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. 2022 May;5(5):e1521.
doi: 10.1002/cnr2.1521. Epub 2021 Aug 5.

Rare cases of medulloblastoma with hypermutation

Aditi Bagchi  1   2   3 , Ian Beddows  4 , Albert Cornelius  2 , Giles W Robinson  3 , Scott D Jewell  1   5
Affiliations

Rare cases of medulloblastoma with hypermutation

Aditi Bagchi et al. Cancer Rep (Hoboken). 2022 May.

Abstract

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.

Keywords: MMRD; POLE-Mutations; SHH-Medulloblastoma; hypermutation; medulloblastoma; signature 10.

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Conflict of interest statement

The authors have stated explicitly that there are no conflicts of interest in connection with this article.

Figures

FIGURE 1
FIGURE 1
(A) Tumor mutational burden (TMB) of medulloblastoma (MB). The figure depicts TMB in the coding region. The Y‐axis depicts the total number of mutations per Mb, and the X‐axis depicts each individual tumor. Panels labeled “Hypermutated Medulloblastoma T‐1” and “Typical Medulloblastoma T‐20” are scatter plots of somatic mutations showing their locations on the X‐axis versus distance to other events on the Y‐axis. (B) Fractions of mutations contributing to different signatures in T‐1 and T‐10, including signature 10, which occurs in both tumors and fractions of 96 substitution types contributing to the signature profile of each tumor. The X‐axis depicts the 96 substitutions, and the Y‐axis shows the fraction of contribution. (C) Schematic plot demonstrating functional derivatives of the POLE protein and location of mutations identified in T‐10. (D) Distribution curve of mutation allele frequency (MAF), the dotted line depicts the MAF of the POLE mutation in the tumor. (E) Mutation (missense and nonsense mutations) detected in list of commonly mutated genes in SHH‐MB
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