Detection of androgen receptor mutations in circulating tumor cells in castration-resistant prostate cancer.
BACKGROUND
Coding mutations in the AR (androgen receptor) gene have been identified in tissue samples from patients with advanced prostate cancer and represent a possible mechanism underlying the development of castration-resistant prostate cancer (CRPC). There is a paucity of tumor-derived tissue available for molecular studies of CRPC patients. Circulating tumor cells (CTCs) in the blood of CRPC patients represent a possible avenue for interrogating the disease of such patients.


METHODS
Circulating tumor cells were captured with the CellSearch Circulating Tumor Cell (CTC) Kit and with the CellSearch Profile Kit plus Qiagen's AllPrep DNA/RNA Micro Kit for the measurement of the CTC count per 7.5 mL of blood and for the isolation of nucleic acids, respectively. The AR gene was amplified by the PCR, and mutation status and relative abundance were analyzed by applying Transgenomic's WAVE denaturing HPLC technology followed by direct sequencing.


RESULTS
AR mutations were detected in 20 of 35 CRPC patients; 19 missense mutations, 2 silent mutations, 5 deletions, and 1 insertion were observed. The relative abundance of the mutants in the amplified products ranged from 5% to 50%. Many of the AR mutations were identified in surgical biopsies or at autopsy and were associated with resistance to androgen-directed therapies.


CONCLUSIONS
AR mutations can be identified in CTC-enriched peripheral blood samples from CRPC patients. This approach has the potential to open new perspectives in understanding CTCs and the mechanisms for tumor progression and metastasis in CRPC.
Jiang
Yuqiu
Y
Veridex, LLC, a Johnson & Johnson company, San Diego, CA, USA. jjiang2@its.jnj.com
Palma
John F
JF
Agus
David B
DB
Wang
Yixin
Y
Gross
Mitchell E
ME
D000726:Androgen Antagonists / Q000627:therapeutic use; D000813:Anilides / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002369:Castration; D000077143:Docetaxel; D006801:Humans; D008297:Male; D009154:Mutation; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D009570:Nitriles / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D011944:Receptors, Androgen / Q000097:blood / Q000235:genetics*; D043823:Taxoids / Q000627:therapeutic use; D014105:Tosyl Compounds / Q000627:therapeutic use
D000726:Androgen Antagonists; D000813:Anilides; D000970:Antineoplastic Agents; D009570:Nitriles; D011944:Receptors, Androgen; D043823:Taxoids; D014105:Tosyl Compounds; D000077143:Docetaxel; C053541:bicalutamide