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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-...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2019
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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. |
format | Online Article Text |
id | pubmed-6824252 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
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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