Frigola Joan, Iturbide Ane, Lopez-Bigas Nuria, Peiro Sandra, Gonzalez-Perez Abel
Research Program on Biomedical Informatics, IMIM Hospital del Mar Medical Research Institute and Universitat Pompeu Fabra, 08003 Barcelona, Catalonia, Spain.
Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain.
Oncotarget. 2016 May 24;7(21):30748-59. doi: 10.18632/oncotarget.8752.
Chromatin regulatory factors (CRFs), are known to be involved in tumorigenesis in several cancer types. Nevertheless, the molecular mechanisms through which driver alterations of CRFs cause tumorigenesis remain unknown. Here, we developed a CRFs Oncomodules Discovery approach, which mines several sources of cancer genomics and perturbaomics data. The approach prioritizes sets of genes significantly miss-regulated in primary tumors (oncomodules) bearing mutations of driver CRFs. We applied the approach to eleven TCGA tumor cohorts and uncovered oncomodules potentially associated to mutations of five driver CRFs in three cancer types. Our results revealed, for example, the potential involvement of the mTOR pathway in the development of tumors with loss-of-function mutations of MLL2 in head and neck squamous cell carcinomas. The experimental validation that MLL2 loss-of-function increases the sensitivity of cancer cell lines to mTOR inhibition lends further support to the validity of our approach. The potential oncogenic modules detected by our approach may guide experiments proposing ways to indirectly target driver mutations of CRFs.
染色质调节因子（CRFs）已知参与多种癌症类型的肿瘤发生过程。然而，CRFs的驱动改变导致肿瘤发生的分子机制仍不清楚。在此，我们开发了一种CRFs肿瘤模块发现方法，该方法挖掘癌症基因组学和扰动组学数据的多个来源。该方法对在携带驱动CRFs突变的原发性肿瘤（肿瘤模块）中显著失调的基因集进行优先级排序。我们将该方法应用于11个TCGA肿瘤队列，并在三种癌症类型中发现了可能与五种驱动CRFs突变相关的肿瘤模块。例如，我们的结果揭示了mTOR通路在头颈部鳞状细胞癌中MLL2功能丧失突变的肿瘤发生中的潜在作用。MLL2功能丧失增加癌细胞系对mTOR抑制的敏感性的实验验证进一步支持了我们方法的有效性。我们的方法检测到的潜在致癌模块可能为提出间接靶向CRFs驱动突变的方法的实验提供指导。
