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

Cold Spring Harb Mol Case Stud. 2019 Oct 23;5(5):a003863. doi: 10.1101/mcs.a003863. Print 2019 Oct.


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.

Keywords: neoplasm of the central nervous system.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Brain Neoplasms / genetics*
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics
  • DNA Mismatch Repair / genetics*
  • DNA Mismatch Repair / physiology
  • DNA-Binding Proteins / genetics
  • Glioblastoma / genetics*
  • Glioblastoma / metabolism
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Mutation
  • Neoplasm Recurrence, Local / genetics
  • Neoplastic Syndromes, Hereditary / genetics*


  • DNA-Binding Proteins

Supplementary concepts

  • Turcot syndrome