Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer

Attard, Gerhardt, Swennenhuis, Joost F, Olmos, David, Reid, Alison H M, Vickers, Elaine, A'Hern, Roger, Levink, Rianne, Coumans, Frank, Moreira, Joana, Riisnaes, Ruth, Oommen, Nikhil Babu, Hawche, George, Jameson, Charles, Thompson, Emilda, Sipkema, Ronald, Carden, Craig P, Parker, Christopher, Dearnaley, David, Kaye, Stan B, Cooper, Colin S, Molina, Arturo, Cox, Michael E, Terstappen, Leon W M M and de Bono, Johann S (2009) Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. Cancer Research, 69 (7). pp. 2912-8. ISSN 0008-5472

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Abstract

Hormone-driven expression of the ERG oncogene after fusion with TMPRSS2 occurs in 30% to 70% of therapy-naive prostate cancers. Its relevance in castration-resistant prostate cancer (CRPC) remains controversial as ERG is not expressed in some TMPRSS2-ERG androgen-independent xenograft models. However, unlike these models, CRPC patients have an increasing prostate-specific antigen, indicating active androgen receptor signaling. Here, we collected blood every month from 89 patients (54 chemotherapy-naive patients and 35 docetaxel-treated patients) treated in phase I/phase II clinical trials of an orally available, highly specific CYP17 inhibitor, abiraterone acetate, that ablates the synthesis of androgens and estrogens that drive TMPRSS2-ERG fusions. We isolated circulating tumor cells (CTC) by anti-epithelial cell adhesion molecule immunomagnetic selection followed by cytokeratin and CD45 immunofluorescence and 4',6-diamidino-2-phenylindole staining. We used multicolor fluorescence in situ hybridization to show that CRPC CTCs, metastases, and prostate tissue invariably had the same ERG gene status as therapy-naive tumors (n=31). We then used quantitative reverse transcription-PCR to show that ERG expression was maintained in CRPC. We also observed homogeneity in ERG gene rearrangement status in CTCs (n=48) in contrast to significant heterogeneity of AR copy number gain and PTEN loss, suggesting that rearrangement of ERG may be an earlier event in prostate carcinogenesis. We finally report a significant association between ERG rearrangements in therapy-naive tumors, CRPCs, and CTCs and magnitude of prostate-specific antigen decline (P=0.007) in CRPC patients treated with abiraterone acetate. These data confirm that CTCs are malignant in origin and indicate that hormone-regulated expression of ERG persists in CRPC.

Item Type: Article
Uncontrolled Keywords: androstenols,antigens, neoplasm,cell adhesion molecules,gene order,humans,immunomagnetic separation,in situ hybridization, fluorescence,keratins,male,neoplasms, hormone-dependent,neoplastic cells, circulating,oncogene proteins, fusion,pten phosphohydrolase,prostatic neoplasms,receptors, androgen,trans-activators
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Pure Connector
Date Deposited: 20 Jan 2014 16:00
Last Modified: 21 Apr 2020 22:31
URI: https://ueaeprints.uea.ac.uk/id/eprint/46143
DOI: 10.1158/0008-5472.CAN-08-3667

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