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Published on: October 3, 2010
Rare cases of medulloblastoma with hypermutation
Aditi Bagchi1,2,3, Ian Beddows4, Albert Cornelius2
1Van Andel Institute Graduate School, St. Jude Children's Research Hospital, Spectrum Health Helen DeVos Children's Hospital, Grand Rapids, Michigan, USA.
Background:
Medulloblastoma is the most common malignant brain tumor of childhood and is considered a tumor with low mutational burden (~1 Mut/Mb). Therefore, though the medulloblastoma genomes have been extensively characterized in literature, reports on potential hypermutations and underlying mutagenic processes in medulloblastomas are limited.
Aim:
In this report, we studied the landscape of mutational burden in primary and recurrent medulloblastoma. Furthermore, we wanted to understand the differences in underlying mutagenic mechanisms in medulloblastoma with low and high mutational burdens.
Methods:
Fifty-three primary and recurrent medulloblastoma genomic sequence were downloaded from the European Genome Archive as BAM files. Thirty-three cases were obtained from formalin-fixed paraffin-embedded tissues from pathology diagnostic archives of Spectrum Health and Cooperative Human Tissue Network. Somatic mutations were called using Mutect2, following best practices guidelines for Genome Analysis Toolkit V4. Mutational signatures were analyzed using deconstructSigs.
Results:
We identified nine medulloblastoma cases with high mutational burden (>5 Mut/Mb). Of them, five cases met the criteria of hypermutation (>10Mut/Mb), two of the five tumors had canonical mutations in the POLE proof-reading domain, where a large proportion of mutations in these tumor genomes contributed to signature 10. The hypermutated cases also demonstrated mutational signatures 14, 15, and 21, indicating the role of mis match repair deficiency in their mutagenesis. Of the four known molecular subgroups in medulloblastoma-SHH, WNT, Group 3, and Group 4-both the POLE-mutated cases belonged to the SHH subgroup. This report identifies rare cases of hypermutation in medulloblastoma driven by defects in DNA repair mechanisms.
Conclusion:
Hypermutation in medulloblastoma can impact therapeutic decisions, especially at recurrence in otherwise fatal high risk SHH-medulloblastomas. A defect in DNA repair leading to SHH -medulloblastoma is yet another important mechanism that should be further investigated in the genesis of these tumors. Therefore, this report provides important scientific and clinical rationale for future research looking for incidence of hypermutation in large cohorts of medulloblastoma patients.
Insights
Rare hypermutations in childhood medulloblastoma were identified, linked to DNA repair defects like POLE mutations and mismatch repair deficiency. These findings offer insights into medulloblastoma genesis and potential therapeutic strategies.
Area of Science:
- Genomics
- Oncology
- Molecular Biology
Background:
- Medulloblastoma is the most common pediatric malignant brain tumor.
- It typically exhibits a low mutational burden, making hypermutation studies rare.
- Understanding mutagenic processes is crucial for this disease.
Purpose of the Study:
- To investigate the mutational burden landscape in primary and recurrent medulloblastoma.
- To differentiate mutagenic mechanisms between low and high mutational burden medulloblastomas.
- To identify potential drivers of hypermutation in medulloblastoma.
Main Methods:
- Downloaded and analyzed 53 primary and recurrent medulloblastoma genomes.
- Utilized Mutect2 for somatic mutation calling and deconstructSigs for mutational signature analysis.
- Examined cases from both European Genome Archive and formalin-fixed paraffin-embedded tissues.
Main Results:
- Identified nine medulloblastoma cases with high mutational burden (>5 Mut/Mb).
- Five cases exhibited hypermutation (>10 Mut/Mb), with two showing POLE proof-reading domain mutations.
- Hypermutated cases displayed signatures indicative of mismatch repair deficiency, predominantly in the SHH subgroup.
Conclusions:
- This study identifies rare hypermutated medulloblastomas driven by DNA repair defects.
- Defects in DNA repair, particularly in SHH-medulloblastoma, warrant further investigation.
- Findings provide rationale for researching hypermutation incidence in larger medulloblastoma cohorts.
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