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

## TL;DR

This study explores the genetic patterns and tumor evolution in a rare type of brain cancer linked to a genetic disorder, finding distinct differences between subgroups that affect patient outcomes.

## Contribution

The study identifies distinct mutational signatures and clonal evolution patterns in CMMRD-associated high-grade gliomas, particularly between MSH6 and PMS2 subgroups.

## Key findings

- MSH6 and PMS2 subgroups show unique mutational signatures (SBS6 and SBS21) linked to prognosis.
- Clonal evolution reveals early POLE/POLD1 events and survival of the founding clone during tumor recurrence.
- Patients with CMMRD-associated gliomas have early onset and poor prognosis.

## 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.

•CMMRD-associated gliomas show distinct mutational and evolutionary profiles•MSH6 and PMS2 subgroups show unique mutational signatures associated with prognosis•Clonal evolution model shows early POLE/POLD1 events and survival of founding clone

CMMRD-associated gliomas show distinct mutational and evolutionary profiles

MSH6 and PMS2 subgroups show unique mutational signatures associated with prognosis

Clonal evolution model shows early POLE/POLD1 events and survival of founding clone

Molecular biology; cancer