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January 22nd, 2025
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BioISI, Faculdade de Ciencias, Universidade de Lisboa, 1749-016 Lisbon, Portugal
cancer biology
biorxiv

When neighbours play a role: a systems-level analysis of protein interactions conditioning cancer driver mutation effects

Vital, M. F.Open in Google Scholar•Miranda, J. A.Open in Google Scholar•Carrolo, M.Open in Google Scholar•Quintela, A.Open in Google Scholar•Pinto, F. R.Open in Google Scholar

Background: Cancer is driven by the accumulation of somatic mutations, including driver mutations that confer a selective advantage to cancer cells. Driver proteins operate within complex interaction networks, and their activity is conditioned by neighbour proteins. Understanding the interplay between driver mutations and the expression of their neighbour proteins can provide insights into cancer biology and potential therapeutic targets. Methods: We assessed associations between expression of neighbour proteins and driver mutation status, comparing both between and within cancer types. We further evaluated if neighbours were enriched in significant associations with multiple drivers and characterised the impact of neighbour expression on overall survival for all cancer types. Results: We found a significant correlation between the number of driver associations a neighbour gene has and the number of sign-coherent survival associations, particularly for neighbours enriched in positive associations, where high neighbour expression correlated with increased driver mutations and poorer survival. We identified 247 neighbours simultaneously enriched in positive driver and survival associations and 39 neighbours simultaneously enriched in negative driver and survival associations. Conclusions: Our study systematically identified neighbours associated with driver mutation status. Complementary evidence from survival analysis and the literature suggests that neighbours enriched in driver associations are promising drug target candidates.

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