Karimzadeh Mehran, Jandaghi Pouria, Papadakis Andreas I, Trainor Sebastian, Rung Johan, Gonzàlez-Porta Mar, Scelo Ghislaine, Vasudev Naveen S, Brazma Alvis, Huang Sidong, Banks Rosamonde E, Lathrop Mark, Najafabadi Hamed S, Riazalhosseini Yasser
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.
McGill University and Genome Quebec Innovation Centre, Montreal, QC H3A 0G1, Canada.
Oncotarget. 2018 May 18;9(38):25166-25180. doi: 10.18632/oncotarget.25382.
Despite efforts for extensive molecular characterization of cancer patients, such as the international cancer genome consortium (ICGC) and the cancer genome atlas (TCGA), the heterogeneous nature of cancer and our limited knowledge of the contextual function of proteins have complicated the identification of targetable genes. Here, we present Aberration Hub Analysis for Cancer (AbHAC) as a novel integrative approach to pinpoint aberration hubs, i.e. individual proteins that interact extensively with genes that show aberrant mutation or expression. Our analysis of the breast cancer data of the TCGA and the renal cancer data from the ICGC shows that aberration hubs are involved in relevant cancer pathways, including factors promoting cell cycle and DNA replication in basal-like breast tumors, and Src kinase and VEGF signaling in renal carcinoma. Moreover, our analysis uncovers novel functionally relevant and actionable targets, among which we have experimentally validated abnormal splicing of spleen tyrosine kinase as a key factor for cell proliferation in renal cancer. Thus, AbHAC provides an effective strategy to uncover novel disease factors that are only identifiable by examining mutational and expression data in the context of biological networks.
尽管国际癌症基因组联盟（ICGC）和癌症基因组图谱（TCGA）等机构为全面分子表征癌症患者付出了诸多努力，但癌症的异质性以及我们对蛋白质背景功能的有限了解，使得可靶向基因的识别变得复杂。在此，我们提出癌症畸变枢纽分析（AbHAC），这是一种全新的综合方法，用于精准定位畸变枢纽，即与显示异常突变或表达的基因广泛相互作用的单个蛋白质。我们对TCGA的乳腺癌数据和ICGC的肾癌数据进行分析后发现，畸变枢纽参与了相关癌症通路，包括在基底样乳腺肿瘤中促进细胞周期和DNA复制的因子，以及在肾癌中涉及的Src激酶和VEGF信号传导。此外，我们的分析还揭示了新的功能相关且可操作的靶点，其中我们通过实验验证了脾酪氨酸激酶的异常剪接是肾癌细胞增殖的关键因素。因此，AbHAC提供了一种有效的策略，以揭示那些只有在生物网络背景下通过检查突变和表达数据才能识别的新型疾病因子。
