FOXA1 mutation

Foxa1 disruption in mouse embryos significantly enhances the integration of human cells in human-mouse interspecies chimeras, thereby facilitating the generation of endoderm-derived organs through blastocyst complementation. Overcoming chimeras' embryonic lethality is crucial for successfully generating humanized NE in Foxa1-deficient mouse embryos.

Overall, we define RA as an instructive signal for glandular identity in adult prostate progenitors. Importantly, we identify cancer-associated FOXA1 indels affecting residue F254 as loss-of-function mutations promoting dedifferentiation of adult prostate progenitors.

Transcriptomes distinguished ETS -fused tumors from SPOP mutants, and PTEN loss from PTEN/AKT1 mutations. Inferred relationships between specific genomic alterations and gene expression signatures of luminal/basal subtypes and of biological pathways/processes, including AR signaling, proliferation, and plasticity signatures, provide a basis to understand differences in treatment response and inform biomarker-guided treatment strategies.

Our findings demonstrated that the methylation signatures of distinct biological processes are associated with immune activity in the cancer microenvironment and predict immunotherapy response.

We further show that FOXA1 negatively regulates SEMA3C via intronic cis elements, and that mutations in FOXA1 forkhead domain attenuate its inhibitory function in reporter assays, presumably by disrupting DNA binding of FOXA1. Our findings underscore the key role of FOXA1 in prostate cancer progression and treatment resistance by regulating SEMA3C expression and suggest that SEMA3C may be a driver of growth and tumor vulnerability of mCRPC harboring FOXA1 alterations.

Lastly, we identified novel positive associations between AMR and driver mutations in PIK3C3A (OR=1.12, p=0.0003) as well as small NS mutations or CNAs in the PI3K/AKT/mTOR pathway genes (OR=1.03, p=0.04). By analyzing a large, diverse real-world cohort and leveraging NGS-inferred genetic ancestry, our study confirms known associations between somatic alterations in PRAD cancer genes and race and ethnicity, while unveiling novel associations in understudied populations of potential significance for understanding disparities in disease outcomes.

Cancer panel testing for cfDNA identified prognostic and predictive biomarkers for palbociclib add-on therapy after acquiring fulvestrant resistance in patients with HR+/HER2- ABC/MBC.

Different FOXA1 alterations exhibit divergent molecular and clinical features, and should not be interpreted in aggregate. In particular, Class 1B mutations are associated with a unique molecular and immunological landscape with potentially better outcomes to ADT, while Class 2 mutations are associated with NEPC phenotype with inferior ADT sensitivity.

The homozygous adrenal-permissive HSD3B1 variant (c.1100 CC) is associated with distinct tumoral features characterized by elevated AR signaling and MAPK activation. It is also associated with a unique immune-cell regulatory landscape, with higher B7-H3 expression, increased intratumoral dendritic cells and decreased immunosuppressive neutrophils. This distinct molecular landscape of HSD3B1 c.1100 CC–associated prostate cancers warrants special therapeutic considerations, including possibly using B7-H3–targeted therapies.

KDM1A, MAOA, PDGFB, and HSP90AB1 emerged as druggable candidate targets, as we found that they have approved drugs throughout the drug database CADDIE. Notably, as most of the approved drugs targeting MAOA and KDM1A were monoamine inhibitors used for mental illness or diabetes, we suggest they have a potential to cure FOXA1 mutant primary prostate cancer without lethal side effects.

Treatment of xenograft mice with the SKP2 inhibitor SZL P1-41 decreased tumor proliferation, SKP2:FOXA1 ratios and colocalization. Thus, our results highlight the significance of the SKP2-FOXA1 interplay on the luminal lineage in PCa and the potential of therapeutically targeting FOXA1 through SKP2 to improve PCa control.

We identified genomic alterations (TP53 mutations, FOXA1 and AR amplification, RB1 and BRCA2 deletions) from primary prostate tumors that are predictive of wide-spread metastases and poor outcomes.