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

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-...

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Autores principales: Yang, Chen, Austin, Frances, Richard, Hope, Idowu, Michael, Williamson, Vernell, Sabato, Fernanda, Ferreira-Gonzalez, Andrea, Turner, Scott A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824252/
https://www.ncbi.nlm.nih.gov/pubmed/31604779
http://dx.doi.org/10.1101/mcs.a003863
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author Yang, Chen
Austin, Frances
Richard, Hope
Idowu, Michael
Williamson, Vernell
Sabato, Fernanda
Ferreira-Gonzalez, Andrea
Turner, Scott A.
author_facet Yang, Chen
Austin, Frances
Richard, Hope
Idowu, Michael
Williamson, Vernell
Sabato, Fernanda
Ferreira-Gonzalez, Andrea
Turner, Scott A.
author_sort Yang, Chen
collection PubMed
description 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.
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spelling pubmed-68242522019-11-15 Lynch syndrome–associated ultra-hypermutated pediatric glioblastoma mimicking a constitutional mismatch repair deficiency syndrome Yang, Chen Austin, Frances Richard, Hope Idowu, Michael Williamson, Vernell Sabato, Fernanda Ferreira-Gonzalez, Andrea Turner, Scott A. Cold Spring Harb Mol Case Stud Research Report 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. Cold Spring Harbor Laboratory Press 2019-10 /pmc/articles/PMC6824252/ /pubmed/31604779 http://dx.doi.org/10.1101/mcs.a003863 Text en © 2019 Yang et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted reuse and redistribution provided that the original author and source are credited.
spellingShingle Research Report
Yang, Chen
Austin, Frances
Richard, Hope
Idowu, Michael
Williamson, Vernell
Sabato, Fernanda
Ferreira-Gonzalez, Andrea
Turner, Scott A.
Lynch syndrome–associated ultra-hypermutated pediatric glioblastoma mimicking a constitutional mismatch repair deficiency syndrome
title Lynch syndrome–associated ultra-hypermutated pediatric glioblastoma mimicking a constitutional mismatch repair deficiency syndrome
title_full Lynch syndrome–associated ultra-hypermutated pediatric glioblastoma mimicking a constitutional mismatch repair deficiency syndrome
title_fullStr Lynch syndrome–associated ultra-hypermutated pediatric glioblastoma mimicking a constitutional mismatch repair deficiency syndrome
title_full_unstemmed Lynch syndrome–associated ultra-hypermutated pediatric glioblastoma mimicking a constitutional mismatch repair deficiency syndrome
title_short Lynch syndrome–associated ultra-hypermutated pediatric glioblastoma mimicking a constitutional mismatch repair deficiency syndrome
title_sort lynch syndrome–associated ultra-hypermutated pediatric glioblastoma mimicking a constitutional mismatch repair deficiency syndrome
topic Research Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824252/
https://www.ncbi.nlm.nih.gov/pubmed/31604779
http://dx.doi.org/10.1101/mcs.a003863
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