A novel network control model for identifying personalized driver genes in cancer

Although existing computational models have identified many common driver genes, it remains challenging to identify the personalized driver genes by using samples of an individual patient. Recently, the methods of exploiting the structure-based control principles of complex networks provide new clues for identifying minimum number of driver nodes to drive the state transition of large-scale complex networks from an initial state to the desired state. However, the structure-based network control methods cannot be directly applied to identify the personalized driver genes due to the unknown network dynamics of the personalized system. Here we proposed the personalized network control model (PNC) to identify the personalized driver genes by employing the structure-based network control principle on genetic data of individual patients. In PNC model, we firstly presented a paired single sample network construction method to construct the personalized state transition network for capturing the phenotype transitions between healthy and disease states. Then, we designed a novel structure-based network control method from the Feedback Vertex Sets-based control perspective to identify the personalized driver genes. The wide experimental results on 13 cancer datasets from The Cancer Genome Atlas firstly showed that PNC model outperforms current state-of-the-art methods, in terms of F-measures for identifying cancer driver genes enriched in the gold-standard cancer driver gene lists. Furthermore, these results showed that personalized driver genes can be explored by their network characteristics even when they are hidden factors in transcription and mutation profiles. Our PNC gives novel insights and useful tools into understanding the tumor heterogeneity in cancer. The PNC package and data resources used in this work can be freely downloaded from https://github.com/NWPU-903PR/PNC.Author summary: Notably there may be unique personalized driver genes for an individual patient in cancer. Identifying personalized driver genes that lead to particular cancer initiation and progression of individual patient is one of the biggest challenges in precision medicine. However, most methods for cancer driver genes identification have focused mainly on the cohort information rather than on individual information and fail to identify personalized driver genes. We here proposed personalized network control model (PNC) to identify personalized driver genes by applying the structure based network control principle on personalized data of individual patients. By considering the progression from the healthy state to the disease state as the network control problem, our PNC aims to detect a small number of personalized driver genes that are altered in response to input signals for triggering the state transition in individual patients on expression level. The impetus behind PNC contains two main respects. One is to design a paired single sample network construction method (namely Paired-SSN) for constructing personalized state transition networks to capture the phenotypic transitions between normal and disease attractors. The other one is to develop a novel structure based network control method (namely NCUA) on personalized state transition networks for identifying personalized driver genes which can drive individual patient system state from healthy state to disease state through oncogene activations. Each part of the proposed method has been deeply examined to be efficient. Compared with other existing models, our PNC shows a higher performance in terms of F-measures of the cancer driver genes in the well-known Cancer Census Genes (CCG) and Network of Cancer Genes (NCG). The wide experimental results on multiple cancer datasets highlight that sample specific network theory and structure based network control theory can contribute to identifying personalized driver genes in cancer.