Glioma oncogenesis in the Constitutional mismatch repair deficiency (CMMRD) syndrome

Background Constitutional mismatch repair deficiency (CMMRD) is a cancer predisposition due to biallelic mutations in one of the mismatch repair (MMR) genes associated with early onset of cancers, especially high-grade gliomas. Our aim was to decipher the molecular specificities of these gliomas.Methods Clinical, histopathological, and whole exome sequencing data were analyzed in 12 children with genetically proven CMMRD and a high-grade glioma.Results PDL1 expression was present in immunohistochemistry in 50% of the samples. In 9 patients, the glioma harbored an ultra-hypermutated phenotype (104-635 coding single nucleotide variants (SNV) per Mb, median 204). Driver mutations in POLE and POLD1 exonuclease domains were described for 8 and 1 patients respectively and were always present in the mutation burst with the highest variant allele frequency (VAF). The mutational signatures were dominated by MMR-related ones and similar in the different mutation bursts of a same patient without subsequent enrichment of the mutation signatures with POL-driven ones. Median number of coding SNV with VAF above one of the driving polymerase mutation per Mb was 57 (17-191). Our findings suggest that somatic polymerase alterations does not entirely explain the ultra-hypermutant phenotype. SETD2, TP53, NF1, EPHB2, PRKDC, and DICER1 genes were frequently mutated with higher VAF than the deleterious somatic polymerase mutation.Conclusions CMMRD-associated gliomas have a specific oncogenesis that does not involve usual pathways and mutations seen in sporadic pediatric or adult glioblastomas. Frequent alterations in other pathways such as MAPK may suggest the use of other targeted therapies along with PD1 inhibitors. Patients with mutations in genes responsible for repairing damaged DNA are at a higher risk of developing cancer at an early age. Gliomas are a type of aggressive brain cancer that can occur in these patients. The authors of this study wanted to understand the differences between gliomas in patients with and without this specific genetic condition. To do this, they reviewed 12 children with the genetic condition who developed gliomas. Their results showed that 9 patients had tumors with a higher than expected number of mutations (ultra-mutated). The genes that are commonly mutated in these patients were not identical to those that are commonly known to occur without this genetic condition.