Pan-Cancer Analysis of Heritable Genetic Variations Reveals Cancer-Specific Activation of Dormant Oncogenic Pathways

Abstract

Somatic variations in the genetic code have been extensively characterized in cancers. However, the contribution of heritable genetic variations to the cancer phenotype has not been studied in detail. Here, we conducted a pan-cancer analysis of the expression quantitative trait loci (eQTLs) across 9 cancers. In addition to eQTLs that were common to both normal and cancer tissues, we also identified eQTLs that confer cancer-specific re-expression of genes that were otherwise dormant in the respective normal tissues (dormant eQTL: deQTL). The expressions of several of these genes were normally restricted to the testis (e.g. LDHC, HORMAD1) or have little to no expression in normal adult tissues (e.g. XKR9, GUCY1B2, RGS17). Interestingly, many of the deQTLs were not sufficient to re-express these genes in cancers; but required co-activation of the oncogenic stemness phenotype, indicating functional interaction of the germline variations with the oncogenic context. We present detailed functional analyses of the expression of HORMAD1 in malignant melanomas, lung and head-and-neck cancers, and show that the re-expression of HORMAD1 by a combination of genetic variations and oncogenic dedifferentiation confers chromosome instability and strong immune cell exclusion in tumors. Our analyses showcase the interaction of heritable genetic variations with the oncogenic programs to re-express dormant pro-oncogenic genes. The collection of eQTLs identified in this study along with their properties and correlation with overall survival are available in a user-friendly web application.