PATH-45. DIFFERENT TYPES OF HYPERMUTATOR PHENOTYPE OF GLIOBLASTOMA ACCORDING TO MUTATION PATTERNS OF MISMATCH REPAIR GENES

Abstract BACKGROUND Although precision medicine has been widely applied to routine care, only few molecular targeted drugs have been developed for glioma. Immune checkpoint inhibitors hold a potential promise to improve outcome of malignant glioma especially with the hypermutator phenotype. Mismatch repair deficiency could induce hypermutation during temozolomide (TMZ) treatment, but the mechanism of mutation acquisition is not well understood. METHODS We present the results of target sequencing of 57 longitudinal specimens from 27 individuals with glioblastoma (GBM). We used Ion AmpliSeq Cancer Hotspot Panel v2 (CHP) and/or Ion AmpliSeq Comprehensive Cancer Panel (CCP) for target sequencing. RESULTS Acquired mutations with G:C >A:T transition at non-CpG sites were found in 70% of recurrent MGMT methylated samples, whereas only 8% in MGMT unmethylated cases (p< 0.001). Two cases of hypermutator phenotype were identified in MGMT methylated, IDH wild type recurrent GBMs after TMZ chemotherapy. One case gained mutations in mismatch repair genes of MLH1, MSH2, MSH6, and PMS1. Most of the acquired mutations were G:C >A:T mutations typical to TMZ-induced hypermutation. The recurrent tumor was highly aggressive with overall survival after recurrence of 3.7 months. The other case gained mutations in mismatch repair genes of MLH1 and PMS1 only. Most of the acquired mutations were insertion mutations. The prognosis after recurrence was much longer. CONCLUSIONS We identified two types of hypermutator phenotype according to mutation pattern of mismatch repair genes. It has been suggested that MSH2-MSH6 complex deficient tumor cannot repair TMZ-induced mismatch mutation, thereby causing hypermutation. Conversely, MLH1-PMS1 complex deficient tumor with intact MSH2-MSH6 complex can repair mismatch mutation but is susceptible to insertion mutation. Taken together, MSH6 mutation plays a key role in TMZ-induced hypermutation, while MLH1 and PMS1 mutations might cause insertion-based hypermutation. Larger and prospective studies are warranted to clarify the mechanism, outcome, and effectiveness of checkpoint inhibitors.