS TO PREDICT DISEASE PROGRESSION

HISTOLOGIC

• Quantitatively captures and analyzes cellular features

• Pathologist selects the most representative tumor area for analysis

MOLECULAR

• Fluorescent in-situ hybridization captures loss or translocation of gene.

• Computer digital imaging quantifies and captures biologic results.

CLINICAL

• Incorporates clinical features to complete patient analysis.

• Biopsy Gleason Score

PTEN

• The PTEN (phosphatase and tensin) gene encodesa phosphatase which counteracts the PI3K/Akt signaling pathway, one of the most critical cancer-promoting pathways identified to date. It is involved in the regulation of DNA repair, genomic instability, stem cell self-renewal, cellular senescence, and cell migration (metastasis).

• Studies published, correlate PTEN deletion with poor clinical outcome in cases of hormone refractory prostate cancer¬, with 42.6% of tumors displaying the PTEN deletion. In addition, it has been observed that the frequency and type of PTEN deletion is correlated to disease progression and early biochemical recurrence.

TMPRSS2:ERG

• TMPRSS2-ERG gene rearrangements are present in 30-50% of prostate cancer and lead to over expression of a truncated ERG protein. The presence of the rearrangement may have prognostic significance and assist in patient stratification to guide therapy.

• Hormonally treated PCa patients having an ERG rearrangement have a significantly increased risk of becoming castration resistant compared to patients without the rearrangement. This is a sign of more aggressive disease and could potentially be used to identify patients less likely to respond to hormone treatment.

At diagnosis

We have used multiple scientific disciplines to predict disease progression at the time of diagnosis.

• Two major mechanisms of carcinogenesis are examined.

• Generates a personalized prediction of risk of disease progression.

• Determines patients’ genetic prognosis for serious disease progression.

• Delivers clinically proven, reliable results.

• Provides physicians and patients with enhance insights for treatment decisions.

P-TEN

TMPRSS2:ERG

PROSTA-GEN DX™ REFERENCES

Yoshimoto M, Joshua AM, Cumha IW, Coudry RA, Fonseca FP, Ludkoski O, Zielensk M, Soares FA, Squire JA. “Absence of TMPRSS2:ERG fusions and PTEN loses in prostate cancer is associated with favorable outcome.” Mod Patho. 2008 Dec;21(12):1451-60. Epub 2008 May 23.

Berger MF, Lawrence MS, Demichelis F, Drier Y, Cibulskkis K, Sivachenko AT, Sboner A, Esgueva R, Pflueger D, Sougnez C, Onofrio R, Carter SL, Park K, Habegger L, Ambrogio L, Fennell T, Parkin M, Saksena G, Voet D, Ramos AH, Pugh TJ, Wilkinson J, Fisher S, Wincler W, Maha S, Ardlie K, Balswin J, Simons JW, Kitabayashi N, MacDonald TY, Kantoff PW, Chin L, Gabriel SB, Gerstein MB, Golub TR, Meyerson M, Tewari A, Lander ES, Getz G, Rubin MA, Grarraway LA,. “The genomic complexity of primary human prostate cancer.” Nature 2011 Feb 10;470(7333):214-20.

Bismar TA, Yoshimoto M, Vollmer RT, Duan Q, Firszt M., Corcos H, Squire JA. “PTEN genomic deletion is an early event associated with ERG gene rearrangements in prostate cancer.” BJU Int 2011 Feb;107(3):477-85. Doi: 10.111/j.1464-410X.2010.09470.x

Carver BS, Tran J, Gopalan A, Chen Z, Shaikh S, Carracedo A, Alimonti A, Nardella C, Varmeh S, Scardino PT, Cordon-Cardo C, Gerald W, Pandolfi PP. “Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate.” Nat Genet 2009 May;41(5):619-24 Epub 2009 Apr 26

Liu S, Yoshimoto M, Trpkov K, Duan Q, Firszt M, Corcos J, Squire JA, Bismar TA. “Detection of ERG gene rearrangements and PTEN deletions in unsuspected prostate cancer of the transition zone.” Cancer Biol Ther. 2011 Mar15:(11(16).

McCall P, Witton CJ, Grimsley S, Nielsen KV, Edwards J. “Is PTEN loss associated with clinical outcome measures in human prostate cnacer?” Br J Cancer 2008;99:1296-301.

Rubin MA, Gerstein A, Reid K, Bostwick DG, Cheng L, Parsons R, Papdoupoulos N. “10q23.3 loss of heterozygosisty is higher in lymph node-positive (pT2-3,N+) versus lymph node-negative (pT2-3,N0) prostate cancer.” Hum Pathol 200 Apr;31(4):504-8.

Torres CH, Soares FA, Squire JA. “FISH analysis of 107 prostate cancers shows that PTEN genomic deletion is associated with poor clinical outcome.” Br J Cancer. 2077 Sep 3;97(5):678-85.

Sircar K, Yoshimoto M, Monzon FA, Koumakpayi IH, Katz RL, Khanna A, Alvarez K, Chen G, Darnel AD, Aprikian AG, Saad F, Bismar TA, Squire JA. “PTEN genomic deletion is associated with p-Akt and AR signaling in poorer outcome, hormone refractory prostate cancer.” J Pathol Aug 2009;218(4):505-13.