Mutation accumulation in mtDNA of cancers resembles mutagenesis in normal stem cells

Freek Manders; Jip van Dinter; Ruben van Boxtel

doi:10.1016/j.isci.2022.105610

Mutation accumulation in mtDNA of cancers resembles mutagenesis in normal stem cells

iScience. 2022 Nov 16;25(12):105610. doi: 10.1016/j.isci.2022.105610. eCollection 2022 Dec 22.

Authors

Freek Manders¹, Jip van Dinter¹, Ruben van Boxtel¹

Affiliation

¹ Princess Máxima Center for Pediatric Oncology and Oncode Institute, Heidelberglaan 25, 3584CS Utrecht, The Netherlands.

Abstract

Mitochondria are small organelles that play an essential role in the energy production of eukaryotic cells. Defects in their genomes are associated with diseases, such as aging and cancer. Here, we analyzed the mitochondrial genomes of 532 whole-genome sequencing samples from cancers and normal clonally expanded single cells. We show that the mitochondria of normal cells accumulate mutations with age and that most of the mitochondrial mutations found in cancer are the result of healthy mutation accumulation. We also show that the normal HSPCs of patients with leukemia have an increased mitochondrial mutation load. Finally, we show that secondary pediatric cancers and chemotherapy treatments do not impact the mitochondrial mutation load and mtDNA copy numbers of most cells, suggesting that damage to the mitochondrial genome is not a major driver for carcinogenesis. Overall, these findings may contribute to our understanding of mitochondrial genomes and their role in cancer.

Keywords: Cancer; Genomics; Stem cells research.