Dissecting the biology of gliomagenesis: Evaluating the interaction between

The CCDC26 germline variant rs55705857 is causal for development of IDH mutant (IDHmut) adult glioma. However, ~60% of IDHmut patients do not carry the rs55705857 risk allele. We aimed to identify variants associated with developing IDHmut glioma among patients that do not have the rs55705857 risk allele and to further understand development of IDHwt glioma. We used three datasets that included 1216 IDHmut and 1442 IDHwt glioma patients and a case-case design to perform genome-wide association (GWAS) analyses comparing IDHmut versus IDHwt 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 IDH status using germline variants, age, and contrast enhancement on MRI. Three regions were identified comparing IDHmut versus IDHwt: rs55705857 (meta P-value [P] = 1.35 × 10-43), PHLDB1 (rs7125115, P = 3.46 × 10-17), and D2HGDH (rs71430382, P = 2.43 × 10-12). When analyzing only patients that do not have the rs55705857 risk allele, PHLDB1 (rs7125115, P = 1.73 × 10-13) and D2HGDH (rs71430382, P = 8.86 × 10-10) were identified. Among patients who have the rs55705857 risk allele, four variants between ROBO1 and ROBO2 (rs4680975, P = 4.65 × 10-7) increased the likelihood of having an IDHwt tumor. Tumor expression of ROBO1 was associated with rs4680975 genotype in IDHwt patients that have the rs55705857 risk allele (P = 0.034). Multivariable logistic analysis demonstrated that rs55705857, rs71430382 (D2HGDH), and age predicted IDH mutation status. To understand the development of adult glioma, we demonstrate that D2HGDH and PHLDB1 should be prioritized for functional studies in IDHmut tumors. The ROBO1 region warrants further investigation in IDHwt tumors.