Although the TMPRSS2-ERG fusion occurs frequently in prostate cancer (PC), its impact on clinical outcomes remains controversial. Roughly half of TMPRSS2-ERG fusions occur through intrachromosomal deletion of interstitial genes and the remainder via insertional chromosomal rearrangements. Because PCs with deletion-derived TMPRSS2-ERG fusions are more aggressive than those with insertional fusions, we investigated the impact of interstitial gene loss on PC progression.
We conducted an unbiased analysis of transcriptome data from large collections of PC samples and employed diverse in vitro and in vivo models combined with genetic approaches to characterize the interstitial gene loss that imposes the most significant impact on clinical outcome.
This analysis identified FAM3B as the top-ranked interstitial gene whose loss is associated with a poor prognosis. The association between FAM3B loss and poor clinical outcome extended to fusion-negative PCs where FAM3B downregulation occurred through epigenetic imprinting. Importantly, FAM3B loss drives disease progression in PC. FAM3B acts as an intermediator of a self-governing androgen receptor (AR) feedback loop. Specifically, AR upregulates FAM3B expression by binding to an intronic enhancer to induce an enhancer-RNA and facilitate enhancer-promoter looping. FAM3B, in turn, attenuates AR signaling.
Loss of FAM3B in PC, whether through the TMPRSS2-ERG translocation or epigenetic imprinting, causes an exit from this autoregulatory loop to unleash AR activity and PC progression.These findings establish FAM3B loss as a new driver of PC progression and support the utility of FAM3B loss as a biomarker to better define aggressive PC.
Journal of the National Cancer Institute. 2023 Oct 17 [Epub ahead of print]
Tianfang Ma, Lianjin Jin, Shanshan Bai, Zhan Liu, Shuo Wang, Beibei Shen, Yeyoung Cho, Subing Cao, Meijuan J S Sun, Ladan Fazli, David Zhang, Chiyaro Wedderburn, Derek Y Zhang, Gavisha Mugon, Nathan Ungerleider, Melody Baddoo, Kun Zhang, Lovisa Holmberg Schiavone, Brant R Burkhardt, Jia Fan, Zongbing You, Erik K Flemington, Xuesen Dong, Yan Dong
Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana, USA., Department of Biochemistry & Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana, USA., Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada., Department of Pathology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana, USA., Department of Computer Science, Bioinformatics Facility of Xavier RCMI Center of Cancer Research, Xavier University of Louisiana, New Orleans, Louisiana, USA., Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden., Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, Florida, USA.