PertInInt: An Integrative, Analytical Approach to Rapidly Uncover Cancer Driver Genes with Perturbed Interactions and Functionalities
PertInInt: An Integrative, Analytical Approach to Rapidly Uncover Cancer Driver Genes with Perturbed Interactions and Functionalities
复制标题
DOI：
10.1016/j.cels.2020.06.005
复制
发表时间：
2020-07-22
期刊：
影响因子：
9.3
通讯作者：
Singh, Mona
中科院分区：
文献类型：
--
作者：
Kobren, Shilpa Nadimpalli;Chazelle, Bernard;Singh, Mona
癌症基因组学中的一个主要挑战是识别在癌症中具有功能作用的基因并揭示其作用机制。我们引入了一个整合框架，该框架通过精确定位那些其相互作用或其他功能位点在肿瘤中富含体细胞突变的基因来识别癌症相关基因。我们推导出分析计算，使我们能够避免时间限制性的基于排列的显著性检验，使得同时考虑蛋白质位点功能性的多个测量在计算上是可行的。我们的配套软件PertInInt将参与与DNA、RNA、肽、离子或小分子相互作用的位点的知识与结构域、进化保守性和基因水平突变数据相结合。当应用于10，037个肿瘤样本时，PertInInt揭示了已知和新预测的癌症基因，同时还揭示了哪些类型的相互作用或其他功能被破坏。珀斯磁共振波谱分析表明，体细胞突变经常富集在相互作用的网站和域，并暗示相互作用扰动作为一个普遍的癌症驱动事件。
A major challenge in cancer genomics is to identify genes with functional roles in cancer and uncover their mechanisms of action, We introduce an integrative framework that identifies cancer-relevant genes by pinpointing those whose interaction or other functional sites are enriched in somatic mutations across tumors, We derive analytical calculations that enable us to avoid time-prohibitive permutation-based significance tests, making it computationally feasible to simultaneously consider multiple measures of protein site functionality. Our accompanying software, PertInInt, combines knowledge about sites participating in interactions with DNA, RNA, peptides, ions, or small molecules with domain, evolutionary conservation, and gene-level mutation data. When applied to 10,037 tumor samples, PertInInt uncovers both known and newly predicted cancer genes, while additionally revealing what types of interactions or other functionalities are disrupted. Perth Mrs analysis demonstrates that somatic mutations are frequently enriched in interaction sites and domains and implicates interaction perturbation as a pervasive cancer-driving event.