Protein domain-based approaches for the identification and prioritization of therapeutically actionable cancer variants

The tremendous number of cancer variants that can be detected by NGS analyses has required the development of computational approaches to prioritize mutations on the basis of their biological and clinical significance. Standard strategies take a gene-centric approach to the problem, allowing exclusively the identification of highly frequent variants. On the contrary, protein domain (PD)-based approaches allow to identify functionally relevant low frequency variants by searching for mutations that recur on analogous residues across homologous proteins (i.e. containing the same PD). Such approaches enable to transfer information about the effects and druggability from one known mutation to unknown ones. Here we describe how PD-based strategies work, and discuss how they could be exploited for mutation prioritization. The principle that mutations clustered on specific residues of PDs have the same functional consequences and are therapeutically actionable in a similar manner could help the choice of patient-specific targeted drugs, eventually improving the management of cancer patients.

Automated summary

Computational approaches have been developed to prioritize cancer mutations based on their biological and clinical significance, with protein domain-based methods allowing the identification of functionally relevant low frequency variants. Prioritizing mutations based on clustered specific residues of protein domains could aid in choosing patient-specific targeted drugs and improving cancer patient management.