While mutations affecting protein-coding regions have been examined across many cancers, structural variants at the genome-wide level are still poorly defined. Through integrative deep whole-genome and -transcriptome analysis of 101 castration-resistant prostate cancer metastases (109X tumor/38X normal coverage), we identified structural variants altering critical regulators of tumorigenesis and progression not detectable by exome approaches. Notably, we observed amplification of an intergenic enhancer region 624 kb upstream of the androgen receptor (AR) in 81% of patients, correlating with increased AR expression. Tandem duplication hotspots also occur near MYC, in lncRNAs associated with post-translational MYC regulation. Classes of structural variations were linked to distinct DNA repair deficiencies, suggesting their etiology, including associations of CDK12 mutation with tandem duplications, TP53 inactivation with inverted rearrangements and chromothripsis, and BRCA2 inactivation with deletions. Together, these observations provide a comprehensive view of how structural variations affect critical regulators in metastatic prostate cancer.
Summary Forkhead box A1 (FOXA1) is a pioneer transcription factor that is essential for the normal development of several endoderm-derived organs, including the prostate gland1,2. FOXA1 is frequently mutated in the hormone-receptor driven prostate, breast, bladder, and salivary gland tumors3–8. However, how FOXA1 alterations affect cancer development is unclear, with FOXA1 previously ascribed both tumor suppressive9–11 and oncogenic12–14 roles. Here we assemble an aggregate cohort of 1546 prostate cancers (PCa) and show that FOXA1 alterations fall into three distinct structural classes that diverge in clinical incidence and genetic co-alteration profiles, with a collective prevalence of 35%. Class1 activating mutations originate in early PCa without ETS/SPOP alterations, selectively recur within the Wing2-region of the DNA-binding Forkhead domain (FKHD), enable enhanced chromatin mobility and binding frequency, and strongly transactivate a luminal androgen receptor (AR) program of prostate oncogenesis. By contrast, class2 activating mutations are acquired in metastatic PCa, truncate the C-terminal domain of FOXA1, enable dominant chromatin binding by increasing DNA affinity, and through TLE3 inactivation promote WNT-pathway driven metastasis. Finally, class3 genomic rearrangements are enriched in metastatic PCa, comprise of duplications and translocations within the FOXA1 locus, and structurally reposition a conserved regulatory element, herein denoted FOXA1 Mastermind (FOXMIND), to drive overexpression of FOXA1 or other oncogenes. Our study reaffirms the central role of FOXA1 in mediating AR-driven oncogenesis, and provides mechanistic insights into how different classes of FOXA1 alterations uniquely promote PCa initiation and/or metastatic progression. Furthermore, these results have direct implications in understanding the pathobiology of other hormone-receptor driven cancers and rationalize therapeutic co-targeting of FOXA1 activity.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, employs two key host proteins to gain entry and replicate within cells, angiotensin-converting enzyme 2 (ACE2) and the cell surface transmembrane protease serine 2 (TMPRSS2). TMPRSS2 was first characterized as an androgen-regulated gene in the prostate. Supporting a role for sex hormones, males relative to females are disproportionately affected by COVID-19 in terms of mortality and morbidity. Several studies, including one employing a large epidemiological cohort, suggested that blocking androgen signaling is protective against COVID-19. Here, we demonstrate that androgens regulate the expression of ACE2, TMPRSS2, and androgen receptor (AR) in subsets of lung epithelial cells. AR levels are markedly elevated in males relative to females greater than 70 y of age. In males greater than 70 y old, smoking was associated with elevated levels of AR and ACE2 in lung epithelial cells. Transcriptional repression of the AR enhanceosome with AR or bromodomain and extraterminal domain (BET) antagonists inhibited SARS-CoV-2 infection in vitro. Taken together, these studies support further investigation of transcriptional inhibition of critical host factors in the treatment or prevention of COVID-19.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.