A novel hypergraph model for identifying and prioritizing personalized drivers in cancer.

Abstract

Cancer development is driven by an accumulation of a small number of driver genetic mutations that confer the selective growth advantage to the cell, while most passenger mutations do not contribute to tumor progression. The identification of these driver genes responsible for tumorigenesis is a crucial step in designing effective cancer treatments. Although many computational methods have been developed with this purpose, the majority of existing methods solely provided a single driver gene list for the entire cohort of patients, ignoring the high heterogeneity of driver events across patients. It remains challenging to identify the personalized driver genes. Here, we propose a novel method (PDRWH), which aims to prioritize the mutated genes of a single patient based on their impact on the abnormal expression of downstream genes across a group of patients who share the co-mutation genes and similar gene expression profiles. The wide experimental results on 16 cancer datasets from TCGA showed that PDRWH excels in identifying known general driver genes and tumor-specific drivers. In the comparative testing across five cancer types, PDRWH outperformed existing individual-level methods as well as cohort-level methods. Our results also demonstrated that PDRWH could identify both common and rare drivers. The personalized driver profiles could improve tumor stratification, providing new insights into understanding tumor heterogeneity and taking a further step toward personalized treatment. We also validated one of our predicted novel personalized driver genes on tumor cell proliferation by vitro cell-based assays, the promoting effect of the high expression of Low-density lipoprotein receptor-related protein 1 (LRP1) on tumor cell proliferation.