Abstract
Diffuse Large B-Cell Lymphoma (DLBCL) is an aggressive hematological cancer for which mitochondrial metabolism may play an important role. Mitochondrial DNA (mtDNA) encodes crucial mitochondrial proteins, yet the relationship between mtDNA and DLBCL remains unclear. We analyzed the functional consequences and mutational spectra of mtDNA somatic mutations and private constitutional variants in 40 DLBCL tumour-normal pairs. While private constitutional variants occurred frequently in the D-Loop, somatic mutations were randomly distributed across the mitochondrial genome. Heteroplasmic constitutional variants showed a trend towards loss of heteroplasmy in the corresponding tumour regardless of whether the reference or variant allele was being lost, suggesting that these variants are selectively neutral. The mtDNA mutational spectrum showed minimal support for ROS damage and revealed strand asymmetry with increased C > T and A > G transitions on the heavy strand, consistent with a replication-associated mode of mutagenesis. These heavy strand transitions carried higher proportions of amino acid changes – which were also more pathogenic – than equivalent substitutions on the light strand. Taken together, endogenous replication-associated events underlie mtDNA mutagenesis in DLBCL and preferentially generate functionally consequential mutations. Yet mtDNA somatic mutations remain selectively neutral, suggesting that mtDNA-encoded mitochondrial functions may not play an important role in DLBCL.
Highlights
The mitochondrial genome plays a crucial role in cellular metabolism
We assessed the distribution of Mitochondrial DNA (mtDNA) variants across different functional regions of the mitochondrial genome (Table 2)
In comparison to the variant distribution expected by chance, it is apparent that private constitutional variants were subject to purifying selection, which lowered the variant load in the coding regions relative to the D-Loop and reduced the number of potentially pathogenic variants persisting in the genome
Summary
The mitochondrial genome plays a crucial role in cellular metabolism. Each mitochondrion within the cell has two to ten copies of the mitochondrial genome. In PolgA mutator mouse models, homozygous PolgA mutants displayed a 3 to 5 fold increase in mtDNA point mutations relative to wild-type PolgA siblings from the heterozygous parents This was accompanied by reduced cytochrome c oxidase activity, increased ROS production and increased risk of lymphoid tumour development[11]. Administration of a ROS scavenger in these same mice reduced ROS levels in the bone marrow and prevented lymphoma development, further supporting a link between mtDNA, ROS and B-cell lymphoma[13] Despite these connections between mtDNA and B-Cell Lymphoma, the mutational landscape of the mitochondrial genome in lymphoma remains unclear. We accessed this data through the NCBI database of Genotypes and Phenotypes (dbGaP), extracted mtDNA information and characterized the somatic mutations and constitutional variants in the mitochondrial genomes of the 40 DLBCL tumour-normal pairs
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