Integrated genomics and comprehensive validation reveal drivers of genomic evolution in esophageal adenocarcinoma.
Integrated genomics and comprehensive validation reveal drivers of genomic evolution in esophageal adenocarcinoma.
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DOI：
10.1038/s42003-021-02125-x
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发表时间：
2021-05-24
影响因子：
5.9
通讯作者：
Shammas MA
中科院分区：
文献类型：
--
作者：
Kumar S;Buon L;Talluri S;Roncador M;Liao C;Zhao J;Shi J;Chakraborty C;Gonzalez G;Tai YT;Prabhala R;Samur MK;Munshi NC;Shammas MA
食管腺癌（EAC）与显著的基因组不稳定性相关，这是疾病进展和耐药发展的基础。在这项研究中，我们使用了一个整合的基因组学方法来识别基因组不稳定性签名。在这里，我们表明，这种标志的表达升高与EAC以及其他三种癌症的生存率低相关。敲除和过表达筛选建立了这些基因与基因组不稳定性的相关性。对三个基因（TTK、TPX 2和RAD 54 B）的深入评估证实了它们在基因组不稳定性和肿瘤生长中的作用。通过全基因组测序和功能研究鉴定的突变特征表明，DNA损伤和同源重组是这些基因诱导的基因组不稳定性的常见机制。我们的数据表明，TTK和本研究中鉴定的可能的其他基因的抑制剂具有抑制/减少EAC和可能的其他癌症中的生长和自发以及化疗诱导的基因组不稳定性的潜力。Subodh Kumar等人使用患者数据的综合基因组分析和细胞系模型和小鼠中的实验室验证的组合，鉴定了与食管腺癌（EAC）中基因组不稳定性和较差存活率相关的基因特征。他们发现，包括TTK在内的一些已鉴定蛋白质的抑制剂可用于减少基因组进化并抑制EAC细胞的生长。
Esophageal adenocarcinoma (EAC) is associated with a marked genomic instability, which underlies disease progression and development of resistance to treatment. In this study, we used an integrated genomics approach to identify a genomic instability signature. Here we show that elevated expression of this signature correlates with poor survival in EAC as well as three other cancers. Knockout and overexpression screens establish the relevance of these genes to genomic instability. Indepth evaluation of three genes (TTK, TPX2 and RAD54B) confirms their role in genomic instability and tumor growth. Mutational signatures identified by whole genome sequencing and functional studies demonstrate that DNA damage and homologous recombination are common mechanisms of genomic instability induced by these genes. Our data suggest that the inhibitors of TTK and possibly other genes identified in this study have potential to inhibit/reduce growth and spontaneous as well as chemotherapy-induced genomic instability in EAC and possibly other cancers. Subodh Kumar et al. identify a gene signature correlated with genomic instability and poor survival in esophageal adenocarcinoma (EAC), using a combination of integrative genomic analysis of patient data and laboratory validation in cell line models and mice. They find that inhibitors of some of the identified proteins, including TTK, could be used to reduce genomic evolution as well as inhibit growth of EAC cells.
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