Mutations in FOXA1 Cluster into Distinct Structural and Phenotypic Classes

FOXA1 is a transcription factor that is frequently mutated in prostate cancer, but the impact of FOXA1 mutations is not known. Using sequencing data from 3,086 patients with primary or metastatic prostate cancer, Adams and colleagues discovered that 11% had mutations in FOXA1. Mutated FOXA1 was associated with higher Gleason Scores, reduced time to biochemical recurrence, and faster metastasis. More than 50% of FOXA1 mutations are in the Wing2 region of the forkhead DNA-binding domain, and mutations also clustered more rarely at R219. Both mutations increased growth of primary mouse prostate organoids, especially without epidermal growth factor, and exhibited histologic abnormalities, with Wing2-hotspot mutants causing increased lumen formation and size and R219 mutations leading to inability to form measurable lumens. Both types of mutations also caused a gain of function in FOXA1′s pioneering activity, changing the chromatin landscape, which may contribute to oncogenesis. In a separate study of an aggregate cohort of 1,546 prostate cancers, Parolia and colleagues found FOXA1 mutations at frequencies of 8%–9% in primary disease and 12%–13% in metastatic castration-resistant prostate cancer, and divided the mutations into three classes. Class 1 mutations were found in Wing2 or another region of the forkhead domain proximal to Wing2 in the protein's structure. These mutations were not enriched in metastatic cases, and, consistent with the work by Adams and colleagues, they are activating. Class 1 mutations enhanced nuclear mobility and caused 3–6-fold greater activation of androgen receptor signaling. Class 2 mutations, which were truncations of the protein's C-terminal domain, were also activating, and were seen at higher frequency in metastatic prostate cancers. Class 2 mutants dominantly engaged DNA and derepressed the WNT pathway that promotes metastasis. Class 3 mutations were genomic rearrangements that involve duplicating or repositioning a regulatory element that the group named FOXA1 mastermind, which caused overexpression of FOXA1 or other oncogenes, respectively. Collectively, these results provide insight into the functional consequences of FOXA1 alterations and highlight the central role of FOXA1 in prostate cancer development.

Parolia A, Cieslik M, Chu SC, Xiao L, Ouchi T, Zhang Y, et al. Distinct structural classes of activating FOXA1 alterations in advanced prostate cancer. Nature 2019 Jun 26 [Epub ahead of print].

Adams EJ, Karthaus WR, Hoover E, Liu D, Gruet A, Zhang Z. FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes. Nature 2019 Jun 26 [Epub ahead of print].

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