71P - When neighbors play a role: The importance of interacting proteins in the tumorigenic effect of cancer driver genes

Background

It has been proposed that around 3.5% of all human genes are directly linked to the onset of cancer. These cancer driver genes accumulate mutations, ultimately leading to tumorigenesis. Despite the known importance of cancer driver genes, their interactions in tissue-specific environments remain poorly understood. One approach to address this gap is to study the protein physical interactions (PPI) between drivers and their neighbors. We propose that when a driver mutation occurs, the PPIs with neighbor proteins can impact the mutation tumorigenic effect.

Methods

To test our hypothesis, we looked at patient mutations and gene expression data from the Cancer Genome Atlas Pan-Cancer Cohort. Cancer driver genes were retrieved from NCG and PPIs were obtained from multiple databases. Statistical analyses were used to detect neighbors whose expression is associated with driver mutation status. We also analyzed the difference in neighbor expression between tumor and the matching non-tumoral tissue; when no difference was detected we excluded that the mutation was influencing the neighbor gene expression.

Results

We identified more than 3000 neighbors significantly associated with at least one driver, within different cancer types and within individuals within the same type of cancer. Around 65% of driver genes analyzed had significant neighbors. Interestingly, most neighbors had coherent associations with multiple interacting drivers, either strictly promoting or strictly inhibiting driver mutation tumorigenic effects. We hypothesized that these neighbors could have a detectable influence in cancer development across multiple cancer types. Selecting the top 50 most frequent significant neighbors with coherent associations, Kaplan-Meier analysis showed a significant impact on patient overall survival.

Conclusions

This study supports that driver PPIs can influence cancer development. Pharmacologically changing the abundance of these neighbor proteins (or the stability of their PPIs) may help to alleviate driver mutation effects. The identification of these neighbor proteins implicated in tumorigenesis is an opportunity to advance both personalized treatment of cancer and provide new targets for drug development.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

UIDB/04046/2020 (DOI: 10.54499/UIDB/04046/2020 ) and UIDP/04046/2020 (DOI: 10.54499/UIDP/04046/2020) Centre grants from FCT, Portugal (to BioISI).

Disclosure

All authors have declared no conflicts of interest.