Distinct structural classes of activating FOXA1 alterations in advanced prostate cancer

Abhijit Parolia, Marcin Cieslik, Shih-Chun Chu, Lanbo Xiao, Takahiro Ouchi, Yuping Zhang, Xiaoju Wang, Pankaj Vats, Xuhong Cao, Sethuramasundaram Pitchiaya, Fengyun Su, Rui Wang, Felix Y. Feng, Yi-Mi Wu, Robert J. Lonigro, Dan R. Robinson and Arul M. Chinnaiyan ()
Additional contact information
Abhijit Parolia: University of Michigan
Marcin Cieslik: University of Michigan
Shih-Chun Chu: University of Michigan
Lanbo Xiao: University of Michigan
Takahiro Ouchi: University of Michigan
Yuping Zhang: University of Michigan
Xiaoju Wang: University of Michigan
Pankaj Vats: University of Michigan
Xuhong Cao: University of Michigan
Sethuramasundaram Pitchiaya: University of Michigan
Fengyun Su: University of Michigan
Rui Wang: University of Michigan
Felix Y. Feng: University of California at San Francisco
Yi-Mi Wu: University of Michigan
Robert J. Lonigro: University of Michigan
Dan R. Robinson: University of Michigan
Arul M. Chinnaiyan: University of Michigan

Nature, 2019, vol. 571, issue 7765, 413-418

Abstract: Abtract 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 hormone-receptor-driven prostate, breast, bladder and salivary-gland tumours3–8. However, it is unclear how FOXA1 alterations affect the development of cancer, and FOXA1 has previously been ascribed both tumour-suppressive9–11 and oncogenic12–14 roles. Here we assemble an aggregate cohort of 1,546 prostate cancers and show that FOXA1 alterations fall into three structural classes that diverge in clinical incidence and genetic co-alteration profiles, with a collective prevalence of 35%. Class-1 activating mutations originate in early prostate cancer without alterations in ETS or SPOP, selectively recur within the wing-2 region of the DNA-binding forkhead domain, enable enhanced chromatin mobility and binding frequency, and strongly transactivate a luminal androgen-receptor program of prostate oncogenesis. By contrast, class-2 activating mutations are acquired in metastatic prostate cancers, truncate the C-terminal domain of FOXA1, enable dominant chromatin binding by increasing DNA affinity and—through TLE3 inactivation—promote metastasis driven by the WNT pathway. Finally, class-3 genomic rearrangements are enriched in metastatic prostate cancers, consist 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 oncogenesis driven by the androgen receptor, and provides mechanistic insights into how the classes of FOXA1 alteration promote the initiation and/or metastatic progression of prostate cancer. These results have direct implications for understanding the pathobiology of other hormone-receptor-driven cancers and rationalize the co-targeting of FOXA1 activity in therapeutic strategies.

Date: 2019
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DOI: 10.1038/s41586-019-1347-4

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