Cancer Relevance of Human Genes

Background: We hypothesize that genes that directly or indirectly interact with core cancer genes (CCGs) in a comprehensive gene-gene interaction network may have functional importance in cancer. Methods: We categorized 12 767 human genes into CCGs (n ¼ 468), 1 (n ¼ 5467), 2 (n ¼ 5573), 3 (n ¼ 915), and more than 3 steps (n ¼ 416) removed from the nearest CCG in the Search Tool for the Retrieval of Interacting Genes/Proteins network. We estimated cancer-relevant functional importance in these neighborhood categories using 1) gene dependency score, which reflects the effect of a gene on cell viability after knockdown; 2) somatic mutation frequency in The Cancer Genome Atlas; 3) effect size that estimates to what extent a mutation in a gene enhances cell survival; and 4) negative selection pressure of germline protein-truncating variants in healthy populations. Results: Cancer biology–related functional importance of genes decreases as their distance from the CCGs increases. Genes closer to cancer genes show greater connectedness in the network, have greater importance in maintaining cancer cell viability, are under greater negative germline selection pressure, and have higher somatic mutation frequency in cancer. Based on these 4 metrics, we provide cancer relevance annotation to known human genes. Conclusions: A large number of human genes are connected to CCGs and could influence cancer biology to various extent when dysregulated; any given mutation may be functionally important in one but not in another individual depending on genomic context.