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

Abstract

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 MSH6 (56.0%), PMS2 (36.0%), MLH1 (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 MSH6 and PMS2 subgroups, showing enriched SBS6 and SBSS21, respectively, which were found to correlate with prognosis. Clonal evolution model indicated early POLE/POLD1 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.