Multiplexed functional genomic analysis of 5' untranslated region mutations across the spectrum of prostate cancer.
Multiplexed functional genomic analysis of 5' untranslated region mutations across the spectrum of prostate cancer.
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DOI：
10.1038/s41467-021-24445-6
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发表时间：
2021-07-09
影响因子：
16.6
通讯作者：
Hsieh AC
中科院分区：
文献类型：
--
作者：
Lim Y;Arora S;Schuster SL;Corey L;Fitzgibbon M;Wladyka CL;Wu X;Coleman IM;Delrow JJ;Corey E;True LD;Nelson PS;Ha G;Hsieh AC
人们对全基因组范围内5'非翻译区（UTR）内遗传变异在疾病中的功能后果知之甚少。在这里，我们开发了一种高通量多层功能基因组学方法，称为PLUMAGE（汇集的全长UTR基因表达多重测定），以量化人前列腺癌中体细胞5' UTR突变的分子后果。我们发现，5' UTR突变可以通过创建DNA结合元件或基于RNA的顺式调控基序来控制转录水平和mRNA翻译速率。我们发现点突变可以同时影响同一基因的转录和翻译水平。我们提供的证据表明，MAP激酶信号通路中的功能性5' UTR突变可以上调通路特异性基因表达，并与临床结局相关。我们的研究揭示了5'UTR的突变景观可以共同选择基因表达的多种机制，并证明了5'UTR内的单核苷酸改变在癌症中具有功能。5'非翻译区（UTR）突变在癌症的基因表达中具有功能性作用。在这里，作者开发了一种名为PLUMAGE的基于测序的高通量功能测定，并显示了这些突变对基因表达的影响及其与前列腺癌临床结果的相关性。
The functional consequences of genetic variants within 5’ untranslated regions (UTRs) on a genome-wide scale are poorly understood in disease. Here we develop a high-throughput multi-layer functional genomics method called PLUMAGE (Pooled full-length UTR Multiplex Assay on Gene Expression) to quantify the molecular consequences of somatic 5’ UTR mutations in human prostate cancer. We show that 5’ UTR mutations can control transcript levels and mRNA translation rates through the creation of DNA binding elements or RNA-based cis-regulatory motifs. We discover that point mutations can simultaneously impact transcript and translation levels of the same gene. We provide evidence that functional 5’ UTR mutations in the MAP kinase signaling pathway can upregulate pathway-specific gene expression and are associated with clinical outcomes. Our study reveals the diverse mechanisms by which the mutational landscape of 5’ UTRs can co-opt gene expression and demonstrates that single nucleotide alterations within 5’ UTRs are functional in cancer. Mutations in 5’ untranslated regions (UTRs) have a functional role in gene expression in cancer. Here, the authors develop a sequencing-based high throughput functional assay named PLUMAGE and show the effects of these mutations on gene expression and their association with clinical outcomes in prostate cancer.
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DOI：
10.1093/annonc/mdu479
发表时间：
2015-01
期刊：
Annals of oncology : official journal of the European Society for Medical Oncology
影响因子：
--
作者：
Favero F;Joshi T;Marquard AM;Birkbak NJ;Krzystanek M;Li Q;Szallasi Z;Eklund AC
通讯作者：
Eklund AC
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
64.8
作者：
Komor AC;Kim YB;Packer MS;Zuris JA;Liu DR
通讯作者：
Liu DR
影响因子：
64.5
作者：
Kumar, Sushant;Warrell, Jonathan;Gerstein, Mark B.
通讯作者：
Gerstein, Mark B.