Intra-tumoural manganese is associated with radioresistance and overall survival in glioblastoma

Abstract

Glioblastoma (GBM) is relatively radioresistant compared to other malignancies. Like other tumours undergoing radiotherapy, there is a variable response in similar patients having identical treatments. Our objective was to identify a predictive biomarker of radioresistance in GBM, that we contend will apply to all solid cancers. This retrospective study includes a homogenous cohort of 13 GBM patients (9 males, 4 females), carefully selected to minimise the influence of many known prognostic factors. Histopathology slides were analysed using laser ablation - inductively coupled plasma - mass spectrometry (LA-ICP-MS), measuring intra-tumoural manganese (Mn), iron (Fe), copper (Cu) and zinc (Zn). Only the Mn score (parts per million - ppm) correlated with outcome. Seven patients died within 13 months, six survived > 20 months. Patients with low Mn score ≤ 0.3279 ppm (median survival 21.7 months) had statistically significantly better outcomes (p = 0.003) compared to those with higher scores > 0.3279 (10.7 months). In our cohort, MGMT promoter methylated patients did better with MGMT promoter methylation correlating with intra-tumoural Mn (p = 0.05). We tested four tumours using formalin fixed paraffin embedded tissue and compared this to fresh frozen tissue from a Biobank. Intra-tumoural Mn closely correlated when testing the two tissue types. Patients undergoing a second surgical procedure for recurrence all had a higher Mn score. Future directions include a larger GBM Study allowing multivariable analysis, and other solid, potentially curable, cancer studies, where we envisage providing a Mn threshold to aid clinicians' decision making.