ATM mutations improve radio-sensitivity in wild-type isocitrate dehydrogenase-associated high-grade glioma: retrospective analysis using next-generation sequencing data

Abstract

Background: To identify the association between somatic ataxia-telangiectasia mutated (ATM) mutations and improved radio-sensitivity, we retrospectively reviewed next-generation sequencing data from patients diagnosed with isocitrate dehydrogenase (IDH)-wildtype high-grade glioma. Methods: We included 39 individuals with (IDH)-wildtype high-grade glioma (diffuse astrocytoma n = 2, anaplastic astrocytoma n = 10, and glioblastoma n = 27) not subjected to gross tumor resection and undergoing radiation therapy with a median total dose of 60 Gy in 30 fractions. The mutational status of the ATM gene was obtained through next-generation sequencing using a TruSight Tumor 170 cancer panel. Disease progression was defined according to the Response Assessment in Neuro-Oncology (RANO) criteria as well as neurologic and clinical findings. Results: Among the 39 samples, ATM mutations (ATM mut(+)) were detected in 26% of cases (n = 10). No significant differences were observed in the characteristics of the patients or tumors. Among the 10 patients in the ATM mut(+) group, there were 6 patients with glioblastoma and 4 patients with anaplastic astrocytoma. Most mutations were missense mutations (n = 8, 80%). With a median follow-up of 16.5 mo (interquartile range, 11.4-19.8), ATM mut(+) exhibited 1-year in-field control of 100% compared with 44.1% in the ATM mut(−) group (p = 0.002). There was no difference in the out-field control rate or overall survival between the two groups (p = 0.861 and p = 0.247, respectively).

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

“…ATM orchestrates the cellular DDR to cytotoxic DNA DSBs induced by radiation (141,142). Overexpression of ATM indicates radiation resistance in breast cancer cells (143), whereas deficiency of ATM showed radiation sensitizer effects in multiple cancer types (144)(145)(146)(147). Interestingly, more studies have focused on the radiation sensitizer effects that are dependent on the cell cycle and proliferation status (148,149).…”

Transcriptomic Profiling of DNA Damage Response in Patient-Derived Glioblastoma Cells before and after Radiation and Temozolomide Treatment

“…Our data also showed that gene expression of the HR pathway was inversely associated with RT response. The inhibition of HR components has enhanced radiosensitivity in glioblastoma cells [ 27 , 28 ], hence cells with a higher expression of HR genes may be more likely to survive than tumours which have a lower baseline expression [ 4 , 6 , 17 , 29 ]. Further investigation is needed to explore these results in more depth.…”

A Head-to-Head Comparison of 18F-Fluorocholine PET/CT and Conventional MRI as Predictors of Outcome in IDH Wild-Type High-Grade Gliomas

“…In our work, Ki-67 had no significant association with the prognosis, probably because most patients had high Ki-67 values. Although the experience is limited, other works have reported more adverse metabolic conditions (higher SUV and MTV) in IDH-wt and high Ki-67 tumors [ 14 , 40 ].…”