Our study reveals that matched initial and recurrent GBM samples harbour potentially actionable variations, and these were most often identified in EGFR, PTEN, BRCA1/2, and ATM. These genetic alterations could potentially be targeted by novel approaches with EGFR-targeting antibodies, tyrosine kinase inhibitors, and DNA damage repair inhibitors either singly or in combination. Here, PTEN is linked to glioblastoma.