Genomics of lethal prostate cancer at diagnosis and castration resistance
JOURNAL OF CLINICAL INVESTIGATION
Authors: Mateo, Joaquin; Seed, George; Bertan, Claudia; Rescigno, Pasquale; Dolling, David; Figueiredo, Ines; Miranda, Susana; Rodrigues, Daniel Nava; Gurel, Bora; Clarke, Matthew; Atkin, Mark; Chandler, Rob; Messina, Carlo; Sumanasuriya, Semini; Bianchini, Diletta; Barrero, Maialen; Petermolo, Antonella; Zafeiriou, Zafeiris; Fontes, Mariane; Perez-Lopez, Raquel; Tunariu, Nina; Fulton, Ben; Jones, Robert; McGovern, Ursula; Ralph, Christy; Varughese, Mohini; Parikh, Omi; Jain, Suneil; Elliott, Tony; Sandhu, Shahneen; Porta, Nuria; Hall, Emma; Yuan, Wei; Carreira, Suzanne; de Bono, Johann S.
Abstract
The genomics of primary prostate cancer differ from those of metastatic castration-resistant prostate cancer (mCRPC). We studied genomic aberrations in primary prostate cancer biopsies from patients who developed mCRPC. also studying matching, same-patient, diagnostic, and mCRPC biopsies following treatment. We profiled 470 treatment-naive prostate cancer diagnostic biopsies and, for 61 cases, mCRPC biopsies, using targeted and low-pass whole-genome sequencing (n = 52). Descriptive statistics were used to summarize mutation and copy number profile. Prevalence was compared using Fisher's exact test. Survival correlations were studied using log-rank test. TP53 (27%) and PTEN (12%) and DDR gene defects (BRCA2 7%; 031(12 5%; ATM 4%) were commonly detected. TPS3, BRCA2, and CDI(12 mutations were ma rkedly more common than described in the TCGA cohort. Patients with P81 loss in the primary tumor had a worse prognosis. Among 61 men with matched hormone-naive and mCRPC biopsies, differences were identified in AR, TP53, P81, and PI3K/AKT mutational status between same-patient samples. In conclusion, the genomics of diagnostic prostatic biopsies acquired from men who develop mCRPC differ from those of the nonlethal primary prostatic cancers. RB1/TP53/AR aberrations are enriched in later stages, but the prevalence of DDR defects in diagnostic samples is similar to mCRPC.
LC-MS/MS analysis of puerarin and 18 beta-glycyrrhetinic acid in human plasma after oral administration of Samso-eum and its application to pharmacokinetic study
BIOMEDICAL CHROMATOGRAPHY
Authors: Lee, Seon Yu; Jeong, Ji Hyun; Kim, Bo Na; Park, So Jung; Park, Yang-Chun; Lee, Guk Yeo
Abstract
The aim of this study was to confirm pharmacokinetic screening of multiple components in healthy Korean subjects after oral administration of Samso-eum and perform quantitation of active components in the human plasma. Thirteen potential bioactive components [puerarin (PRR), daidzin, nodakenin, ginsenoside Rb1, 18 beta-glycyrrhetinic acid (18 beta-GTA), 6-shogaol, naringin, glycyrrhizin, hesperidin, platycodin D, naringenin, hesperetin, and 6-gingerol] were screened based on literature. The results showed that three analytes (daidzin, naringenin, and hesperetin) were detected in trace amounts. In addition, PRR and 18 beta-GTA were detected in human plasma after the oral administration of Samso-eum. In this study, a liquid chromatography-electrospray ionization-tandem mass spectrometry method was validated for the simultaneous determination of PRR and 18 beta-GTA in human plasma. This was the first study to evaluate pharmacokinetics of PRR and 18 beta-GTA after the usual oral dose of Samso-eum (30 g containing 102.48 mg PRR, 48.18 mg glycyrrhizin) in human subjects.