Dissecting the biology of gliomagenesis: Evaluating the interaction between tumor mutation and germline variants.

Background: The germline variant rs55705857 is causal for development of mutant (mut) adult glioma. However, ~60% of mut patients do not carry the rs55705857 risk allele. We aimed to identify variants associated with developing mut glioma among patients that do not have the rs55705857 risk allele and to further understand development of wt glioma.

Methods: We used three datasets that included 1216 mut and 1442 wt glioma patients and a case-case design to perform genome-wide association (GWAS) analyses comparing mut versus wt glioma. Analyses were performed overall and stratified by rs55705857 genotype and sex. Multivariable logistic regression and regression trees were used to develop models to predict status using germline variants, age, and contrast enhancement on MRI.

Results: Three regions were identified comparing mut versus wt: rs55705857 (meta -value [] = 1.35 × 10), (rs7125115,  = 3.46 × 10), and (rs71430382,  = 2.43 × 10). When analyzing only patients that do not have the rs55705857 risk allele, (rs7125115,  = 1.73 × 10) and (rs71430382,  = 8.86 × 10) were identified. Among patients who have the rs55705857 risk allele, four variants between and (rs4680975,  = 4.65 × 10) increased the likelihood of having an wt tumor. Tumor expression of was associated with rs4680975 genotype in wt patients that have the rs55705857 risk allele ( = 0.034). Multivariable logistic analysis demonstrated that rs55705857, rs71430382 (), and age predicted mutation status.

Conclusions: To understand the development of adult glioma, we demonstrate that and should be prioritized for functional studies in mut tumors. The region warrants further investigation in wt tumors.