An H3F3A K27M-mutation in a sonic hedgehog medulloblastoma

Abstract

Medulloblastomas are malignant embryonal brain tumours that may harbour mutations in histone-modifying genes, while mutations in histone genes have not been detected to date. We here describe the first SHH medulloblastoma with H3 K27M mutation. This may have diagnostic implications as H3 K27M mutations are the hallmark of diffuse midline gliomas, H3 K27M mutant, WHO grade IV. Medulloblastomas arise in midline structures and thus must not be mistaken for DMG when using an antibody detecting the H3 K27M mutation.

Keywords: H3F3A; H3K27me3; H3 K27M; NGS; SHH; medulloblastoma.

FIGURE 1

A desmoplastic/nodular SHH medulloblastoma with H3 K27M mutation. (A and B) Representative axial MRI images of the tumour showing a partial contrast enhancement in the T ₁‐weighted image plus contrast medium (A) and hyperintensity in the T ₂‐weighted image (B). (C–H) Histology. The H&E staining showed a small blue round cell tumour with a nodular architecture also visible in a Gomori silver impregnation (D). The internodal areas were positive for p75 (E). A mutation‐specific antibody indicated a nuclear expression of H3 K27M (F), whereas H3K27me3 trimethylation was lost in the tumour cells (G). (H) The Ki67 proliferation index amounted up to 30–60%, depending on the tumour area. Scale bar for (C–H): 150 µm. (I, J) Molecular features. (I) Copy number profile calculated from DNA methylation data. (J) H3F3A K27M mutation, detected by DNA panel sequencing. Top: genomic position on chromosome 1q, indicated by the red bar (cf. arrow). Middle: base exchange from A to T with an allele frequency of 46% (exemplary reads). Bottom: reference sequences of bases and amino acids