ID #1128 Lynch syndrome-associated high-grade glioma in adolescence: implications of integrated molecular profiling for diagnosis and therapy
Leanne Super, Paul Wood, Michelle Martin, Pranav Dorval, Beena Kumar, Amanda St john, Christine White, Dianne Sylvester, Noemi Fuentes-Bolanos, Lucie Stengs, Adrian Levine, Cynthia Hawkins, Anirban Das, Uri Tabori, David Ziegler, Loretta Lau, Paulette Barahona, Nataliya Zhukova, Jobe QuickAbstract
Lynch syndrome is an autosomal dominant cancer predisposition syndrome caused by germline defects in DNA mismatch repair (MMR) genes, resulting in microsatellite instability and a high tumour mutational burden (TMB). While classically associated with colorectal and endometrial cancers, high-grade glioma represents a rare but clinically significant manifestation within the Lynch syndrome spectrum. These tumours frequently arise in childhood or adolescence, exhibit marked hypermutation, and may demonstrate limited sensitivity to conventional alkylating chemotherapy, creating significant therapeutic challenges. However, their biological profile provides a strong rationale for immune checkpoint inhibition, underscoring the importance of accurate molecular diagnosis.
We report the case of a 14-year-old male who presented with a short history of headaches and right-sided focal seizures. Neuroimaging revealed a large high-grade parietal lesion. He underwent two-stage surgical debulking, and histopathological assessment confirmed a non-H3 K27M mutant, IDH-wildtype high-grade glioma. The patient was enrolled in the ZERO2.0 precision oncology program and registered with the International Replication Repair Deficiency Consortium, enabling comprehensive molecular and immune profiling, including LOGIC assay analysis.
Molecular testing identified a heterozygous likely pathogenic germline MSH6 missense variant alongside a heterozygous somatic MSH6 alteration, consistent with Lynch syndrome. The tumour demonstrated microsatellite instability, a mismatch repair–deficiency mutational signature, and high TMB (21.65 mutations/Mb; 298 SNVs/exome). LOGIC assay classification placed the tumour within the priMMRD-2 subgroup with additional CTLA4 expression. Based on these findings, immune checkpoint inhibition was recommended. The patient commenced nivolumab monotherapy, which was well tolerated with no grade ≥3 toxicities, and demonstrated moderate clinical and radiological improvement. Persistently detectable cerebrospinal fluid circulating tumour DNA supported escalation to combination nivolumab and ipilimumab therapy.
This case illustrates the critical role of comprehensive molecular analysis in guiding diagnosis and treatment selection in rare, therapeutically challenging paediatric gliomas, and highlights the value of multidisciplinary and international collaboration in delivering precision oncology care.