期刊
CANCER RESEARCH
卷 69, 期 7, 页码 2912-2918出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-08-3667
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资金
- Cancer Research UK
- Experimental Cancer Medical Centre
- Department of Health [C51/A7401]
- Medical Research Council [G0601308]
- Royal Marsden Hospital General Research Council Fund
- Prostate Cancer Foundation
- ESMO fellowship
- Grand Charity of Freemasons
- National Cancer Research Institute Prostate Cancer Collaborative
- Terry Fox Foundation
- National Cancer Institute of Canada
- NIHR Biomedical Research Centre
- MRC [G0501019, G0601308] Funding Source: UKRI
- Medical Research Council [G0601308, G0501019] Funding Source: researchfish
- National Institute for Health Research [CL-2008-22-001] Funding Source: researchfish
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',6diamidino-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
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