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Purpose: 10-15% of prostate cancers (PCa) harbor recurrent FOXA1 aberrations whereby the alteration type and the effect on the forkhead( FKH) domain impacts protein-function. We developed a FOXA1 classification system to inform clinical management., Experimental Design: 5,014 PCa were examined using whole exome and transcriptome sequencing from the Caris database. We denoted class 1 FOXA1 alterations as missense and in-frame insertions/deletions with subclasses oriented with respect to the FKH domain: these were in the first part of the FKH domain (class 1A: amino acids [AA] 168-246), within the Wing2 region of FKH (class 1B: AA 247-269), or outside FKH (class 1C: AA 1-167, 270+). Two hotspot missense mutations at R219 were denoted class 2. Class 3 included predicted-truncating mutations with subclasses partitioned based on the FKH domain (class 3A: AA 1-269, class 3B: AA 270+). Class 4 represented FOXA1 amplifications. Real-world overall survival and therapy outcomes were determined from insurance claims., Results: FOXA1 alterations did not influence survival when considered in aggregate, but had distinct prognostic effects when stratified by class. Class 1A alterations were associated with overall improved survival (HR=0.57, p=0.03); a similar trend was seen with Class 1B (HR=0.88, p=0.07). Conversely, class 1C exhibited worse survival upon 2nd-generation androgen receptor signaling inhibitor (ARSI) treatment (HR=1.93, p<0.001). Class 2 mutations (R219C/S) were enriched in neuroendocrine prostate cancers and were associated with overall poor survival (HR=2.05, p<0.001) and worse outcomes to first-line androgen-deprivation therapies (HR=2.5, p<0.001). Class 3A alterations indicated improved survival (HR=0.70; p=0.01) whereas class 3B alterations portended poor outcomes (HR=1.50; p<0.001). Amplifications (class 4) indicated poor outcomes (HR=1.48; p=0.02). Molecularly, different FOXA1 alteration classes harbored distinct mutational and immunologic features as well as unique transcriptional programs. Finally, relative to European-Americans, African-Americans had increased class 1C alterations whereas Asian-Pacific patients had increased class 1B alterations., Conclusions: FOXA1alterations should not be interpreted in aggregate, as different classes are associated with divergent molecular features and clinical outcomes. Our revised classification schema facilitates clinical decision making for PCa patients and uncovers important racial differences.

Pancreatic ductal adenocarcinoma (PDAC) is an intractable cancer with a dismal prognosis. miR-29a is commonly downregulated in PDAC; however, mechanisms for its loss and role still remain unclear. Here, we show that in PDAC, repression of miR-29a is directly mediated by MYC via promoter activity. RNA sequencing analysis, integrated with miRNA target prediction, identified global miR-29a downstream targets in PDAC. Target enrichment coupled with gene ontology and survival correlation analyses identified the top five miR-29a-downregulated target genes ( LOXL2 , MYBL2 , CLDN1 , HGK , and NRAS ) that are known to promote tumorigenic mechanisms. Functional validation confirmed that upregulation of miR-29a is sufficient to ablate translational expression of these five genes in PDAC. We show that the most promising target among the identified genes, LOXL2 , is repressed by miR-29a via 3'-untranslated region binding. Pancreatic tissues from a PDAC murine model and patient biopsies showed overall high LOXL2 expression with inverse correlations with miR-29a levels. Collectively, our data delineate an antitumorigenic, regulatory role of miR-29a and a novel MYC-miR-29a-LOXL2 regulatory axis in PDAC pathogenesis, indicating the potential of the molecule in therapeutic opportunities. IMPLICATIONS: This study unravels a novel functional role of miR-29a in PDAC pathogenesis and identifies an MYC-miR-29a-LOXL2 axis in regulation of the disease progression, implicating miR-29a as a potential therapeutic target for PDAC. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/18/2/311/F1.large.jpg., (©2019 American Association for Cancer Research.)