Network resilience of the human interactome to pan-cancer mutations reveals conserved pathway vulnerabilities

Area of Science:

• Systems Biology
• Genomics
• Network Science

Background:

• Cellular molecular components are interconnected in interactomes.
• Gene mutations can be viewed as failures impacting biological information flow and disease.
• Understanding interactome topology is crucial for disease mechanism research.

Purpose of the Study:

• To analyze the impact of tumor-related mutations on human interactome topology using an information-based resilience measure.
• To reveal common mechanisms underlying cancer by studying network fragmentation and gene importance.
• To identify pivotal genes critical for maintaining network integrity and cellular functionality.

Main Methods:

• Utilized an information-based resilience measure to quantify interactome disruption.
• Analyzed the effect of pan-cancer mutations on network topology and fragmentation.
• Identified and ranked genes based on their impact on network resilience.
• Performed enrichment analysis on identified crucial genes.

Main Results:

• Cancer-associated mutations cause significantly greater disruption and faster network fragmentation than random failures.
• Identified two distinct groups of gene impacts on resilience; most mutations behave randomly.
• A small subset of 664 genes, previously undetectable by standard metrics, is pivotal for network integrity.
• These crucial genes are involved in apoptosis and other conserved cancer-related biological processes.

Conclusions:

• Cancer mutations severely impact interactome resilience, leading to system-level dysregulation.
• A small set of critical genes plays a vital role in maintaining cellular function and network integrity.
• This study identifies key genes and biological processes implicated in cancer, offering new insights into disease mechanisms.