Landscape of Germline and Somatic Mitochondrial DNA Mutations in Pediatric Malignancies

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 simula-tions 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.

Massively parallel single-cell mitochondrial DNA genotyping and chromatin profiling

“…In addition to pathogenic mitochondrial variants, such as 8344A>G, our high-throughput platform should facilitate the examination of functional mtDNA mutations in relatively common disease settings 1 . Specifically, alterations in mtDNA have been associated with a variety of complex human diseases, including Alzheimer’s Disease 52 , Parkinson’s Disease 53 , cardiomyopathies 54 , pediatric cancers 55 and more generally aging phenotypes 1 , 56 . As our approach facilitates rapid genotyping and concomitant chromatin profiles in thousands of cells, potential molecular consequences of mtDNA variants may now be dissected ( Fig.…”

Identification of unique and shared mitochondrial DNA mutations in neurodegeneration and cancer by single-cell mitochondrial DNA structural variation sequencing (MitoSV-seq)

“…In cancer cells, defective complex I potentiates tumour formation, resistance to cell death stimuli, and metastasis by increasing ROS levels [87]. Further, mutations in MT-ND5 have been linked to MDS [88], AML [89], colon adenocarcinoma [74], and breast cancer [90]. The accumulation of mutations in MT-ND5 has been suggested to inhibit oxidative phosphorylation, causing the malfunction of mitochondria and thus conferring selective growth advantages early in oncogenesis [87], also implicating the clinical use of MT-ND5 mutations as tumour biomarkers.…”

Specifications of the ACMG/AMP standards and guidelines for mitochondrial DNA variant interpretation

“…">Similarly, these specifications are not meant for interpretation of clinical significance of mtDNA variants in other diseases such as cancer. In many cases, the functional significance of an mtDNA variant is context dependent, as some cancers acquire the same variant(s) that are ancient haplogroup founding variants in human populations (Brandon, Baldi, & Wallace, 2006; Triska et al, 2019). …”