Synthetic lethality across normal tissues is strongly associated with cancer risk, onset, and tumor suppressor specificity

Various characteristics of cancers exhibit tissue specificity, including lifetime cancer risk, onset age, and cancer driver genes. Previously, the large variation in cancer risk across human tissues was found to strongly correlate with the number of stem cell divisions and abnormal DNA methylation levels. Here, we study the role of synthetic lethality in cancer risk. Analyzing normal tissue transcriptomics data in the Genotype-Tissue Expression project, we quantify the extent of co-inactivation of cancer synthetic lethal (cSL) gene pairs and find that normal tissues with more down-regulated cSL gene pairs have lower and delayed cancer risk. Consistently, more cSL gene pairs become up-regulated in cells treated by carcinogens and throughout premalignant stages in vivo. We also show that the tissue specificity of numerous tumor suppressor genes is associated with the expression of their cSL partner genes across normal tissues. Overall, our findings support the possible role of synthetic lethality in tumorigenesis.

Automated summary

This study investigates the role of synthetic lethality in cancer risk, finding that the extent of co-inactivation of cancer synthetic lethal (cSL) gene pairs in normal tissues is associated with lower and delayed cancer risk. The up-regulation of more cSL gene pairs in cells exposed to carcinogens and in premalignant stages suggests a potential role of synthetic lethality in tumorigenesis. Moreover, the tissue specificity of tumor suppressor genes is linked to the expression of their cSL partner genes in normal tissues.