Distinct mutational signature and clonal evolution in constitutional mismatch repair deficiency-associated high-grade gliomas

Constitutional mismatch repair deficiency (CMMRD) is a rare cancer-predisposing syndrome. Recent studies have advanced our understanding of the genomic and epigenomic features of this disease, however, the mutational signatures and clonal evolution of CMMRD-associated high-grade gliomas (HGGs) requires further investigation. Herein, we analyzed the mutational signature and clonal evolution of 25 CMMRD-associated HGGs. Germline biallelic mutations in <i>MSH6</i> (56.0%), <i>PMS2</i> (36.0%), <i>MLH1</i> (8.0%) were identified. Patients showed early onset (5.8 ± 4.2 years) and poor prognosis (progression-free survival 16 ± 18.0 months). Notably, we identified distinct mutational signatures, evolution pattern and clinical outcome between <i>MSH6</i> and <i>PMS2</i> subgroups, showing enriched SBS6 and SBSS21, respectively, which were found to correlate with prognosis. Clonal evolution model indicated early <i>POLE</i>/<i>POLD1</i> events and survival of founding clone during tumor recurrence. These findings provide valuable insights into the genomic landscape and clinical outcomes of CMMRD-associated HGGs, emphasizing the critical role of mutational signature and tumor evolution in tumorigenesis and patient prognosis.