Mitochondrial DNA mutations in Medulloblastoma

Abstract

To date, several studies on genomic events underlying medulloblastoma (MB) biology have expanded our understanding of this tumour entity and led to its division into four groups-WNT, SHH, group 3 (G3) and group 4 (G4). However, there is little information about the relevance of pathogenic mitochondrial DNA (mtDNA) mutations and their consequences across these. In this report, we describe the case of a female patient with MB and a mitochondriopathy, followed by a study of mtDNA variants in MB groups. After being diagnosed with G4 MB, the index patient was treated in line with the HIT 2000 protocol with no indications of relapse after five years. Long-term side effects of treatment were complemented by additional neurological symptoms and elevated lactate levels ten years later, resulting in suspected mitochondrial disease. This was confirmed by identifying a mutation in the MT-TS1 gene which appeared homoplasmic in patient tissue and heteroplasmic in the patient's mother. Motivated by this case, we explored mtDNA mutations across 444 patients from ICGC and HIT cohorts. While there was no statistically significant enrichment of mutations in one MB group, both cohorts encompassed a small group of patients harbouring potentially deleterious mtDNA variants. The case presented here highlights the possible similarities between sequelae caused by MB treatment and neurological symptoms of mitochondrial dysfunction, which may apply to patients across all MB groups. In the context of the current advances in characterising and interpreting mtDNA aberrations, recognising affected patients could enhance our future knowledge regarding the mutations' impact on carcinogenesis and cancer treatment.

Keywords: DNA mutational analysis; DNA, Mitochondrial; Medulloblastoma; Mitochondrial diseases.

Fig. 1

Pathogenic mtDNA variants with high levels of heteroplasmy in MB patients a Overview of the variant filtering and classification workflow created with Biorender.com. The numbers shown refer to the number of calls at each analysis stage regardless of the number of patients harbouring these calls. b Circle plots illustrating the proportion of patients with and without mtDNA variants in ICGC (top) and HIT (bottom) cohorts. A patient was counted as mutated if an observed variant had been classified as (likely) pathogenic or disease-associated and showed a heteroplasmy of at least 50%