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FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes

机译：Foxa1突变改变开创性活动，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，而是这些突变的功能后果以及它们是否授予功能或丧失功能是未知的（1-9）。这里，通过向3,086人前列腺癌的FoxA1突变的景观，我们在叉头域中定义两个热点：Wing2（占所有突变的50％）和高度保守的DNA接触残留物R219（约占所有突变的5％） 。在所有阶段的腺癌中检测Wing2突变，而R219突变富集在具有神经内分泌组织学的转移性肿瘤中。野生型FOXA1和14个FOXA1突变体的生物学性质的询问揭示了小鼠前列腺有机体增殖测定中的功能的增益。这些突变体和野生型FOXA1的十二次促进了夸张的亲腔分化计划，而两种不同的R219突变体阻断腔分化并激活间充质和神经内分泌转录程序。使用野生型FoxA1的测序（ATAC-SEQ）和代表性翼2和R219突变体的测定法测定，揭示了在数千种基因组基因汀（FoxA1结合和相关的氟呋肽）和外露位点的明显的突变体特异性变化表达。值得注意的是，表达R219突变体的细胞中的ATAC-SEQ峰缺乏规范核心FOXA1结合基序（GTAAAC / T），但富含相关的非规范基序（GTAAAG / A），其优先由R219-突变体激活报告管理中的Foxa1。因此，FOXA1突变改变其先进功能和扰动正常腔上皮分化计划，从而进一步支持谱系可塑性在癌症进展中的作用。

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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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