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FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes

机译：FOXA1突变改变开拓性活动，分化和前列腺癌表型

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摘要

Mutations in the transcription factor FOXA1 define a unique subset of prostate cancers but the functional consequences of these mutations and whether they confer gain or loss of function is unknown(1-9). Here, by annotating the landscape of FOXA1 mutations from 3,086 human prostate cancers, we define two hotspots in the forkhead domain: Wing2 (around 50% of all mutations) and the highly conserved DNA-contact residue R219 (around 5% of all mutations). Wing2 mutations are detected in adenocarcinomas at all stages, whereas R219 mutations are enriched in metastatic tumours with neuroendocrine histology. Interrogation of the biological properties of wild-type FOXA1 and fourteen FOXA1 mutants reveals gain of function in mouse prostate organoid proliferation assays. Twelve of these mutants, as well as wild-type FOXA1, promoted an exaggerated pro-luminal differentiation program, whereas two different R219 mutants blocked luminal differentiation and activated a mesenchymal and neuroendocrine transcriptional program. Assay for transposase-accessible chromatin using sequencing (ATAC-seq) of wild-type FOXA1 and representative Wing2 and R219 mutants revealed marked, mutant-specific changes in open chromatin at thousands of genomic loci and exposed sites of FOXA1 binding and associated increases in gene expression. Of note, ATAC-seq peaks in cells expressing R219 mutants lacked the canonical core FOXA1-binding motifs (GTAAAC/T) but were enriched for a related, non-canonical motif (GTAAAG/A), which was preferentially activated by R219-mutant FOXA1 in reporter assays. Thus, FOXA1 mutations alter its pioneering function and perturb normal luminal epithelial differentiation programs, providing further support for the role of lineage plasticity in cancer progression.
机译：转录因子FOXA1中的突变定义了前列腺癌的独特子集，但这些突变的功能后果以及它们是否赋予功能获得或丧失的功能尚不清楚（1-9）。在这里，通过注释来自3086种人类前列腺癌的FOXA1突变的概况，我们在前叉域中定义了两个热点：Wing2（约占所有突变的50％）和高度保守的DNA接触残基R219（约占所有突变的5％） 。在所有阶段的腺癌中均检测到Wing2突变，而R219突变在具有神经内分泌组织学的转移性肿瘤中富集。对野生型FOXA1和14个FOXA1突变体的生物学特性的询问揭示了在小鼠前列腺类器官增殖试验中获得的功能。这些突变体中的十二个以及野生型FOXA1促进了夸大的腔内分化程序，而两个不同的R219突变体阻止了腔内分化并激活了间充质和神经内分泌转录程序。使用野生型FOXA1以及代表性Wing2和R219突变体的测序（ATAC-seq）分析转座酶可接近的染色质表达。值得注意的是，表达R219突变体的细胞中的ATAC-seq峰缺乏典型的核心FOXA1结合基序（GTAAAC / T），但富含相关的非经典基序（GTAAAG / A），该基序优先被R219突变体激活报告基因分析中的FOXA1。因此，FOXA1突变改变了其先驱功能并扰乱了正常的管腔上皮分化程序，为谱系可塑性在癌症进展中的作用提供了进一步的支持。

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  • 来源
    《Nature》 |2019年第7765期|408-412|共5页
  • 作者

    Adams Elizabeth J.; Karthaus Wouter R.; Hoover Elizabeth; Liu Deli; Gruet Antoine; Zhang Zeda; Cho Hyunwoo; DiLoreto Rose; Chhangawala Sagar; Liu Yang; Watson Philip A.; Davicioni Elai; Sboner Andrea; Barbieri Christopher E.; Bose Rohit; Leslie Christina S.; Sawyers Charles L.;

  • 作者单位

    Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA;

    Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA;

    Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA;

    Weill Cornell Med, Sandra & Edward Meyer Canc Ctr, New York, NY USA|Weill Cornell Med, Dept Urol, New York, NY USA|Weill Cornell Med Coll, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY USA;

    Mem Sloan Kettering Canc Ctr, Ctr Epigenet Res, 1275 York Ave, New York, NY 10021 USA;

    Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA|Mem Sloan Kettering Canc Ctr, Louis V Gerstner Jr Grad Sch Biomed Sci, 1275 York Ave, New York, NY 10021 USA;

    Mem Sloan Kettering Canc Ctr, Computat & Syst Biol Program, 1275 York Ave, New York, NY 10021 USA|Weill Cornell Grad Sch, Physiol Biophys & Syst Biol Program, New York, NY USA;

    Weill Cornell Grad Sch, Physiol Biophys & Syst Biol Program, New York, NY USA|Weill Cornell Med, Triinst Training Program Computat Biol & Med, New York, NY USA;

    Mem Sloan Kettering Canc Ctr, Computat & Syst Biol Program, 1275 York Ave, New York, NY 10021 USA|Weill Cornell Grad Sch, Physiol Biophys & Syst Biol Program, New York, NY USA;

    GenomeDx Biosci, Vancouver, BC, Canada;

    Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA;

    GenomeDx Biosci, Vancouver, BC, Canada;

    Weill Cornell Med, Sandra & Edward Meyer Canc Ctr, New York, NY USA|Weill Cornell Med Coll, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY USA|Weill Cornell Med, Englander Inst Precis Med, New York, NY USA|NewYork Presbyterian Hosp, New York, NY USA;

    Weill Cornell Med, Sandra & Edward Meyer Canc Ctr, New York, NY USA|Weill Cornell Med, Dept Urol, New York, NY USA|Weill Cornell Med, Englander Inst Precis Med, New York, NY USA|NewYork Presbyterian Hosp, New York, NY USA;

    Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA|Univ Calif San Francisco, Dept Med, San Francisco, CA USA|Univ Calif San Francisco, Dept Urol, San Francisco, CA USA;

    Weill Cornell Grad Sch, Physiol Biophys & Syst Biol Program, New York, NY USA;

    Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA|Howard Hughes Med Inst, Chevy Chase, MD 20815 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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