Nongenic cancer-risk SNPs affect oncogenes, tumour-suppressor genes, and immune function
A partir notamment des données du projet "The Genotype-Tissue Expression" portant sur 13 tissus biologiques, cette étude analyse la distribution des polymorphismes à simple nucléotide non codants et associés au risque de cancer, puis démontre que ces polymorphismes se situent préférentiellement au niveau des promoteurs des oncogènes et des gènes suppresseurs de tumeurs et sont surreprésentés au niveau des gènes impliqués dans les mécanismes immunitaires
Background : Genome-wide association studies (GWASes) have identified many noncoding germline single-nucleotide polymorphisms (SNPs) that are associated with an increased risk of developing cancer. However, how these SNPs affect cancer risk is still largely unknown. Methods : We used a systems biology approach to analyse the regulatory role of cancer-risk SNPs in thirteen tissues. By using data from the Genotype-Tissue Expression (GTEx) project, we performed an expression quantitative trait locus (eQTL) analysis. We represented both significant cis- and trans-eQTLs as edges in tissue-specific eQTL bipartite networks. Results : Each tissue-specific eQTL network is organised into communities that group sets of SNPs and functionally related genes. When mapping cancer-risk SNPs to these networks, we find that in each tissue, these SNPs are significantly overrepresented in communities enriched for immune response processes, as well as tissue-specific functions. Moreover, cancer-risk SNPs are more likely to be ‘cores’ of their communities, influencing the expression of many genes within the same biological processes. Finally, cancer-risk SNPs preferentially target oncogenes and tumour-suppressor genes, suggesting that they may alter the expression of these key cancer genes. Conclusions : This approach provides a new way of understanding genetic effects on cancer risk and provides a biological context for interpreting the results of GWAS cancer studies.