FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes,Nature

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FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes
Nature ( IF 50.5 ) Pub Date : 2019-06-26 , DOI: 10.1038/s41586-019-1318-9
Elizabeth J Adams ₁ , Wouter R Karthaus ₁ , Elizabeth Hoover ₁ , Deli Liu _{2,

3,

4} , Antoine Gruet ₅ , Zeda Zhang _{1,

6} , Hyunwoo Cho _{7,

8} , Rose DiLoreto _{8,

9} , Sagar Chhangawala _{7,

8} , Yang Liu ₁₀ , Philip A Watson ₁ , Elai Davicioni ₁₀ , Andrea Sboner _{2,

4,

11} , Christopher E Barbieri _{2,

3,

11} , Rohit Bose ₁₂ , Christina S Leslie ₈ , Charles L Sawyers _{1,

13}

Affiliation

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
Department of Urology, Weill Cornell Medicine, New York, NY, USA.
HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY, USA.
Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Louis V. Gerstner Jr Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Physiology, Biophysics, and Systems Biology Program, Weill Cornell Graduate School, New York, NY, USA.
Tri-Institutional Training Program in Computational Biology & Medicine, Weill Cornell Medicine, New York, NY, USA.
GenomeDx Bioscience, Vancouver, British Columbia, Canada.
Englander Institute for Precision Medicine of Weill Cornell Medicine and NewYork-Presbyterian Hospital, New York, NY, USA.
Departments of Anatomy, Medicine and Urology, University of California, San Francisco, San Francisco, CA, USA.
Howard Hughes Medical Institute, Chevy Chase, MD, USA.

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 unknown1–9. 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.Mutations in the transcription factor FOXA1 that are common in prostate cancer result in gain-of-function effects that promote changes in the differentiation of tumour cells.

中文翻译：

FOXA1 突变改变了开创性活动、分化和前列腺癌表型

转录因子 FOXA1 的突变定义了前列腺癌的一个独特子集，但这些突变的功能后果以及它们是否会导致功能的获得或丧失尚不清楚 1-9。在这里，通过注释来自 3,086 个人类前列腺癌的 FOXA1 突变情况，我们定义了叉头结构域中的两个热点：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都检测到 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研究揭示了小鼠前列腺类器官增殖试验中的功能增益。这些突变体中的十二个，以及野生型 FOXA1，促进了夸大的前腔分化程序，而两种不同的 R219 突变体阻断了腔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 和代表性 Wing2 和 R219 突变体的测序 (ATAC-seq) 对转座酶可及的染色质进行测定，揭示了在数千个基因组位点和暴露的 FOXA1 结合位点和相关基因增加的开放染色质中显着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 峰缺乏典型的核心 FOXA1 结合基序 (GTAAAC/T)，但富含相关的非典型基序 (GTAAAG/A)，该基序优先被 R219 突变体激活报告基因检测中的 FOXA1。因此，

更新日期：2019-06-26

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