posted on 2023-03-31, 02:40authored byPetr Triska, Kristiyana Kaneva, Daria Merkurjev, Noor Sohail, Marni J. Falk, Timothy J. Triche, Jaclyn A. Biegel, Xiaowu Gai
Supplementary Figure 5 illustrates that mtDNA mutations in the mtDNA hypermutated pediatric tumor samples tend to occur at low heteroplasmy levels and are more likely to be benign in nature.
Funding
Unravel Childhood Cancer Foundation
United Mitochondrial Disease Foundation
NIH
History
ARTICLE ABSTRACT
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.
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.