Lynch syndrome–associated ultra-hypermutated pediatric glioblastoma mimicking a constitutional mismatch repair deficiency syndrome

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.

Diagnosis of Lynch Syndrome and Strategies to Distinguish Lynch-Related Tumors from Sporadic MSI/dMMR Tumors

“…The proportion of MSI/dMMR brain cancers is very low (2% to 3%) [ 8 , 102 ]. Some studies focused on these tumors (related to somatic MMR mutations, to LS, or to CMMRD (Constitutional MisMatch Repair Deficiency) syndrome, which is caused by biallelic germline MMR mutations) [ 103 , 104 ] and showed that they can acquire a secondarily proofreading defect due to a mutation in the POLE (DNA polymerase epsilon, catalytic subunit) gene, resulting in an ultra-mutant phenotype (>100 mutations/Mb) and a unique mutational signature (“MMR first/POLE second”) [ 103 , 104 , 105 ]. Additionally, these tumors seem to be more frequently of a particular and very rare histotype characterized by the presence of multinucleated giant cells [ 106 ].…”

“…The sensitivity of MSI has been shown to be lower in non-CRC tumors, especially in endometrium, brain, and urothelial tumors, as a consequence of fewer unstable markers and a shorter instability length [ 25 , 69 , 117 , 118 , 121 , 122 , 123 , 124 , 125 ]. For example, MSI is particularly difficult to detect in brain tumors, with less than 20% of brain tumors from patients with LS (or CMMRD) exhibiting MSI [ 69 , 105 , 126 , 127 , 128 ]. These observations have led to the recommendation to analyze normal DNA in parallel for non-CRC tumors [ 114 , 122 , 124 , 125 ].…”

Comparison of Genomic Characterization in Upper Tract Urothelial Carcinoma and Urothelial Carcinoma of the Bladder

“…POLE mutational signature is related to recurrent POLE somatic mutations, which may suggest that DNA replication is associated with errors in proofreading activity of Pol ε (32). DNA mismatch repair mutational signatures are usually microsatellite-unstable, serving as a better indicator of response (33). In this study, AA and POLE mutational signatures were only observed in the UTUC cohorts.…”

Glioblastoma Immune Landscape and the Potential of New Immunotherapies

“…Despite these promising results, a recent study reported that PD-1 blockade did not impact mOS in hypermutated gliomas, consistent with an observed lack of TILs in these cancers ( 68 ). However, another study reported significant clinical and radiological responses of nivolumab in two young siblings with biallelic mismatch repair deficiency ( 66 ), suggesting that ICI therapy might benefit pediatric GBM with high mutational burden [e.g., with MSH6 mutations ( 69 )]. It is plausible that treatments that increase mutational burden might synergize with ICI, as has been shown in other cancers ( 70 ).…”