Gene isoforms as expression-based biomarkers predictive of drug response in vitro.,Nature Communications

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Gene isoforms as expression-based biomarkers predictive of drug response in vitro.
Nature Communications ( IF 14.7 ) Pub Date : 2017-10-24 , DOI: 10.1038/s41467-017-01153-8
Zhaleh Safikhani _{1,

2} , Petr Smirnov ₁ , Kelsie L Thu _{1,

3} , Jennifer Silvester _{1,

3} , Nehme El-Hachem ₃ , Rene Quevedo _{1,

2} , Mathieu Lupien _{1,

2} , Tak W Mak _{1,

2,

4} , David Cescon _{1,

4,

5} , Benjamin Haibe-Kains _{1,

2,

6,

7}

Affiliation

Next-generation sequencing technologies have recently been used in pharmacogenomic studies to characterize large panels of cancer cell lines at the genomic and transcriptomic levels. Among these technologies, RNA-sequencing enable profiling of alternatively spliced transcripts. Given the high frequency of mRNA splicing in cancers, linking this feature to drug response will open new avenues of research in biomarker discovery. To identify robust transcriptomic biomarkers for drug response across studies, we develop a meta-analytical framework combining the pharmacological data from two large-scale drug screening datasets. We use an independent pan-cancer pharmacogenomic dataset to test the robustness of our candidate biomarkers across multiple cancer types. We further analyze two independent breast cancer datasets and find that specific isoforms of IGF2BP2, NECTIN4, ITGB6, and KLHDC9 are significantly associated with AZD6244, lapatinib, erlotinib, and paclitaxel, respectively. Our results support isoform expressions as a rich resource for biomarkers predictive of drug response.

中文翻译：

基因亚型作为基于表达的生物标志物预测体外药物反应。

新一代测序技术最近已用于药物基因组学研究，以在基因组和转录组水平上表征大量癌细胞系。在这些技术中，RNA 测序能够对可变剪接转录本进行分析。鉴于癌症中 mRNA 剪接的频率很高，将这一特征与药物反应联系起来将为生物标志物发现的研究开辟新途径。为了确定跨研究药物反应的稳健转录组生物标志物，我们开发了一个荟萃分析框架，结合了来自两个大规模药物筛选数据集的药理学数据。我们使用独立的泛癌药物基因组数据集来测试候选生物标志物在多种癌症类型中的稳健性。我们进一步分析了两个独立的乳腺癌数据集，发现 IGF2BP2、NECTIN4、ITGB6 和 KLHDC9 的特定亚型分别与 AZD6244、拉帕替尼、厄洛替尼和紫杉醇显着相关。我们的结果支持同种型表达作为预测药物反应的生物标志物的丰富资源。

更新日期：2017-10-24

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