The landscape of selection in 551 esophageal adenocarcinomas defines genomic biomarkers for the clinic
The landscape of selection in 551 esophageal adenocarcinomas defines genomic biomarkers for the clinic
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DOI：
10.1038/s41588-018-0331-5
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发表时间：
2019-03-01
期刊：
影响因子：
30.8
通讯作者：
Fickling, Will
中科院分区：
文献类型：
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作者：
Frankell, Alexander M.;Jammula, SriGanesh;Fickling, Will
食管腺癌（EAC）是一种预后不良的癌症类型，发病率迅速上升。对驱动EAC发展的遗传事件的理解是有限的，并且很少有用于诊断或治疗的分子生物标志物。使用一组551个基因组特征的EAC与匹配的RNA测序数据，我们发现了77个EAC驱动基因和21个非编码驱动元件。我们确定了每个肿瘤平均4.4个驱动事件，这些事件更常见于突变而不是拷贝数改变，并将这些突变的发生率与使用非同义突变与同义突变比率（dN/dS）计算的外显子组范围内的突变过量进行了比较。我们观察到几个失调的EAC通路内和之间的事件的相互排他性或共同发生，这一结果提示了强烈的功能关系。在具有显著预测价值的独立队列中验证了预后不良的指标（SMAD 4和GATA 4）。超过50%的EAC含有CDK 4和CDK 6抑制剂的致敏事件，这与一组EAC细胞系和类器官中的临床相关敏感性高度相关。
Esophageal adenocarcinoma (EAC) is a poor-prognosis cancer type with rapidly rising incidence. Understanding of the genetic events driving EAC development is limited, and there are few molecular biomarkers for prognostication or therapeutics. Using a cohort of 551 genomically characterized EACs with matched RNA sequencing data, we discovered 77 EAC driver genes and 21 noncoding driver elements. We identified a mean of 4.4 driver events per tumor, which were derived more commonly from mutations than copy number alterations, and compared the prevelence of these mutations to the exome-wide mutational excess calculated using non-synonymous to synonymous mutation ratios (dN/dS). We observed mutual exclusivity or co-occurrence of events within and between several dysregulated EAC pathways, a result suggestive of strong functional relationships. Indicators of poor prognosis (SMAD4 and GATA4) were verified in independent cohorts with significant predictive value. Over 50% of EACs contained sensitizing events for CDK4 and CDK6 inhibitors, which were highly correlated with clinically relevant sensitivity in a panel of EAC cell lines and organoids.