Computational identification of mutator-derived lncRNA signatures of genome instability for improving the clinical outcome of cancers: a case study in breast cancer
Computational identification of mutator-derived lncRNA signatures of genome instability for improving the clinical outcome of cancers: a case study in breast cancer
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突变衍生的基因组不稳定性 lncRNA 特征的计算识别可改善癌症的临床结果：乳腺癌案例研究
DOI：
10.1093/bib/bbz118
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发表时间：
2020-09-01
影响因子：
9.5
通讯作者：
Zhou, Meng
中科院分区：
文献类型：
--
作者：
Bao, Siqi;Zhao, Hengqiang;Zhou, Meng
新的证据揭示了长链非编码 RNA (lncRNA) 在维持基因组稳定性方面的关键作用。然而，与基因组不稳定相关的 lncRNA 的鉴定及其在癌症中的临床意义仍未得到充分探索。在这里，我们开发了一个突变假说衍生的计算框架，结合了肿瘤基因组中的 lncRNA 表达谱和体细胞突变谱，并鉴定了乳腺癌中 128 个新型基因组不稳定相关的 lncRNA 作为案例研究。然后，我们确定了基因组不稳定性衍生的两个基于 lncRNA 的基因特征 (GILncSig)，将患者分为高风险组和低风险组，结果显着不同，并在多个独立患者队列中得到进一步验证。此外，GILncSig 与卵巢癌和乳腺癌的基因组突变率相关，表明其作为基因组不稳定程度测量的潜力。 GILncSig能够将TP53宽型患者分为两个风险组，与TP53突变患者相比，低风险组的预后明显改善，而高风险组则没有显着差异。总之，这项研究为进一步研究 lncRNA 在基因组不稳定性中的作用提供了关键方法和资源，并为识别基因组不稳定性相关的癌症生物标志物引入了潜在的新途径。
Emerging evidence revealed the critical roles of long non-coding RNAs (lncRNAs) in maintaining genomic instability. However, identification of genome instability-associated lncRNAs and their clinical significance in cancers remain largely unexplored. Here, we developed a mutator hypothesis-derived computational frame combining lncRNA expression profiles and somatic mutation profiles in a tumor genome and identified 128 novel genomic instability-associated lncRNAs in breast cancer as a case study. We then identified a genome instability-derived two lncRNA-based gene signature (GILncSig) that stratified patients into high- and low-risk groups with significantly different outcome and was further validated in multiple independent patient cohorts. Furthermore, the GILncSig correlated with genomic mutation rate in both ovarian cancer and breast cancer, indicating its potential as a measurement of the degree of genome instability. The GILncSig was able to divide TP53 wide-type patients into two risk groups, with the low-risk group showing significantly improved outcome and the high-risk group showing no significant difference compared with those with TP53 mutation. In summary, this study provided a critical approach and resource for further studies examining the role of lncRNAs in genome instability and introduced a potential new avenue for identifying genomic instability-associated cancer biomarkers.