PATH-09. THE IMPACT OF MISMATCH REPAIR DEFICIENCY ON GLIOMAS IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS; A MULTI-CENTRIC, COLLABORATIVE STUDY LED BY THE IRRDC AND GLIOMA TASKFORCE Free

Primary mismatch repair deficiency (pMMRD) is a pan-cancer mechanism caused by somatic mutations or inherited as part of Lynch Syndrome (LS) or constitutional mismatch repair deficiency (CMMRD). PMMRD results in universal hypermutation and microsatellite instability leading to chemoradiation resistance but sensitivity to immunotherapy. The prevalence of pMMRD in gliomas of children, adolescents, and young adults (CAYA), and the impact of germline inheritance is unknown.

We harnessed functional genomic tools across population-based (Toronto), and multiple institutional (SJ, CBTN) cancer databases (n=1276) to determine the prevalence, subgroups, and impact of germline mutations in pMMRD gliomas.

Data from Toronto, SJ and CBTN reveals prevalence of 10%, 5% and 5% in pediatric high-grade gliomas (HGG). Molecularly, pMMRD is absent in gliomas harboring pediatric-type fusions, BRAF-V600E, and histone mutations, but enriched in HGG harboring IDH and TP53 mutations. In AYA (n=660), pMMRD was detected in 5% of IDH-WT and IDH-mutant high-grade astrocytomas, but notably absent in all oligodendrogliomas and other low-grade gliomas. Across this entire CAYA dataset, all except one pMMRD gliomas harbored germline MMR mutations (97%). Strikingly, LS predominated over CMMRD with significant difference in age of glioma onset (LS: 29-years versus CMMRD: 11-years; p< 0.001, IRRDC dataset). Survival analysis (Kaplan-Meier) confirmed the poor overall survival (OS) for pMMRD and other pediatric subtypes of HGG (3-year OS < 25%). In contrast, IDH-mutant pMMRD HGG have significantly worse OS than IDH-mutant non-pMMRD counterparts. Remarkably, immunotherapy significantly improves survival not only in children, but also for AYA patients with refractory pMMRD HGG (3-year OS > 50%).

This large study demonstrates that pMMRD drives a significant proportion of HGG across CAYA with an alarming impact of germline predisposition. Specifically, unrecognized AYA LS patients with MMRD HGG. These findings support universal screening for MMRD in HGG to identify patients for surveillance and immunotherapy.