Novel kinase fusion transcripts found in endometrial cancer.
Novel kinase fusion transcripts found in endometrial cancer.
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DOI：
10.1038/srep18657
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发表时间：
2015-12-22
影响因子：
4.6
通讯作者：
Enomoto T
中科院分区：
文献类型：
--
作者：
Tamura R;Yoshihara K;Yamawaki K;Suda K;Ishiguro T;Adachi S;Okuda S;Inoue I;Verhaak RG;Enomoto T
RNA测序技术的最新进展使得能够在癌细胞的转录组中发现基因融合转录物。然而，它仍然难以区分治疗靶向融合乘客事件。我们分析了25个子宫内膜癌细胞系的RNA测序数据和DNA拷贝数数据，以确定潜在的治疗靶向融合转录本，并确定了124个高置信度的融合转录本，其中69%与基因扩增相关。作为靶向融合候选物，我们专注于保留激酶结构域的三种框内激酶融合转录物（CPQ-PRKDC、CAPZA 2-MET和VGLL 4-PRKG 1）。我们在122例原发性子宫内膜癌组织中的3例中仅检测到CPQ-PRKDC融合转录本。通过敲低野生型PRKDC的表达而不是通过阻断CPQ-PRKDC融合转录物表达来抑制融合阳性细胞系的细胞增殖。定量实时RT-PCR表明，CPQ-PRKDC融合转录本的表达显著低于野生型PRKDC的表达，对应于该融合体的低转录等位基因分数，基于RNA测序读取计数。在子宫内膜癌中，CPQ-PRKDC融合转录物可能是与基因扩增相关的乘客畸变。我们的研究结果表明，转录等位基因分数是一个有用的预测，以找到真正的治疗靶向融合转录。
Recent advances in RNA-sequencing technology have enabled the discovery of gene fusion transcripts in the transcriptome of cancer cells. However, it remains difficult to differentiate the therapeutically targetable fusions from passenger events. We have analyzed RNA-sequencing data and DNA copy number data from 25 endometrial cancer cell lines to identify potential therapeutically targetable fusion transcripts, and have identified 124 high-confidence fusion transcripts, of which 69% are associated with gene amplifications. As targetable fusion candidates, we focused on three in-frame kinase fusion transcripts that retain a kinase domain (CPQ-PRKDC, CAPZA2-MET, and VGLL4-PRKG1). We detected only CPQ-PRKDC fusion transcript in three of 122 primary endometrial cancer tissues. Cell proliferation of the fusion-positive cell line was inhibited by knocking down the expression of wild-type PRKDC but not by blocking the CPQ-PRKDC fusion transcript expression. Quantitative real-time RT-PCR demonstrated that the expression of the CPQ-PRKDC fusion transcript was significantly lower than that of wild-type PRKDC, corresponding to a low transcript allele fraction of this fusion, based on RNA-sequencing read counts. In endometrial cancers, the CPQ-PRKDC fusion transcript may be a passenger aberration related to gene amplification. Our findings suggest that transcript allele fraction is a useful predictor to find bona-fide therapeutic-targetable fusion transcripts.