Jürgens Lara, Manske Felix, Hubert Elvira, Kischka Tabea, Flötotto Lea, Klaas Oliver, Shabardina Victoria, Schliemann Christoph, Makalowski Wojciech, Wethmar Klaus
Department of Medicine A, Hematology, Oncology, Hemostaseology and Pneumology, University Hospital Münster, 48149 Münster, Germany.
Faculty of Medicine, Institute of Bioinformatics, University of Münster, 48149 Münster, Germany.
Biomedicines. 2021 May 29;9(6):618. doi: 10.3390/biomedicines9060618.
Upstream open reading frame (uORF)-mediated translational control has emerged as an important regulatory mechanism in human health and disease. However, a systematic search for cancer-associated somatic uORF mutations has not been performed. Here, we analyzed the genetic variability at canonical (uAUG) and alternative translational initiation sites (aTISs), as well as the associated upstream termination codons (uStops) in 3394 whole-exome-sequencing datasets from patient samples of breast, colon, lung, prostate, and skin cancer and of acute myeloid leukemia, provided by The Cancer Genome Atlas research network. We found that 66.5% of patient samples were affected by at least one of 5277 recurrent uORF-associated somatic single nucleotide variants altering 446 uAUG, 347 uStop, and 4733 aTIS codons. While twelve uORF variants were detected in all entities, 17 variants occurred in all five types of solid cancer analyzed here. Highest frequencies of individual somatic variants in the TLSs of NBPF20 and CHCHD2 reached 10.1% among LAML and 8.1% among skin cancer patients, respectively. Functional evaluation by dual luciferase reporter assays identified 19 uORF variants causing significant translational deregulation of the associated main coding sequence, ranging from 1.73-fold induction for an AUG.1 > UUG variant in SETD4 to 0.006-fold repression for a CUG.6 > GUG variant in HLA-DRB1. These data suggest that somatic uORF mutations are highly prevalent in human malignancies and that defective translational regulation of protein expression may contribute to the onset or progression of cancer.
上游开放阅读框（uORF）介导的翻译控制已成为人类健康和疾病中的一种重要调控机制。然而，尚未对与癌症相关的体细胞uORF突变进行系统搜索。在此，我们分析了来自癌症基因组图谱研究网络提供的3394个乳腺癌、结肠癌、肺癌、前列腺癌、皮肤癌患者样本以及急性髓系白血病患者样本的全外显子测序数据集中，经典（uAUG）和替代翻译起始位点（aTISs）的遗传变异性，以及相关的上游终止密码子（uStops）。我们发现，66.5%的患者样本受到5277个与uORF相关的复发性体细胞单核苷酸变异中的至少一个影响，这些变异改变了446个uAUG、347个uStop和4733个aTIS密码子。虽然在所有实体中都检测到了12个uORF变异，但17个变异出现在此处分析的所有五种实体癌类型中。NBPF20和CHCHD2的TLSs中个体体细胞变异的最高频率分别在急性髓系白血病患者中达到10.1%，在皮肤癌患者中达到8.1%。通过双荧光素酶报告基因检测进行的功能评估确定了导致相关主要编码序列显著翻译失调的19个uORF变异，范围从SETD4中AUG.1 > UUG变异的1.73倍诱导到HLA - DRB1中CUG.6 > GUG变异的0.006倍抑制。这些数据表明，体细胞uORF突变在人类恶性肿瘤中高度普遍，并且蛋白质表达的翻译调控缺陷可能有助于癌症的发生或进展。
