Systematic Prioritization of Druggable Mutations in ∼5000 Genomes Across 16 Cancer Types Using a Structural Genomics-based Approach

摘要

A massive amount of somatic mutations has been cataloged in large-scale projects such as The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium projects. The majority of the somatic mutations found in tumor genomes are neutral 'passenger' rather than damaging “driver” mutations. Now, understanding their biological consequences and prioritizing them for druggable targets are urgently needed. Thanks to the rapid advances in structural genomics technologies (e.g. X-ray), large-scale protein structural data has now been made available, providing critical information for deciphering functional roles of mutations in cancer and prioritizing those alterations that may mediate drug binding at the atom resolution and, as such, be druggable targets. We hypothesized that mutations at protein–ligand binding-site residues are likely to be druggable targets. Thus, to prioritize druggable mutations, we developed SGDriver, a structural genomics-based method incorporating the somatic missense mutations into protein–ligand binding-site residues using a Bayes inference statistical framework. We applied SGDriver to 746,631 missense mutations observed in 4997 tumor-normal pairs across 16 cancer types from The Cancer Genome Atlas. SGDriver detected 14,471 potential druggable mutations in 2091 proteins (including 1,516 recurrently mutated proteins) across 3558 cancer genomes (71.2%), and further identified 298 proteins harboring mutations that were significantly enriched at protein–ligand binding-site residues (adjusted p value < 0.05). The identified proteins are significantly enriched in both oncoproteins and tumor suppressors. The follow-up drug-target network analysis suggested 98 known and 126 repurposed druggable anticancer targets (e.g. SPOP and NR3C1). Furthermore, our integrative analysis indicated that 13% of patients might benefit from current targeted therapy, and this –proportion would increase to 31% when considering drug repositioning. This study provides a testable strategy for prioritizing druggable mutations in precision cancer medicine.