FOXA1 mutation

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.

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.

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.

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.

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.

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.

This data suggests that IDC-P harbors targetable molecular alterations in DDR genes (BRCA1/2 and CDK12) with approved targeted agents (e.g. PARP inhibitors). These findings should underscore the importance of germline and somatic mutation testing when IDC-P is identified.

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

Finally, contrary to conventional understanding, our study reveals that driver mutations in FOXA1 induced by APOBEC3B, not mutations in AR, evolutionarily outcompete other driver mutations and eventually dominate the resistant tumors. Collectively, these results uncover a cell-intrinsic mechanism that unleashes APOBEC-driven mutagenesis, which plays a significant role in conferring targeted therapy resistance and could be the potential therapeutic targets to overcome resistance.

Interestingly, these cells were located in the lumen and did not co-express Ck8. Overall, this study reveals that loss of Foxp1 increases cell proliferation, whereas loss of Foxa1 induces epithelial plasticity in prostate cancer.

Future efforts need to focus on mechanisms underlying mutation of FOXA1 in advanced prostate cancer. We believe that FOXA1 would be a prognostic marker and therapeutic target in prostate cancer.

Knockdown of FOXA1 suppressed the migration in prostate cancer cells in vitro. Our findings indicate that targeting TP53 mutation and FOXA1 might be a promising therapeutic target for prostate cancer metastasis.

RB1, consistent with previous findings, is enriched in NEPC. The inability to detect RB1 alterations in pre-NEPC samples supports divergent evolution, although technical limits of tissue panel sequencing make it difficult to rule out the presence of sub-clonal alterations. Further study of additional genes which contribute to histologic transformation and the development of NEPC is warranted.

gDNA sequencing of 48 cancer tissues by NGS allowed to detect new tumor variants as well as confirmed lesions in genes linked to prostate cancer. Overall, somatic and germline mutations linked to good/poor prognosis could represent new prognostic tools to improve the management of PCa patients.

FOXA1, NCOR2, and TP53 somatic mutations associated with higher BRCA1/2 germline pathogenic mutations. Our description of BRCA germline mutations in the Chinese PCa patients provides more reference data for the precise diagnosis and treatment of Chinese PCa patients.

Biallelic inactivation was frequently observed in PCa patients harboring gATM and gBRCA2 mutations, but not in those with gCHEK2 mutations. gBRCA2-altered patients were enriched for somatic AR (and FOXA1) mutations and were depleted for TMPRSS2-ERG fusions. gATM-altered patients were depleted for somatic TP53 mutations, while gCHEK2-altered patients were enriched for somatic CDK12 mutations.

Using Guardant ctDNA assays in men with CRPC, clear distinctions were found in AA men as compared to C men. It is unclear why these results differ from that reported by others, however distinctions in both the assays and the populations are notable.

Tumor genomics differed by race even after accounting for clinical characteristics. Equalizing access to care may not fully eliminate such differences. Therapies for alterations more common in racial minorities are needed. Tumor genomic differences should not be assumed to be entirely due to germline genetics.

The ETS family and androgen response genes were significantly enriched in prostate cancer-specific fusion genes. Transcription activity was significantly repressed, and the DNA methylation was significantly increased in samples carrying ERG fusion.

Mutations in FOXA1 are recurrent in breast cancer but the functional consequences of these mutations remain unknown. We identified that FOXA1 mutations are associated with worse outcomes to endocrine therapy by inducing alternative chromatin profiles and gene activity in breast cancer.