Zheng Han, Zhang Gang, Jiang Bin, Zhang Luyi, Duan Qianqian, Shi Hangyu
Department of Neurosurgery, Xi'an Children's Hospital Affiliated to Xi'an Jiaotong University, No. 69, Xiju Yuan Lane, Lianhu District, Xi'an, 710000, China.
The State Key Laboratory of Neurology and Oncology Drug Development, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing Simcere Medical Laboratory Science Co., Ltd., Nanjing, 210000, China.
Invest New Drugs. 2025 May 19. doi: 10.1007/s10637-025-01527-6.
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.
林奇综合征（LS）是一种常染色体显性遗传病，其特征是DNA错配修复功能受损（dMMR），导致对各种类型癌症的易感性增加。LS患者患脑癌的发生率为2%至8%，其中胶质母细胞瘤、星形细胞瘤和少突胶质细胞瘤的风险最高。林奇综合征相关的髓母细胞瘤（MB）是儿童常见的恶性脑肿瘤，极为罕见。在此病例中，我们报告了一名根据临床和病理结果诊断为MB的儿科患者，通过下一代测序（NGS）和甲基化分析进一步确定为TP53突变、SHH激活型MB。发现其肿瘤存在体细胞MSH2突变和疑似致病的种系MLH1杂合变异。同时，肿瘤表现为微卫星高度不稳定（MSI-H）且肿瘤突变负荷异常升高（TMB = 297.17 Mut/Mb）。通过测序证实患者母亲和外祖母存在MLH1种系变异，且患者外祖母有结直肠癌病史。最终，该患者被诊断为与LS相关的MB。此病例是第三例与髓母细胞瘤相关的LS病例，为与LS相关的癌症谱提供了更多证据，并为患者治疗提供了新途径。
