Genetic Profiling of Oligodendrogliomas (IDH Mutated and 1p19q Co-deleted) Treated with Adjuvant Radiation Therapy or Observation Informs Prognosis

Abstract

Recent international sequencing efforts have allowed for the molecular taxonomy of low-grade gliomas (LGG) (The Cancer Genome Atlas (TCGA), 2015). Based on clinical and pathological factors, patients with resected oligodendrogliomas are usually treated with adjuvant radiation or observed. We sought to analyze TCGA gene expression and copy number datasets on oligodendrogliomas patients treated with adjuvant radiation or those observed to discover prognostic markers and pathways. Our cohort consists of patients with oligodendroglioma in the TCGA dataset (accessed through http://www.cbioportal.org/). The mRNA expression, copy number, and clinical information were taken from the TCGA “Brain Lower Grade Glioma” provisional dataset. Survival modeling and ANOVA analysis was performed using the R packages “plsRCox” and “survival”. 10-fold bootstrap, cross-validation was performed using the “rms” and “pec” packages. From 530 potential LGG dataset patients, 164 were included in our analysis with oligodendroglioma or oligoastrocytoma, and both IDH mutation and 1p19q codeletion. Out of our cohort of 164 patients, 137 had documentation of treatment, with 65 receiving adjuvant radiation (median dose 5,940 cGy) and 62 observed. In the cohort that received adjuvant radiotherapy, expression of members of the PDGFRA module (GSTA4, CXXC4, KLRC3, DSCAM, OLIG2, SOX4, SOX8) was associated with shorter progression-free survival (HR=7.8, p < 0.02, median C-index=55.3%). This increased risk was not seen in patients who were observed (HR=0.86, p=0.83). In addition, expression of circadian clock genes (CSNK1E, CRY2, PER1) was also associated with shorter progression-free survival (HR=4.9, p < 0.03, median C-index=68.6%)) when treated with radiation versus observation (HR=0.33, p=0.11). Median progression-free survival in the radiotherapy cohort positive for the circadian gene signature was 64 months versus 97.2 months for those negative for the signature. Within the observation cohort, expression of genes in the polycomb repressive complex-2 (EZH1, EZH2, SUZ12, EED, and RBBP4) was associated with poor progression-free survival (HR=1.65, p < 0.008, median C-index=68.5%)). This risk was abrogated in the adjuvant radiation cohort (HR=1.03, p=0.55). Decreased expression of genes targeted and down-regulated by this complex also was associated with shorter progression-free survival (Chi-sq=7.4, p < 0.007 median C-index=66.3%). We identified genes in the PDGFRA and circadian signaling pathways that are associated with poor prognosis in patients with IDH mutated and 1p19q codeleted oligodendroglioma treated with adjuvant radiotherapy. These patients would be potential candidates for treatment intensification. We also identified a PRC-2 gene signature for patients who were more likely to progress on observation. This potentially identifies a cohort who would benefit from upfront adjuvant radiotherapy.