The precise molecular alterations driving castration-resistant prostate cancer (CRPC) are not clearly understood. Using a novel network-based integrative approach, here, we show distinct alterations i Show more
The precise molecular alterations driving castration-resistant prostate cancer (CRPC) are not clearly understood. Using a novel network-based integrative approach, here, we show distinct alterations in the hexosamine biosynthetic pathway (HBP) to be critical for CRPC. Expression of HBP enzyme glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) is found to be significantly decreased in CRPC compared with localized prostate cancer (PCa). Genetic loss-of-function of GNPNAT1 in CRPC-like cells increases proliferation and aggressiveness, in vitro and in vivo. This is mediated by either activation of the PI3K-AKT pathway in cells expressing full-length androgen receptor (AR) or by specific protein 1 (SP1)-regulated expression of carbohydrate response element-binding protein (ChREBP) in cells containing AR-V7 variant. Strikingly, addition of the HBP metabolite UDP-N-acetylglucosamine (UDP-GlcNAc) to CRPC-like cells significantly decreases cell proliferation, both in-vitro and in animal studies, while also demonstrates additive efficacy when combined with enzalutamide in-vitro. These observations demonstrate the therapeutic value of targeting HBP in CRPC. Show less
Primary clear-cell adenocarcinoma of the urethra, a rare tumor that histomorphologically resembles clear-cell carcinoma of the female genital tract, occurs predominantly in women and is associated wit Show more
Primary clear-cell adenocarcinoma of the urethra, a rare tumor that histomorphologically resembles clear-cell carcinoma of the female genital tract, occurs predominantly in women and is associated with a relatively poor prognosis. The histogenesis of this rare urethral neoplasm has not been completely resolved, but it is thought to arise from either müllerian rests or metaplastic urothelium. Herein, we present comprehensive surgical pathological and cytopathological findings from a patient with primary urethral clear-cell adenocarcinoma and describe next-generation sequencing results for this patient's unique tumor-the first such reported characterization of molecular aberrations in urethral clear-cell adenocarcinoma at the transcriptomic and genomic levels. Transcriptome analysis revealed novel gene fusion candidates, including ANKRD28-FNDC3B. Whole-exome analysis demonstrated focal copy number loss at the SMAD4 and ARID2 loci and 38 somatic mutations, including a truncating mutation in ATM and a novel nonsynonymous mutation in ALK. Show less