Contribution and clinical relevance of germline variation to the cancer transcriptome

Somatic alterations in the cancer genome, some of which are associated with changes in gene expression, have been characterized in multiple studies across diverse cancer types. However, less is known about germline variants that influence tumor biology by shaping the cancer transcriptome.

We performed expression quantitative trait loci (eQTL) analyses using multi-dimensional data from The Cancer Genome Atlas to explore the role of germline variation in mediating the cancer transcriptome. After accounting for associations between somatic alterations and gene expression, we determined the contribution of inherited variants to the cancer transcriptome relative to that of somatic variants. Finally, we performed an interaction analysis using estimates of tumor cellularity to identify cell type-restricted eQTLs.

The proportion of genes with at least one eQTL varied between cancer types, ranging between 0.8% in melanoma to 28.5% in thyroid cancer and was correlated more strongly with intratumor heterogeneity than with somatic alteration rates. Although contributions to variance in gene expression was low for most genes, some eQTLs accounted for more than 30% of expression of proximal genes. We identified cell type-restricted eQTLs in genes known to be cancer drivers including LPP and EZH2 that were associated with disease-specific mortality in TCGA but not associated with disease risk in published GWAS. Together, our results highlight the need to consider germline variation in interpreting cancer biology beyond risk prediction.