Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China.
Department of Radiology, Harbin Medical University Cancer Hospital, Harbin, China.
J Transl Med. 2022 Sep 30;20(1):438. doi: 10.1186/s12967-022-03651-w.
Diverse drug vulnerabilities owing to the Chromatin regulators (CRs) genetic interaction across various cancers, but the identification of CRs genetic interaction remains challenging.
In order to provide a global view of the CRs genetic interaction in cancer cells, we developed a method to identify potential drug response-related CRs genetic interactions for specific cancer types by integrating the screen of CRISPR-Cas9 and pharmacogenomic response datasets.
Totally, 625 drug response-related CRs synthetic lethality (CSL) interactions and 288 CRs synthetic viability (CSV) interactions were detected. Systematically network analysis presented CRs genetic interactions have biological function relationship. Furthermore, we validated CRs genetic interactions induce multiple omics deregulation in The Cancer Genome Atlas. We revealed the colon adenocarcinoma patients (COAD) with mutations of a CRs set (EP300, MSH6, NSD2 and TRRAP) mediate a better survival with low expression of MAP2 and could benefit from taxnes. While the COAD patients carrying at least one of the CSV interactions in Vorinostat CSV module confer a poor prognosis and may be resistant to Vorinostat treatment.
The CRs genetic interaction map provides a rich resource to investigate cancer-associated CRs genetic interaction and proposes a powerful strategy of biomarker discovery to guide the rational use of agents in cancer therapy.
由于染色质调节剂（CRs）在各种癌症中的遗传相互作用，导致药物的脆弱性多种多样，但识别 CRs 遗传相互作用仍然具有挑战性。
为了全面了解癌细胞中 CRs 的遗传相互作用，我们开发了一种方法，通过整合 CRISPR-Cas9 筛选和药物基因组反应数据集，来识别特定癌症类型中与药物反应相关的潜在 CRs 遗传相互作用。
总共检测到 625 个与药物反应相关的 CRs 合成致死（CSL）相互作用和 288 个 CRs 合成存活（CSV）相互作用。系统的网络分析表明，CRs 遗传相互作用具有生物学功能关系。此外，我们还在癌症基因组图谱中验证了 CRs 遗传相互作用会导致多个组学的失调。我们揭示了具有一组 CRs（EP300、MSH6、NSD2 和 TRRAP）突变的结肠腺癌患者（COAD），其 MAP2 低表达可带来更好的生存，并且可能受益于紫杉烷类药物。而 COAD 患者至少携带一个 Vorinostat CSV 模块中的 CSV 相互作用，则预示着预后不良，可能对 Vorinostat 治疗有抗性。
CRs 遗传相互作用图谱为研究与癌症相关的 CRs 遗传相互作用提供了丰富的资源，并提出了一种强大的生物标志物发现策略，以指导癌症治疗中药物的合理使用。
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