Medulloblastoma associated with Lynch syndrome: a case report of germline MLH1 variant and tumor molecular characterization.

Abstract

Lynch syndrome (LS) is an autosomal autosomal dominant inherited disease characterized by impaired DNA mismatch repair (dMMR), resulting in an elevated susceptibility to various types of cancer. The incidence of brain cancers in individuals with LS ranges from 2 to 8%, with the highest risk observed for glioblastoma, astrocytoma, and oligodendroglioma. Medulloblastoma (MB) with Lynch syndrome, a common malignant brain tumor in children, is exceedingly rare. In this case, we present a case of a pediatric patient diagnosed with MB based on clinical and pathological findings, which was further characterized as an TP53-mutant, SHH-activated MB through next-generation sequencing (NGS), and methylation profiling. His tumor was found to harbor a somatic MSH2 mutation and a suspected pathogenic germline MLH1 heterozygous variant. Simultaneously, the tumor exhibited microsatellite instability-high (MSI-H) and an exceptionally elevated tumor mutation burden (TMB = 297.17 Mut/Mb). The presence of the MLH1 germline variant in the patient's mother and maternal grandmother was confirmed by sequencing, and the patient's maternal grandmother had a history of colorectal cancer. Ultimately, the patient was diagnosed with MB associated with LS. This case is the third case of LS with medulloblastoma, which contributes additional evidence to the cancer spectrum associated with LS and presents a novel avenue for patient treatment.