FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes Research Letter

Authors: Adams, E. J.; Karthaus, W. R.; Hoover, E.; Liu, D.; Gruet, A.; Zhang, Z.; Cho, H.; DiLoreto, R.; Chhangawala, S.; Liu, Y.; Watson, P. A.; Davicioni, E.; Sboner, A.; Barbieri, C. E.; Bose, R.; Leslie, C. S.; Sawyers, C. L.
Title: FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes
Abstract: Mutations in the transcription factor FOXA1 define a unique subset of prostate cancers but the functional consequences of these mutations and whether they confer gain or loss of function is unknown1–9. Here, by annotating the landscape of FOXA1 mutations from 3,086 human prostate cancers, we define two hotspots in the forkhead domain: Wing2 (around 50% of all mutations) and the highly conserved DNA-contact residue R219 (around 5% of all mutations). Wing2 mutations are detected in adenocarcinomas at all stages, whereas R219 mutations are enriched in metastatic tumours with neuroendocrine histology. Interrogation of the biological properties of wild-type FOXA1 and fourteen FOXA1 mutants reveals gain of function in mouse prostate organoid proliferation assays. Twelve of these mutants, as well as wild-type FOXA1, promoted an exaggerated pro-luminal differentiation program, whereas two different R219 mutants blocked luminal differentiation and activated a mesenchymal and neuroendocrine transcriptional program. Assay for transposase-accessible chromatin using sequencing (ATAC-seq) of wild-type FOXA1 and representative Wing2 and R219 mutants revealed marked, mutant-specific changes in open chromatin at thousands of genomic loci and exposed sites of FOXA1 binding and associated increases in gene expression. Of note, ATAC-seq peaks in cells expressing R219 mutants lacked the canonical core FOXA1-binding motifs (GTAAAC/T) but were enriched for a related, non-canonical motif (GTAAAG/A), which was preferentially activated by R219-mutant FOXA1 in reporter assays. Thus, FOXA1 mutations alter its pioneering function and perturb normal luminal epithelial differentiation programs, providing further support for the role of lineage plasticity in cancer progression. © 2019, The Author(s), under exclusive licence to Springer Nature Limited.
Journal Title: Nature
Volume: 571
Issue: 7765
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2019-07-18
Start Page: 408
End Page: 412
Language: English
DOI: 10.1038/s41586-019-1318-9
PUBMED: 31243370
PROVIDER: scopus
PMCID: PMC6661172
Notes: Letter -- Erratum, issued, see DOI: 10.1038/s41586-020-2678-x --Source: Scopus
Citation Impact
MSK Authors
  1. Charles L Sawyers
    211 Sawyers
  2. Philip A Watson
    24 Watson
  3. Zeda Zhang
    13 Zhang
  4. Hyunwoo   Cho
    7 Cho
  5. Elizabeth Janine Adams
    4 Adams
  6. Elizabeth   Hoover
    9 Hoover
  7. Antoine Gruet
    4 Gruet