Genetic predisposition to altered blood cell homeostasis is associated with glioma risk and survival

Abstract

Glioma is a highly fatal brain tumor comprised of molecular subtypes with distinct clinical trajectories. Observational studies have suggested that variability in immune response may play a role in glioma etiology. However, their findings have been inconsistent and susceptible to reverse causation due to treatment effects and the immunosuppressive nature of glioma. We applied genetic variants associated (p<5×10-8) with blood cell traits to a meta-analysis of 3418 glioma cases and 8156 controls. Genetically predicted increase in the platelet to lymphocyte ratio (PLR) was associated with an increased risk of glioma (odds ratio (OR)=1.25, p=0.005), especially in IDH-mutant (IDHmutOR=1.38, p=0.007) and IDHmut 1p/19q non-codeleted (IDHmut-noncodelOR=1.53, p=0.004) tumors. However, reduced glioma risk was observed for higher counts of lymphocytes (IDHmut-noncodelOR=0.70, p=0.004) and neutrophils (IDHmutOR=0.69, p=0.019; IDHmut-noncodelOR=0.60, p=0.009), which may reflect genetic predisposition to enhanced immunosurveillance. In contrast to susceptibility, there was no association with survival in IDHmut-noncodel; however, in IDHmut1p/19q co-deleted tumors we observed higher mortality with increasing genetically predicted counts of lymphocytes (hazard ratio (HR)=1.65, 95% CI: 1.24-2.20), neutrophils (HR=1.49, 1.13-1.97), and eosinophils (HR=1.59, 1.18-2.14). Polygenic scores for blood cell traits were also associated with tumor immune microenvironment features, with heterogeneity by IDH status observed for 17 signatures related to interferon signaling, PD-1 expression, and T-cell/Cytotoxic responses. In summary, we identified novel, immune-mediated susceptibility mechanisms for glioma with potential disease management implications.