Little is known about the spectrum of
mitochondrial DNA (
mtDNA) mutations across pediatric
malignancies. In this study, we analyzed matched
tumor and normal whole genome sequencing data from 616 pediatric patients with
hematopoietic malignancies, solid
tumors, and
brain tumors. We identified 391
mtDNA mutations in 284
tumors including 45 loss-of-function mutations, which clustered at four statistically significant hotspots in MT-COX3, MT-ND4, and MT-ND5, and at a mutation hotspot in MT-
tRNA-MET. A skewed ratio (4.83) of nonsynonymous versus synonymous (dN/dS)
mtDNA mutations with high statistical significance was identified on the basis of Monte Carlo simulations in the
tumors. In comparison, opposite ratios of 0.44 and 0.93 were observed in 616 matched normal tissues and in 249 blood samples from children without
cancer, respectively.
mtDNA mutations varied by
cancer type and
mtDNA haplogroup. Collectively, these results suggest that deleterious
mtDNA mutations play a role in the development and progression of pediatric
cancers. SIGNIFICANCE: This pan-
cancer mtDNA study establishes the landscape of germline and
tumor mtDNA mutations and identifies hotspots of
tumor mtDNA mutations to pinpoint key mitochondrial functions in pediatric
malignancies.