Abstract
Pediatric glioblastoma multiforme (GBM) has a poor prognosis as a result of recurrence after treatment of surgery and radiochemotherapy. A small subset of pediatric GBMs presenting with an ultra-high tumor mutational burden (TMB) may be sensitive to immune checkpoint inhibition. Here we report a 16-yr-old male with an ultra-hypermutated GBM. After incomplete surgical resection, molecular analysis of the tumor identified unusually high numbers of mutations and intratumor heterogeneity by a hotspot next-generation sequencing (NGS) panel. Further comprehensive molecular profiling identified a TMB of 343 mutations/Mb. An ultra-hypermutation genotype in pediatric GBMs is suggestive of a constitutive mismatch repair deficiency syndrome (CMMRD), which often acquires additional somatic driver mutations in replicating DNA polymerase genes. Tumor sequencing identified two MSH6 nonsense variants, a hotspot POLE mutation and a mutational signature supportive of a germline MMR deficiency with a somatic POLE mutation. However, constitutional testing identified only one nonsense MSH6 variant consistent with a Lynch syndrome diagnosis. This case represents the first confirmed Lynch syndrome case mimicking CMMRD by manifesting as an ultra-hypermutated pediatric GBM, following somatic mutations in MSH6 and POLE. These findings permitted the patient's enrollment in an anti-PD-1 clinical trial for children with ultra-hypermutated GBM. Immunotherapy response has resulted in the patient's stable condition for over more than 1 year postdiagnosis.
Highlights
Pediatric glioblastoma multiforme (GBM) is associated with a poor prognosis and is a common cause of death among children diagnosed with brain cancer (Durno et al 2012; Ostrom et al 2018)
Pediatric constitutive mismatch repair deficiency syndrome (CMMRD) patients presenting with brain tumors commonly have biallelic loss of PSM2 or MSH6 (Bakry et al 2014; Vasen et al 2014; Wimmer et al 2014), ultra-hypermutated pediatric GBM, and a unique MMR first/POLE second mutational signature (Shlien et al 2015; Campbell et al 2017)
We presented a case with similar features but showing only one identified germline MSH6 nonsense variant, diagnostic of Lynch syndrome and not the suspected CMMRD
Summary
Pediatric glioblastoma multiforme (GBM) is associated with a poor prognosis and is a common cause of death among children diagnosed with brain cancer (Durno et al 2012; Ostrom et al 2018). 7% of GBMs are diagnosed in children ages 0–19 yr with a median time of survival after recurrence of
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